Search

Alexander disease (AxD) is a progressive neurodegenerative disease caused by a mutation in the glial fibrillary acid protein (GFAP) gene. A 4-year-old boy presented several times with hemiclonic seizures with eye deviation for a few minutes at 28 days after birth. Electroencephalogram showed independent sharp waves in the right and left temporal area. Magnetic resonance imaging showed high intensity T1-weighted images in the white matter of the frontal lobe and basal ganglia. He showed no head control at 4 years of age, and his weight gain was insufficient. He did not show macrocephaly. At 4 years of age, he died of bacterial pneumonia and septic shock. He was diagnosed with AxD, and direct sequencing revealed a de novo known mutation, c. 239 T > C, p.(F80S), in GFAP. Hela and U2-OS cells transfected with GFAP cDNA with c. 239 T > C showed dot-like cytoplasmic aggregation, similar to R239C, a common mutation found in severe infantile AxD. Aggregation in the cytoplasm caused by a GFAP mutation is a hallmark of AxD. Although there is only one previous report of a patient with an F80S mutation, our data support that F80S can cause the severe, infantile form of AxD.

Background Reversible cerebral vasoconstriction syndrome is characterized by thunderclap headache and reversible cerebral vasoconstriction on angiographic findings. It can be difficult to diagnose when initial angiography is normal. Case results A 30-year-old woman was admitted because of sudden-onset thunderclap headache and seizure on postpartum day 7. Brain MRI on fluid-attenuated inversion recovery (FLAIR) showed hyperintense vessel sign (HVS), which usually means slow flow due to severe proximal arterial stenosis. However, magnetic resonance angiography (MRA) indicated that proximal arteries was normal. After nicardipine treatment, her symptoms improved dramatically. Follow-up FLAIR on day 7 showed complete resolution of HVS, while a series of MRAs revealed reversible multifocal segmental vasoconstriction. Conclusions HVS on initial FLAIR is useful for an early diagnosis of reversible cerebral vasoconstriction syndrome. As the delayed vasoconstriction on MRA can be observed, reversible cerebral vasoconstriction syndrome may progress from distal small to proximal larger arteries.

We report a 45-year-old Japanese man with SCA19/22. Whole-exome sequencing revealed a heterozygous missense mutation (c.1169G>A, p.S390N) in the KCND3 gene. Although this mutation has been reported to cause SCA19 in a Dutch patient, a co-segregation study of the mutation has not been carried out. In the present family, since the S390M mutation was found in the patient but not in the unaffected siblings, we suspected co-segregation of this mutation with the disease in our family. Our patient presented with juvenile-onset pure cerebellar ataxia associated with pes cavus, which has not been previously described in SCA19/22. Thus, our patient would expand the clinical spectrum of SCA19/22. In the case of juvenile-onset pure cerebellar ataxia with autosomal dominant transmission, SCA19/22 should be considered.

A 73-year-old woman who had hypertension developed a slight fever and general malaise with laboratory-proven hepatic dysfunction as well as frequent syncopal attacks 3 months before admission to our hospital. One month later, she developed urinary retention and distal limb numbness. Upon admission, her neurological examination showed reduced limb tendon reflexes, glove and stocking-type numbness, and diminished senses of touch, temperature, pain, and distal leg vibration and position. Serum cytomegalovirus (CMV) IgM antibody and CMV IgG antibody were elevated on admission, and both decreased thereafter, confirming CMV infection. No serum anti-ganglioside antibody was detected. Cerebrospinal fluid revealed a mild pleocytosis and elevated proteins. Compound muscle action potential (CMAP) amplitudes of the tibial and peroneal nerve were slightly reduced. Sensory nerve action potential (SNAP) amplitudes of the median and ulnar nerves were reduced, and sural SNAP was not evoked. Systolic blood pressure dropped 48 mmHg when the patient assumed a standing position from a supine one, demonstrating orthostatic hypotension, and a cold pressor test was abnormal, both indicating an obvious hypofunction of the sympathetic nerve. The postganglionic autonomic nerve appeared to be damaged because the accumulation of [(123)I] meta-iodobenzylguanidine was reduced on myocardial scintigraphy. These findings combined together led us to make a diagnosis of subacute autonomic and sensory neuropathy associated with CMV infection in this case. Following an eventless administration of oral fludrocortisones, intravenous immuno-globulin (IVIg) was given after one month of the hospitalization with a remarkable reduction of the syncope. This case is instructive in two points. One is that there may be a couple of months with syncope alone before the sensory disturbance appearance, and the other is that IVIg may be considerably effective for the patient-annoying syncopes. To our knowledge, this is the first report of subacute autonomic and sensory neuropathy caused by CMV infection.

