Yoko Sugie

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 Case of Paroxysmal Tonic Upward Gaze Associated with Psychomotor Retardation

The authors report a female with paroxysmal tonic upward gaze similar to the cases reported by Ouvrier and Billson (1988). She developed abnormal eye‐movements at the age of six months. Several anticonvulsants and levodopa were not effective in the control of the episodes; however, her upward eye‐deviations spontaneously decreased during the one‐year observation. Her clinical features were almost identical to those reported by Ouvrier and Billson, except that she had neurodcvelopmental disorder and abnormal brain MRL More data are required to clarify this unique phenomenon.

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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Recurrent Myoglobinuria in a Child With Mental Retardation: Phosphoglycerate Kinase Deficiency:

We report the case of an 11-year-old mentally retarded boy with recurrent myoglobinuria precipitated after a generalized tonic-clonic convulsion. No hemolysis was noted. Ischemic forearm test revealed no rise of venous lactate, suggesting a metabolic defect in an anaerobic glycolytic pathway. Histochemistry studies of the quadriceps muscle showed a normal appearance, but electron microsopy confirmed a moderate increase of the glycogen content in muscle. Direct measurement of glycolytic enzymes demonstrated a marked decrease of phosphoglycerate kinase (PGK) activity in muscle (4.4% of control mean) and hemolysate (8% of control mean). Enzyme characteristics of PGK from our patient (PGK Hamamatsu) using hemolysate demonstrated that it had normal Michaelis constants (Km), normal thermal stability, and a normal pH curve. The reason that hemolytic anemia was absent is uncertain. We concluded that a systematic enzyme analysis of the glycolytic pathway, especially of PGK, should be performed on myoglobinuric patients who are males, or who have an X-linked inheritance as suggested by the family history. ( J Child Neurol 1989;4:95-99).

Infantile muscle glycogen storage disease Phosphoglucomutase deficiency with decreased muscle and serum carnitine levels

We report a 5-month-old boy with recurrent vomiting, lethargy, and poor weight gain. He had profound metabolic acidosis and nonketotic dicarboxylic aciduria. The serum and muscle carnitine levels were significantly low (60% and 10% of the control means, respectively), suggesting that the patient had a systemic carnitine deficiency syndrome. The patient showed apparent clinical improvement on oral carnitine administration. A quadriceps muscle biopsy revealed a slight increase in intrafiber lipid droplets and mild accumulation of glycogen in the subsarcolemmal portion. An anaerobic glycolysis in vitro study showed a block after glucose-1-phosphate and before glucose-6-phosphate. Direct measurement of individual glycolytic enzymes in muscle of the patient demonstrated a marked decrease in phosphoglucomutase (PGM) activity (13% of the control mean). The specific defect of PGM activity in this patient suggests that the block in the anaerobic glycolytic pathway is the primary abnormality. PGM deficiency can be added as a newly recognized cause of secondary systemic carnitine deficiency syndromes.

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.

Novel exon 11 skipping mutation in a patient with glycogen storage disease type IIId

We report the molecular genetic abnormalities of a patient with GSD IIId presenting with progressive myopathy and cardiopathy leading to a fatal outcome. We identified two independent deletions including a 4 bp deletion (1117–1120) and a 98 bp deletion (1135–1232) in cDNA. Sequencing of the genomic DNA of the corresponding region revealed a 4 bp deletion in exon 10; however, the other 98 bp deletion corresponding to exon 11, which was deleted in cDNA, was present in genomic DNA. We therefore concluded that skipping of exon 11 occurred in the cDNA of the patient. Intron/exon boundary analysis of the skipped exon 11 revealed no mutation in the consensus splice-site sequence. If normal splicing had occurred, a stop codon would have appeared within exon 11 due to frameshift mutation. The mechanism of exon skipping observed in our patient is as yet unknown, and it is still not clear whether intraexonal mutation of the preceding exon can influence splice-site selection. It is possible that a unique exon skipping occurred, preventing the appearance of a stop codon in our patient

A case of polymyositis associated with Kawasaki disease

We report a 3-year-old boy with proximal painful muscle weakness associated with Kawasaki disease. The muscle biopsy revealed inflammatory cell infiltration with vasculopathy. This unique coexistence of polymyositis and Kawasaki disease is quite uncommon and suggests a newly recognized complication during Kawasaki disease.

De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism

SETD1B (SET domain containing 1B) is a component of SET1 histone methyltransferase complex, which mediates the methylation of histone H3 on lysine 4 (H3K4). Here, we describe two unrelated individuals with de novo variants in SETD1B identified by trio-based whole exome sequencing: c.5524C>T, p.(Arg1842Trp) and c.5575C>T, p.(Arg1859Cy). The two missense variants occurred at evolutionarily conserved amino acids and are located within the SET domain, which plays a pivotal role in catalyzing histone methylation. Previous studies have suggested that de novo microdeletions in the 12q24.3 region encompassing SETD1B were associated with developmental delays, intellectual disabilities, autism/autistic behavior, large stature and craniofacial anomalies. Comparative mapping of 12q24.3 deletions refined the candidate locus, indicating KDM2B and SETD1B to be the most plausible candidate genes for the pathogenicity of 12q24.3 deletion syndrome. Our cases showed epilepsy, developmental delay, intellectual disabilities, autistic behavior and craniofacial dysmorphic features, which are consistent with those of individuals with de novo 12q24.31 deletions. Therefore, our study suggests that SETD1B aberration is likely to be the core defect in 12q24.3 deletion syndrome.