Kentaro Shirakawa

Mutations in a Thiamine-Transporter Gene and Wernicke's-like Encephalopathy

To the Editor: We report on two previously healthy Japanese brothers with a newly discovered recessively inherited syndrome similar to Wernickes encephalopathy that developed in the second decade ...

Cerebral sparganosis: the wandering lesion.

A 38-year-old Japanese man presented with a 2-year history of cerebellar ataxia, fever, and headaches. MRI revealed migration of the lesion (figure, A–C). CSF cytology showed eosinophilic meningitis (figure, D); serum and CSF ELISA were positive for Spirometra erinaceieuropaei . Human sparganosis is a rare parasitic …

Dopaminergic neuronal dysfunction associated with parkinsonism in both a Gaucher disease patient and a carrier

A clinical association between Gaucher disease and parkinsonism has been demonstrated. We herein report a Japanese patient with type 3 Gaucher disease who was compound heterozygous for F213I and L444P mutations in the glucocerebrosidase gene while his father was heterozygous for the L444P mutation. They both presented with parkinsonism characterized by a predominance of akinetic-rigid signs and a favorable response to anti-Parkinson therapies. We investigated the dopaminergic neuronal function using positron emission tomography (PET) with radioligands, [(11)C] CFT and [(11)C] raclopride. PET studies of both patients demonstrated the [(11)C] CFT uptake to be severely decreased in the putamen and the caudate nucleus, however, the [(11)C] raclopride uptake was normal in the basal ganglia. Although the majority of Gaucher disease patients with parkinsonism tend to be refractory to anti-Parkinson therapies. The clinical features and the findings of the PET studies suggest that patients with parkinsonism associated with the mutation in the glucocerebrosidase gene, even in heterozygosis, may be related to the presynaptic dopaminergic neuronal dysfunction reported in Parkinsons disease. A PET study to evaluate the dopaminergic neuronal function in Gaucher disease would provide both a better understanding of the effects of anti-Parkinson therapies and a help to improve our ability to make an early diagnosis of parkinsonism associated with Gaucher disease.

Novel compound heterozygous ALS2 mutations cause juvenile amyotrophic lateral sclerosis in Japan.

Homozygous mutations in ALS2 on chromosome 2q33 are responsible for autosomal recessive, early-onset forms of upper motor neuron diseases such as infantile ascending hereditary spastic paraplegia (IAHSP) and juvenile primary lateral sclerosis (JPLS).1 These mutations are rarely associated with lower motor neuron involvement in juvenile amyotrophic lateral sclerosis (JALS).2 Seventeen mutations from 16 families have been reported, but the phenotype–genotype correlation remains unclear.3–5 We searched for ALS2 mutations in 2 Japanese siblings presenting with infantile-onset ascending spastic paraplegia, pseudobulbar palsy, and amyotrophy of the extremities. ### Case reports. The older sibling was a 32-year-old Japanese man who started walking on tiptoes at 13 months of age and had never run. He developed dysarthria at 11 years of age and lost the ability to speak at 14. He displayed spasticity predominantly in the lower limbs, bilateral extensor plantar responses, and complete paralysis of the tongue without atrophy or fasciculation at 32 years of age. He also had discrete signs of lower motor neuron involvement manifesting as muscular atrophy of the distal upper and lower limbs. However, he was ambulatory with support and there was no evidence of cognitive dysfunction. Brain and spinal MRI showed no abnormalities. The peripheral nerve conduction velocities and latencies were …

Biochemical features of ceruloplasmin gene mutations linked to aceruloplasminemia.

