CURRENT Diagnosis and Treatment Pediatrics, (Current Pediatric Diagnosis & Treatment) 22nd Edition

36. Inborn Errors of Metabolism

Janet A. Thomas, MD

Johan L.K. Van Hove, MD, PhD, MBA

Disorders in which single gene defects cause clinically significant blocks in metabolic pathways are called inborn errors of metabolism. Once considered rare, the number of recognized inborn errors has increased dramatically and they are now recognized to affect 1:1500 children. Many of these disorders can be treated effectively. Even when treatment is not available, correct diagnosis permits parents to make informed decisions about future offspring.

The pathology in metabolic disorders usually results from accumulation of enzyme substrate behind a metabolic block or deficiency of a reaction product. In some cases, the accumulated enzyme substrate is diffusible and has adverse effects on distant organs; in other cases, as in lysosomal storage diseases, the substrate primarily accumulates locally. The clinical manifestations of inborn errors vary widely with both mild and severe forms of virtually every disorder. Many patients do not match the classic phenotype because mutations are not identical in different patients, even though they occur in the same gene.

A first treatment strategy is to enhance the reduced enzyme activity. Gene replacement is a long-term goal, but problems of gene delivery to target organs and control of gene action make this an unrealistic option at present. Enzyme-replacement therapy using intravenously administered recombinant enzyme has been developed as an effective strategy in lysosomal storage disorders. Organ transplantation (liver or bone marrow) can provide a source of enzyme for some conditions. Pharmacologic doses of a cofactor such as a vitamin can sometimes be effective in restoring enzyme activity. Residual activity can be increased by pharmacologically promoting transcription (transcriptional upregulation) or by stabilizing the protein product through therapy with chaperones. Alternatively, some strategies are designed to cope with the consequences of enzyme deficiency. Strategies used to avoid substrate accumulation include restriction of precursor in the diet (eg, low-phenylalanine diet for phenylketonuria), avoidance of catabolism, inhibition of an enzyme in the synthesis of the precursor (eg, NTBC in tyrosinemia type I (see Hereditary Tyrosinemia), or removal of accumulated substrate pharmacologically (eg, glycine therapy for isovaleric acidemia) or by dialysis. An inadequately produced metabolite can also be supplemented (eg, glucose administration for glycogen storage disease type I).

Inborn errors can manifest at any time, can affect any organ system, and can mimic many common pediatric problems. This chapter focuses on when to consider a metabolic disorder in the differential diagnosis of common pediatric problems. A few of the more important disorders are then discussed in detail.

DIAGNOSIS

SUSPECTING INBORN ERRORS

Inborn errors must be considered in the differential diagnosis of critically ill newborns, children with seizures, neurodegeneration, recurrent vomiting, Reye-like syndrome, parenchymal liver disease, cardiomyopathy, unexplained metabolic acidosis, hyperammonemia, and hypoglycemia. Mental retardation, developmental delay, and failure to thrive are often present but have little specificity. Inborn errors should be suspected when (1) symptoms accompany changes in diet, (2) the child’s development regresses, (3) the child shows specific food preferences or aversions, or (4) the family has a history of parental consanguinity or problems suggestive of inborn error such as retardation or unexplained deaths in first- and second-degree relatives.

Physical findings associated with inborn errors include alopecia or abnormal hair, retinal cherry-red spot or retinitis pigmentosa, cataracts or corneal opacity, hepatomegaly or splenomegaly, coarse features, skeletal changes (including gibbus), neurologic regression, and intermittent or progressive ataxia or dystonia. Other features that may be important in the context of a suspicious history include failure to thrive, microcephaly, rash, jaundice, hypotonia, and hypertonia.

Finding an immediate cause of symptoms does not rule out an underlying inborn error. For example, renal tubular acidosis and cirrhosis may be due to an underlying inborn error. Acute crises may be brought on by intercurrent infections in some inborn errors. Some inborn errors suggest a diagnosis of nonaccidental trauma (eg, glutaric acidemia type I) or poisoning (eg, methylmalonic acidemia). In addition, children with inborn errors may be at higher risk for child abuse or neglect because of their frustrating irritability.

LABORATORY STUDIES

Table 36–1 lists common clinical and laboratory features of different groups of inborn errors. Table 36–2 lists the most common laboratory tests used to diagnose these diseases and offers suggestions about their use.

Table 36–1. Presenting clinical and laboratory features of inborn errors.

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Table 36–2. Obtaining and handling samples to diagnose inborn errors.

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Laboratory studies are almost always needed for the diagnosis of inborn errors. Serum electrolytes and pH should be used to estimate anion gap and acid-base status. Serum lactate, pyruvate, and ammonia levels are available in most hospitals, but care is needed in obtaining samples appropriately. Amino acid, acylcarnitine, and organic acid studies must be performed at specialized facilities to ensure accurate analysis and interpretation. An increasing number of inborn errors are diagnosed with DNA sequencing, but interpretation of private mutations, that is, mutations only seen in a particular family, can be problematic. Knowing the causative mutation in the family allows prenatal diagnosis to be done by molecular analysis. This can be done on any material that contains fetal DNA such as chorionic villi, amniotic cells, or fetal blood obtained through umibilical cord blood sampling.

The physician should know what conditions a test can detect and when it can detect them. For example, urine organic acids may be normal in patients with medium-chain acyl-CoA dehydrogenase deficiency or biotinidase deficiency; glycine may be elevated only in cerebrospinal fluid (CSF) in patients with glycine encephalopathy. A result that is normal in one physiologic state may be abnormal in another. For instance, the urine of a child who becomes hypoglycemic upon prolonged fasting should be positive for ketones. In such a child, the absence of ketones in the urine suggests a defect in fatty acid oxidation.

Samples used to diagnose metabolic disease may be obtained at autopsy. Samples must be obtained in a timely fashion and may be analyzed directly or stored frozen until a particular analysis is justified by the results of postmortem examination, new clinical information, or developments in the field. Studies of other family members may help establish the diagnosis of a deceased patient. It may be possible to demonstrate that parents are heterozygous carriers of a particular disorder or that a sibling has the condition.

COMMON CLINICAL SITUATIONS

1. Mental Retardation

Some inborn errors can cause mental retardation without other distinguishing characteristics. Measurements of serum amino acids, urine organic acids, and serum uric acid should be obtained in every patient with nonspecific mental retardation. Urine screens for mucopolysaccharides and succinylpurines, and serum testing for carbohydrate-deficient glycoproteins are useful because these disorders do not always have specific physical findings. Absent speech can point to disorders of creatine. Abnormalities of the brain detected by magnetic resonance imaging can suggest specific groups of disorders (eg, cortical migrational abnormalities in peroxisomal biogenesis disorders).

2. Acute Presentation in the Neonate

Acute metabolic disease in the neonate is most often a result of disorders of protein or carbohydrate metabolism and may be clinically indistinguishable from sepsis. Prominent symptoms include poor feeding, vomiting, altered mental status or muscle tone, jitteriness, seizures, and jaundice. Acidosis, alkalosis, or altered mental status out of proportion to systemic symptoms should increase suspicion of a metabolic disorder. Laboratory measurements should include electrolytes, ammonia, lactate, glucose, blood pH, and urine ketones and reducing substances. Amino acids in CSF should be measured if glycine encephalopathy is suspected. Serum and urine amino acid, urine organic acid, and serum acylcarnitine analysis should be performed urgently. Neonatal cardiomyopathy or ventricular arrhythmias should be investigated with serum acylcarnitine analysis.

3. Vomiting & Encephalopathy in the Infant or Older Child

Electrolytes, ammonia, glucose, urine pH, urine reducing substances, and urine ketones should be measured in all patients with vomiting and encephalopathy before any treatment affects the results. Samples for serum amino acids, serum acylcarnitine profile, and urine organic acid analysis should be obtained early. In the presentation of a Reye-like syndrome (ie, vomiting, encephalopathy, and hepatomegaly), amino acids, acylcarnitines, carnitine levels, and organic acids should be assessed immediately. Hypoglycemia with inappropriately low urine or serum ketones suggests the diagnosis of fatty acid oxidation defects.

4. Hypoglycemia

Duration of fasting, presence or absence of hepatomegaly, and Kussmaul breathing provide clues to the differential diagnosis of hypoglycemia. Serum insulin, cortisol, and growth hormone should be obtained on presentation. Urine ketones, urine organic acids, plasma lactate, serum acylcarnitine profile, carnitine levels, ammonia, triglycerides, and uric acid should be measured. Ketone body production is usually not efficient in the neonate, and ketonuria in a hypoglycemic or acidotic neonate suggests an inborn error. In the older child, inappropriately low urine ketone levels suggest an inborn error of fatty acid oxidation. Assessment of ketone generation requires simultaneous measurements of quantitative serum 3-hydroxybutyrate, acetoacetate, and free fatty acids in relation to a sufficient duration of fasting and age. Metabolites obtained during the acute episode can be very helpful and avoid the need for a formal fasting test.

5. Hyperammonemia

Symptoms of hyperammonemia may appear and progress rapidly or insidiously. Decreased appetite, irritability, and behavioral changes appear first with vomiting, ataxia, lethargy, seizures, and coma appearing as ammonia levels increase. Tachypnea inducing respiratory alkalosis due to a direct effect on respiratory drive is characteristic. Physical examination cannot exclude the presence of hyperammonemia, and serum ammonia should be measured whenever hyperammonemia is possible. Severe hyperammonemia may be due to urea cycle disorders, organic acidemias, or fatty acid oxidation disorders (such as carnitine-acylcarnitine translocase deficiency) or, in the premature infant, transient hyperammonemia of the newborn. The cause can usually be ascertained by measuring quantitative serum amino acids (eg, citrulline), plasma carnitine and acylcarnitine esters, and urine organic acids and orotic acid. Respiratory alkalosis is usually present in urea cycle defects and transient hyperammonemia of the newborn, while acidosis is characteristic of hyperammonemia due to organic acidemias.

6. Acidosis

Inborn errors may cause chronic or acute acidosis at any age, with or without an increased anion gap. Inborn errors should be considered when acidosis occurs with recurrent vomiting or hyperammonemia and when acidosis is out of proportion to the clinical status. Acidosis due to an inborn error can be difficult to correct. The main causes of anion gap metabolic acidosis are lactic acidosis, ketoacidosis (including abnormal ketone body production such as in β-ketothiolase deficiency), methylmalonic aciduria or other organic acidurias, intoxication (ethanol, methanol, ethylene glycol, and salicylate), and uremia. Causes of non–anion gap metabolic acidosis include loss of base in diarrhea or renal tubular acidosis (isolated renal tubular acidosis or renal Fanconi syndrome). If renal bicarbonate loss is found, a distinction must be made between isolated renal tubular acidosis and a more generalized renal tubular disorder or renal Fanconi syndrome by testing for renal losses of phosphorus and amino acids. Inborn errors associated with renal tubular acidosis or renal Fanconi syndrome include cystinosis, tyrosinemia type I, carnitine palmitoyltransferase I, galactosemia, hereditary fructose intolerance, Lowe syndrome, and mitochondrial diseases. Serum glucose and ammonia levels and urinary pH and ketones should be examined. Samples for amino acids and organic acids should be obtained at once and may be evaluated immediately or frozen for later analysis, depending on how strongly an inborn error is suspected. It is useful to test blood lactate and pyruvate levels in the chronically acidotic patient even if urine organic acid levels are normal. Lactate and pyruvate levels are difficult to interpret in the acutely ill patient, but in the absence of shock, high levels of lactic acid suggest primary lactic acidosis.

MANAGEMENT OF METABOLIC EMERGENCIES

Patients with severe acidosis, hypoglycemia, and hyperammonemia may be very ill; initially mild symptoms may worsen quickly, and coma and death may ensue within hours. With prompt and vigorous treatment, however, patients can recover completely, even from deep coma. All oral intake should be stopped. Sufficient glucose should be given intravenously to avoid or minimize catabolism in a patient with a known inborn error who is at risk for crisis. Most conditions respond favorably to glucose administration, although a few (eg, primary lactic acidosis due to pyruvate dehydrogenase deficiency) do not. After exclusion of fatty acid oxidation disorders, immediate institution of intravenous fat emulsions (eg, intralipid) can provide crucial caloric input. Severe or increasing hyperammonemia should be treated pharmacologically or with dialysis (see Disorders of the Urea Cycle), and severe acidosis should be treated with bicarbonate. More specific measures can be instituted when a diagnosis is established.

