Defects of amino acid transport in the renal tubule are discussed in Congenital Renal Transport Abnormalities. For a more complete listing of amino acid and organic amino acid metabolism disorders, see Table Disorders of Amino Acid and Organic Acid Metabolism.
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Phenylketonuria (PKU) is a clinical syndrome of intellectual disability with cognitive and behavioral abnormalities caused by elevated serum phenylalanine. The primary cause is deficient phenylalanine hydroxylase activity. Diagnosis is by detecting high phenylalanine levels and normal or low tyrosine levels. Treatment is lifelong dietary phenylalanine restriction. Prognosis is excellent with treatment.
PKU is most common among all white populations and relatively less common among Ashkenazi Jews, Chinese, and blacks. Inheritance is autosomal recessive; incidence is about 1/10,000 births among whites.
Excess dietary phenylalanine (ie, that not used for protein synthesis) is normally converted to tyrosine by phenylalanine hydroxylase; tetrahydrobiopterin (BH4) is an essential cofactor for this reaction. When one of several gene mutations results in deficiency or absence of phenylalanine hydroxylase, dietary phenylalanine accumulates; the brain is the main organ affected, possibly due to disturbance of myelination. Some of the excess phenylalanine is metabolized to phenylketones, which are excreted in the urine, giving rise to the term phenylketonuria. The degree of enzyme deficiency, and hence severity of hyperphenylalaninemia, varies among patients depending on the specific mutation.
Although nearly all cases (98 to 99%) of PKU result from phenylalanine hydroxylase deficiency, phenylalanine can also accumulate if BH4 is not synthesized because of deficiencies of dihydrobiopterin synthase or not regenerated because of deficiencies of dihydropteridine reductase. Additionally, because BH4 is also a cofactor for tyrosine hydroxylase, which is involved in the synthesis of dopamine and serotonin, BH4 deficiency alters synthesis of neurotransmitters, causing neurologic symptoms independently of phenylalanine accumulation.
Symptoms and Signs
Most children are normal at birth but develop symptoms and signs slowly over several months as phenylalanine accumulates. The hallmark of untreated PKU is severe intellectual disability. Children also manifest extreme hyperactivity, gait disturbance, and psychoses and often exhibit an unpleasant, mousy body odor caused by phenylacetic acid (a breakdown product of phenylalanine) in urine and sweat. Children also tend to have a lighter skin, hair, and eye color than unaffected family members, and some may develop a rash similar to infantile eczema.
In the US and many developed countries, all neonates are screened for PKU 24 to 48 h after birth with one of several blood tests; abnormal results are confirmed by directly measuring phenylalanine levels. In classic PKU, neonates often have phenylalanine levels > 20 mg/dL (1.2 mM/L). Those with partial deficiencies typically have levels < 8 to 10 mg/dL while on a normal diet (levels > 6 mg/dL require treatment); distinction from classic PKU requires a liver phenylalanine hydroxylase activity assay showing activity between 5% and 15% of normal or a mutation analysis identifying mild mutations in the gene.
BH4 deficiency is distinguished from other forms of PKU by elevated concentrations of biopterin or neopterin in urine, blood, CSF, or all 3; recognition is important, and the urine biopterin profile should be determined routinely at initial diagnosis because standard PKU treatment does not prevent neurologic damage.
Children in families with a positive family history can be diagnosed prenatally by using direct mutation studies after chorionic villus sampling or amniocentesis.
Adequate treatment begun in the first days of life prevents all manifestations of disease. Treatment begun after 2 to 3 yr may be effective only in controlling the extreme hyperactivity and intractable seizures. Children born to mothers with poorly controlled PKU (ie, they have high phenylalanine levels) during pregnancy are at high risk of microcephaly and developmental deficit.
