Motohiro Akagi

Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome, characterized by mandibular hypoplasia, acroosteolysis affecting distal phalanges and clavicles, delayed closure of the cranial sutures, atrophic skin, and lipodystrophy. Recently, mutations in lamin A/C (LMNA) and zinc metalloprotease (ZMPSTE24), involved in post‐translational processing of prelamin A to mature lamin A, have been identified in MAD kindreds. We now report novel compound heterozygous mutations in exon 1 (c.121C>T; p.Q41X) and exon 6 (c.743C>T; p.P248L) in ZMPSTE24 in two Japanese sisters, 7‐ and 3‐year old, with severe MAD and characteristic facies and atrophic skin. The older sister had lipodystrophy affecting the chest and thighs but sparing abdomen. Their parents and a brother, who were healthy, had heterozygous mutations. The missense mutation, P248L, was not found in 100 normal subjects of Japanese origin. The mutant Q41X was inactive in a yeast halo assay; however, the mutant P248L retained near normal ZMPSTE24 activity. Immunoblots demonstrated accumulation of prelamin A in the patients’ cell lysates from lymphoblasts. The lymphoblasts from the patients also revealed less intense staining for lamin A/C on immunofluorescence. We conclude that ZMPSTE24 deficiency results in accumulation of farnesylated prelamin A, which may be responsible for cellular toxicity and the MAD phenotype.

Mutational analysis of MECP2 in Japanese patients with atypical Rett syndrome

Rett syndrome (RTT) is one of the most common neurodevelopmental disorders in females. Recently, this disease was found to be linked with mutations in the methyl-CpG-binding protein 2 gene (MECP2) and various mutations have been reported. To explore the spectrum of phenotypes resulting from MECP2 mutations, we searched for mutations in the MECP2 of 20 Japanese patients who had more than five of the criteria necessary for RTT diagnosis proposed in 1988 (The Rett Syndrome Diagnostic Criteria Work Group, Ann Neurol 23 (1988) 425) and compared the phenotype between patients with and without mutation by giving a score to each diagnostic criterion. We found four missense mutations (T158M, R133C, Y120D, and R306C), two nonsense mutations (R168X and R270X), one frameshift (726delAAAG) mutation, and one polymorphism (A201V) in ten patients (50%). This included two novel mutations (726delAAAG and Y120D). All mutations were found in the highly conserved methyl-binding and transcription repression domains. Comparison of the mean total diagnostic criterion score of the groups with and without mutation did not reveal any statistically significantly difference (P=0.28). The only difference between the groups, which was of borderline significance (P=0.051), was the sum of the scores for diagnostic criteria 2 (apparently normal psychomotor development through the first 6 months) and 5 (loss of acquired purposeful hand skills between the ages of 6 and 30 months). From these results, it is suggested that the clinical phenotype of RTT is variable and it is important to investigate the MECP2 genotype for patients having more than five criteria and not only in those who exhibit all RTT diagnostic criteria. The diagnosis of RTT is clinically difficult before 3 years of age, especially in atypical cases, but molecular analysis of the MECP2 will assist diagnosis in some patients.

A point mutation of mitochondrial ATPase 6 gene in Leigh syndrome

A T-to-G transition at nucleotide 9176 (T9176G) in the mitochondrial adenosine triphosphate 6 gene (MTATP6) was detected in two siblings with Leigh syndrome. Heteroplasmy was observed in the mothers leukocytes. The T9176G mutation changes a highly conserved leucine residue to an arginine in subunit 6 of ATPase and is maternally inherited like mutations in the other mitochondrial genes. Another mutation in the same codon (T9176C) has been previously reported in Leigh syndrome. This gives strong support to the relevance of MTATP6 dysfunction in Leigh syndrome and the importance of leucine at that position.

A case of chronic infantile type of fucosidosis: clinical and magnetic resonance image findings

Fucosidosis is a rare autosomal recessive disorder resulting from a deficiency of alpha-L-fucosidase. In this report, we describe clinical and magnetic resonance image (MRI) findings of a chronic infantile type patient heterozygous for a nonsense mutation and a large deletion. The disease onset occurred at 2-3 years of age. She was bound to a wheelchair at 6 years of age, and developed dystonia at the age of 13 years. Brain MRI at 13 years of age showed marked cerebral and cerebellar atrophy, high intensities in the white matter of the frontal and occipital lobes, and low intensities of the bilateral thalamus, striatum, substantia nigra, red nucleus and mamillary bodies on T2-weighted images. The low intensities of basal ganglia on T2-weighted images seems characteristic of lesions in fucosidosis.