NEWBORN SCREENING

Criteria for screening newborns for a disorder include its frequency, its consequences if untreated, the ability of therapy to mitigate consequences, the cost of testing, and the cost of treatment. With the availability of tandem mass spectrometry, newborn screening has expanded greatly to now include 20 core conditions and multiple secondary conditions screened by most states. In general, amino acidopathies, organic acidurias, and disorders of fatty acid oxidation are the disorders for which screening now occurs. Most states also screen for hypothyroidism, congenital adrenal hyperplasia, hemoglobinopathies, biotinidase deficiency, galactosemia, and cystic fibrosis. Screening for severe combined immune deficiency has been recently added. Screening should occur for all infants between 24 and 72 hours of life or before hospital discharge.

Some screening tests measure a metabolite (eg, phenylalanine) that becomes abnormal with time and exposure to diet. In such instances, the disease cannot be detected reliably until intake of the substrate is established. Other tests measure enzyme activity and can be performed at any time (eg, for biotinidase deficiency). Transfusions may cause false-negative results in this instance, and exposure of the sample to heat may cause false-positive results. Technologic advances have extended the power of newborn screening but have brought additional challenges. For example, although tandem mass spectrometry can detect many more disorders in the newborn period, consensus on diagnosis and treatment for some conditions is still under development.

Screening tests are not diagnostic, and diagnostic tests must be undertaken when an abnormal screening result is obtained. Further, because false-negative results occur, a normal newborn screening test does not rule out a condition.

The appropriate response to an abnormal screening test depends on the condition in question and the predictive value of the test. For example, when screening for galactosemia by enzyme assay, complete absence of enzyme activity is highly predictive of classic galactosemia. Failure to treat may rapidly lead to death. In this case, treatment must be initiated immediately while diagnostic studies are pending. In phenylketonuria, however, a diet restricted in phenylalanine is harmful to the infant whose screening test is a false-positive, while diet therapy produces an excellent outcome in the truly affected infant if treatment is established within the first weeks of life. Therefore, treatment for phenylketonuria should only be instituted when the diagnosis is confirmed. Physicians should review American College of Medical Genetics recommendations, state laws and regulations, and consult with their local metabolic center to arrive at appropriate strategies for each hospital and practice.

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Lindner M et al: Efficacy and outcome of expanded newborn screening for metabolic diseases: report of 10 years from South-West Germany. Orphanet J Rare Dis 2011;6:44 [PMID: 21689452].

Michelson DJ, Shevell MI, Sherr EH, Moeschler JB, Gropman AL, Ashwal S: Evidence report: genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2011;77(17):1629 [PMID: 21956720].

Shanmugam NP, Bansal S, Greenough A, Verma A, Dhawan A: Neonatal liver failure: aetiologies and management—state of the art. Eur J Pediatr 2011;170(5):573 [PMID: 20886352].

Sun A, Lam C, Wong DA: Expanded newborn screening for inborn errors of metabolism: overview and outcomes. Adv Pediatr 2012;59(1):209 [PMID: 22789580].

van Karnebeek CD, Stockler S: Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. Mol Genet Metab 2012;105(3):368 [PMID: 22212131].

Wilcken B: Newborn screening: how are we traveling, and where should we be going? J Inherit Metab Dis 2011;34(3):569 [PMID: 21499716].

DISORDERS OF CARBOHYDRATE METABOLISM

GLYCOGEN STORAGE DISEASES

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Types 0, I, III, VI, and IX manifest with hypoglycemia in infants.

image Types II, V, and VII manifest with rhabdomyolysis or muscle weakness.

image Types IV and IX manifest with hepatic cirrhosis.

Glycogen is a highly branched polymer of glucose that is stored in liver and muscle. Different enzyme defects affect its biosynthesis and degradation. The hepatic forms of the glycogenoses cause growth failure, hepatomegaly, and severe fasting hypoglycemia. They include glucose-6-phosphatase deficiency (type I; von Gierke disease), debrancher enzyme deficiency (type III), hepatic phosphorylase deficiency (type VI), and phosphorylase kinase deficiency (type IX), which normally regulates hepatic phosphorylase activity. Glycogen synthase deficiency (GSD0) causes hypoglycemia usually after about 12 hours fasting, and can cause mild postprandial hyperglycemia and hyperlactatemia. There are two forms of glucose-6-phosphatase deficiency: in type Ia, the catalytic glucose-6-phosphatase is deficient, and in type Ib, the glucose-6-phosphate transporter is deficient. The latter form also has neutropenia. Glycogenosis type IV, brancher enzyme deficiency, usually presents with progressive liver cirrhosis, as do some rare forms of phosphorylase kinase deficiency.

The myopathic forms of glycogenosis affect skeletal muscle. Skeletal myopathy with weakness or rhabdomyolysis may be seen in muscle phosphorylase deficiency (type V), phosphofructokinase deficiency (type VII), and acid maltase deficiency (type II; Pompe disease). The infantile form of Pompe disease also has hypertrophic cardiomyopathy and macroglossia. The gluconeogenetic disorder fructose-1,6-bisphosphatase deficiency presents with major lactic acidosis and delayed hypoglycemia on fasting.

image Diagnosis

Initial tests include glucose, lactate, triglycerides, cholesterol, uric acid, transaminases, and creatine kinase. Functional testing includes responsiveness of blood glucose and lactate to fasting; for myopathic forms, an ischemic exercise test is helpful. Most glycogenoses can now be diagnosed by molecular analysis, including next-generation panels. Other diagnostic studies include enzyme assays of leukocytes, fibroblasts, liver, or muscle. Disorders diagnosable from analysis of red or white blood cells include deficiency of debrancher enzyme (type III) and phosphorylase kinase (type IX). Pompe disease can usually be diagnosed by assaying acid maltase in a blood spot with confirmation in fibroblasts.

image Treatment

Treatment is designed to prevent hypoglycemia and avoid secondary metabolite accumulations such as elevated lactate in glycogenosis type I. In the most severe hepatic forms, the special diet must be strictly monitored with restriction of free sugars and measured amounts of uncooked cornstarch, which slowly releases glucose in the intestinal lumen. Good results have been reported following continuous nighttime carbohydrate feeding or uncooked cornstarch therapy. Late complications even after years of treatment include focal segmental glomerulosclerosis, hepatic adenoma or carcinoma, and gout. Enzyme-replacement therapy in Pompe disease corrects the cardiomyopathy, but the response in skeletal myopathy is variable with optimal results seen in patients treated early and who have mutations that allow formation of some residual protein which is detected as cross-reacting material on Western blotting. Immunomodulation is used for patients whose treatment response declines due to antibodies to the recombinant enzyme.

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Hicks J, Wartchow E, Mierau G: Glycogen storage diseases: a brief review and update on clinical features, genetic abnormalities, pathologic features, and treatment. Ultrastruct Pathol 2011;35(5):183 [PMID: 21910565].

Kishnani PS, Beckemeyer AA, Mendelsohn NJ: The new era of Pompe disease: advances in the detection, understanding of the phenotypic spectrum, pathophysiology, and management. Am J Med Genet C Semin Med Genet 2012;160(1):1 [PMID: 22253049].

Kishnani PS et al: Glycogen storage disease type III diagnosis and management guidelines. Genet Med 2010;12:446 [PMID: 20631546].

Patient and parent support group website with useful information for families: http://www.agsdus.org.

Rake JP et al: Guidelines for management of glycogen storage disease type I—European Study on Glycogen Storage Disease Type I (ESGSD I). Eur J Pediatr 2002;161(Suppl 1):S112 [PMID: 12373584].

Visser G et al: Consensus guidelines for management of glycogen storage disease type 1b—European Study on Glycogen Storage Disease Type 1. Eur J Pediatr 2002;161(Suppl 1):S120 [PMID: 12373585].

GALACTOSEMIA

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Severely deficient neonates present with vomiting, jaundice, and hepatomegaly on initiation of lactose-containing feedings.

image Renal Fanconi syndrome, cataracts of the ocular lens, hepatic cirrhosis, and sepsis occur in untreated children.

image Delayed, apraxic speech and ovarian failure occur frequently even with treatment. Developmental delay, tremor, and ataxia occur less frequently.

Classic galactosemia is caused by almost total deficiency of galactose-1-phosphate uridyltransferase. Accumulation of galactose-1-phosphate causes hepatic parenchymal disease and renal Fanconi syndrome. Onset of the severe disease is marked in the neonate by vomiting, jaundice (both direct and indirect), hepatomegaly, and rapid onset of liver insufficiency after initiation of milk feeding. Hepatic cirrhosis is progressive. Without treatment, death frequently occurs within a month, often from Escherichia coli sepsis. Cataracts usually develop within 2 months in untreated cases but usually reverse with treatment. With prompt institution of a galactose-free diet, the prognosis for survival without liver disease is excellent. Even when dietary restriction is instituted early, patients with galactosemia are at increased risk for speech and language deficits and ovarian failure. Some patients develop progressive mental retardation, tremor, and ataxia. Milder variants of galactosemia with better prognosis exist.

The disorder is autosomal recessive with an incidence of approximately 1:40,000 live births.

image Diagnosis

In infants receiving foods containing galactose, laboratory findings include liver dysfunction, particularly PT prolongation, together with proteinuria and aminoaciduria. Absence of reducing substances in urine does not exclude the diagnosis. Galactose-1-phosphate is elevated in red blood cells. When the diagnosis is suspected, galactose-1-phosphate uridyltransferase should be assayed in erythrocytes. Blood transfusions give false-negative results and sample deterioration false-positive results.

Newborn screening by demonstrating enzyme deficiency in red cells with the Beutler test or by demonstrating increased serum galactose allows timely institution of treatment.

image Treatment

A galactose-free diet should be instituted as soon as the diagnosis is made. Compliance with the diet must be monitored by following galactose-1-phosphate levels in red blood cells. Appropriate diet management requires not only the exclusion of milk but an understanding of the galactose content of foods. Avoidance of galactose should be lifelong with appropriate calcium replacement, intake of which tends to be low due to the restriction of dairy products.

Berry GT: Galactosemia: when is it a newborn screening emergency? Mol Genet Metab 2012;106(1):7 [PMID: 22483615].

Berry GT, Elsas LJ: Introduction to the Maastricht workshop: lessons from the past and new directions in galactosemia. J Inherit Metab Dis 2011;34(2):249 [PMID: 21116719].

Bosch AM: Classic galactosemia: dietary dilemmas. J Inherit Metab Dis 2011;34(2):257 [PMID: 20625932].

Fridovich-Keil JL, Gubbels CS, Spencer JB, Sanders RD, Land JA, Rubio-Gozalbo E: Ovarian function in girls and women with GALT-deficiency galactosemia. J Inherit Metab Dis 2011;34(2):357 [PMID: 20978943].

Hoffmann B, Wendel U, Schweitzer-Krantz S: Cross-sectional analysis of speech and cognitive performance in 32 patients with classic galactosemia. J Inherit Metab Dis 2011;34(2):421 [PMID: 21347587].

Patient and parent support group website with useful information for families: http://www.galactosemia.org.

Timmers I, van den Hurk J, Di Salle F, Rubio-Gozalbo ME, Jansma BM: Language production and working memory in classic galactosemia from a cognitive neuroscience perspective: future research directions. J Inherit Metab Dis 2011;34(2):367 [PMID: 21290187].

HEREDITARY FRUCTOSE INTOLERANCE

Hereditary fructose intolerance is an autosomal recessive disorder in which deficient activity of fructose-1-phosphate aldolase causes hypoglycemia and tissue accumulation of fructose-1-phosphate on fructose ingestion. Other abnormalities include failure to thrive, vomiting, jaundice, hepatomegaly, proteinuria, and renal Fanconi syndrome. The untreated condition can progress to death from liver failure.

image Diagnosis

The diagnosis is suggested by finding fructosuria or an abnormal transferrin glycoform in the untreated patient. Diagnosis is made by sequencing the HFI gene. An alternative method for diagnosis is enzyme assay of fructose-1-phosphate aldolase in liver biopsy.

image Treatment

Treatment consists of strict dietary avoidance of fructose. Vitamin supplementation is usually needed. Drugs and vitamins dispensed in a sucrose base should be avoided. Treatment monitoring can be done with transferrin glycoform analysis. If diet compliance is poor, physical growth retardation may occur. Growth will resume when more stringent dietary restrictions are reinstituted. If the disorder is recognized early, the prospects for normal development are good. As affected individuals grow up, they may recognize the association of nausea and vomiting with ingestion of fructose-containing foods and selectively avoid them.

Bouteldja N, Timson DJ: The biochemical basis of hereditary fructose intolerance. J Inherit Metab Dis 2010;33(2):105 [PMID: 20162364].

Website with useful information for families: http://www.bu.edu/aldolase.

