Disorders of Protein Metabolism Amino Acid Disorders

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Amino-acidopathies are due to an enzyme deficiency early in the catabolic pathway of one or more amino-acids that results in the accumulation of the amino-acid(s); they are detected by amino-acid analysis of serum or plasma. Symptoms may be due to the chronic accumulation of toxic amino-acid(s) or due to acute

Succinyl acetone -----Fumarylacetoacetate

Fumarate Acetoacetate Figure 1 Catabolic pathway of phenylalanine. PAH, phenylalanine hydroxylase; TAT, tyrosine aminotransferase; FAH, fumarylaceto-acetase; 1, PKU; 2, tyrosinaemia type II; 3, tyrosinaemia type I.

best outcomes achieved when recommended phenylalanine levels are attained by 2 weeks of age.

Untreated patients develop progressive severe mental retardation, often with seizures and Parkinson-disease-like neurological symptoms. The primary pathogenesis is due to the toxic effect of phenylalanine on the central nervous system; secondary symptoms may be due to a deficiency of tyrosine, which is an important precursor for the synthesis of some neuro-transmitters. These symptoms include anxiety and depression.

Benign or mild hyperphenylalaninemia is due to allelic variants of PAH that result in greater residual enzyme activity. On an unrestricted diet, levels are typically in the range 120-360 mmolL"1, and no dietary treatment is necessary.

Moderate elevation of phenylalanine is also present in patients with defects of tetrahydrobiopterin (BH4), the cofactor for PAH. BH4 is also the cofac-tor for other enzymes, tryptophan hydroxylase and tyrosine hydroxylase. These amino-acids are important precursors of the neurotransmitters 5-hydroxy-tryptophan and dopamine. A deficiency causes a neurological syndrome characterized by hypotonia, seizures, and movement disorder (dystonia).

MSUD has an incidence of approximately 1 in 185 000 births. It is due to a deficiency of the branched chain ketoacid dehydrogenase enzyme and the resulting accumulation of the branched chain amino-acids (BCAAs) leucine, isoleucine, and valine, which are detected by plasma amino-acid analysis. Elevation of alloisoleucine (a derivative of isoleucine) is pathognomonic. In classic MSUD, symptoms typically occur in the first week of life and, if untreated, rapidly progress to cerebral oedema, coma, and death. Toxicity is due primarily to high levels of leucine. The characteristic maple syrup (or burnt sugar) odour is due to the presence of sotolone, a metabolite of isoleucine or allo-isoleucine. It is detectable only when the BCAAs are significantly elevated; the ester is concentrated in the urine and the earwax of affected patients.

Variant forms of MSUD also occur. Intermediate MSUD typically presents in infancy with developmental delay; seizures may occur. Moderate levels of the BCAAs (including alloisoleucine) are present. Intermittent MSUD is associated with intermittent symptoms during acute infections or periods of prolonged fasting. Typical symptoms include ataxia, vomiting, and seizures. Acute severe decompensation may occur, similar to the classic form of MSUD. The BCAAs are elevated only during the episode of acute symptoms. Other disorders are listed in Table 1.

Urea cycle defects are due to enzyme deficiencies associated with the elimination of waste nitrogen produced by the normal catabolism of protein. There are six enzymatic steps involved in this process (Figure 2): a deficiency in any of the first five enzymes causes accumulation of nitrogen, in the form of ammonia (NH3), and increased levels of the amino-acids glutamine and glycine.

Symptoms typically occur in the newborn period, except in the case of arginase deficiency, but milder late-onset variants have been well described. Symptoms include lethargy, poor feeding, vomiting, tachypnea, and progressive encephalopathy. Routine biochemical testing shows respiratory alkalosis and hyperammonemia. The liver transaminases are usually elevated. Hypoglycemia is not typical.

Plasma amino-acid and urine organic acid analyses are necessary to make a presumptive diagnosis.

Table 1 Disorders of amino-acid metabolism

Disorder (Deficient enzyme)

Elevated analyte

Clinical features


Tyrosinemia type I (fumarylacetoacetase)

Tyrosinemia type II (tyrosine aminotransferase)

Homocystinuria (cystathionine ß synthase)

Nonketotic hyperglycinemia (glycine cleavage enzyme deficiency)

Tyrosine SA

Methionine Total homocysteine Free homocystine+ Mixed disulfides Glycine ("") (plasma and CSF)

Cirrhosis Liver failure Failure to thrive Renal tubular acidosis Rickets

Hepatocellular Carcinoma (late)


Palmar keratosis

Mental retardation

Mental retardation


Lens dislocation



Developmental delay

NTBC (inhibits SA production) Tyrosine restriction

Tyrosine restriction

Vitamin B6 (50% respond) Methionine restriction

Sodium benzoate (decreases glycine)

CSF, cerebrospinal Fluid; SA, Succinylacetone; NTBC, 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione.

Acetyl CoA


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