Aceruloplasminemia is a neurodegenerative disease characterized by parenchymal iron accumulation owing to mutations in the ceruloplasmin gene. Ceruloplasmin is expressed in the central nervous system in which most of the ceruloplasmin is located on the surface of astrocytes in a glycosylphosphatidy linositol (GPI)-anchored form. We herein describe the biochemical features of wild-type and mutant GPI-anchored ceruloplasmin. An overexpression of wild-type GPI-anchored ceruloplasmin in Chinese hamster ovary cells led to the formation of aggresomelike inclusions, especially in the presence of proteasome inhibitors. As expected from the properties of aggresomes, the inclusions were colocalized with γ-tubulin and a disruption of microtubules using nocodazole blocked the formation of such inclusions. Aceruloplasminemia-linked mutant proteins failed to form such inclusions even after treatment with proteasomal inhibitors. Animmunofluorescent analysis indicated that the mutant proteins were thus retained in the endoplasmic reticulum (ER), whereas the transfected cells showed a decreased viability. The expression of glucose-regulated protein 78 that is one of the ER stress sensor proteins, and the activity of glucose-regulated protein 78 promoter was upregulated in the cells transfected with the mutants. These findings indicated that when the overexpressed cytoplasmic wild-type cerulop lasmin was not subjected to degradation by the proteasome-ubiquitin system, then the wild-type protein was transported along the microtubules, thus forming inclusions at the microtubule organizing center, whereas the mutant ceruloplasmin failed to form any such inculsions, because the mutant protein might not have been translocated across the ER into the cytoplasm. Therefore, the mutant protein was considered to have accumulated in the ER thus leading to the ER stress, which resulted in cell death.

Intronic mutation in the PGK1 gene may cause recurrent myoglobinuria by aberrant splicing

A 33-year-old man with mental retardation and recurrent myoglobinuria demonstrated a deficiency in the phosphoglycerate kinase 1 (PGK1) activity of his muscles and erythrocytes. His PGK1 gene had intronic G-to-A substitution 5 nucleotides downstream from the normal exon 7 5′ splice site (IVS7 + 5 G>A). This novel mutation results in a frame shift due to the insertion of 52 bp of intron 7 in the mature mRNA by aberrant splicing.

Ataxia with vitamin E deficiency with a mutation in a phospholipid transfer protein gene

Sirs, Ataxia with isolated vitamin E deficiency (AVED) is an autosomal-recessive spinocerebellar degeneration caused by a mutation of the a-tocopherol transfer protein gene (aTTP) [3, 8]. This report presents a case of juvenile spinocerebellar ataxia caused by mutations in the phospholipid transfer protein (PLTP) gene as well as the aTTP gene. This is the first report to indentify a mutation in the PLTP gene associated with vitamin E-mediated spinocerebellar ataxia. The proband was a 54-year-old female who had developed resting tremors in her right hand and ataxia at 14 years of age. At around 30 years of age, her bilateral visual acuity was decreased by retinitis pigmentosa. Her parents were second-degree cousins. On neurological examination she exhibited ataxia, dysarthria, hyporeflexia, decreased proprioceptive and vibratory sensations, and resting tremors of the extremities. The serum vitamin E concentration was observed to be about half normal level, 4.2 mg/l (normal: 10.8 ± 3.3 mg/l). The results of the following laboratory tests were normal: other fat-soluble vitamins, liverand pancreas-function tests, serum lipids, lipoproteins and apoproteins. The gene analysis revealed a homozygous H101Q mutation in the aTTP gene (Fig. 1a). In AVED, the genotype–phenotype correlation is confirmed, thus indicating that the H101Q mutation is associated with retinitis pigmentosa, late onset during the 3rd decade of life and very low serum vitamin E levels (Table 1) [3, 10, 11]. The clinical findings of the current patient characteristic of juvenile onset and a mild decrease in the serum vitamin E level suggested that other genes associated with vitamin E metabolism might affect the phenotype. Genomic analyses in the PLTP gene revealed the patient and her mother were heterozygous for a H154R mutation (Fig. 1b, c). This mutation was not found in 96 healthy subjects and was different from any previously reported polymorphisms. Following intestinal absorption of vitamin E, aTTP incorporates vitamin E into VLDL resulting in secretion from the liver to the circulation. The plasma PLTP transfers vitamin E from VLDL to HDL. HDL is the predominant source of vitamin E for the brain capillary endothelial cells which facilitates uptake of vitamin E to deliver it to the central nervous system [2, 9]. The PLTP is expressed in the brain, and PLTP knock-out studies showed that PLTP deficiency caused a decrease of vitamin E content in the brain and elevated plasma concentration of vitamin E [1, 6]. The proband and mother heterozygous for the H154R mutation showed a normal plasma PLTP concentration measured by ELISA [7]; however, the plasma PLTP activity was decreased to half the normal level measured by a PLTP assay kit (BioVision, Mountain View, CA) (Table 2). His154 is located in the N-terminal domain with conserved lipid-binding pockets associated with biochemical activity [4], and therefore this H154R mutation may induce the biological dysfunction of the PLTP without causing any impairment of intracellular trafficking. PLTP is an important factor regulating the size and composition of HDL and controlling plasma HDL levels [5]. The identification of the PLTP mutation may thus make it S. Kono (&) A. Otsuji K. Shirakawa H. Suzuki H. Miyajima First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan e-mail: satokono@hama-med.ac.jp

