First Aid for the Pediatrics Clerkship, 3 Ed.

Metabolic Disease

 

INBORN ERRORS OF METABOLISM

DEFINITION

Inherited biochemical disorders.

PATHOPHYSIOLOGY

Mutations affecting proteins involved in the many metabolic pathways of the body. Typically result in deficiency of enzyme production or build-up of toxic metabolites, or both.

EPIDEMIOLOGY

Disorders involving deficiencies of enzymes are often autosomal recessive (please see noted exceptions in this chapter).

SIGNS AND SYMPTOMS

Image Often normal at birth, but can show signs early, including metabolic acidosis, poor feeding, vomiting, lethargy, and convulsion.

Image Mental retardation, organomegaly, unusual body odor, episodic decompensation.

DIAGNOSIS

Image Newborn metabolic screening:

Image Standard in United States: Allows for early detection and treatment and can potentially prevent serious consequences.

Image Panel of test varies state by state but phenylketonuria (PKU), hypothyroidism, galactosemia, and hemoglobinopathies are nearly universal.

Image Tandem mass spectrometry is the usual method used for screening.

Image The following conditions are screened in most states:

Image Galactosemia.

Image Hypothyroidism.

Image Hemoglobinopathy.

Image Tyrosinemia.

Image Biotinidase deficiency.

Image Congenital adrenal deficiency.

Image Maple syrup urine disease.

Image Homocystinuria.

Image Cystic fibrosis.

Image Medium-chain acyl-CoA dehydrogenase deficiency (MCAD).

Image Urea cycle defects.

Image HIV is screened in some states.

Image Classification:

Image Amino acid and urea cycle disorders:

Image Homocystinuria.

Image Maple syrup urine disease.

Image Phenylketonuria.

Image Tyrosinemia.

Image Urea cycle (arginase deficiency, argininosuccinic academia, citrullinemia, ornithine transport defect).

Image Fatty acid oxidation disorders:

Image Carnitine transport defect.

Image Citrullinemia.

Image Glutaric acidemia type 2.

Image Medium-chain acyl-CoA dehydrogenase deficiency.


Image

Medium-chain acyl-CoA dehydrogenase deficiency is the most common fatty acid oxidation disorder and may be associated with intermittent severe metabolic crises or sudden death.


TABLE 8-1. Newborn Screening of Amino Acid Disorders

Image

Image Organic acid disorders:

Image 3-hydroxy-3-methyglutaryl-CoA lyase deficiency

Image Glutaric acidemia type I

Image Isovaleric acidemia

Image Methylmalonic acidemia

Image Propionic acidemia

Image Many can be detected in the neonatal period or infancy, and some are included in newborn screening (see Table 8-1).


Image

Most fatty acid oxidation disorders present with hypoglycemia.


TREATMENT

Image Treatment varies but is often supportive/symptomatic.

Image Frequently includes dietary modifications.

Image Increasing availability of enzyme or gene-related treatment options.

DEFECTS OF AMINO ACID METABOLISM

See Table 8-2.

TABLE 8-2. Disorders of Amino Acid Metabolism

Image

Phenylketonuria (PKU)

DEFINITION

Inherited disorder of amino acid metabolism in which phenylalanine cannot be converted to tyrosine.

ETIOLOGY

Deficiency of phenylalanine hydroxylase (or its cofactor tetrahydrobiopterin—2% of cases).


Image

Phenylketones: phenylacetate, -lactate, and -pyruvate, in urine.


PATHOPHYSIOLOGY

Image Accumulation of phenylalanine and its phenylketone metabolites disrupt normal metabolism and cause brain damage.

Image Tyrosine becomes essential amino acid.

EPIDEMIOLOGY

Image Autosomal recessive.

Image One in 10,000–20,000 live births.

Image Routinely screened for in the United States.


Image

Aspartame contains phenylalanine.


SIGNS AND SYMPTOMS

Image Normal at birth.

Image Severe mental retardation with IQ of 30 may develop at the end of 1 year (progressive and irreversible).

