Kirsti Näntö-Salonen and Ollie Simell
Inherited defects in amino acid transport at the cell membrane (Fig. 143-1) are expressed as selective renal aminoaciduria and impaired intestinal absorption. Their symptoms result from excess of certain amino acids in the urine or lack of them in the tissues. Consequently, in cystinuria, renal stones are formed because of high urinary concentration of poorly soluble cystine. In lysinuric protein intolerance, lack of the urea cycle intermediates arginine and ornithine leads to hyperammonemia and protein intolerance. The pellagra-like dermatitis and ataxia in Hartnup disorder are attributed to deficiency of tryptophan, the precursor of niacin synthesis (Fig. 143-1).1-3
Cystinuria (OMIM 220100; OMIM 600918) causes a lifelong risk of urolithiasis.4-9 Its average incidence is 1:7000 but varies considerably between different populations. A defect of the high-affinity luminal transporter for cystine and dibasic amino acids in the epithelial cells in the jejunal mucosa and in the proximal renal tubulus leads to poor intestinal absorption and poor reabsorption of these amino acids in the kidney. If the intratubular cystine concentration exceeds the threshold of solubility, crystals and stones will form.
Cystinuria has been classified into two subtypes: type I is the pure autosomal recessive form of the disease that represents over 60% of the cases, and non-type 1 is inherited in a dominant mode with incomplete penetrance.
Type I cystinuria is caused by at least 103 mutations in the SLC3A1 gene on chromosome 2p. Non-type I cystinuria is caused by at least 66 mutations in the SLC7A9 gene on chromosome 19q.8 These genes encode the heavy and the light subunits of the amino acid transporter, respectively. A new genetics-based classification has been suggested: type A for SLC3A1 homozygotes, type B for SLC7A9 homozygotes, and type AB for the mixed type.9
Some patients never develop kidney stones, but others have recurrent symptoms from early childhood, with acute episodes of abdominal or lower-back pain, hematuria, pyuria, or passing of stones.
Cystine stones are usually radio-opaque and visible on ultrasonography. They are often located in the bladder. A positive urinary nitroprusside test and analysis of urinary amino acids lead to the diagnosis. Plasma concentrations of cystine and the dibasic amino acids are normal or slightly decreased. Excessive hydration to dilute the urine and alkalinization, preferably with potassium citrate, to improve cystine solubility are the cornerstones of therapy. Restriction of dietary animal protein to limit endogenous cystine synthesis from methionine may be helpful, and moderate sodium restriction also decreases cystine excretion.7,19,20
If the standard therapy fails a thiol derivative, D-penicillamine or mercaptopropionylglycine (tiopronin), is added to decrease urinary free cystine concentration by forming water-soluble compounds and by cleaving the disulfide bond of cystine to more soluble cysteine.7,19,20 Captopril is well tolerated but may not be as effective as the other thiol compounds.7,19,20 New, minimally invasive urological techniques minimize the need for open surgery for stone removal. Recurrent urinary tract infections, urinary obstruction, and renal insufficiency are possible complications.
Regular follow-up is essential to support treatment compliance, to monitor renal function, and to detect developing stones early.
LYSINURIC PROTEIN INTOLERANCE (LPI)
METABOLIC DERANGEMENT AND PATHOPHYSIOLOGY
Hyperammonemia after protein ingestion and protective aversion to high-protein foods make lysinuric protein intolerance (LPI; OMIM 222700) resemble urea cycle enzyme deficiencies (see Chapter 145). Only 130 patients have been reported, with the highest incidence in Finland.27 The transport of the dibasic cationic amino acids lysine, arginine, and ornithine is defective at the basolateral membranes of epithelial cells in the renal tubules and small intestine.28-31 Limited intestinal absorption of these amino acids and massive urinary loss of especially lysine result in low plasma concentrations.
FIGURE 143-1. Simplified schematic representation of amino acid transport in proximal tubular epithelial cell. Transport systems for negatively charged dicarboxylic amino acids (AA-), imino acids, (glycine, proline, and hydroxyproline); neutral amino acids (AA); and cystine and positively charged dibasic amino acids (AA+) are shown. The special transporters, some of which are formed of light and heavy subunits, act on the luminal and basolateral membranes of the epithelial cell. In man, the transporters for neutral amino acids (B0 AT1/SLC6A19), for cationic dibasic amino acids and cystine at the luminal surface (formed by subunits b0,+ AT/SLC7A9 and rBAT/SLC3A1), and for dibasic amino acids at the basolateral surface (formed by subunits +LAT1/SLC7A7 and 4F2hc/SLC3A2) have been characterized at the gene and molecular level. The subunits that carry mutations that cause Hartnup disorder, cystinuria and lysinuric protein intolerance, are shown in red.