Subacute progressive ophthalmoplegia associated with dermatomyositis

Dermatomyositis is a systemic autoimmune disorder that primarily affects the skin and skeletal muscle in the extremities, and is characterized by weakness of the proximal groups of limb muscles. Extraocular muscle involvement is a very rare manifestation of dermatomyositis [5, 8]. We herein report a patient who manifested dermatomyositis with subacute progressive ophthalmoplegia. The patient was a 53-year-old Japanese male who presented with myalgia and difficulty in climbing stairs. He developed progressive diplopia with eyelid edema and ocular pain 2 weeks after presentation, followed by difficulties in raising his arms. No autoimmune, endocrinopathy, or malignant diseases were observed. The physical examination revealed the presence of Gottron’s papules on the dorsal surface of the hands, and a neurological examination showed symmetrical weakness of the proximal muscles, including the upper limbs muscles, and bilateral ophthalmoplegia with total limitations of eye movements (Fig. 1). There was no weakness of the facial muscles or bulbar palsy. Laboratory tests revealed an increased creatine kinase (CK) level (10,808 U/l; normal range, 25–190). There was no abnormal thyroid function or serum autoantibody, including antinuclear antibody, anti-acetylcholine receptor antibody, and anti-thyroid antibodies. No malignant tumors, including thymoma or thymic hyperplasia, were observed using whole-body CT and PET imaging. Intravenous edrophonium had no effect on the ophthalmoplegia. The repetitive nerve stimulation test was normal. The muscle biopsy at the left vastus medialis muscle revealed inflammatory myopathic changes, which showed the invasion of mononuclear cells into the interfascicular septae and within the fascicles, perifascicular atrophy, and variations in the muscle fiber size. An immunohistochemical analysis showed the mononuclear cells to be CD4and CD8-positive lymphocytes. Ragged red fiber or cytochrome c oxidase-negative fibers were absent. The patient was treated with 60 mg/day oral prednisolone. His ocular impairment, weakness of the proximal muscles, and elevated CK values became markedly improved 1 month after the steroid therapy. Orbital magnetic resonance imaging (MRI) scans revealed an increased thickness of the extraocular muscles on T1-weighted images (Fig. 2a) and high-intensity signals of the extraocular muscles on fat-suppressed T2-weighted images (Fig. 2c), which were both improved after the steroid therapy (Fig. 2b, d). No myositis-associated autoantibodies, including anti Jo-1, PM-Scl-100, PL-7, PL-12, EJ, OJ, KS, M2, Ku (p70/80), SRP, Rib-P antibodies and the antimitochondrial antibody of M2 subtype, were detectable in the serum. Previous reports have suggested that the ophthalmoplegia observed in inflammatory myopathies is caused by the S. Kono (&) T. Bunai T. Konishi K. Shirakawa H. Miyajima First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1, Handayama, Hamamatsu 431-3192, Japan e-mail: satokono@hama-med.ac.jp