Treatment is lifelong dietary phenylalanine restriction. All natural protein contains about 4% phenylalanine. Therefore dietary staples include low-protein natural foods (eg, fruits, vegetables, certain cereals), protein hydrolysates treated to remove phenylalanine, and phenylalanine-free elemental amino acid mixtures. Examples of commercially available phenylalanine-free products include XPhe products (XP Analog for infants, XP Maxamaid for children 1 to 8 yr, XP Maxamum for children > 8 yr); Phenex I and II; Phenyl-Free I and II; PKU-1, -2, and -3; PhenylAde (varieties); Loflex; and Plexy10. Some phenylalanine is required for growth and metabolism; this requirement is met by measured quantities of natural protein from milk or low-protein foods.
Frequent monitoring of plasma phenylalanine levels is required; recommended targets are between 2 mg/dL and 4 mg/dL (120 to 240μmol/L) for children < 12 yr and between 2 mg/dL and 10 mg/dL (120 to 600 μmol/L) for children > 12 yr. Dietary planning and management need to be initiated in women of childbearing age before pregnancy to ensure a good outcome for the child. Tyrosine supplementation is increasingly used because it is an essential amino acid in patients with PKU. In addition, sapropterin is increasingly being used.
For those with BH4 deficiency, treatment also includes tetrahydrobiopterin 1 to 5 mg/kg po tid; levodopa, carbidopa, and 5-OH tryptophan; and folinic acid 10 to 20 mg po once/day in cases of dihydropteridine reductase deficiency. However, treatment goals and approach are the same as those for PKU.
Disorders of Tyrosine Metabolism
Tyrosine is a precursor of several neurotransmitters (eg, dopamine, norepinephrine, epinephrine), hormones (eg, thyroxine), and melanin; deficiencies of enzymes involved in its metabolism lead to a variety of syndromes.
Transient tyrosinemia of the newborn:
Transient immaturity of metabolic enzymes, particularly 4-hydroxyphenylpyruvic acid dioxygenase, sometimes leads to elevated plasma tyrosine levels (usually in premature infants, particularly those receiving high-protein diets); metabolites may show up on routine neonatal screening for PKU.
Most infants are asymptomatic, but some have lethargy and poor feeding.
Tyrosinemia is distinguished from PKU by elevated plasma tyrosine levels.
Most cases resolve spontaneously. Symptomatic patients should have dietary tyrosine restriction (2 g/kg/day) and be given vitamin C 200 to 400 mg po once/day.
Tyrosinemia type I:
This disorder is an autosomal recessive trait caused by deficiency of fumarylacetoacetate hydroxylase, an enzyme important for tyrosine metabolism.
Disease may manifest as fulminant liver failure in the neonatal period or as indolent subclinical hepatitis, painful peripheral neuropathy, and renal tubular disorders (eg, normal anion gap metabolic acidosis, hypophosphatemia, vitamin D–resistant rickets) in older infants and children. Children who do not die from associated liver failure in infancy have a significant risk of developing liver cancer.
Diagnosis is suggested by elevated plasma levels of tyrosine; it is confirmed by a high level of succinylacetone in plasma or urine and by low fumarylacetoacetate hydroxylase activity in blood cells or liver biopsy specimens. Treatment with 2(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclo-hexanedione (NTBC) is effective in acute episodes and slows progression.
A diet low in phenylalanine and tyrosine is recommended. Liver transplantation is effective.
Tyrosinemia type II:
This rare autosomal recessive disorder is caused by tyrosine transaminase deficiency.
Accumulation of tyrosine causes cutaneous and corneal ulcers. Secondary elevation of phenylalanine, though mild, may cause neuropsychiatric abnormalities if not treated.
Diagnosis is by elevation of tyrosine in plasma, absence of succinylacetone in plasma or urine, and measurement of decreased enzyme activity in liver biopsy.
This disorder is easily treated with mild to moderate restriction of dietary phenylalanine and tyrosine.
This rare autosomal recessive disorder is caused by homogentisic acid oxidase deficiency; homogentisic acid oxidation products accumulate in and darken skin, and crystals precipitate in joints.