DISORDERS OF ENERGY METABOLISM

The most common disorders of central mitochondrial energy metabolism are pyruvate dehydrogenase deficiency and deficiencies of respiratory chain components. Disorders of the Krebs cycle include deficiencies in fumarase, 2-ketoglutarate dehydrogenase, and succinyl-CoA ligase. In many, but not in all, patients lactate is elevated in either blood or CSF. In pyruvate dehydrogenase deficiency, the lactate-pyruvate ratio is normal, whereas in respiratory chain disorders the ratio is often increased. Care must be taken to distinguish an elevated lactate level that is due to these conditions (called primary lactic acidoses) from elevated lactate that is a consequence of hypoxia, ischemia, or sampling problems. Table 36–3 lists some causes of primary lactic acidosis.

Table 36–3. Causes of primary lactic acidosis in childhood.

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Patients with a defect in the pyruvate dehydrogenase complex often have agenesis of the corpus callosum or Leigh syndrome (lesions in the globus pallidus, dentate nucleus, and periaqueductal gray matter). They can have mild facial dysmorphism. Recurrent altered mental status, recurrent ataxia, and recurrent acidosis are typical of many disturbances of pyruvate metabolism. The most common genetic defect is in the X-linked E1-α component, with males carrying milder mutations and females carrying severe mutations leading to periventricular cystic brain lesions.

The respiratory chain disorders are frequent (1:5000) and involve a heterogenous group of genetic defects that produce a variety of clinical syndromes (now > 50) of varying severity and presentation. The disorders can affect multiple organs. The following set of symptoms (not intended as a comprehensive listing) can indicate a respiratory chain disorder:

1. General: Failure to thrive

2. Brain: Progressive neurodegeneration, Leigh syndrome, myoclonic seizures, brain atrophy, and subcortical leukodystrophy

3. Eye: Optic neuropathy, retinitis pigmentosa, progressive external ophthalmoplegia, and cataracts

4. Ears: Nerve deafness

5. Muscle: Myopathy with decreased endurance or rhabdomyolysis

6. Kidney: Renal Fanconi syndrome, proteinuria (in CoQ deficiency)

7. Endocrine: Diabetes mellitus and hypoparathyroidism

8. Intestinal: Pancreatic or liver insufficiency or pseudoobstruction

9. Skin: Areas of hypopigmentation

10. Heart: Cardiomyopathy, conduction defects, and arrhythmias

Respiratory chain disorders are among the more common causes of static, progressive, or self-limited neurodevelopmental problems in children. Patients may present with nonspecific findings such as hypotonia, failure to thrive, or renal tubular acidosis, or with more specific features such as ophthalmoplegia or cardiomyopathy. Symptoms are often combined in recognizable clinical syndromes with ties to specific genetic causes. Ragged red fibers and mitochondrial abnormalities may be noted on histologic examination of muscle. Thirteen of the more than 100 genes that control activity of the respiratory chain are part of the mitochondrial genome. Therefore, inheritance of defects in the respiratory chain may be mendelian or maternal.

image Diagnosis

Pyruvate dehydrogenase deficiency is diagnosed by enzyme assay in leukocytes or fibroblasts. Confirmation can be obtained by molecular analysis. Diagnosis of respiratory chain disorders is based on a convergence of clinical, biochemical, morphologic, enzymatic, and molecular data. Classic pathologic features of mitochondrial disorders are the accumulation of mitochondria, which produces ragged red fibers in skeletal muscle biopsy, and abnormal mitochondrial shapes and inclusions inside mitochondria on electron microscopy. However, these findings are only present in 5% of children. Enzyme analysis on skeletal muscle or liver tissue is complicated by an overlap between normal and affected range. Blue native polyacrylamide gel electrophoresis (PAGE) analyzes the assembly of the respiratory chain enzyme complexes. Mitochondrial DNA (mtDNA) analysis in blood or tissue may identify a diagnostic mutation. A rapidly increasing number of nuclear genes (now > 100) causing respiratory chain defects are recognized. Children with defects in mtDNA maintenance (such as mtDNA polymerase γ, POLG1 gene) often present with liver disease and neurodegeneration and are diagnosed by sequencing the causative nuclear genes. Next-generation sequencing of panels of genes or exome sequencing is increasingly used due to the large number of genes involved, but functional testing is often required for confirmation of the pathogenicity of identified mutations. Although diagnostic criteria have been published, the cause of respiratory chain defects still cannot be defined in many patients. In some instances, the genetics and prognosis may be clear, but in many cases neither prognosis nor genetic risk can be predicted. Because of the high complexity of this group of disorders, many patients require a high degree of expertise and multiple studies to arrive at a final diagnosis.

image Treatment

A ketogenic diet is useful in pyruvate dehydrogenase deficiency. In rare patients with primary coenzyme Q deficiency, coenzyme Q treatment is very effective. Other treatments are of theoretical value, with little data on efficacy. Thiamine and lipoic acid have been tried in patients with pyruvate dehydrogenase complex deficiencies, and coenzyme Q and riboflavin have been helpful in some patients with respiratory chain defects. Dichloroacetic acid has limited clinical response in pyruvate dehydrogenase deficiency and has adverse effects. Avoidance of catabolism and of medications that impair mitochondrial function is an important component of treating patients with respiratory chain defects. Transcriptional upregulation in partial deficiencies of nuclear origin and new antioxidants such as EPI-743 offer new hope for the treatment of respiratory chain defects.

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Patient and parent support group website with useful information for families: http://www.umdf.org.

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DISORDERS OF AMINO ACID METABOLISM

DISORDERS OF THE UREA CYCLE

Ammonia is derived from the catabolism of amino acids and is converted to an amino group in urea by enzymes of the urea cycle. Patients with severe defects (often those enzymes early in the urea cycle) usually present in infancy with severe hyperammonemia, vomiting, and encephalopathy, which is rapidly fatal. Patients with milder genetic defects may present with vomiting, encephalopathy, or liver failure after increased protein ingestion or infection. Although defects in argininosuccinic acid synthetase (citrullinemia) and argininosuccinic acid lyase (argininosuccinic acidemia) may cause severe hyperammonemia in infancy, the usual clinical course is chronic with mental retardation. Ornithine transcarbamylase deficiency is X-linked; the others are autosomal recessive. Age at onset of symptoms varies with residual enzyme activity, protein intake, growth, and stresses such as infection. Even within a family, males with ornithine transcarbamylase deficiency may differ by decades in the age of symptom onset. Many female carriers of ornithine transcarbamylase deficiency have protein intolerance. Some develop migraine-like symptoms after protein loads, and others develop potentially fatal episodes of vomiting and encephalopathy after protein ingestion, infections, or during labor and delivery. Trichorrhexis nodosa is common in patients with argininosuccinic aciduria.

image Diagnosis

Blood ammonia should be measured in any acutely ill newborn in whom a cause is not obvious. In urea cycle defects, early hyperammonemia is associated with hyperventilation and respiratory alkalosis. Serum citrulline is low or undetectable in carbamoyl phosphate synthetase and ornithine transcarbamylase deficiency, high in argininosuccinic acidemia, and very high in citrullinemia. Large amounts of argininosuccinic acid are found in the urine of patients with argininosuccinic acidemia. Urine orotic acid is increased in infants with ornithine transcarbamylase deficiency. Citrullinemia and argininosuccinic acidemia can be diagnosed in utero by appropriate enzyme assays in uncultured chorionic villus sample (CVS) material or in amniocytes, but carbamoyl phosphate synthetase and ornithine transcarbamylase deficiency can be diagnosed in utero only by molecular methods.

image Treatment

During treatment of acute hyperammonemic crisis, protein intake should be stopped, and glucose and lipids should be given to reduce endogenous protein breakdown from catabolism. Careful administration of essential amino acids facilitates protein anabolism. Arginine is given intravenously. It is an essential amino acid for patients with urea cycle defects and increases the excretion of waste nitrogen in citrullinemia and argininosuccinic acidemia. Sodium benzoate and sodium phenylacetate are given intravenously to increase excretion of nitrogen as hippuric acid and phenylacetylglutamine. Additionally, hemodialysis or hemofiltration is indicated for severe or persistent hyperammonemia, as is usually the case in the newborn. Peritoneal dialysis and exchange transfusion are ineffective. Long-term treatment includes low-protein diet, oral administration of arginine or citrulline, and sodium benzoate or sodium phenylbutyrate (a prodrug of sodium phenylacetate). Symptomatic heterozygous female carriers of ornithine transcarbamylase deficiency should also receive such treatment. Liver transplantation may be curative and is indicated for patients with severe disorders.

The outcome of urea cycle disorders depends on the genetic severity of the condition (residual activity) and the severity and prompt treatment of hyperammonemic episodes. Brain damage depends on the duration and the degree of elevation of ammonia (and glutamine). Many patients with urea cycle defects, no matter what the enzyme defect, develop permanent neurologic and intellectual impairments, with cortical atrophy and ventricular dilation seen on computed tomographic scan. Rapid identification and treatment of the initial hyperammonemic episode improve outcome.

Auron A, Brophy PD: Hyperammonemia in review: pathophysiology, diagnosis, and treatment. Pediatr Nephrol 2012;27(2):207 [PMID: 21431427].

Bireley WR, Van Hove JL, Gallagher RC, Fenton LZ: Urea cycle disorders: brain MRI and neurological outcome. Pediatr Radiol 2012:42(4):455 [PMID: 21989980].

Braissant O: Current concepts in the pathogenesis of urea cycle disorders. Mol Genet Metab 2010;100(Suppl 1):S3 [PMID: 20227314].

Darwish AA, McKiernan P, Chardot C: Paediatric liver transplantation for metabolic disorders. Part 1: Liver-based metabolic disorders without liver lesions. Clin Res Hepatol Gastroenterol 2011;35(3):194 [PMID: 21376697].

Häberle J: Clinical practice: the management of hyperammonemia. Eur J Pediatr 2011;170(1):21 [PMID: 21165747].

Patient and parent support group website with useful information for families: http://www.nucdf.org.

Scaglia F: New insights in nutritional management and amino acid supplementation in urea cycle disorders. Mol Genet Metab 2010;100(Suppl 1):S72 [PMID: 20299258].

Summar ML et al: Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr 2008;97:1420 [PMID: 18647279].

Urea Cycle Disorders Consortium: http://rarediseasesnetwork.epi.usf.edu/ucdc/about/index.htm.

PHENYLKETONURIA & THE HYPERPHENYLALANINEMIAS

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Mental retardation, hyperactivity, seizures, light complexion, and eczema characterize untreated patients.

image Newborn screening for elevated serum phenylalanine identifies most infants.

image Disorders of cofactor metabolism also produce elevated serum phenylalanine level.

image Early diagnosis and treatment with phenylalanine-restricted diet prevents mental retardation.

Probably the best-known disorder of amino acid metabolism is the classic form of phenylketonuria caused by decreased activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine. In classic phenylketonuria, there is little or no phenylalanine hydroxylase activity. In the less severe hyperphenylalaninemia there may be significant residual activity. Rare variants can be due to deficiency of dihydropteridine reductase or defects in biopterin synthesis.

Phenylketonuria is an autosomal recessive trait, with an incidence in Caucasians of approximately 1:10,000 live births. On a normal neonatal diet, affected patients develop hyperphenylalaninemia. Patients with untreated phenylketonuria exhibit severe mental retardation, hyperactivity, seizures, a light complexion, and eczema.

Success in preventing severe mental retardation in phenylketonuric children by restricting phenylalanine starting in early infancy led to screening programs to detect the disease early. Because the outcome is best when treatment is begun in the first month of life, infants should be screened during the first few days. A second test is necessary when newborn screening is done before 24 hours of age, and should be completed by the third week of life.

image Diagnosis & Treatment

The diagnosis of phenylketonuria is based on finding elevated serum phenylalanine and an elevated phenylalanine/tyrosine ratio in a child on a normal diet. The condition must be differentiated from other causes of hyperphenylalaninemia by examining pterins in urine and dihydropteridine reductase activity in blood.

Determination of carrier status and prenatal diagnosis of phenylketonuria or pterin defects is possible using molecular methods.

A. Phenylalanine Hydroxylase Deficiency: Classic Phenylketonuria and Hyperphenylalaninemia

In phenylketonuria, serum phenylalanine levels are persistently elevated above 1200 μM (20 mg/dL) on a regular diet, with normal or low serum levels of tyrosine, and normal pterins. Poor phenylalanine tolerance persists throughout life. Treatment to decrease phenylalanine levels is always indicated. Hyperphenylalaninemia is diagnosed in infants whose serum phenylalanine levels are usually 240–1200 μM (4–20 mg/dL), and pterins are normal while receiving a normal protein intake. Treatment to reduce phenylalanine levels is indicated if phenylalanine levels consistently exceed 600 μM (10 mg/dL). In contrast, in the rare case of transient hyperphenylalaninemia, serum phenylalanine levels are elevated early but progressively decline toward normal. Dietary restriction is only temporary, if required at all.