Table 143-1. Transport Defects of Amino Acids at the Cell Membrane
Many pathogenetic mechanisms of the variable multiorgan involvement in LPI are still unknown.38,39 The malfunction of urea cycle in LPI is best explained by “functional deficiency” of the intermediates arginine and ornithine in the hepatocytes.36
Postprandial episodes of hyperammonemia usually begin when the infants start receiving foods with higher protein content than breast milk.47,48 Strong aversion to high-protein foods with failure to thrive is evident by the age of 1 year, aggravating the protein malnutrition and amino acid deficiencies. Children present with growth failure, hepatosplenomegaly, muscular hypotonia, and occasional fractures. Bone maturation is retarded, and there is often marked delay of puberty.49,50 In adults, the clinical heterogeneity of LPI is obvious. Most affected adults are of moderately short stature, and have marked hepatomegaly and osteopenia.49 Mental capacity depends on previous history of hyperammonemia.
The diagnosis is based on the combination of increased urinary excretion and low plasma concentrations of the cationic amino acids, especially lysine, together with hyperammonemia and orotic aciduria after protein-rich meals. Unspecific but consistent findings include elevated serum lactate dehydrogenase activity and increased serum concentrations of ferritin and zinc. Diagnosis can be confirmed by mutation analysis.
At least 43 different mutations have been reported in the SLC7A7 gene on chromosome 14q, encoding the light subunit of the dibasic amino acid transporter.27,55 The mode of inheritance is autosomal recessive.
TREATMENT AND OUTCOME
The principal aims of treatment are to prevent hyperammonemia and to provide sufficient protein and essential amino acids for normal metabolism and growth. As a neutral amino acid, citrulline is readily absorbed and partially converted to arginine and ornithine, improving the function of the urea cycle. Sodium benzoate or sodium phenyl butyrate may help to diminish the nitrogen load if necessary, and small doses of L-lysine-HCl elevate plasma lysine concentration to low-normal range without side effects. Carnitine supplementation is indicated in evident carnitine deficiency. Due to the restricted diet, the patients need supplementary calcium, vitamins, and trace elements.
The rare hyperammonemic crisis is treated following the guidelines for urea cycle disorders.63
Varicella infections can be fatal, and the patients should be immunized and treated with acyclovir.64 Other complications include systemic lupus erythematosus65-67; bone-marrow involvement with erythrophagocytosis; and interstitial pulmonary disease with alveolar proteinosis, in some cases progressing to fatal multiorgan failure.51,68-72 The treatment with immunosuppression or intravenous immunoglobulin is still experimental.65,73 In alveolar proteinosis, bronchoalveolar lavage and steroid therapy have shown some effect.51,68-72,74,75 Recent reports indicate that variable degree of renal dysfunction is common in LPI, with Fanconi-type tubular problems and slowly deteriorating glomerular filtration that has led to end-stage renal disease and renal transplantation in individual cases.77,78
In Hartnup disorder (MIM 234500), pellagra-like dermatitis and neurological symptoms are associated with a characteristic pattern of hyperaminoaciduria can be present. Due to a renal transport defect of neutral monoamino-monocarboxylic amino acids, the patients excrete alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, histidine, citrulline, asparagine and glutamine into the urine in five- to twentyfold excess, while the plasma concentrations are decreased or low normal. The autosomal recessive disorder is caused by at least 10 mutations in the gene encoding the neutral amino acid transporter SLC6A19 at the luminal border of the epithelial cells in the renal tubuli and intestinal epithelium.81,83-86 The clinical manifestations resembling niacin deficiency probably reflect deficient production of nicotinamide, a tryptophan metabolite. On a protein-rich diet, most patients remain asymptomatic, most likely due to sufficient amino acid supply in peptide form.87 In the few patients who develop clinical symptoms, the skin lesions on light-exposed areas and neurological problems, including intermittent cerebellar ataxia, headache, muscle pain, and weakness,88,89 usually appear in early childhood and often ameliorate with age. Exposure to sunlight, infection, poor nutrition, or stress may precipitate the symptoms. Growth and developmental outcome are generally normal. The characteristic excess of neutral amino acids in the urine and reduced or low-normal concentrations in plasma confirm the diagnosis. The symptoms usually disappear rapidly with oral nicotinamide. Early recognition of the condition in newborn screening programs permits adequate follow-up and treatment. Clinical and molecular aspects of amino acid transport defects are summarized in Table 143-1.