Tokiko Fukuda

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

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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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.

Bilateral Facial Palsy Caused by Bilateral Masked Mastoiditis

Acquired simultaneous bilateral facial palsy caused by bilateral masked mastoiditis in a 25-month-old girl is reported. After the administration of antibiotics for 10 days for treatment of bilateral acute otitis media, overt signs of otitis media diminished as bilateral facial palsy ensued. For diagnosis of masked mastoiditis, brain magnetic resonance imaging was of significant value in our case. The findings in this case suggest that masked mastoiditis should be considered as a cause of bilateral facial palsy, as well as unilateral facial palsy.

Study of HOXD genes in autism particularly regarding the ratio of second to fourth digit length

Multiple genes are involved in the pathogenesis of autism. To study the causative gene, the relationship between autism endophenotypes and their closely related genes has been analyzed. There is a subgroup of autism spectrum disorder (ASD) in which the ratio of second digit length to fourth digit length (2D/4D) is low (short digit group, SDG). We studied the relationship between ASD and HOXD genes, which are located in the candidate locus for ASD and are associated with digit morphogenesis, with a particular focus on SDG. We analyzed 25 SNPs of HOXD11, HOXD12, and HOXD13 in the subject of 98 ASD, 89 healthy controls, and 16 non-autistic patients (non-ASD). There was no significant difference in the genotype frequencies between the ASD and the healthy controls. However, the G-112T heterozygote in the promoter region of HOXD11 was observed in only four patients with ASD and in none of the healthy controls or non-ASD subjects. Moreover, this HOXD11 G-112T was observed in three of 11 SDG with ASD but in none of the 15 non-SDG patients with ASD. There were eight SDG patients among the non-ASD ones, but this polymorphism was observed in none of them. Considering the above results, it is expected that candidate genes will be further identified, using HOXD11 G-112T polymorphism as a marker, by analyzing genes located near 2q in a larger number of ASD subjects with clinical signs of SDG.

Congenital form of glycogen storage disease type IV: a case report and a review of the literature.

Glycogen storage disease (GSD) type IV is a very rare autosomal recessive disorder, which is caused by deficiency of alpha-1,4-glucan:alpha-1,4-glucan 6-glycosyl transferase, also known as the branching enzyme. The most common clinical feature is hepatosplenomegaly in the infantile period, and progressive liver cirrhosis results in death by 5 years of age. The disease, however, has been revealed to include three other clinical subtypes: congenital subtype, which is characterized by severe neonatal hypotonia or fetal death; childhood subtype, which starts between 2 and 7 years of age with cardiomyopathy; and adult subtype, in which adult onset myopathy is predominant. 1 Among the four clinical subtypes, the congenital one is the most severe variant of the disease and only a few cases have been reported. 1–9 Here we report additional cases, in whom the clinical and pathological findings were consistent with the congenital form of GSD type IV and the diagnosis was made enzymologically.

A novel PYGM mutation in a Korean patient with McArdle disease: The role of nonsense-mediated mRNA decay

We have identified a compound heterozygous mutation of PYGM in a Korean patient with McArdle disease, which is composed of a novel single codon deletion (p.779delE) and a common nonsense mutation (p.R50X). Our study also showed an evidence of nonsense-mediated mRNA decay (NMD) caused by p.R50X mutation, supporting the importance of RNA processing defects in the molecular pathology of McArdle disease.