Treatment of all forms of phenylketonuria is aimed at maintaining phenylalanine levels less than 360 μM (6 mg/dL). Treatment can consist of dietary restriction of phenylalanine, increasing enzyme activity with pharmacologic doses of R-tetrahydrobiopterin, or new methods to interfere with phenylalaine absorption or to breakdown phenylalanine.

Dietary restriction of phenylalanine intake to amounts that permit normal growth and development is the most common therapy and results in good outcome if instituted in the first month of life and carefully maintained. Metabolic formulas deficient in phenylalanine are available but must be supplemented with normal milk and other foods to supply enough phenylalanine to permit normal growth and development. Serum phenylalanine concentrations must be monitored frequently while ensuring that growth, development, and nutrition are adequate. This monitoring is best done in experienced clinics. Children with classic phenylketonuria who receive treatment promptly after birth and achieve phenylalanine and tyrosine homeostasis will develop well physically and can be expected to have normal or near-normal intellectual development.

Phenylalanine restriction should continue throughout life. Patients who discontinued diet after treatment for several years have developed subtle changes in intellect and behavior, and risk neurologic damage. Counseling should be given during adolescence particularly to girls about the risk of maternal phenylketonuria (see as follows), and women’s diets should be monitored closely prior to conception and throughout pregnancy. Late treatment may still be of benefit in reversing behaviors such as hyperactivity, irritability, and distractibility, but it does not reverse the mental retardation.

Treatment with R-tetrahydrobiopterin results in improved phenylalanine tolerance in up to 50% of patients with a deficiency in phenylalanine hydroxylase. The best results and the most frequent responsiveness are seen in patients with hyperphenylalaninemia. Provision of high doses of large neutral amino acids results in a moderate reduction in phenylalanine and is used as an adjunctive treatment in some adults with phenylketonuria. Treatment trials with pegylated phenylalanine ammonia lyase administration to decrease phenylalanine levels show promise.

B. Biopterin Defects: Dihydropteridine Reductase Deficiency and Defects in Biopterin Biosynthesis

In these patients, serum phenylalanine levels vary. The pattern of pterin metabolites is abnormal. Clinical findings include myo-clonus, tetraplegia, dystonia, oculogyric crises, and other movement disorders. Seizures and psychomotor regression occur even with diet therapy, probably because the enzyme defect also causes neuronal deficiency of serotonin and dopamine. These deficiencies require treatment with levodopa, carbidopa, 5-hydroxytryptophan, and folinic acid. Tetrahydrobiopterin may be added for some biopterin synthesis defects.

C. Tyrosinemia of the Newborn

Serum phenylalanine levels are lower than those associated with phenylketonuria and are accompanied by marked hypertyrosinemia. Tyrosinemia of the newborn usually occurs in premature infants and is due to immaturity of 4-hydroxyphenylpyruvic acid oxidase, resulting in increase in tyrosine and its precursor phenylalanine. The condition resolves spontaneously within 3 months, almost always without sequelae.

D. Maternal Phenylketonuria

Offspring of phenylketonuric mothers may have transient hyperphenylalaninemia at birth. Elevated maternal phenylalanine causes mental retardation, microcephaly, growth retardation, and often congenital heart disease or other malformations in the offspring. The risk to the fetus is lessened considerably by maternal phenylalanine restriction with maintenance of phenylalanine levels below 360 μM (6 mg/dL) throughout pregnancy and optimally started before conception.

American College of Obstetricians and Gynecologists Committee on Genetics: ACOG Committee Opinion No. 449: Maternal phenylketonuria. Obstet Gynecol 2009;114:1432 [PMID: 20134300].

Bélanger-Quintana A, Burlina A, Harding CO, Muntau AC: Up to date knowledge on different treatment strategies for phenylketonuria. Mol Genet Metab 2011;104(Suppl):S19 [PMID: 21967857].

Blau N, Hennermann JB, Langenbeck U, Lichter-Konecki U: Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab 2011;104(Suppl):S2 [PMID: 21937252].

Cunningham A et al: Recommendations for the use of sapropterin in phenylketonuria. Mol Genet Metab 2012;106(3):269 [PMID: 22575621].

Hanley WB: Non-PKU mild hyperphenylalaninemia (MHP)—the dilemma. Mol Genet Metab 2011;104(1–2):23 [PMID: 21632269].

Mitchell JJ, Trakadis YJ, Scriver CR: Phenylalanine hydroxylase deficiency. Genet Med 2011;13(8):697 [PMID: 21555948].

Patient and parent support group websites with useful information for families: http://www.pkunews.orgwww.pkunetwork.org, and www.npkua.org.

van Spronsen FJ, Huijbregts SC, Bosch AM, Leuzzi V: Cognitive, neurophysiological, neurological, and psychosocial outcomes in early-treated PKU-patients: a start toward standardized outcome measurement across development. Mol Genet Metab 2011;104(Suppl):S45 [PMID: 22018724].

HEREDITARY TYROSINEMIA

Type I hereditary tyrosinemia is an autosomal recessive condition caused by deficiency of fumarylacetoacetase. It presents with acute or progressive hepatic parenchymal damage with elevated α-fetoprotein, renal tubular dysfunction with generalized aminoaciduria, hypophosphatemic rickets, or neuronopathic crises. Tyrosine and methionine are increased in blood and tyrosine metabolites and δ-aminolevulinic acid in urine. The key diagnostic metabolite is elevated succinylacetone in urine. Liver failure may be rapidly fatal in infancy or somewhat more chronic, with a high incidence of liver cell carcinoma in long-term survivors. Tyrosinemia type II presents with corneal ulcers and keratotic lesions on palms and soles and very high serum tyrosine levels (> 600 μM).

image Diagnosis

Similar clinical and biochemical findings may occur in other liver diseases such as galactosemia and hereditary fructose intolerance. Increased succinylacetone occurs only in fumarylacetoacetase deficiency and is diagnostic. Diagnosis is confirmed by mutation analysis or by enzyme assay in liver tissue. Prenatal diagnosis is possible. Tyrosinemia type II is diagnosed by molecular methods.

image Treatment

A diet low in phenylalanine and tyrosine ameliorates liver disease, but it does not prevent carcinoma development. Pharmacologic therapy to inhibit the upstream enzyme 4-hydroxyphenylpyruvate dehydrogenase using 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) decreases the production of toxic metabolites, maleylacetoace-tate and fumarylacetoacetate. It improves the liver disease and renal disease, prevents acute neuronopathic attacks, and greatly reduces the risk of hepatocellular carcinoma. Liver transplantation is effective therapy. Tyrosinemia type II symptoms respond well to treatment with dietary tyrosine restriction.

Kitagawa T: Hepatorenal tyrosinemia. Proc Jpn Acad Ser B Phys Biol Sci 2012;88(5):192 [PMID: 22687740].

Larochelle J et al: Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec. Mol Genet Metab 2012;107(1–2):49 [PMID: 22885033].

Thimm E et al: Neurocognitive outcome in patients with hypertyrosinemia type I after long-term treatment with NTBC. J Inherit Metab Dis 2012;35(2);263 [PMID: 22069142].

MAPLE SYRUP URINE DISEASE (BRANCHED-CHAIN KETOACIDURIA)

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Typical presentation is infantile encephalopathy.

Maple syrup urine disease is due to deficiency of the enzyme-catalyzing oxidative decarboxylation of the branched-chain keto acid derivatives of leucine, isoleucine, and valine. Accumulated keto acids of leucine and isoleucine cause the characteristic odor. Only leucine and its corresponding keto acid have been implicated in causing central nervous system (CNS) dysfunction. Many variants of this disorder have been described, including mild, intermittent, and thiamine-dependent forms. All are autosomal recessive traits.

Patients with classic maple syrup urine disease are normal at birth, but after about 1 week they develop feeding difficulties, coma, and seizures. Unless diagnosis is made and dietary restriction of branched-chain amino acids is begun, most will die in the first month of life. Nearly normal growth and development may be achieved if treatment is begun before about age 10 days, which is facilitated by newborn screening.

image Diagnosis

Amino acid analysis shows marked elevation of branched-chain amino acids including alloisoleucine, a diagnostic transamination product of the keto acid of isoleucine. Urine organic acids demonstrate the characteristic keto acids. The magnitude and consistency of metabolite changes are altered in mild and intermittent forms. Prenatal diagnosis is possible by enzyme assay in cultured amniocytes or chorionic villi, and by molecular analysis of the mutation is known.

image Treatment

Dietary leucine restriction and avoidance of catabolism are the cornerstones of treatment. Infant formulas deficient in branched-chain amino acids must be supplemented with normal foods to supply enough branched-chain amino acids to permit normal growth. Serum levels of branched-chain amino acids must be monitored frequently to deal with changing protein requirements. Acute episodes must be aggressively treated to prevent catabolism and negative nitrogen balance. Very high leucine levels may require hemodialysis.

Knerr I et al: Advances and challenges in the treatment of branched-chain amino/keto acid metabolic defects. J Inherit Metab Dis 2011;Feb 3 [Epub ahead of print] [PMID: 21290185].

Mazariegos GV et al: Liver transplantation for classical maple syrup urine disease: long-term follow-up in 37 patients and comparative United Network for Organ Sharing experience. J Pediatr 2012;160(1):116 [PMID: 21839471].

Patient and parent support group website with useful information for families: http://www.msud-support.org.

HOMOCYSTINURIA

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Consider in a child of any age with a marfanoid habitus, dislocated lenses, or thrombosis.

image Newborn screening allows early diagnosis and treatment resulting in a normal outcome.

Homocystinuria is most often due to deficiency of cystathionine β-synthase (CBS), but may also be due to deficiency of methylenetetrahydrofolate reductase (MTHFR) or to defects in the biosynthesis of methyl-B12, the coenzyme for methionine synthase. All inherited forms of homocystinuria are autosomal recessive traits.

About 50% of patients with untreated CBS deficiency are mentally retarded, and most have arachnodactyly, osteoporosis, and a tendency to develop dislocated lenses and thromboembolic phenomena. Mild variants of CBS deficiency present with thromboembolic events. Patients with severe remethylation defects usually exhibit failure to thrive and a variety of neurologic symptoms, including brain atrophy, microcephaly, and seizures in infancy and early childhood. Very mild elevations of homocysteine, such as caused by a polymorphism of MTHFR resulting in a heat sensitive protein, are increasingly recognized as a factor in the etiology of vascular disease leading to myocardial infarction and stroke.

image Diagnosis

Diagnosis is made by demonstrating elevated total serum homocysteine or by identifying homocystinuria in a patient who is not severely deficient in vitamin B12. Serum methionine levels are usually high in patients with CBS deficiency and often low in patients with remethylation defects. Cystathionine levels are low in CBS deficiency. When the remethylation defect is due to deficiency of methyl-B12, megaloblastic anemia or hemolytic uremic syndrome may be present and an associated deficiency of adenosyl-B12 may cause methylmalonic aciduria. Mutation analysis or studies of cultured fibroblasts can make a specific diagnosis.

image Treatment

About 50% of patients with CBS deficiency respond to large oral doses of pyridoxine. Pyridoxine nonresponders are treated with dietary methionine restriction and oral administration of betaine, which increases methylation of homocysteine to methionine and improves neurologic function. Early treatment prevents mental retardation, lens dislocation, and thromboembolic manifestations, which justifies the screening of newborn infants. Large doses of vitamin B12 (eg, 1–5 mg hydroxocobalamin administered daily intramuscularly or subcutaneously) are indicated in some patients with defects in cobalamin metabolism.

Blom HJ, Smulders Y: Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis 2011;34(1):75 [PMID: 20814827].

Mudd SH: Hypermethioninemias of genetic and non-genetic origin: a review. Am J Med Genet C Semin Med Genet 2011;157:3 [PMID: 21308989].

NONKETOTIC HYPERGLYCINEMIA

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Severely affected newborns have apnea, hypotonia, lethargy, myoclonic seizures, and hiccups.

image Mental and motor retardation in most patients.

image Mildly affected children have developmental delay, hyperactivity, mild chorea, and seizures.

image Electroencephalography (EEG) shows burst suppression.

image CSF glycine is elevated.