Image Hypopigmentation due to low tyrosine (fair hair and skin, blue eyes).

Image Eczema, mousy/musty body odor, hypertonia.

DIAGNOSIS

Image Screened in all newborns.

Image Serum tested 72 hours after initiation of first protein feed (test may be negative prior to 72 hours).

Image If not screened neonatally, diagnosis usually made at 4–6 months of age.

Image Prenatal and carrier testing possible.


Image

↓ pigmentation in PKU is secondary to the inhibition of tyrosinase by phenylalanine.


TREATMENT

Image Limit dietary phenylalanine (eg, in artificial sweeteners) and ↑ tyrosine; if started within first 10 days of life, infants can have normal intelligence.

Image Strict dietary restriction during pregnancy.

Homocystinemia/Homocystinuria

DEFINITION

Inherited disorder of amino acid metabolism in which homocysteine is present in greater than trace amounts in the urine.

ETIOLOGY

Most commonly a deficiency of cystathionine β-synthase, but can also be a defect of methylcobalamin formation or deficiency of methyltetrahydrofolate reductase.


Image

Lethargy, anorexia, anemia, rashes, and diarrhea are signs of tyrosine deficiency.


Image

FIGURE 8-1. Homocysteine pathway.

PATHOPHYSIOLOGY

Homocysteine is not remethylated to methionine (see Figure 8-1).


Image

Ectopia lentis is subluxation of the lens, signaled by iridodonesis (quivering of iris) and myopia.


EPIDEMIOLOGY

Autosomal recessive (1 in 200,000 live births).

SIGNS AND SYMPTOMS

Image Depends on particular enzyme deficiency.

Image Most commonly normal at birth, with failure to thrive and developmental delay subsequently occurring.

Image Shares several skeletal and ocular features with Marfan syndrome.

Image Later, ectopia lentis, marfanoid body habitus, progressive mental retardation, vaso-occlusive disease, osteoporosis, or fair skin with malar flush can occur.


Image

Late complications:

Image Astigmatism

Image Optic atrophy

Image Glaucoma

Image Cataracts

Image Retinal detachment


Image

FIGURE 8-2. Methionine metabolism.

DIAGNOSIS

Image Normal at birth; diagnosis usually made after 3 years of age.

Image Elevated methionine and homocysteine in body fluids.

Image Prenatal diagnosis possible.

Image Marfan phenotype–differential diagnosis:

Image Homocystinuria: Marfanoid habitus, ectopia lentis, mental retardation, osteoporosis.

Image Ehlers-Danlos syndrome types 1 and 3: Marked joint hypermobility, mitral valve prolapse.

Image Stickler syndrome (hereditary arthro-ophthalmopathy): Tall stature, retrognathia, mitral valve prolapse, midfacial hypoplasia, retinal detachment.

Image Klinefelter syndrome: Marfanoid habitus, small testes and genitalia, learning difficulty.


Image

Branched-chain amino acids are: leucine, isoleucine, valine.


TREATMENT

Image Pyridoxine responsive form: 50% are this form and easily missed in the neonatal period. High-dose vitamin B6.

Image Pyridoxine unresponsive form: Restriction of methionine intake and supplementation of cysteine. (May require concurrent folic acid to show response.) Betaine can also play a role in this group.

Image Other types may require vitamin B12 or methionine supplementation.

Maple Syrup Urine Disease (MSUD) or Branched-Chain Ketoaciduria

DEFINITION

Inherited disorder of branched-chain amino acid metabolism in which elevated quantities of leucine, isoleucine, valine, and corresponding oxoacids accumulate in the body fluids.


Image

In MSUD, plasma leucine levels are usually higher than those of the other accumulating branched amino acids.


ETIOLOGY

Deficiency of branched-chain ketoacid dehydrogenase.

PATHOPHYSIOLOGY

Defect in the decarboxylation of leucine, isoleucine, and valine by a branched-chain ketoacid dehydrogenase.