Mutation analysis of two Japanese patients with Fanconi-Bickel syndrome

AbstractFanconi-Bickel syndrome (FBS), or glycogen storage disease type XI, is a rare autosomal recessive disorder characterized by hepatorenal glycogen accumulation, Fanconi nephropathy, and impaired utilization of glucose and galactose. Recently, this disease was elucidated to link mutations in the glucose transporter 2 (GLUT2) gene. Only three mutations in three FBS families have been reported. Therefore, it is important to elucidate mutations in the GLUT2 gene in FBS by answering the question of whether the syndrome is a single gene disease. In this report, we describe two patients in two unrelated families clinically diagnosed with FBS. No mutation in the entire protein coding region of the GLUT2 gene was detected in patient 1, which suggested that no mutation existed in the GLUT 2 gene, or that some mutations had affected the expression of the GLUT 2 gene. In patient 2, a novel homozygous nonsense mutation (W420X, Trp at codon 420 to stop codon) was detected. These results support the correlation between GLTU2 gene mutation and FBS syndrome. However, many patients must be analyzed to determine whether other genes are involved in FBS.

Coexistence of TDP‐43 and tau pathology in neurodegeneration with brain iron accumulation type 1 (NBIA‐1, formerly Hallervorden‐Spatz syndrome)

We report here an autopsy case of sporadic adult‐onset Hallervorden‐Spatz syndrome, also known as neurodegeneration with brain iron accumulation type 1 (NBIA1), without hereditary burden. A 49‐year‐old woman died after a 27‐year disease course. At the age of 22, she suffered from akinesia, resting tremor, and rigidity. At the age of 28, she was admitted to our hospital because of worsening parkinsonism and dementia. Within several years, she developed akinetic mutism. At the age of 49, she died of bleeding from a tracheostomy. Autopsy revealed a severely atrophic brain weighing 460 g. Histologically, there were iron deposits in the globus pallidus and substantia nigra pars reticulata, and numerous axonal spheroids in the subthalamic nuclei. Neurofibrillary tangles were abundant in the hippocampus, cerebral neocortex, basal ganglia, and brain stem. Neuritic plaques and amyloid deposits were absent. Lewy bodies and Lewy neurites, which are immunolabeled by anti‐α‐synuclein, were absent. We also observed the presence of TDP‐43‐positive neuronal perinuclear cytoplasmic inclusions, with variable frequency in the dentate gyrus granular cells, frontal and temporal cortices, and basal ganglia. TDP‐43‐positive glial cytoplasmic inclusions were also found with variable frequency in the frontal and temporal lobes and basal ganglia. The present case was diagnosed with adult‐onset NBIA‐1 with typical histological findings in the basal ganglia and brainstem. However, in this case, tau and TDP‐43 pathology was exceedingly more abundant than α‐synuclein pathology. This case contributes to the increasing evidence for the heterogeneity of NBIA‐1.

Clinicogenetical features of a Japanese patient with giant axonal neuropathy

Giant axonal neuropathy (GAN) is a rare autosomal recessive disorder that affects both the peripheral nerves and central nervous system. Since the discovery in 2000 of the gigaxonin gene on chromosome 16q24.1 to be causative, more than 40 GAN mutations have been reported from different racial backgrounds. We report the clinicogenetic findings of a 24-year-old Japanese man with GAN. He had consanguineous parents and showed the phenotype of classical severe GAN. We found a novel homozygous nonsense mutation (p.R162X) in the GAN gene. This is the first genetically-determined Japanese case of GAN, with a follow-up period of more than 15 years. In addition, this mutation is novel. We also reviewed previous reports of GAN to see whether there is any genotype-phenotype correlation.

Mutation analysis of a Japanese patient with fucosidosis

AbstractFucosidosis is a rare autosomal recessive disorder resulting from a deficiency of α-L-fucosidase. Recently, various mutations have been reported in this disease, but it is difficult to elucidate the phenotype from the genetic mutations. We report a patient with chronic infantile type fucosidosis, with a compound heterozygote of a nonsense mutation (W148X, Trp at codon 148 to stop codon) and a large deletion, including all exons. This is the first report of a large deletion demonstrated in fucosidosis. It is interesting that this patient has a relatively mild clinical course despite the absence of the mRNA. This case also indicates the difficulty in determining the phenotype from the genotype in fucosidosis.

Novel mutation of gene coding for glial fibrillary acidic protein in a Japanese patient with Alexander disease

We report the mutation analysis of a Japanese patient diagnosed with infantile-type Alexander disease. The genetic analysis revealed a new missense mutation, an A to G transition at nucleotide position 1026 in exon 6, leading to the substitution of glycine for glutamic acid at amino acid position 371(E371G). This mutation was not detected in 50 Japanese controls using denaturing high-performance liquid chromatography.

Intravenous Flunitrazepam for Status Epilepticus

Flunitrazepam (FZP) was administered intravenously, with success, to two patients with status epilepticus. Case 1 was a patient with a tonicclonic status epilepticus. Intravenous phenytoin had no effect. Case 2 had minor status epilepticus. With the intravenous administration of FZP, diluted 1:10 with distilled water at a dose of 0.03 mg/kg at a slow rate, both patients were relieved of the status epilepticus. Unlike diazepam, FZP neither looks cloudy when diluted with distilled water nor causes angialgia. No disturbances in circulation or respiration occurred. Considering that FZP has a strong anticonvulsant action on status epilepticus, it can be expected to be a useful therapeutic agent for status epilepticus in infants and children.