Rare aminoacidopathies (other than PKU)

Homocystinuria (cystathionine synthase deficiency)

Clinical features:

Untreated children and adults with homocystinuria may have dislocation of the lenses, generalised osteoporosis, premature clotting in arteries or veins (thromboembolic disease), and intellectual retardation. Affected individuals have a 30% risk of a blood clotting event by the age of 30 years.

Laboratory tests:

Elevation of the amino acid, methionine, is determined using tandem mass spectrometry.

Treatment:

Treatments that reduce plasma homocysteine levels prevent or delay the onset of symptoms. Approximately half the patients are responsive to medication with vitamin B6 (pyridoxine) and folate. The other patients require the addition of betaine. Babies can be started on a low-methionine diet with methionine-free aminoacid supplement. All patients will need extra vitamin B12 also.

Screening considerations:

Detection depends on the amount of protein ingested by the infant. Not all infants may develop methionine levels high enough to be detected in the first days of life. B6-responsive patients are especially likely to be missed. Homocystinuria due to remethylation defects, (cobalamin C,D,E,F, and G defects) may also be missed by screening as methionine is not elevated in these cases. These cases may however have a mild elevation of another analyte, propionyl carnitine, and may therefore be detected.

Maple Syrup Urine Disease (MSUD)

Clinical features:

MSUD is a rare disorder associated with progressive neurological damage within a few days of birth. A high pitched cry, irritability, convulsions, spasticity, and central nervous system depression leading to coma are usual. If not treated, the disease leads to death in 2-4 weeks. Biochemically, there is pronounced ketosis, without a metabolic acidosis in the neonate, and hypoglycaemia may occur. Urine has a sweet maple syrup odour which gives the disease its name. As with all hereditary disorders, there are less severe variants, the mildest of which may go undetected for months or years until some intercurrent illness unmasks the biochemical abnormalities.

Laboratory test:

Elevation of the amino acids, leucine + isoleucine, are determined using tandem mass spectrometry.

Treatment:

Rapid assessment is needed. Detected babies may need intensive care for a few days. A low-protein diet with amino acid formula free of branched chain amino acids is the long-term regimen.

Screening considerations:

Detection depends on protein ingestion. An affected infant must be detected early if major problems are to be prevented. Mild forms of MSUD may be missed as the blood levels may not be elevated in the first few weeks of life.

Tyrosinaemia types I and II

Clinical features: Type I

If untreated may include liver disease (acute liver failure or cirrhosis) and renal tubular acidosis and rickets. Later development of liver cancer.

Clinical features: Type II

Photophobia and corneal ulceration, palmar and plantar hyperkeratosis (painful thickened skin).

Laboratory test:

Elevation of the amino acid, tyrosine, is determined using tandem mass spectrometry. Confirmation and quantitation are performed using capillary electrophoresis.

Treatment:

Low phenylalanine and tyrosine diet for both types. For Type I, specific drug, NTBC. Later liver transplantation.

Screening considerations:

Type I tyrosinaemia will not be detected reliably by the current strategy without a very high resample rate, as tyrosine levels may not be very high in the first days. Type II will be reliably detected.

Urea cycle disorders

Three urea cycle disorders may be detected: argininosuccinnate synthase deficiency (citrullinaemia) and argininosuccinnate lyase deficiency (argininosuccinic aciduria) in which blood citrulline levels are high, and some cases of ornithine transcarbamylase (OTC) deficiency, where citrulline levels are very low.

Clinical features:

All three disorders can present with severe life-threatening high blood ammonia levels in the first days of life, or with a milder late onset form, symptoms including intellectual impairment.

Laboratory test:

Measurement of the amino acid, citrulline, is determined using tandem mass spectrometry.

Treatment:

Low protein diet and medications - arginine, and use of specific medications to reduce ammonia levels.

Screening considerations:

Necessity for rapid telephone response to both low and very high citrulline levels, but not to modest elevations. Detection of OTC deficiency may not be reliable.