Inherited deficiency of various subunits of the glycine cleavage enzyme causes nonketotic hyperglycinemia, also called glycine encephalopathy. Glycine accumulation in the brain disturbs neurotransmission of the glycinergic receptors and the N-methyl-D-aspartate type of glutamate receptor. In its most severe form, the condition presents in the newborn as hypotonia, lethargy proceeding to coma, myoclonic seizures, and hiccups, with a burst suppression pattern on EEG. Respiratory depression may require ventilator assistance in the first 2 weeks, followed by spontaneous recovery. The majority of patients develop severe mental retardation and seizures. Some patients have agenesis of the corpus callosum or posterior fossa malformations. Most patients have restricted diffusion on MRI in the already myelinated long tracts at birth. Some patients with an attenuated form present with seizures, developmental delay, and mild chorea later in infancy or in childhood. All forms of the condition are autosomal recessive.

image Diagnosis

Nonketotic hyperglycinemia should be suspected in any neonate or infant with seizures, particularly those with burst suppression pattern on EEG. Diagnosis is confirmed by demonstrating a large increase in glycine in non-bloody CSF, with an abnormally high ratio of CSF glycine to serum glycine. Molecular analysis is diagnostic in more than 90% of cases. Enzyme analysis on liver tissue can confirm the diagnosis. Prenatal diagnosis is possible by molecular analysis if both mutations are known or by enzyme assay on uncultured CVS.

image Treatment

In patients with mild disease, treatment with sodium benzoate (to normalize serum glycine levels) and dextromethorphan or ketamine (to block N-methyl-D-aspartate type of glutamate receptors) controls seizures and improves outcome. Treatment of severely affected patients is generally unsuccessful. High-dose benzoate therapy can aid in seizure control but does not prevent severe mental retardation.

Aburahma S, Khassawneh M, Griebel M, Sharp G, Gibson J: Pitfalls in measuring cerebrospinal fluid glycine levels in infants with encephalopathy. J Child Neurol 2011;26(6):703 [PMID: 21335543].

Hennermann JB, Berger JM, Grieben U, Scharer G, Van Hove JL: Prediction of long-term outcome in glycine encephalopathy: a clinical survey. J Inherit Metab Dis 2012;35(2);253 [PMID:22002442].

Patient and parent support group website with useful information for families: http://www.nkh-network.org.

Suzuki Y et al: Nonketotic hyperglycinemia: proposal of a diagnostic and treatment strategy. Pediatr Neurol 2010;43:221 [PMID: 20691948].

ORGANIC ACIDEMIAS

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Consider in any child presenting with metabolic acidosis and ketosis in early infancy.

Organic acidemias are disorders of amino and fatty acid metabolism in which non-amino organic acids accumulate in serum and urine. These conditions are usually diagnosed by examining organic acids in urine, a complex procedure that requires considerable interpretive expertise and is usually performed only in specialized laboratories. Table 36–4 lists the clinical features of organic acidemias, together with the urine organic acid patterns typical of each. Additional details about some of the more important organic acidemias are provided in the sections that follow.

Table 36–4. Clinical and laboratory features of organic acidemias.

Image

PROPIONIC & METHYLMALONIC ACIDEMIA (KETOTIC HYPERGLYCINEMIAS)

The oxidation of threonine, valine, methionine, and isoleucine results in propionyl-CoA, which propionyl-CoA carboxylase converts into L-methylmalonyl-CoA, which is metabolized through methylmalonyl-CoA mutase to succinyl-CoA. Gut bacteria and the breakdown of odd-chain-length fatty acids also substantially contribute to propionyl-CoA production. Propionic acidemia is due to a defect in the biotin-containing enzyme propionyl-CoA carboxylase, and methylmalonic aciduria is due to a defect in methylmalonyl-CoA mutase. In most cases the latter is due to a defect in the mutase apoenzyme, but in others it is due to a defect in the biosynthesis of its adenosyl-B12coenzyme. In some of these defects, only the synthesis of adenosyl-B12 is blocked; in others, the synthesis of methyl-B12 is also blocked, and hence homocysteine is also elevated in blood in addition to methylmalonic acid.

Clinical symptoms in propionic and methylmalonic acidemia vary according to the location and severity of the enzyme block. Children with severe blocks present with acute, life-threatening metabolic acidosis, hyperammonemia, and bone marrow depression in early infancy or with metabolic acidosis, vomiting, and failure to thrive during the first few months of life. Most patients with severe disease have mild or moderate mental retardation. Late complications include pancreatitis, cardiomyopathy, and basal ganglia stroke, and in methylmalonic aciduria, interstitial nephritis.

All forms of propionic and methylmalonic acidemia are autosomal recessive traits (except for CblX [cobalamin X]) and can be diagnosed in utero.

image Diagnosis

Laboratory findings consist of increases in urinary organic acids derived from propionyl-CoA or methylmalonic acid (see Table 36–4). Hyperglycinemia can be present. In some forms of abnormal vitamin B12 metabolism, homocysteine can be elevated. Confirmation is by molecular analysis or by assays in fibroblasts.

image Treatment

Patients with enzyme blocks in B12 metabolism usually respond to massive doses of vitamin B12 given intramuscularly. Vitamin B12 non-responsive methylmalonic acidemia and propionic acidemia require amino acid restriction, strict prevention of catabolism, and carnitine supplementation to enhance propionylcarnitine excretion. Intermittent metronidazole can help reduce the propionate load from the gut. In the acute setting, hemodialysis or hemofiltration may be needed. Combined liver-renal transplantation is an option for patients with renal insufficiency, and liver transplantation has shown promise for patients with life-threatening cardiomyopathy.

Carrillo-Carrasco N, Chandler RJ, Venditti CP: Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis, and management. J Inherit Metab Dis 2012;35(1):91 [PMID: 21748409].

Carrillo-Carrasco N, Venditti CP: Combined methylmalonic acidemia and homocystinuria, cblC type. II. Complications, pathophysiology, and outcomes. J Inherit Metab Dis 2012;35(1):103 [PMID: 21748408].

Chapman KA et al: Acute management of propionic acidemia. Mol Genet Metab 2012;105(1):16 [PMID: 22000903].

Knerr I, Weinhold N, Vockley J, Gibson KM: Advances and challenges in the treatment of branched-chain amino/keto acid metabolic defects. J Inherit Metab Dis 2012;35(1):29 [PMID: 21290185].

O’Shea CJ, Sloan JL, Wiggs EA: Neurocognitive phenotype of isolated methylmalonic acidemia. Pediatrics 2012;129(6):e1541 [PMID: 22614770].

Pena L et al: Natural history of propionic acidemia. Mol Genet Metab 2012;105(1):5 [PMID: 21986446].

Patient and parent support group websites with useful information for families: http://www.oaanews.org and www.pafoundation.com.

Prada CE et al: Cardiac disease in methylmalonic acidemia. J Pediatr 2011;159(5):862 [PMID: 21784454].

Schreiber J et al: Neurologic considerations in propionic acidemia. Mol Genet Metab 2012;105(1):10 [PMID: 22078457].

Sutton VR et al: Chronic management and health supervision of individuals with propionic acidemia. Mol Genet Metab 2012;105(1):26 [PMID: 21963082].

Vara R et al: Liver transplantation for propionic acidemia in children. Liver Transpl 2011;17:661 [PMID: 21618686].

Watkins D, Rosenblatt DS: Inborn errors of cobalamin absorption and metabolism. Am J Med Genet C Semin Med Genet 2011;157(1):33 [PMID: 21312325].

ISOVALERIC ACIDEMIA

Isovaleric acidemia, caused by deficiency of isovaleryl-CoA dehydrogenase in the leucine oxidative pathway, was the first organic acidemia to be described in humans. Patients with this disorder usually present with poor feeding, metabolic acidosis, seizures, and an odor of sweaty feet during the first few days of life, with coma and death occurring if the condition is not recognized and treated. Other patients have a more chronic course, with episodes of vomiting and lethargy, hair loss, and pancreatitis precipitated by intercurrent infections or increased protein intake. The condition is autosomal recessive and can be diagnosed in utero.

image Diagnosis

Isovalerylglycine is consistently detected in the urine by organic acid chromatography.

image Treatment

Providing a low-protein diet or a diet low in leucine is effective. Conjugation with either glycine or carnitine helps in maintaining metabolic stability by removing toxic isovaleryl-CoA. Outcome is usually good.

Ensenauer R et al: Newborn screening for isovaleric acidemia using tandem mass spectrometry: data from 1.6 million newborns. Clin Chem 2011;57(4):623 [PMID: 21335445].

Grünert SC et al: Clinical and neurocognitive outcome in symptomatic isovaleric acidemia. Orphanet J Rare Dis 2012;7:9 [PMID: 22277694].

CARBOXYLASE DEFICIENCY

Isolated pyruvate carboxylase deficiency presents with lactic acidosis and hyperammonemia in early infancy. Even if biochemically stabilized, the neurologic outcome is dismal. Isolated 3-methylcrotonyl-CoA carboxylase deficiency is frequently recognized on newborn screening using acylcarnitine analysis. It is usually a benign condition that only rarely causes symptoms of acidosis and neurologic depression. All carboxylases require biotin as a cofactor. Holocarboxylase synthetase and biotinidase are two enzymes of biotin metabolism. Holocarboxylase synthetase covalently binds biotin to the apocarboxylases for pyruvate, 3-methylcrotonyl-CoA, and propionyl-CoA; biotinidase releases biotin from these proteins and from proteins in the diet. Recessively inherited deficiency of either enzyme causes deficiency of all three carboxylases (ie, multiple carboxylase deficiency). Patients with holocarboxylase synthetase deficiency usually present as neonates with hypotonia, skin problems, and massive acidosis. Those with biotinidase deficiency present later with a syndrome of ataxia, seizures, seborrhea, and alopecia. Untreated patients can develop mental retardation, hearing loss, and optic nerve atrophy. Newborn screening is justified because the neurologic sequellae of the disorder in many patients are preventable if treated early.

image Diagnosis

This diagnosis should be considered in patients with typical symptoms or in those with primary lactic acidosis. Urine organic acids are usually but not always abnormal (see Table 36–4). Diagnosis is made by enzyme assay of carboxylase activities in fibroblasts or leucocytes. Biotinidase can be assayed in serum, and holocarboxylase synthetase in leukocytes or fibroblasts.

image Treatment

Oral administration of biotin in large doses often reverses the organic aciduria within days and the clinical symptoms within days to weeks. Hearing loss can occur in patients with biotinidase deficiency despite treatment.

Arnold GL et al: Outcome of infants diagnosed with 3-methyl-crotonyl-CoA-carboxylase deficiency by newborn screening. Mol Genet Metab 2012;106(4):439 [PMID: 22658692].

Tammachote R et al: Holocarboxylase synthetase deficiency: novel clinical and molecular findings. Clin Genet 2010;78:88 [PMID: 20095979].

Wolf B: The neurology of biotinidase deficiency. Mol Genet Metab 2011;104(1–2):27 [PMID: 21696988].

GLUTARIC ACIDEMIA TYPE I

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Suspect in children with acute basal ganglia necrosis and macrocrania with subdural bleeds.

image Presymptomatic diagnosis by newborn screening and treatment reduces the incidence of acute encephalopathic crises.

Glutaric acidemia type I is due to deficiency of glutaryl-CoA dehydrogenase. Patients have frontotemporal atrophy with enlarged sylvian fissures and macrocephaly. Sudden or chronic neuronal degeneration in the caudate and putamen causes an extrapyramidal movement disorder in childhood with dystonia and athetosis. Children with glutaric acidemia type I may present with retinal hemorrhages and intracranial bleeding, and may thus be falsely considered victims of child abuse. Severely debilitated children often die in the first decade, but several reported patients have had only mild neurologic abnormalities. Most patients develop symptoms in the first 6 years of life. The condition is autosomal recessive and prenatal diagnosis is possible.

image Diagnosis

Glutaric acidemia type I should be suspected in patients with acute or progressive dystonia in the first 6 years of life. Magnetic resonance imaging of the brain is highly suggestive. The diagnosis is supported by finding glutaric, 3-hydroxyglutaric acid, and glutarylcarnitine in urine or serum or by finding two mutations in the GCDH gene. Demonstration of deficiency of glutaryl-CoA dehydrogenase in fibroblasts can further confirm the diagnosis. Prenatal diagnosis is by mutation analysis, enzyme assay, or quantitative metabolite analysis in amniotic fluid.

image Treatment

Strict catabolism prevention during any intercurrent illness is very important. Supplementation with large amounts of carnitine and provision of a lysine and tryptophan restricted diet may prevent degeneration of the basal ganglia, warranting newborn screening. Early diagnosis via newborn screening does not prevent neurologic disease in all patients, but it clearly reduces the risk. Neurologic symptoms, once present, do not resolve. Symptomatic treatment of severe dystonia is important for affected patients.

Jafari P, Braissant O, Bonafé L, Ballhausen D: The unsolved puzzle of neuropathogenesis in glutaric aciduria type I. Mol Genet Metab 2011;104(4):425 [PMID: 21944461].