Image

Correcting the serum glucose level in MSUD does not improve the clinical state.


EPIDEMIOLOGY

One in 250,000 live births in general population.

SIGNS AND SYMPTOMS

Image Deficiency of different subunits of enzyme account for wide clinical variability.

Image Poor feeding, vomiting in first week of life, proceeding to lethargy and coma.

Image Alternating hypertonicity and flaccidity, convulsions, hypoglycemia.

Image Odor of maple syrup in urine, sweat, cerumen (burnt sugar smell).


Image

Suspect MSUD:

Image Intermittent symptoms (feeding difficulties and apnea) related to protein ingestion

Image Sweet-smelling cerumen


DIAGNOSIS

Image Elevated plasma and urine levels if leucine, isoleucine, valine, and alloisoleucine; ↓ plasma alanine.

Image Urine precipitant test.

Image Neuroimaging in the acute state shows cerebral edema.

TREATMENT

Image Chronically, low branched-chain amino acid diet.

Image Frequent serum level monitoring.

Image Acutely, intravenous administration of amino acids other than branched chain.

Image Hemodialysis or peritoneal dialysis can save the patient’s life in acidotic crisis, but liver transplantation can definitely treat MSUD.

Hartnup Disease

DEFINITION

Inherited defect in transport of neutral amino acids by intestinal mucosa and renal tubules.

ETIOLOGY

Deficient activity of a sodium-dependent transport system.


Image

Urinary proline, hydroxyproline, and arginine remain normal in Hartnup disease (unlike in other causes of generalized aminoaciduria, such as Fanconi’s).


PATHOPHYSIOLOGY

Deficiency of tryptophan results in the clinical manifestations.

EPIDEMIOLOGY

Autosomal recessive.

SIGNS AND SYMPTOMS

Image Usually asymptomatic.

Image Rarely, cutaneous photosensitivity, episodic psychiatric changes.

Image Marginal nutrition results in clinical manifestations in predisposed individuals.

DIAGNOSIS

Image Aminoaciduria (neutral: alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, histidine).

Image Normal plasma amino acid levels.

TREATMENT

Nicotinic acid/nicotinamide and a high-protein diet in symptomatic patients.

DEFECTS OF LIPID METABOLISM–LYSOSOMAL STORAGE DISEASES

Lipidoses

See Table 8-3.


Image

Gaucher is the most common lysosomal storage disease (1 in 75,000). Splenomegaly is the most common presenting sign.


TABLE 8-3. Lysosomal Storage Diseases–Lipidoses

Image

Image

Image

Image

DEFINITION/ETIOLOGY/PATHOPHYSIOLOGY

Inherited deficiencies of lysosomal hydrolases cause lysosomal accumulation of sphingolipids in brain and viscera.


Image

Fabry is X-linked recessive.


EPIDEMIOLOGY

Most are autosomal recessive.

SIGNS AND SYMPTOMS

Depends on site of abnormal accumulations:

Image Nervous system: Neurodegeneration, ocular findings.

Image Viscera: Organomegaly, skeletal abnormalities, pulmonary infiltration.

DIAGNOSIS

Measurement of specific enzymatic activity in leukocytes or cultured fibroblasts.

TREATMENT

Image Usually no specific treatment.

Image Supportive/symptomatic therapy.

Image Gaucher disease: Recombinant enzyme.

Image Krabbe disease: Hematopoietic stem cell transplant.


Image

Gangliosidoses (eg, GM1 and Tay-Sachs) have cherry red spot on macula in 50% of cases, as does Niemann-Pick.


Mucopolysaccharidoses

DEFINITION/ETIOLOGY/PATHOPHYSIOLOGY

Inherited deficiencies of lysosomal enzymes needed for the degradation of glycosaminoglycans (GAGs) resulting in widespread lysosomal storage of dermatan and heparan sulfates and severe clinical abnormalities. Keratan sulfates accumulate in other mucopolysaccharidoses not mentioned. See Table 8-4.