The condition is usually diagnosed in adults and causes dark skin pigmentation (ochronosis) and arthritis. Urine turns dark when exposed to air because of oxidation products of homogentisic acid. Diagnosis is by finding elevated urinary levels of homogentisic acid (> 4 to 8 g/24 h).
There is no effective treatment, but ascorbic acid 1 g po once/day may diminish pigment deposition by increasing renal excretion of homogentisic acid.
Tyrosinase deficiency results in absence of skin and retinal pigmentation, causing a much increased risk of skin cancer and considerable vision loss. Nystagmus is often present, and photophobia is common (see Pigmentation Disorders: Albinism).
Disorders of Branched-Chain Amino Acid Metabolism
Valine, leucine, and isoleucine are branched-chain amino acids; deficiency of enzymes involved in their metabolism leads to accumulation of organic acids with severe metabolic acidosis.
Maple syrup urine disease:
This is a group of autosomal recessive disorders caused by deficiency of one or more subunits of a dehydrogenase active in the 2nd step of branched-chain amino acid catabolism. Although quite rare, incidence is significant (perhaps 1/200 births) in Amish and Mennonite populations.
Clinical manifestations include body fluid odor that resembles maple syrup (particularly strong in cerumen) and overwhelming illness in the first days of life, beginning with vomiting and lethargy, and progressing to seizures, coma, and death if untreated. Patients with milder forms of the disease may manifest symptoms only during stress (eg, infection, surgery).
Biochemical findings are profound ketonemia and acidemia. Diagnosis is by finding elevated plasma levels of branched-chain amino acids (particularly leucine).
Acutely, treatment with peritoneal dialysis or hemodialysis may be required, along with IV hydration and nutrition (including high-dose dextrose). Long-term management is restriction of dietary branched-chain amino acids; however, small amounts are required for normal metabolic function. Thiamin is a cofactor for the decarboxylation, and some patients respond favorably to high-dose thiamin (up to 200 mg po once/day). Liver transplantation is curative.
The 3rd step of leucine metabolism is the conversion of isovaleryl CoA to 3-methylcrotonyl CoA, a dehydrogenation step. Deficiency of this dehydrogenase results in isovaleric acidemia, also known as “sweaty feet” syndrome, because accumulated isovaleric acid emits an odor that smells like sweat.
Clinical manifestations of the acute form occur in the first few days of life with poor feeding, vomiting, and respiratory distress as infants develop profound anion gap metabolic acidosis, hypoglycemia, and hyperammonemia. Bone marrow suppression often occurs. A chronic intermittent form may not manifest for several months or years.
Diagnosis is made by detecting elevated levels of isovaleric acid and its metabolites in blood or urine.
Acute treatment is with IV hydration and nutrition (including high-dose dextrose) and measures to increase renal isovaleric acid excretion by conjugation with glycine. If these measures are insufficient, exchange transfusion and peritoneal dialysis may be needed. Long-term treatment is with dietary leucine restriction and continuation of glycine and carnitine supplements. Prognosis is excellent with treatment.
Deficiency of propionyl CoA carboxylase, the enzyme responsible for metabolizing propionic acid to methylmalonate, causes propionic acid accumulation.
Illness begins in the first days or weeks of life with poor feeding, vomiting, and respiratory distress due to profound anion gap metabolic acidosis, hypoglycemia, and hyperammonemia. Seizures may occur, and bone marrow suppression is common. Physiologic stresses may trigger recurrent attacks. Survivors may have tubular nephropathies, intellectual disability, and neurologic abnormalities. Propionic acidemia can also be seen as part of multiple carboxylase deficiency, biotin deficiency, or biotinidase deficiency.
Diagnosis is suggested by elevated levels of propionic acid metabolites, including methylcitrate and tiglate and their glycine conjugates in blood and urine, and confirmed by measuring propionyl CoA carboxylase activity in WBCs or cultured fibroblasts.