Kölker S et al: Complementary dietary treatment using lysine-free, arginine-fortified amino acid supplements in glutaric aciduria type I—a decade of experience. Mol Genet Metab 2012;107(1-2):72 [PMID: 22520952].

Kölker S et al: Diagnosis and management of glutaric aciduria type I—revised recommendations. J Inherit Metab Dis 2011;34(3):677 [PMID: 21431622].

Viau K, Ernst SL, Vanzo RJ, Botto LD, Pasquali M, Longo N: Glutaric acidemia type 1: outcomes before and after expanded newborn screening. Mol Genet Metab 2012;106(4):430 [PMID: 22728054].

DISORDERS OF FATTY ACID OXIDATION & CARNITINE

FATTY ACID OXIDATION DISORDERS

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Obtain an acylcarnitine profile for any child with hypoglycemia to evaluate for a fatty acid oxidation defect.

image Early diagnosis and treatment can prevent cardiomyopathy in affected children.

Deficiencies of very-long-chain and medium-chain acyl-CoA dehydrogenase (VLCAD, MCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), three enzymes of fatty acid β-oxidation, usually cause Reye-like episodes of hypoketotic hypoglycemia, mild hyperammonemia, hepatomegaly, and encephalopathy. Sudden death in infancy is a less common presentation. The long-chain defects, which also include carnitine palmitoyltransferase deficiency I and II and carnitine-acylcarnitine translocase deficiency, often also cause skeletal myopathy with hypotonia and episodic rhabdomyolysis. They also cause cardiomyopathy and ventricular arrhythmias. LCHAD deficiency may produce progressive liver cirrhosis, peripheral neuropathy, and retinitis pigmentosa. Mothers of affected infants can have acute fatty liver of pregnancy or HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets). Mild carnitine palmitoyltransferase I deficiency may cause renal tubular acidosis and hypertriglyceridemia. MCAD deficiency is common, occurring in perhaps 1:9000 live births. Reye-like episodes may be fatal or cause residual neurologic damage. Episodes tend to become less frequent and severe with time. After the diagnosis is made and treatment instituted, morbidity decreases and mortality is avoided in MCAD deficiency.

Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is characterized by the presence of ethylmalonic acid in the urine, and although some patients have symptoms similar to those in MCAD deficiency, many are asymptomatic. Glutaric acidemia type II results from defects in the transfer of electrons from fatty acid oxidation and some amino acid oxidation into the respiratory chain. Some patients with glutaric acidemia type II have a clinical presentation resembling MCAD deficiency. Patients with a severe neonatal presentation also have renal cystic disease and dysmorphic features. The least affected patients can present with late-onset myopathy and be riboflavin responsive. Some develop cardiomyopathy or leukodystrophy. Deficiency of the ketogenic enzyme 3-hydroxymethylglutaryl-CoA synthase presents with hypoketotic hypoglycemia. These conditions are autosomal recessive.

image Diagnosis

The hypoglycemic presentation of Reye-like episodes is associated with a lack of an appropriate ketone response to fasting. Urine organic acid analysis in patients with MCAD deficiency reveals dicarboxylic acids and increased hexanoylglycine, suberylglycine, and phenylpropionylglycine. The finding of normal urine organic acids does not exclude these conditions, because the excretion of these acids is intermittent. Urine and blood findings in glutaric acidemia type II and SCAD deficiency are often diagnostic. The analysis of acylcarnitine esters is a first-line diagnostic test used in neonatal screening because it reveals diagnostic metabolites regardless of clinical status. MCAD deficiency is characterized by elevated octanoylcarnitine. A typical pattern can be recognized in deficiencies of VLCAD, LCHAD, carnitine-acylcarnitine translocase, and severe carnitine palmitoyltransferase. Further confirmation can be obtained from analysis of fatty acid oxidation in fibroblasts. Molecular sequencing is available for each defect with MCAD and LCHAD deficiencies, each having a common mutation. Assays for each enzyme can be done on fibroblasts in specialized laboratories.

image Treatment

Management involves prevention of hypoglycemia by avoiding prolonged fasting (> 8–12 hours). This includes providing carbohydrate snacks before bedtime and vigorous treatment of fasting associated with intercurrent infections. Because fatty acid oxidation can be compromised by associated carnitine deficiency, young patients with MCAD deficiency usually receive oral carnitine. Restriction of dietary long-chain fats is not necessary in MCAD deficiency but is required for severe VLCAD and LCHAD deficiencies. Medium-chain triglycerides are contraindicated in MCAD deficiency but are an essential energy source for patients with severe VLCAD and LCHAD deficiencies or carnitine-acylcarnitine translocase deficiency. Riboflavin may be beneficial in some patients with glutaric acidemia type II. Outcome in MCAD deficiency is excellent but is more guarded in patients with the other disorders.

Bennett MJ: Pathophysiology of fatty acid oxidation disorders. J Inherit Metab Dis 2010;33(5):533 [PMID: 20824345].

Dykema DM: Carnitine palmitoyltransferase-1A deficiency: a look at classic and arctic variants. Adv Neonatal Care 2012;12(1):23 [PMID: 22301540].

Hoffmann L, Haussmann U, Mueller M, Spiekerkoetter U: VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis 2012;35(2):269 [PMID: 21932095].

Houten SM, Wanders RJ: A general introduction to the biochemistry of mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis 2010;33(5):469 [PMID: 20195903].

Lindner M, Hoffmann GF, Matern D: Newborn screening for disorders of fatty-acid oxidation: experience and recommendations from an expert meeting. J Inherit Metab Dis 2010;33(5):521 [PMID: 20373143].

Lund AM, Skovby F, Vestergaard H, Christensen M, Christensen E: Clinical and biochemical monitoring of patients with fatty acid oxidation disorders. J Inherit Metab Dis 2010;33(5):495 [PMID: 20066495].

Patient and parent support group website with useful information for families: http://www.fodsupport.org.

Schatz UA, Ensenauer R: The clinical manifestation of MCAD deficiency: challenges toward adulthood in the screened population. J Inherit Metab Dis 2010;33(5):513 [PMID: 20532824].

Spiekerkoetter U: Mitochondrial fatty acid oxidation disorders: clinical presentation of long-chain fatty acid oxidation defects before and after newborn screening. J Inherit Metab Dis 2010;33(5):527 [PMID: 20449660].

Spiekerkoetter U, Bastin J, Gillingham M, Morris A, Wijburg F, Wilcken B: Current issues regarding treatment of mitochondrial fatty acid oxidation disorders. J Inherit Metab Dis 2010;33(5):555 [PMID: 20830526].

Spiekerkoetter U et al: Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: Results from a workshop. J Inherit Metab Dis 2009;32:488 [PMID: 19399638].

Spiekerkoetter U et al: Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop. J Inherit Metab Dis 2009;32:498 [PMID: 19452263].

van Maldegem BT et al: Clinical aspects of short-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis 2010;33:507 [PMID: 20429031].

Wilcken B: Fatty acid oxidation disorders: outcome and long-term prognosis. J Inherit Metab Dis 2010;33(5):501 [PMID: 20049534].

CARNITINE

Carnitine is an essential nutrient found in highest concentration in red meat. Its primary function is to transport long-chain fatty acids into mitochondria for oxidation. Primary defects of carnitine transport may manifest as Reye syndrome, cardiomyopathy, or skeletal myopathy with hypotonia. These disorders are rare compared with secondary carnitine deficiency, which may be due to diet (vegan diet, intravenous alimentation, or ketogenic diet), renal losses, drug therapy (especially valproic acid), and other metabolic disorders (especially disorders of fatty acid oxidation and organic acidemias). The prognosis depends on the cause of the carnitine abnormality. Primary carnitine deficiency is one of the most treatable causes of dilated cardiomyopathy in children.

Free and esterified carnitine can be measured in blood. Muscle carnitine may be low despite normal blood levels, particularly in respiratory chain disorders. If carnitine insufficiency is suspected, the patient should be evaluated to rule out disorders that might cause secondary carnitine deficiency.

Oral or intravenous L-carnitine is used in carnitine deficiency or insufficiency in doses of 25–100 mg/kg/d or higher. Treatment is aimed at maintaining normal carnitine levels. Carnitine supplementation in patients with some disorders of fatty acid oxidation and organic acidosis may also augment excretion of accumulated metabolites, although supplementation may not prevent metabolic crises in such patients.

Indiveri C et al: The mitochondrial carnitine/acylcarnitine carrier: function, structure and physiopathology. Mol Aspects Med 2011;32(4–6):223 [PMID: 22020112].

Lee NC et al: Diagnoses of newborns and mothers with carnitine uptake defects through newborn screening. Mol Genet Metab 2010;100:46 [PMID: 20074989].

Nasser M et al: Carnitine supplementation for inborn errors of metabolism. Cochrane Database Syst Rev 2009;2:CD006659 [PMID: 19370646].

Rose EC, di San Filippo CA, Ndukwe Erlingsson UC, Ardon O, Pasquali M, Longo N: Genotype-phenotype correlation in primary carnitine deficiency. Hum Mutat 2012;33(1):118 [PMID: 21922592].

PURINE METABOLISM DISORDERS

Hypoxanthine-guanine phosphoribosyltransferase is an enzyme that converts the purine bases hypoxanthine and guanine to inosine monophosphate and guanosine monophosphate, respectively. Hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome) is an X-linked recessive disorder. The complete deficiency is characterized by CNS dysfunction and purine overproduction with hyperuricemia and hyperuricosuria. Depending on the residual activity of the mutant enzyme, male hemizygous individuals may be severely disabled by choreoathetosis, spasticity, and compulsive, mutilating lip and finger biting, or they may have only gouty arthritis and urate ureterolithiasis. Enzyme deficiency can be measured in erythrocytes, fibroblasts, and cultured amniotic cells; this disorder can thus be diagnosed in utero. Adenylosuccinate lyase deficiency involves a defect in the synthesis of purines. Patients present with static mental retardation, hypotonia, and seizures.

image Diagnosis

Diagnosis of Lesch-Nyhan syndrome is made by demonstrating an elevated uric acid-creatinine ratio in urine, followed by demonstration of enzyme deficiency in red blood cells or fibroblasts. Screening for adenylosuccinate lyase deficiency is by measurement of succinylpurines in urine, with confirmation by further metabolite and molecular assays.

image Treatment

Hyperhydration and alkalinization are essential to prevent kidney stones and urate nephropathy. Allopurinol and probenecid may be given to reduce hyperuricemia and prevent gout but do not affect the neurologic status. Physical restraints are often more effective than neurologic medications for automutilation. No effective treatment exists for adenylosuccinate lyase deficiency.

Micheli V et al: Neurological disorders of purine and pyrimidine metabolism. Curr Top Med Chem 2011;11(8):923 [PMID: 21401501].

Torres RJ, Puig JG, Jinnah HA: Update on the phenotypic spectrum of Lesch-Nyhan disease and its attenuated variants. Curr Rheumatol Rep 2012;14(2):189 [PMID: 22198833].

LYSOSOMAL DISEASES

Lysosomes are cellular organelles in which complex macromolecules are degraded by specific acid hydrolases. Deficiency of a lysosomal enzyme causes its substrate to accumulate in the lysosomes, resulting in a characteristic clinical picture. These storage disorders are classified as mucopolysaccharidoses, lipidoses, or mucolipidoses, depending on the nature of the stored material. Two additional disorders, cystinosis and Salla disease, are caused by defects in lysosomal proteins that normally transport material from the lysosome to the cytoplasm. Table 36–5 lists clinical and laboratory features of these conditions. Most are inherited as autosomal recessive traits, and all can be diagnosed in utero.

Table 36–5. Clinical and laboratory features of lysosomal storage diseases.

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image Diagnosis

The diagnosis of mucopolysaccharidosis is suggested by certain clinical and radiologic findings (dysostosis multiplex, which includes enlarged sella turcia, scaphocephaly, broad ribs, hook shaped vertebrae [L1 and L2 most affected], and prominent pointing of the metacarpals and broad phalanges). Urine screening tests can detect increased mucopolysaccharides and further identify which specific mucopolysaccharides are present. Diagnosis must be confirmed by enzyme assays of leukocytes or cultured fibroblasts. Analysis of urinary oligosaccharides indicates a specific disorder prior to enzymatic testing. Lipidoses present with visceral symptoms or neurodegeneration. The pattern of the leukodystrophy associated with many lipidoses can indicate a specific condition. Diagnosis is made by appropriate enzyme assays of peripheral leukocytes or cultured skin fibroblasts. Molecular analysis is also available for most conditions.

image Treatment

Most conditions cannot be treated effectively, but new avenues have given hope in many conditions. Hematopoietic stem cell transplantation can greatly improve the course of some lysosomal diseases and is first-line treatment in some, such as infantile Hurler syndrome. Several disorders are treated with infusions of recombinant modified enzyme. Treatment of Gaucher disease is very effective, and long-term data suggest excellent outcome. Similar treatments have been developed for Fabry disease, several mucopolysaccharidoses, and Pompe disease. Substantial improvements in these conditions have been reported but with limitations. New avenues for treatment through substrate inhibition and chaperone therapy are being developed. Treatment of cystinosis with cysteamine results in depletion of stored cystine and prevention of complications including renal disease.

