Hideo Sugie

Clinical and genetic analysis of lipid storage myopathies

Causative genes have been identified only in four types of lipid storage myopathies (LSMs): SLC22A5 for primary carnitine deficiency (PCD); ETFA, ETFB, and ETFDH for multiple acyl‐coenzyme A dehydrogenation deficiency (MADD); PNPLA2 for neutral lipid storage disease with myopathy (NLSDM); and ABHD5 for neutral lipid storage disease with ichthyosis. However, the frequency of these LSMs has not been determined. We found mutations in only 9 of 37 LSM patients (24%): 3 in SLC22A5; 4 in MADD‐associated genes; and 2 in PNPLA2. This low frequency suggests the existence of other causative genes. Muscle coenzyme Q10 levels were normal or only mildly reduced in two MADD patients, indicating that ETFDH mutations may not always be associated with CoQ10 deficiency. The 2 patients with PNPLA2 mutations had progressive, non‐episodic muscle disease with rimmed vacuoles. This suggests there is a different pathomechanism from other LSMs. Muscle Nerve 39: 333–342, 2009

Distal lipid storage myopathy due to PNPLA2 mutation

Distal myopathy is a group of heterogeneous disorders affecting predominantly distal muscles usually appearing from young to late adulthood with very rare cardiac complications. We report a 27-year-old man characterized clinically by distal myopathy and dilated cardiomyopathy, pathologically by lipid storage, and genetically by a PNPLA2 mutation. The patient developed weakness in his lower legs and fingers at age 20 years. Physical examination at age 27 years revealed muscle weakness and atrophy predominantly in lower legs and hands, and severe dilated cardiomyopathy. The patient had a homozygous four-base duplication (c.475_478dupCTCC) in exon 4 of PNPLA2.

Genetic analysis of Japanese patients with myophosphorylase deficiency (McArdle's disease): single-codon deletion in exon 17 is the predominant mutation

We report molecular genetic analysis of 11 Japanese patients with myophosphorylase deficiency (McArdles disease). Four reported mutations, frequently observed in patients with McArdles disease, in exons 1, 5, 14 and 17 were investigated. Seven patients out of 11 were homozygous for a single-codon deletion at codon 708/709 in exon 17 and one patient was heterozygous for a single-codon deletion with an unknown mutant allele. In contrast, the predominant mutation reported in US and UK patients (CGA to TGA at codon 49 in exon 1), accounting for 75% and 83% of the cases, respectively, was not found in any of the Japanese patients. Results suggest that the predominant mutation in Japanese patients is a single-codon deletion at codon 708/709 in exon 17 (found in 73% of our patients) and differs from the most common mutation in US or UK patients.

Neonatal factors in infants with Autistic Disorder and typically developing infants

The prenatal and neonatal factors of 225 children diagnosed with Autistic Disorder were compared with those of 1580 typically developing children. Each of the neonatal factors was compared between the Autistic Disorder and control groups, and between males and females. The results showed that males in the ‘Autistic Disorder’ group had a significantly longer gestational age and a heavier birth weight than the male controls. No significant differences in these factors were observed between females in the two groups. Both male and female children with Autistic Disorder showed a significantly higher incidence of neonatal complications than their respective controls. In the Autistic Disorder group, males had a heavier mean birth weight, and there were more post-term infants among females.

A Novel Missense Mutation (837T→C) in the Phosphoglycerate Kinase Gene of a Patient With a Myopathic Form of Phosphoglycerate Kinase Deficiency

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Glycogen storage disease with normal acid maltase: Skeletal and cardiac muscles

We report a 5-year-old boy with lysosomal glycogen storage disease and normal acid maltase activity. This patient, the fourth reported in the literature, was referred to our hospital for evaluation of elevated serum GOT, GPT, and CK activities. He had neither muscle weakness nor atrophy. Echocardiography demonstrated marked thickening of the intraventricular septum and left ventricular wall which indicated hypertrophic cardiomyopathy. Biopsied skeletal muscle disclosed massive accumulation of glycogen and autophagic vacuoles. Electron microscopy of biopsied cardiac muscle revealed severe myofibrillar disruption with marked accumulation of free and intralysosomal glycogen. Activities of all major glycolytic enzymes in skeletal muscle, including acid maltase, were normal. It is unknown why muscle lysosomes appeared to be unable to digest the trapped glycogen despite the presence of acid maltase. Our findings illustrate the importance of performing skeletal muscle investigation during childhood in patients with hypertrophic cardiomyopathy.

A case of MERRF associated with chronic pancreatitis

We report the first case to our knowledge of chronic pancreatitis associated with mitochondrial encephalopathy with the A8344G mitochondrial DNA (mtDNA) mutation. This 10-year-old-girl had suffered from recurrent abdominal pain with elevated serum amylase and lipase since the age of 6, and easy fatigability, tremor and astatic seizures since the age of 8. A biopsy of quadriceps muscle revealed ragged-red-fibers and cytochrome c oxidase deficiency. Analysis of mtDNA in peripheral blood identified an A8344G mutation in the mitochondrial tRNA(Lys) gene. Taken together with physical signs of myoclonic seizures and cerebellar dysfunction, we diagnosed her as myoclonic epilepsy with ragged-red fibers associated with chronic pancreatitis. Although no association between mitochondrial disease and pancreatitis has yet been established, this case suggests it is necessary to consider the participation of mitochondrial abnormality in the pathogenesis of recurrent pancreatitis.

Confirmation of the efficacy of vitamin B6 supplementation for McArdle disease by follow-up muscle biopsy

No effective treatment for McArdle disease exists.We report a Japanese patient with McArdle disease who was treated with vitamin B6 supplementation (60–90 mg/day). After treatment, increased muscle phosphorylase activity was confirmed by follow‐up muscle biopsy (3.8 times higher than pretreatment levels). Increased lactate levels were seen on the forearm exercise test, and regular work activities could be resumed. Vitamin B6 supplementation can enhance residual phosphorylase activity and improve insufficient anaerobic glycolysis of skeletal muscle. Muscle Nerve, 2012

Muscle glycogen storage disease 0 presenting recurrent syncope with weakness and myalgia.

Muscle glycogen storage disease 0 (GSD0) is caused by glycogen depletion in skeletal and cardiac muscles due to deficiency of glycogen synthase 1 (GYS1), which is encoded by the GYS1 gene. Only two families with this disease have been identified. We report a new muscle GSD0 patient, a Japanese girl, who had been suffering from recurrent attacks of exertional syncope accompanied by muscle weakness and pain since age 5 years until she died of cardiac arrest at age 12. Muscle biopsy at age 11 years showed glycogen depletion in all muscle fibers. Her loss of consciousness was gradual and lasted for hours, suggesting that the syncope may not be simply caused by cardiac event but probably also contributed by metabolic distress.

Acid phosphatase-positive globular inclusions is a good diagnostic marker for two patients with adult-onset Pompe disease lacking disease specific pathology

Diagnosis of adult-onset Pompe disease is sometimes challenging because of its clinical similarities to muscular dystrophy and the paucity of disease-specific vacuolated fibers in the skeletal muscle pathology. We describe two patients with adult-onset Pompe disease whose muscle pathology showed no typical vacuolated fibers but did show unique globular inclusions with acid phosphatase activity. The acid phosphatase-positive globular inclusions may be a useful diagnostic marker for adult-onset Pompe disease even when typical vacuolated fibers are absent.