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Myopathy with deficiency of succinate dehydrogenase and aconitase is a recessively inherited disorder characterized by childhood-onset early fatigue, dyspnoea and palpitations on trivial exercise. The disease is non-progressive, but life-threatening episodes of widespread weakness, severe metabolic acidosis and rhabdomyolysis may occur. The disease has so far only been identified in northern Sweden. The clinical, histochemical and biochemical phenotype is very homogenous and the patients are homozygous for a deep intronic IVS5 + 382G greater than C splicing affecting mutation in "ISCU", which encodes the differently spliced cytosolic and mitochondrial iron-sulphur cluster assembly protein IscU. Iron-sulphur cluster containing proteins are essential for iron homeostasis and respiratory chain function, with IscU being among the most conserved proteins in evolution. We identified a shared homozygous segment of only 405 000 base pair with the deep intronic mutation in eight patients with a phenotype consistent with the original description of the disease. Two other patients, two brothers, had an identical biochemical and histochemical phenotype which is probably pathognomonic for muscle iron-sulphur cluster deficiency, but they presented with a disease where the clinical phenotype was characterized by early onset of a slowly progressive severe muscle weakness, severe exercise intolerance and cardiomyopathy. The brothers were compound heterozygous for the deep intronic mutation and had a c.149 G greater than A missense mutation in exon 3 changing a completely conserved glycine residue to a glutamate. The missense mutation was inherited from their mother who was of Finnish descent. The intronic mutation affects mRNA splicing and results in inclusion of pseudoexons in most transcripts in muscle. The pseudoexon inclusion results in a change in the reading frame and appearance of a premature stop codon. In western blot analysis of protein extracts from fibroblasts, there was no pronounced reduction of IscU in any of the patients, but the analysis revealed that the species corresponding to mitochondrial IscU migrates slower than a species present only in whole cells. In protein extracted from isolated skeletal muscle mitochondria the western blot analysis revealed a severe deficiency of IscU in the homozygous patients and appearance of a faint new fraction that could represent a truncated protein. There was only a slight reduction of mitochondrial IscU in the compound heterozygotes, despite their severe phenotype, indicating that the IscU expressed in these patients is non-functional.

A case study of three siblings having profound muscle glycogen deficiency and homozygous stop mutations in glycogen synthase 1 gene is presented. It is revealed that glycogen storage is crucial for glucose homeostatis and for providing energy supplement during exercise.

Leber's hereditary optic neuropathy (LHON) is an inherited disorder that has been found to result from a mutation in a gene within the mitochondria. In addition to the characteristic optic atrophy of LHON, there are likely to be other abnormal signs, including abnormalities of heart conduction and neurological abnormalities. A specific mutation has been found in some affected families; this mutation is related to the structure of an enzyme called NADH ubiquinone oxidoreductase. This enzyme is a part of the enormous complex I structure, which serves as a part of the series of enzymes involved a cell's respiration. However, since much of what is known about LHON has been learned by the clinical examination of patients prior to the discovery of this genetic mutation in 1988, it is important to evaluate the function of complex I enzymes in many patients and their families. Such studies have now been performed on a male patient, his mother, and three siblings. Although only one of these five subjects had LHON, metabolic abnormalities involving the function of complex I were identified in all five. In four of these individuals, microscopic investigation of biopsy specimens revealed abnormal shapes among the mitochondria. Genetic analysis revealed that all maternally related family members were homoplasmic. In contrast with many cases of LHON, which are heteroplasmic, this means that all, not just some, of the mitochondria appear to contain the defect. In this family, therefore, both the affected patient and his healthy relatives possessed the same mutation and the same measured enzyme defect. There is some suggestion that although LHON results from a mitochondrial mutation, other genetic and environmental factors may be required for the expression of the genetic defect. The majority of patients with LHON are male, despite the fact that a mitochondrial defect will be inherited by males and females with equal probability. The expression of LHON may result from the action of another gene, not yet identified, on the function of the mutant mitochondria. The predominance of male patients hints that this gene may be on the X chromosome. (Consumer Summary produced by Reliance Medical Information, Inc.)

Abstract A male patient, born to unrelated Belgian parents, presented at 4 months with epistaxis, haematemesis and haematochezia. On physical examination he presented petechiae and haematomas, and a slightly enlarged liver. Serum transaminases were elevated to 5-10 times upper limit of normal, alkaline phosphatases were 1685 U/L (180 s ( Fumarylacetoacetase (FAH) protein and activity in cultured fibroblasts and liver tissue were decreased but not absent. 4-hydroxyphenylpyruvate dioxygenase activity in liver was normal, which is atypical for tyrosinemia type I. A novel mutation was found in the FAH gene: c.103G>A (Ala35Thr). In vitro expression studies showed this mutation results in a strongly decreased FAH protein expression. Dietary treatment with phenylalanine and tyrosine restriction was initiated at 4 months, leading to complete clinical and biochemical normalisation. The patient, currently aged 12 years, shows a normal physical and psychomotor development. This is the first report of mild tyrosinemia type I disease caused by an Ala35Thr mutation in the FAH gene, presenting atypically without increase of the diagnostically important toxic metabolites succinylacetone and succinylacetoacetate.