Anson DS et al: Therapies for neurological disease in the mucopolysaccharidoses. Curr Gene Ther 2011;11:132 [PMID: 21291356].

Beck M: Mucopolysaccharidosis type II (Hunter syndrome): clinical picture and treatment. Curr Pharm Biotechnol 2011;12(6):861 [PMID: 21235446].

Caciotti A et al: GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings. Biochim Biophys Acta 2011;1812:782 [PMID: 21497194].

Campos D, Monaga M: Mucopolysaccharidosis type I: current knowledge on its pathophysiological mechanisms. Metab Brain Dis 2012;27(2):121 [PMID: 22527994].

D’Aco K et al: Diagnosis and treatment trends in mucopolysaccharidosis I: findings from the MPS I Registry. Eur J Pediatr 2012;171(6):911 [PMID: 22234477].

de Ru MH et al: Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure. Orphanet J Rare Dis 2011;6:55 [PMID: 21831279].

de Ruijter J, Valstar MJ, Wijburg FA: Mucopolysaccharidosis type III (Sanfilippo syndrome): emerging treatment strategies. Curr Pharm Biotechnol 2011;12(6):923 [PMID: 21235449].

Desnick RJ, Schuchman EH: Enzyme replacement therapy for lysosomal diseases: lessons from 20 years of experience and remaining challenges. Annu Rev Genomics Hum Genet 2012;13:307 [PMID: 22970722].

Kohan R et al: Therapeutic approaches to the challenge of neuronal ceroid lipofuscinoses. Curr Pharm Biotechnol 2011;12(6):867 [PMID: 21235444].

Lehman TJ, Miller N, Norquist B, Underhill L, Keutzer J: Diagnosis of the mucopolysaccharidoses. Rheumatology (Oxford) 2011;50(Suppl 5):v41 [PMID: 22210670].

Mistry PK et al: A reappraisal of Gaucher disease—diagnosis and disease management algorithms. Am J Hematol 2011;86(1);110 [PMID: 21080341].

Muenzer J: Overview of the mucopolysaccharidoses. Rheumatology (Oxford) 2011;50(Suppl 5):v4 [PMID: 22210669].

Muenzer J et al: Mucopolysaccharidosis I: management and treatment guidelines. Pediatrics 2009;123:19 [PMID: 19117856].

Muenzer J et al: Multidisciplinary management of Hunter syndrome. Pediatrics 2009;124:e1228 [PMID: 19901005].

Patient and parent support group websites with useful information for families: http://www.mpssociety.orgwww.ulf.orgwww.lysosomallearning.comwww.fabry.orgwww.gaucherdisease.org, and www.ntsad.org.

Patterson MC et al: Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update. Mol Genet Metab 2012;106(3):330 [PMID: 22572546].

Patterson MC et al: Disease and patient characteristics in NP-C patients: findings from an international disease registry. Orphanet J Rare Dis 2013;8:12 [PMID: 23324478].

Renaud DL: Lysosomal disorders associated with leukoencephalopathy. Semin Neurol 2012;32(1):51 [PMID: 22422206].

Rozenfeld P, Neumann PM: Treatment of Fabry disease: current and emerging strategies. Curr Pharm Biotechnol 2011;12(6):916 [PMID: 21235448].

Tomatsu S et al: Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment. Curr Pharm Biotechnol 2011;12(6):931 [PMID: 21506915].

Wang RY et al: Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med 2011;13:457 [PMID: 21502868].

Wakabayashi K, Gustafson AM, Sidransky E, Goldin E: Mucolipidosis type IV: an update. Mol Genet Metab 2011;104(3):206 [PMID: 21763169].

PEROXISOMAL DISEASES

Peroxisomes are intracellular organelles that contain a large number of enzymes, many of which are oxidases linked to catalase. The enzyme systems in peroxisomes include β-oxidation of very-long-chain fatty acids, phytanic acid, and bile acids and the biosynthesis of plasmalogens. In addition, peroxisomes contain oxidases for D- and L-amino acids, pipecolic acid, and phytanic acid, and an enzyme (alanine-glyoxylate aminotransferase) that affects transamination of glyoxylate to glycine.

In some peroxisomal diseases, many enzymes are deficient. Zellweger (cerebrohepatorenal) syndrome, the best known among these, is caused by severe defects in organelle assembly. Patients present in infancy with seizures, hypotonia, characteristic facies with a large forehead and fontanel, and cholestatic hepatopathy. At autopsy renal cysts and absent peroxisomes are seen. Patients with a similar but milder biochemical and clinical phenotype have neonatal adrenoleukodystrophy or neonatal Refsum disease. They often have detectable peroxisomes.

In other peroxisomal diseases, only a single enzyme is deficient. Primary hyperoxaluria (alanine-glyoxylate aminotransferase deficiency) causes renal stones and nephropathy. Mutations in the X-linked very-long-chain fatty acid transporter gene, ABCD1, cause either a rapid leukodystrophy with loss of function (adrenoleukodystrophy), slow progressive spasticity and neuropathy (adrenomyeloneuropathy), or adrenal insufficiency. Defective phytanic acid oxidation in adult Refsum disease causes ataxia, leukodystrophy, cardiomyopathy, neuropathy, and retinal dystrophy. Other isolated enzyme deficiencies can mimic Zellweger syndrome.

Abnormalities of plasmalogen synthesis are clinically associated with rhizomelic chondrodysplasia punctata. Except for adrenoleukodystrophy, all peroxisomal diseases are autosomal recessive and can be diagnosed in utero.

image Diagnosis

The best screening test for Zellweger syndrome and other biogenesis disorders is determination of very-long-chain fatty acids in serum or plasma. Urine bile acids are abnormal in other peroxisomal disorders. Phytanic acid and plasmalogens can also be measured. Together, these studies identify most peroxisomal diseases. Fibroblast enzyme assays followed by molecular analysis are needed for confirmation, especially when the parents plan further pregnancies.

image Treatment

Bone marrow transplantation may be an effective treatment at the early stages of adrenoleukodystrophy, and close monitoring of affected males is necessary. Adrenal insufficiency requires hydrocortisone substitution. Lorenzo’s oil, a mixture of glyceryl-trierucate and glyceryl-trioleate that suppresses endogenous very-long-chain fatty acid synthesis, in combination with a very-low-fat diet and essential fatty acid supplementation, is ineffective in patients with established symptoms but is under evaluation for prevention of neurologic symptoms in presymptomatic males with adrenoleukodystrophy. Dietary treatment is used and effective for adult Refsum disease. Liver transplantation protects the kidneys in severe primary hyperoxaluria.

Cappa M, Bizzarri C, Vollono C, Petroni A, Banni S: Adrenoleukodystrophy. Endocr Dev 2011;20:149 [PMID: 21164268].

Ebberink MS et al: Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder. Hum Mutat 2011;32:59 [PMID: 21031596].

Kemp S, Berger J, Aubourg P: X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects. Biochim Biophys Acta 2012;1822(9):1465 [PMID: 22483867].

Poll-The BT, Gärtner J: Clinical diagnosis, biochemical findings and MRI spectrum of peroxisomal disorders. Biochim Biophys Acta 2012;1822(9):1421 [PMID: 22483868].

Shimozawa N: Molecular and clinical findings and diagnostic flowchart of peroxisomal diseases. Brain Dev 2011;33(9):770 [PMID: 21470807].

Waterham HR, Ebberink MS: Genetics and molecular basis of human peroxisome biogenesis disorders. Biochim Biophys Acta 2012;1822(9):1430 [PMID: 22871920].

CONGENITAL DISORDERS OF GLYCOSYLATION

Many proteins, including many enzymes, require glycosylation for normal function. The carbohydrate-deficient glycoprotein syndromes are an ever-increasing family of disorders that result from defects in the synthesis of glycans or in the attachment of glycans to other compounds. N-linked, O-linked, and combined N- and O-linked glycosylation defects have been described. The most common N-linked defect is phosphomannomutase 2 deficiency or congenital disorders of glycosylation type Ia (CDG-Ia). Children with type Ia disease usually present with prenatal growth disturbance, often with abnormal fat distribution, cerebellar hypoplasia, typical facial dysmorphic features, and mental retardation. The typical course includes chronic liver disease, peripheral neuropathy, endocrinopathies, retinopathy, and in some patients, acute life-threatening events. Patients with type Ib disease have a variable combination of liver fibrosis, protein-losing enteropathy, and hypoglycemia. More than a dozen other forms are characterized by additional key symptoms, including coloboma, cutis laxa, severe epilepsy, ichthyosis, immunoglobulin deficiency, and Dandy-Walker malformation. Biochemical differences and variations in clinical course (eg, the absence of peripheral neuropathy) characterize the other types. Pathophysiology probably relates to defects of those biochemical pathways that require glycosylated proteins. Recently, O-linked glycosylation defects have been found to underlie more classically described genetic syndromes such as multiple exostoses syndrome, Walker-Warburg syndrome, muscle-eye-brain disease, and a number of α-dystroglycanopathies. The syndromes appear to be inherited in an autosomal recessive manner with the exception of multiple exostoses syndrome which is autosomal dominant. The frequency of N-linked glycosylation defects is estimated to be as high as 1:20,000 in northern Europe.

image Diagnosis

Diagnosis is supported by finding altered levels of glycosylated enzymes or other proteins such as transferrin, thyroxine-binding globulin, lysosomal enzymes, and clotting factors (IX, XI, antithrombin III, and proteins C and S). However, these levels may be normal in carbohydrate-deficient glycoprotein syndromes or abnormal in other conditions. Diagnosis is confirmed by finding typical patterns of abnormal glycosylation of selected proteins. Most diagnostic laboratories examine serum transferrin to screen for N-linked defects and apoC1 for O-linked defects. Confirmatory diagnosis is by assaying enzyme activity, analysis of lipid-linked oligosaccharides in fibroblasts, and mutation analysis.

image Treatment

Treatment is supportive, including monitoring and providing early treatment for expected clinical features. Mannose treatment is curative for patients with type Ib deficiency only.

Goreta SS, Dabelic S, Dumic J: Insights into complexity of congenital disorders of glycosylation. Biochem Med (Zagreb) 2012;22(2):156 [PMID: 22838182].

Lefeber DJ, Morava E, Jaeken J: How to find and diagnose a CDG due to defective N-glycosylation. J Inherit Metab Dis 2011;34(4):849 [PMID: 21739167].

Jaeken J: Congenital disorders of glycosylation (CDG): it’s (nearly) all in it! J Inherit Metab Dis 2011;34(4):853 [PMID: 21384229].

Mohamed M et al: Clinical and diagnostic approach in unsolved CDG patients with a type 2 transferrin pattern. Biochim Biophys Acta 2011;1812(6):691 [PMID: 21362476].

Mohamed M, Kouwenberg D, Gardeitchik T, Kornak U, Wevers RA, Morava E: Metabolic cutis laxa syndromes. J Inherit Metab Dis 2011 34(4):907 [PMID: 21431621].

Patient and parent support group website with useful information for families: http://www.cdgs.com.

Reynders E, Foulquier F, Annaert W, Matthijs G: How Golgi glycosylation meets and needs trafficking: the case of the COG complex. Glycobiology 2011;21(7):853 [PMID: 21112967].

SMITH-LEMLI-OPITZ SYNDROME & DISORDERS OF CHOLESTEROL SYNTHESIS

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Elevated 7- and 8-dehydrocholesterol in serum and other tissue is diagnostic in Smith-Lemli-Opitz (SLO) syndrome which presents with developmental delay and malformations.

image Chondrodysplasia punctata, skin defects, and neurological symptoms can indicate other cholesterol synthetic defects.