Acute treatment is with IV hydration (including high-dose dextrose) and nutrition; carnitine may be helpful. If these measures are insufficient, peritoneal dialysis or hemodialysis may be needed. Long-term treatment is dietary restriction of precursor amino acids and odd-chain fatty acids and possibly continuation of carnitine supplementation. A few patients respond to high-dose biotin because it is a cofactor for propionyl CoA and other carboxylases.
This disorder is caused by deficiency of methylmalonyl CoA mutase, which converts methylmalonyl CoA (a product of the propionyl CoA carboxylation) into succinyl CoA. Adenosylcobalamin, a metabolite of vitamin B12, is a cofactor; its deficiency also may cause methylmalonic acidemia (and also homocystinuria and megaloblastic anemia). Methylmalonic acid accumulates. Age of onset, clinical manifestations, and treatment are similar to those of propionic acidemia except that cobalamin, instead of biotin, may be helpful for some patients.
Disorders of Methionine Metabolism
A number of defects in methionine metabolism lead to accumulation of homocysteine (and its dimer, homocystine) with adverse effects including thrombotic tendency, lens dislocation, and CNS and skeletal abnormalities.
Homocysteine is an intermediate in methionine metabolism; it is either remethylated to regenerate methionine or combined with serine in a series of transsulfuration reactions to form cystathionine and then cysteine. Cysteine is then metabolized to sulfite, taurine, and glutathione. Various defects in remethylation or transsulfuration can cause homocysteine to accumulate, resulting in disease.
The first step in methionine metabolism is its conversion to adenosylmethionine; this conversion requires the enzyme methionine adenosyltransferase. Deficiency of this enzyme results in methionine elevation, which is not clinically significant except that it causes false-positive neonatal screening results for homocystinuria.
This disorder is caused by an autosomal recessive deficiency of cystathionine β-synthase, which catalyzes cystathionine formation from homocysteine and serine. Homocysteine accumulates and dimerizes to form the disulfide homocystine, which is excreted in the urine. Because remethylation is intact, some of the additional homocysteine is converted to methionine, which accumulates in the blood. Excess homocysteine predisposes to thrombosis and has adverse effects on connective tissue (perhaps involving fibrillin), particularly the eyes and skeleton; adverse neurologic effects may be due to thrombosis or a direct effect.
Arterial and venous thromboembolic phenomena can occur at any age. Many patients develop ectopia lentis (lens subluxation), intellectual disability, and osteoporosis. Patients can have a marfanoid habitus even though they are not usually tall.
Diagnosis is by neonatal screening for elevated serum methionine; elevated total plasma homocysteine levels are confirmatory. Enzymatic assay in skin fibroblasts can also be done.
Treatment is a low-methionine diet, combined with high-dose pyridoxine (a cystathionine synthetase cofactor) 100 to 500 mg po once/day. Because about half of patients respond to high-dose pyridoxine alone, some clinicians do not restrict methionine intake in these patients. Betaine (trimethylglycine), which enhances remethylation, can also help lower homocysteine; dosage is 100 to 125 mg/kg po bid. Folate 500 to 1000 μg once/day is also given. With early treatment, intellectual outcome is normal or near normal.
Other forms of homocystinuria:
Various defects in the remethylation process can result in homocystinuria. Defects include deficiencies of methionine synthase (MS) and MS reductase (MSR), delivery of methylcobalamin and adenosylcobalamin, and deficiency of methylenetetrahydrofolate reductase (MTHFR, which is required to generate the 5-methyltetrahydrofolate needed for the MS reaction). Because there is no methionine elevation in these forms of homocystinuria, they are not detected by neonatal screening.
Clinical manifestations are similar to other forms of homocystinuria. In addition, MS and MSR deficiencies are accompanied by neurologic deficits and megaloblastic anemia. Clinical manifestation of MTHFR deficiency is variable, including intellectual disability, psychosis, weakness, ataxia, and spasticity.