Image

Hepatosplenomegaly occurs in the GM1 gangliosidoses and Sandhoff disease, but not in Tay-Sachs disease.


EPIDEMIOLOGY

Most are autosomal recessive.

SIGNS AND SYMPTOMS

Image Normal at birth, diagnosis at 1+ years.

Image “Gargoyle” cells containing lysosomes engorged with mucopolysaccharide.


Image

Hunter syndrome is X-linked recessive.


TABLE 8-4. Lysosomal Storage Diseases–Mucopolysaccharidoses

Image

MPS, mucopolysaccharidosis.

Image Excessive urinary excretion of GAGs.

Image Progressive mental and physical deterioration.

Image Coarse features.

Image Corneal clouding.

Image Stiff joints (abnormal hyalinization of collagen).

Image Organomegaly.

Image Skeletal abnormalities.

DIAGNOSIS

Image Detection of enzyme deficiency in leukocytes or cultured fibroblasts.

Image Roentgenographic changes consistent with dystosis multiplex.

Image Urinary excretion of dermatan and heparan sulfates.

TREATMENT

Supportive therapy. Hurler’s can be treated with bone marrow transplant.


Image

Dysostosis Multiplex

Image Large dolichocephalic skull

Image Thickened calvarium

Image Ovoid vertebral bodies

Image Flared iliac bones

Image Shallow acetabulae

Image Irregular widening of long bones


DEFECTS OF CARBOHYDRATE METABOLISM–GLYCOGEN STORAGE DISEASES

See Table 8-5.

von Gierke Disease

Image

A 3-month-old, breast-fed infant has failure to thrive, severe hepatomegaly, thin extremities, fasting hypoglycemia, lipemia, and metabolic acidosis. Think: von Gierke disease.

von Gierke is an inherited disorder that affect glycogen metabolism. It is due to the deficiency of glucose-6-phosphatase, which results in accumulation of glucose-6-phosphate, which in turns causes ↑ glycolysis and lactic acidosis. It is characterized by growth retardation, hypoglycemia, hepatomegaly, hyperlipidemia, hyperuricemia, lactic acidemia, and seizure. In neonatal period, hypoglycemia and lactic acidosis are the common presentation. Hepatomegaly becomes evident by 3–4 months of age.

TABLE 8-5. Glycogen Storage Diseases

Image

DEFINITION

Inherited disorder of glycogen metabolism characterized by deposition of glycogen in the liver, kidney, and intestine.

ETIOLOGY

Deficiency of glucose-6-phosphatase.

PATHOPHYSIOLOGY

Glycogen-to-glucose metabolism stops at glucose-6-phosphate.

EPIDEMIOLOGY

Autosomal recessive.

SIGNS AND SYMPTOMS

Image Fasting hypoglycemia (due to impaired gluconeogenesis, glycogenolysis, and recycling of glucose through the glucose-6-phosphate to glucose system).

Image Massive hepatomegaly.

Image Elevated serum levels of lactate, uric acid, cholesterol, triglycerides.

Image Renal complications (Fanconi’s, nephrocalcinosis, focal segmental glomerulosclerosis).

Image Slow growth, diarrhea, bleeding disorders, hypotonia, and gout.

DIAGNOSIS

Image Normal at birth; diagnosis usually at 5 months.

Image Administration of epinephrine, glucagons, galactose, fructose, or glycerol does not provoke normal hyperglycemic response (may precipitate acidosis).

Image DNA tests form common mutations.

Image In cases where mutation testing is not easily done, enzyme measurements can confirm the diagnosis.

Image Liver biopsy demonstrates accumulation of glycogen in cells.

TREATMENT

Image Avoid fasting.

Image Supportive therapy aimed at maintaining normal glucose levels.

Image Nocturnal intragastric, frequent, high-carbohydrate meals, are the main stay of treatment up to 1–2 years age.

Image After 2 years of age, snacks or nocturnal intragastric feedings of uncooked cornstarch may be sufficient.