Several defects of cholesterol synthesis are associated with malformations and neurodevelopmental disability. SLO syndrome is an autosomal recessive disorder caused by a deficiency of the enzyme 7-dehydrocholesterol Δ7-reductase. It is characterized by microcephaly, poor growth, mental retardation, typical dysmorphic features of face and extremities (particularly two- to three-toe syndactyly), and often malformations of the heart and genitourinary system. It is further described in Chapter 37. Other cholesterol synthetic defects are seen in Conradi Hünnermann syndrome, which includes chondrodysplasia punctata and atrophic skin. Cholestanolosis (cerebrotendinous xanthomatosis) manifests with progressive ataxia and cataracts.

image Diagnosis

In SLO, elevated 7- and 8-dehydrocholesterol in serum or other tissues, including amniotic fluid, is diagnostic. Serum cholesterol levels may be low or in the normal range. Enzymes of cholesterol synthesis may be assayed in cultured fibroblasts or amniocytes, and mutation analysis is possible.

image Treatment

Although postnatal treatment does not resolve prenatal injury, supplementation with cholesterol in SLO improves growth and behavior. The role of supplemental bile acids is controversial. Simvastatin reduces 7- and 8-dehydrocholesterol and increases cholesterol levels by induction of its synthetic enzymes, but its effect on clinical symptoms is limited.

DeBarber AE, Eroglu Y, Merkens LS, Pappu AS, Steiner RD: Smith-Lemli-Opitz syndrome. Expert Rev Mol Med 2011;13;e24 [PMID: 21777499].

Patient and parent support group website with useful information for families: http://www.smithlemliopitz.org.

Porter FD, Herman GE: Malformation syndromes caused by disorders of cholesterol synthesis. J Lipid Res 2011;52(1):6 [PMID: 20929975].

Quélin C et al: Phenotypic spectrum of fetal Smith-Lemli-Opitz syndrome. Eur J Med Genet 2012;55(2):81 [PMID: 22226660].

DISORDERS OF NEUROTRANSMITTER METABOLISM

image ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

image Movement disorder, especially dystonia and oculogyric crises.

image Severe seizures, abnormal tone, ataxia, and mental retardation occur in severely affected infants.

image Mildly affected patients have dopa-responsive dystonia with diurnal variability.

image Deficient serine synthesis causes microcephaly, seizures, and failure of myelination in neonates.

Abnormalities of neurotransmitter metabolism are increasingly recognized as causes of significant neurodevelopmental disabilities. These disorders typically affect the biosynthesis of the neurotransmitters dopamine and serotonin or the metabolism of glycine. Affected patients may present with movement disorders (especially dystonia and oculogyric crises), seizures, abnormal tone, or mental retardation, and are often considered to have cerebral palsy. Patients may be mildly affected (eg, dopa-responsive dystonia with diurnal variation) or severely affected (eg, intractable seizures with profound mental retardation). Deficient serine synthesis leads to congenital microcephaly, infantile seizures, and failure of myelination.

Pyridoxine-dependent epilepsy manifests as a severe seizure disorder in the neonatal or early infantile period that responds to high doses of pyridoxine. The disorder is caused by deficient activity of the enzyme α-amino adipic semialdehyde dehydrogenase resulting from mutations in the antiquitin (ALDH7A1) gene. Pyridoxal-phosphate–responsive encephalopathy manifests as a severe seizure disorder in infancy that responds to pyridoxal-phosphate. This disorder is caused by mutations in the PNPO gene encoding pyridox(am) ine oxidase, which is necessary for activation of pyridoxine.

image Diagnosis

Although some disorders can be diagnosed by examining serum amino acids or urine organic acids (eg, 4-hydroxybutyric aciduria), in most cases, diagnosis requires analysis of CSF. Spinal fluid samples for neurotransmitter analysis require special collection and handling, as the neurotransmitter levels are graduated along the axis of the CNS and are highly unstable once the sample is collected. A phenylalanine loading test can be diagnostic for mild defects in GTP-cyclohydrolase deficiency, in which neurotransmitter analysis may be insufficiently sensitive. Analysis of CSF shows elevated threonine and decreased pyridoxal-phosphate in pyridoxal-phosphate–responsive disease, and decreased serine and glycine in serine biosynthetic defects. Urine α-aminoadipic acid or piperideine-6-carboxylate can be used to identify infants with seizures that may be pyridoxine dependent.

image Treatment

Biosynthesis defects of dopamine and serotonin are usually treated with a combination of levodopa, 5-hydroxytryptophan, and carbidopa. Pyridoxine-dependent epilepsy is treated with pyridoxine in high doses and can benefit from a lysine-restricted diet, whereas pyridoxal-phosphate–responsive encephalopathy requires pyridoxal-phosphate. For some conditions, such as pyridoxine-responsive seizures, pyridoxal-phosphate–responsive encephalopathy, or dopa-responsive dystonia, response to treatment can be dramatic. For others, response to therapy is less satisfactory in part because of poor penetration of the blood-brain barrier. Supplementation with serine and glycine can substantially improve outcome in serine deficiency.

Arsov T et al: Glucose transporter 1 deficiency in the idiopathic generalized epilepsies. Ann Neurol 2012;72(5):807 [PMID: 23280796].

Banka S et al: Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency. Am J Hum Genet 2011;88(2):216 [PMID: 21310276].

Friedman J et al: Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann Neurol 2012;71(4):520 [PMID: 22522443].

Kurian MA et al: The monoamine neurotransmitter disorders: an expanding range of neurological syndromes. Lancet Neurol 2011;10:721 [PMID: 21777827].

Mangold S et al: Cerebral folate deficiency: a neurometabolic syndrome? Mol Genet Metab 2011;104(3):369 [PMID: 21737328].

Pénez-Dueñas B et al: Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects. Arch Neurol 2011;68(5):615 [PMID: 21555636].

Pong AW, Geary BR, Engelstad KM, Natarajan A, Yang H, DeVivo DC: Glucose transporter type I deficiency syndrome: epilepsy phenotypes and outcomes. Epilepsia 2012;53(9):1503 [PMID: 22812641].

Stockler S et al: Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab 2011;104(1–2):48 [PMID: 21704546].

Verrotti A, D’Egidio C, Agostinelli S, Gobbi G: Glut1 deficiency: when to suspect and how to diagnose? Eur J Paediatr Neurol 2012;16(1):3 [PMID: 21962875].

CREATINE SYNTHESIS DISORDERS

Creatine and creatine phosphate are essential for storage and transmission of phosphate-bound energy in muscle and brain. They spontaneously convert to creatinine. Three disorders of creatine synthesis are now known: arginine:glycine amidinotransferase (AGAT) deficiency, guanidinoacetate methyltransferase (GAMT) deficiency, and creatine transporter (CrT1) deficiency. GAMT and AGAT deficiencies are autosomal recessive disorders, whereas CrT1 deficiency is X-linked. All patients demonstrate developmental delay, mental retardation, autistic behavior, seizures, and severe expressive language disturbance. Patients may also show developmental regression and brain atrophy. Patients with GAMT deficiency have more severe seizures and an extrapyramidal movement disorder. The seizure disorder is milder in CrT1-deficient patients. Some female heterozygotes of CrT1 deficiency may also show developmental delay or learning disabilities.

image Diagnosis

The common feature of all creatine synthesis defects is a severe depletion of creatine and creatinephosphate in the brain demonstrable by reduction to absence of signal on magnetic resonance spectroscopy. In GAMT deficiency, guanidinoacetate accumulates, whereas in AGAT deficiency, guanidinoacetate is decreased, particularly in urine. Guanidinoacetate seems to be responsible for the severe seizures and movement disorder found in GAMT deficiency. Blood, urine, and CSF creatine levels are decreased in GAMT deficiency but normal in AGAT deficiency. Urine excretion of creatine is elevated in CrT1 deficiency. Enzyme and molecular analyses are available for diagnostic confirmation.

image Treatment

Treatment with oral creatine supplementation is in part successful in GAMT and AGAT deficiencies. It is not beneficial in CrT1 deficiency. Treatment by combined arginine restriction and ornithine substitution in GAMT deficiency can decrease guanidinoacetate concentrations and improve the clinical course.

Alcaide P et al: Defining the pathogenicity of creatine deficiency syndrome. Hum Mutat 2011;32(3):282 [PMID: 21140503].

Braissant O, Henry H, Béard E, Uldry J: Creatine deficiency syndromes and the importance of creatine synthesis in the brain. Amino Acids 2011;40(5): 1315 [PMID: 21390529].

Hinnell C et al: Creatine deficiency syndromes: diagnostic pearls and pitfalls. Can J Neurol Sci 2011;38(5):765 [PMID: 21856584].

Longo N, Ardon O, Vanzo R, Schwartz E, Pasquali M: Disorders of creatine transport and metabolism. Am J Med Genet C Semin Med Genet 2011;157(1):72 [PMID: 21308988].

Mercimek-Mahmutoglu S et al: Evaluation of two year treatment outcome and limited impact of arginine restriction in a patient with GAMT deficiency. Mol Genet Metab 2012;105(1):155 [PMID: 22019491].

Valayannopoulos V et al: Treatment by oral creatine, l-arginine and l-glycine in six severely affected patients with creatine transporter defect. J Inherit Metab Dis 2011;35(1):151 [PMID: 21660517].

van de Kamp JM et al: Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect. J Inherit Metab Dis 2012;35(1):141 [PMID: 21556832].

QUALITY INITIATIVES IN THE FIELD OF METABOLIC DISEASE

Expanded newborn screening has had a large impact on the field of metabolic disorders. As desired, patients are being diagnosed earlier, and for some patients, this dramatically reduces the disease burden. Expanded newborn screening, however, has also uncovered problems or revealed unexpected consequences that need to be addressed. For example, the clinical spectrum of many disorders is being expanded to include mildly affected or asymptomatic patients. This raises care questions particularly in regard to the need for aggressive management in the more mildly affected patients or if therapy is needed at all for some patients. It is unclear whether some patients diagnosed who are on the milder end of a disease spectrum would have ever become symptomatic or presented to care. Consequently, for some disorders, disease incidence appears to be changing. In addition, newborn screening for several conditions has brought to light our ability to detect maternal disease. Disorders such as maternal B12 deficiency and maternal carnitine uptake deficiency pose management as well as risk questions for this largely asymptomatic population. Conditions felt by most to be benign are also being diagnosed as a consequence of expanded newborn screening. Further, owing to limitations in diagnostic testing, patients who may be carriers for a condition are now being treated, as the carrier status cannot be entirely confirmed nor the condition entirely excluded. This is particularly true for disorders such as glutaric acidemia, type I, and VLCAD deficiency. This not only adds to parental anxiety, but treatment of an unaffected child may entail risk to the child or to family dynamics.

Improvement in diagnostic testing, especially the sensitivity of molecular and enzymatic testing, may help improve the diagnostic conundrum. National initiatives are underway in an attempt to clarify other issues. Initiated under regional programs and now under the guidance of the American College of Medical Genetics and the Newborn Screening Translational Research Network (NBSTRN), uniform clinical data sets for disorders diagnosed via newborn screening have been developed. The hope is also for a national database for data collection integrating clinical care, public health, and state laboratories. The overall goal is to track the long-term outcome of individuals diagnosed with inborn errors of metabolism, to define best practice guidelines, and to determine the benefit of newborn screening. In addition, the NBSTRN seeks to stimulate research in newborn screening, advocate pilot screening programs, and establish a national, virtual dried blood spot repository for research. This national initiative is inclusive of all disorders for which newborn screening occurs, not just inborn errors of metabolism.

Another national focus is the expansion of newborn screening to other genetic disorders. Currently, some states are beginning to implement newborn screening for severe combined immunodeficiency (SCID) and for lysosomal storage disorders such as Pompe disease, Fabry disease, Gaucher disease, and Krabbe disease. A pilot study is also underway for screening for spinal muscular atrophy, and screening for disorders such as Fragile X syndrome and Prader Willi syndrome is being considered. As technology for early detection and treatment strategies advance, more disorders will likely be considered candidates for newborn screening. Additionally, some conditions being considered for screening affect an individual after the newborn period. Second-tier, childhood screening for such late-onset disorders may be a consideration in the future. Careful consideration will need to be given regarding the risks and benefits to screening for such conditions. The U.S. Secretary for Health and Human Services’ Advisory Committee on Heritable Disorders in Newborns and Children has established a rigorous process for disease review before recommending a disorder be considered for screening.

Buchbinder M, Timmermans S: Newborn screening and maternal diagnosis: rethinking family benefit. Soc Sci Med 2011;73(7):1014 [PMID: 21835525].

Hinton CF et al: What questions should newborn screening long-term follow-up be able to answer? A statement of the U.S. Secretary for Health and Human Services’ Advisory Committee on Heritable Disorders in Newborns and Children. Genet Med 2011;13(10):861 [PMID: 21716119].

Nakamura K, Hattori K, Endo F: Newborn screening for lysosomal storage disorders. Am J Med Genet C Semin Med Genet 2011;157(1):63 [PMID: 21312327].

Scala I, Parenti G, Andria G: Universal screening for inherited metabolic diseases in the neonate (and the fetus). J Matern Fetal Neonatal Med 2012;25(Suppl 5):4 [PMID: 23025760].