Diagnosis of MS and MSR deficiencies is suggested by homocystinuria and megaloblastic anemia and confirmed by DNA testing. Patients with cobalamin defects have megaloblastic anemia and methylmalonic acidemia. MTHFR deficiency is diagnosed by DNA testing.
Treatment is by replacement of hydroxycobalamin 1 mg IM once/day (for patients with MS, MSR, and cobalamin defects) and folate in supplementation similar to characteristic homocystinuria.
This disorder is caused by deficiency of cystathionase, which converts cystathionine to cysteine. Cystathionine accumulation results in increased urinary excretion but no clinical symptoms.
Sulfite oxidase deficiency:
Sulfite oxidase converts sulfite to sulfate in the last step of cysteine and methionine degradation; it requires a molybdenum cofactor. Deficiency of either the enzyme or the cofactor causes similar disease; inheritance for both is autosomal recessive.
In its most severe form, clinical manifestations appear in neonates and include seizures, hypotonia, and myoclonus, progressing to early death. Patients with milder forms may present similarly to cerebral palsy (see Neurologic Disorders in Children: Cerebral Palsy (CP) Syndromes) and may have choreiform movements.
Diagnosis is suggested by elevated urinary sulfite and confirmed by measuring enzyme levels in fibroblasts and cofactor levels in liver biopsy specimens. Treatment is supportive.
Urea Cycle Disorders
Urea cycle disorders (UCDs) are characterized by hyperammonemia under catabolic or protein-loading conditions.
Primary UCDs include carbamoyl phosphate synthase (CPS) deficiency, ornithine transcarbamylase (OTC) deficiency, argininosuccinate synthetase deficiency (citrullinemia), argininosuccinate lyase deficiency (argininosuccinic aciduria), and arginase deficiency (argininemia). In addition, N-acetylglutamate synthetase (NAGS) deficiency has been reported. The more “proximal” the enzyme deficiency is, the more severe the hyperammonemia; thus, disease severity in descending order is NAGS deficiency, CPS deficiency, OTC deficiency, citrullinemia, argininosuccinic aciduria, and argininemia.
Inheritance for all UCDs is autosomal recessive, except for OTC deficiency, which is X-linked.
Symptoms and Signs
Clinical manifestations range from mild (eg, failure to thrive, intellectual disability, episodic hyperammonemia) to severe (eg, altered mental status, coma, death). Manifestations in females with OTC deficiency range from growth failure, developmental delay, psychiatric abnormalities, and episodic (especially postpartum) hyperammonemia to a phenotype similar to that of affected males.
Diagnosis is based on amino acid profiles. For example, elevated ornithine indicates CPS deficiency or OTC deficiency, whereas elevated citrulline indicates citrullinemia. To distinguish between CPS deficiency and OTC deficiency, orotic acid measurement is helpful because accumulation of carbamoyl phosphate in OTC deficiency results in its alternative metabolism to orotic acid.
Treatment is dietary protein restriction that still provides adequate amino acids for growth, development, and normal protein turnover. Arginine has become a staple of treatment. It supplies adequate urea cycle intermediates to encourage the incorporation of more nitrogen moieties into urea cycle intermediates, each of which is readily excretable. Arginine is also a positive regulator of acetylglutamate synthesis. Recent studies suggest that oral citrulline is more effective than arginine in patients with OTC deficiency. Additional treatment is with Na benzoate, phenylbutyrate, or phenylacetate, which by conjugating glycine (Na benzoate) and glutamine (phenylbutyrate and phenylacetate) provides a “nitrogen sink.”
Despite these therapeutic advances, many UCDs remain difficult to treat, and liver transplantation is eventually required for many patients. Timing of liver transplantation is critical. Optimally, the infant should grow to an age when transplantation is less risky (> 1 yr), but it is important to not wait so long as to allow an intercurrent episode of hyperammonemia (often associated with illness) to cause irreparable harm to the CNS.
Last full review/revision February 2010 by Chin-To Fong, MD
Content last modified February 2012