Image High-protein diet is not effective.

Image Granulocyte colony–stimulating factors to combat neutropenia and inflammation.

Image Allopurinol to lower urate levels, bicarbonate or potassium citrate for lactic acidosis.

Image Liver transplant for refractory disease.

McArdle Disease

DEFINITION

Inherited disorder of glycogen metabolism characterized by deposition of glycogen in skeletal muscle.


Image

McArdle affects the

Muscles.


ETIOLOGY

Deficiency of muscle glycogen phosphorylase (myophosphorylase).

EPIDEMIOLOGY

Autosomal recessive.

SIGNS AND SYMPTOMS

Image Involves only skeletal muscles (accumulations of glycogen predominant in subsarcolemmal location).

Image Temporary weakness and cramping of skeletal muscles during or after exercise.

Image No rise in blood lactate during exercise.

Image Characteristic “second wind” with initiation of fatty acid metabolism.

DIAGNOSIS

Image Asymptomatic during infancy. Presents in adolescence/early childhood.

Image Muscle biopsy and assay show deficiency of enzyme.

Image Myoglobinuria, serum creatine kinase always elevated (elevated CK at rest).

TREATMENT

Image Dietary modification (high fat and protein); sucrose prior to aerobic exercise; proper “warm-up” period.

Image Prognosis is good with sedentary lifestyle.

Pompe Disease

DEFINITION

Inherited disorder of glycogen metabolism characterized by deposition of glycogen in cardiac and skeletal muscle.


Image

Pompe affects the “Pump.”


ETIOLOGY

Deficiency of acid α-1, 4-glucosidase (acid maltase).

PATHOPHYSIOLOGY

Image Generalized glycogenesis because the defect is in all cells.

Image Results in inability to convert mannose to glucose.

EPIDEMIOLOGY

Autosomal recessive.

SIGNS AND SYMPTOMS

Image Rapid, progressive cardiomyopathy with massive cardiomegaly, macroglossia, hypotonia, hepatomegaly; death by 1–2 years.

Image Juvenile form milder, slowly progressive myopathy, little to no cardiac abnormality. Death usually secondary to respiratory failure.


Image

Lactose = galactose + glucose.


DIAGNOSIS

Image Electrocardiogram (ECG): May show shortened PR interval.

Image Electromyogram (EMG).

TREATMENT

Enzyme replacement with recombinant α-glucosidase delays disease progression.

Galactosemia

Image

A 2-week-old neonate has jaundice, hepatomegaly, and positive urinary-reducing substance. Odor of urine is normal. Think: Galactosemia.

Since galactosemia is included in the newborn screening, it is diagnosed before the symptoms develop. Jaundice, hepatomegaly, vomiting, lethargy, and feeding difficulties are the common initial presentation. Presence of a reducing substance in urine in infants with galactosemia who are ingesting lactose establishes the diagnosis.

DEFINITION

Inborn errors of carbohydrate metabolism that result in elevated galactose and metabolite levels in blood and urine.

ETIOLOGY

Three types:

Image Classic: Absence of galactose-1-phosphate uridyltransferase (inability to process lactose/galactose).

Image Others: Galactokinase, uridine diphosphate galactose-4-epimerase.


Image

When diagnosis of galactosemia is not made at birth, damage to the liver and brain become irreversible.


PATHOPHYSIOLOGY

Image Ingestion of galactose → ↑ concentrations in the blood and urine.

Image Toxic substances, including galactitol, cause organ damage.

EPIDEMIOLOGY

Image Autosomal recessive.

Image One in 60,000.


Image

Neonates with galactosemia are at ↑ risk for Escherichia coli sepsis.


SIGNS AND SYMPTOMS

Image Cataracts, hepatosplenomegaly, mental retardation, sepsis (E coli).

Image Triad: Liver failure (jaundice and coagulation disorder), renal tubular dysfunction (glucosuria, aminoaciduria, and acidosis), and cataract.

