Organic acidurias and aminoacidurias

These are autosomal recessive conditions. The most common is phenylketonuria due to defects in phenylalanine hydrolase, and over 400 disease-causing mutations in the gene have been described. The prevalence shows marked geographical and racial differences, ranging between 1 in 2600 and 1 in 200,000 live births, and carrier rates between 1 in 26 and 1 in 225 (in Turkey and Finland, respectively). It can and should be detected by neonatal screening, and early dietary treatment will prevent any abnormalities. If the condition is missed, mental retardation, epilepsy, microcephaly, motor and behavioural disturbance occur. A less common cause of phenylalaninaemia is tetrahydrobiopterin deficiency. Other acidurias in which epilepsy occurs include argininosuccini-caciduria, tyrosinaemia and histidinaemia. They commonly result in epilepsy associated with learning disability and other neurological and systemic features. Diagnosis is made by screening blood and urine for abnormal amino acids.

Lactic acidosis is present in blood and urine in Leigh's syndrome. This is usually due to X-linked or autosomal recessive nuclear gene mutations of one of the mitochon-drial respiratory chain complex I or IV enzymes or pyruvate dehydrogenase (X-linked PDHA1 gene). About 30% are due to mutations in mitochondrial DNA, which have been identified in at least 11 mitochondrial genes. The diagnostic features are a subacute encephalopathy, seizures (myoclonic or tonic-clonic), and progressive dementia with cerebellar and brainstem signs. Motor abnormalities include hypotonia, spasticity, ataxia, involuntary movements and bulbar problems. Vomiting, hyperventilation and abnormalities of thermoregulation are common. Optic atrophy, pigmentary retinopathy, deafness and cardiomyopathy are sometimes present. On imaging, basal ganglia lucencies are highly characteristic, and proton magnetic resonance spectro scopy (MRS) can detect high cerebral lactic acid levels. High alanine levels are found in plasma. The condition typically presents in infancy after a viral disease, but less commonly can occur at any age. Leigh-like conditions also occur without the full complement of features, and the complex 'neurogenic weakness, ataxia and retinitis pigmentosa' (NARP) is considered to be part of the spectrum of this condition. Genetic testing is available.

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