The clinical phenotype of 45 genetically confirmed McArdle patients is described.In the majority of patients (84%), the onset of symptoms was from early childhood, but diagnosis was frequently delayed until after 30 years of age. Not all patients could recognise a second wind, although it was always seen with exercise assessment. A history of myoglobinuria was not universal, and episodes of acute renal failure had occurred in a minority (11%). The condition does not appear to adversely affect pregnancy and childbirth. Clinical examination was normal in most patients, muscle hypertrophy was present in 24% and mild muscle wasting and weakness was seen only in patients over 40 years of age and was limited to shoulder girdle and axial muscles. The serum creatine kinase (CK) was elevated in all but one pregnant patient. Screening for the mutations p.Arg50X (R50X) and p.Gly205Ser (G205S) showed at least one mutated allele in 96% of Caucasian British patients, with an allele frequency of 77% for p.Arg50X in this population. A 12-minute walking test to evaluate patients is described, results demonstrated a wide spectrum of severity with the range of distance walked being 195-1980 metres, the mean distance walked was 512m suggesting significant functional impairment in most patients.

We have identified 12 patients with autosomal recessive mitochondrial encephalomyopathy with elevated methylmalonic acid. The disorder has a high incidence of 1 in 1700 in the Faroe Islands due to a founder effect, and a carrier frequency of 1 in 33. The symptoms comprise hypotonia, muscle atrophy, hyperkinesia, severe hearing impairment and postnatal growth retardation. Neuroimaging showed demyelination and central and cortical atrophy, including atrophy of the basal ganglia, and some of the patients fulfilled the criteria for Leigh syndrome. Urine and plasma methylmalonic acid were elevated. Homozygosity mapping with the Affymetrix 10 K array revealed a homozygous region on chromosome 13q14 harbouring the SUCLA2 gene. Mutations in SUCLA2 were recently shown to cause a similar disorder in a small Israeli family. Mutation analysis identified a novel splice site mutation in SUCLA2, IVS4 + 1G --> A, leading to skipping of exon 4. The SUCLA2 gene encodes the ATP-forming beta subunit of the Krebs cycle enzyme succinyl-CoA ligase. The hallmark of the condition, elevated methylmalonic acid, can be explained by an accumulation of the substrate of the enzyme, succinyl-CoA, which in turn leads to elevated methylmalonic acid, because the conversion of methylmalonyl-CoA to succinyl-CoA is inhibited.