DIAGNOSIS

Image Should be considered in newborn, infant, or child if jaundice, hepatomegaly, vomiting, hypoglycemia, convulsions, lethargy, irritability, feeding difficulties, poor weight gain, diarrhea, aminoaciduria, cataracts, vitreous hemorrhage, hepatic cirrhosis, ascites, splenomegaly, or mental retardation are noted.

Image Presence of reducing substance in urine after ingestion of human or cow’s milk is suggestive.

Image Routinely screened for in the United States (Table 8-6).


Image

Elimination of galactose from diet in galactosemia does not ensure reversal of cataract formation.


TABLE 8-6. Screening for Galactosemia and Urea Cycle Defect

Image

TREATMENT

Image Exclude galactose and lactose from diet (example: dairy and breast milk).

Image Soy-based formula.


Image

There is almost no renal threshold for fructose.


Fructosuria

DEFINITION

Inborn errors of carbohydrate metabolism that result in elevated fructose and metabolite levels in blood and urine.

ETIOLOGY

Deficiency of fructokinase.

PATHOPHYSIOLOGY

Image Enzyme is normally found in the liver, kidney, and intestine.

Image Ingested fructose is not metabolized.

EPIDEMIOLOGY

Autosomal recessive.

SIGNS AND SYMPTOMS

Image Asymptomatic until fructose introduced into diet

Image Fructosemia and fructosuria.


Image

Do not confuse fructosuria with heriditary fructose intolerance (aldolase B deficiency), which presents with failure to thrive, hypoglycemia, lactic acidosis, vomiting, and seizures. Typically discovered during infancy at time of weaning with the introduction of fructose or sucrose into diet. Also autosomal recessive.


DIAGNOSIS

Presence of urinary-reducing substrate without clinical symptoms.

TREATMENT

None indicated.

DEFECTS IN PURINE METABOLISM

Lesch-Nyhan Syndrome

DEFINITION

Image An X-linked-recessive disorder of purine metabolism resulting in deposition of purines in tissues and subsequent clinical abnormalities.

Image Up to 1% of patients with gout may have Lesch-Nyhan syndrome.

ETIOLOGY

Deficiency of hypoxanthine–guanine phosphoribosyl transferase (HGPRT).

SIGNS AND SYMPTOMS

Image Delayed motor development.

Image Extrapyramidal sign resulting in choreoathetosis at approximately 1 year of age.

Image Spastic cerebral palsy, self-injurious behavior.

Image Hyperuricemia, uricosuria, urinary tract calculi, nephropathy, tophi, gouty arthritis.


Image

Self-injurious behavior in Lesch-Nyhan syndrome can include banging head against wall and biting/mutilating one’s fingers.


DIAGNOSIS

Image Normal at birth; diagnosis usually made at 3 months when delayed motor development becomes apparent.

Image Uric acid crystalluria may first be noted as orange crystals in the diaper during the first weeks of life.

Image Serum uric acid levels.

Image Gout generally does not develop until puberty.

TREATMENT

Image No specific treatment; supportive therapy.

Image Allopurinol to reduce serum uric acid levels.

Image Prevention of self-injury.

Image Death (due to infection or renal failure) in the second or third decade.


Image

Think Lesch-Nyhan syndrome in the presence of self-mutilation and characteristic choreoathetosis; mental retardation.


FAMILIAL HYPERCHOLESTEROLEMIAS

See Table 8-7.

CONCEPTS IN HEREDITARY DISEASE

Image Complex heterozygosity: Different mutations in each gene allele–each individually “silent,” but when combined produce clinical or biochemical manifestations.

Image Consanguinity (children of first-degree relatives): ↑ risk for inherited disorders, as many are autosomal recessive.

Image Sudden infant death syndrome (SIDS) or apparent life-threatening event (ALTE) may be the initial presentation of an inborn error of metabolism.

Image Unexplained developmental delay may indicate an underlying metabolic disease.

TABLE 8-7. Familial Hyperlipidemias

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