Background Autosomal recessive hereditary spastic paraplegias (AR-HSP) constitute a heterogeneous group of neurodegenerative diseases involving pyramidal tracts dysfunction. The genes responsible for many types of AR-HSPs remain unknown. We attempted to identify the gene responsible for AR-HSP with optic atrophy and neuropathy. Methods The present study involved two patients in a consanguineous Japanese family. Neurologic examination and DNA analysis were performed for both patients, and a skin biopsy for one. We performed genome-wide linkage analysis involving single nucleotide polymorphism arrays, copy-number variation analysis, and exome sequencing. To clarify the mitochondrial functional alteration resulting from the identified mutation, we performed immunoblot analysis, mitochondrial protein synthesis assaying, blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis, and respiratory enzyme activity assaying of cultured fibroblasts of the patient and a control. Results We identified a homozygous nonsense mutation (c.394C>T, p.R132X) in C12orf65 in the two patients in this family. This C12orf65 mutation was not found in 74 Japanese AR-HSP index patients without any mutations in previously known HSP genes. This mutation resulted in marked reduction of mitochondrial protein synthesis, followed by functional and structural defects in respiratory complexes I and IV. Conclusions This novel nonsense mutation in C12orf65 could cause AR-HSP with optic atrophy and neuropathy, resulting in a premature stop codon. The truncated C12orf65 protein must lead to a defect in mitochondrial protein synthesis and a reduction in the respiratory complex enzyme activity. Thus, dysfunction of mitochondrial translation could be one of the pathogenic mechanisms underlying HSPs.

Alexander disease (AxD) is a rare neurodegenerative disorder characterized by white matter degeneration and formation of cytoplasmic inclusions. Glial fibrillary acidic protein (GFAP) mutations have been reported in various forms of AxD since 2001. However, a definitive diagnosis remains difficult because of uncertain prevalence, and different clinical features seen in infantile AxD and adult AxD may lead to confusion and misdiagnosis. Here we report an epidemiological study conducted in Japan. Two nationwide questionnaire-based surveys were conducted using tentative diagnostic criteria. We gathered information regarding prevalence, neurological findings, magnetic resonance imaging (MRI) findings, electrophysiological findings, genetic information, and the results of therapeutic interventions and home care. Prevalence of various forms of AxD was determined as 27.3% (infantile), 24.2% (juvenile), and 48.5% (adult). Prevalence of AxD in Japan was estimated to be approximately 1 case per 2.7 million individuals. The main characteristics of infantile and juvenile AxD include delayed psychomotor development or mental retardation, convulsions, macrocephaly, and predominant cerebral white matter abnormalities in the frontal lobe on brain MRI. The main characteristics of adult AxD include bulbar signs, muscle weakness with hyperreflexia, and signal abnormalities and/or atrophy of medulla oblongata and cervical spinal cord on MRI. To ensure correct diagnosis of AxD, the physician should understand the importance of the process of GFAP genetic testing, which provides definitive diagnosis. Therefore, we propose new clinical guidelines for diagnosing AxD based on simplified classifications: cerebral AxD (type 1), bulbospinal AxD (type 2), and intermediate form (type 3).

Rheumatoid meningitis (RM) has been considered to be an extremely rare complication of rheumatoid arthritis (RA), which itself is very common [1]. However, due to better access to MRI, RM has been increasingly diagnosed. More than 30 cases diagnosed by MRI and pathology have been reported [2–4]. In most cases, onset occurred after the age of 50 in both sexes. The clinical symptoms and signs and the MRI findings were those of non-specific chronic leptomeningitis [5]. Of interest, there were no associations between the onset and activity of RM, the severity and activity of synovitis, the duration of RA or the way it treated [3]. We have described here for the first time a patient with pathologically proven RM the initial symptom of which was parkinsonism. A 68-year-old Japanese man with a 10-year history of RA treated successfully with prednisolone (6 mg/day) was referred to a regional hospital because of a bilateral resting tremor predominating on the right side, progressive gait instability that began by hesitation and bradykinesia. He was diagnosed as having Parkinson’s disease, but his symptoms did not respond to levodopa. He soon developed a progressive cognitive dysfunction, accompanied by a slight fever, followed 2 months later by urinary incontinence. In spite of more than 3 months of treatment with antibiotics, antiviral agents and antimycotics, his condition gradually deteriorated and he was transferred to our university hospital. On admission, he was apathetic and bedridden. Disuse atrophy was generalized, and he had severe bilateral swanneck deformities of his fingers due to RA. His face was mask-like, and his verbal responses were very slow with muted monotonous voice. His Mini-Mental State Examination (MMSE) score was 11. Bradykinesia was remarkable, and rigidity was seen in the neck and all extremities. Resting tremor was observed intermittently in both hands. Laboratory data suggested inactive RA. Cerebrospinal fluid (CSF), analyzed after lumbar puncture, was clear, and pressure was normal. The cell count was slightly increased (13/mm), but there were no atypical cells. Protein levels were increased (75 mg/dL), but glucose levels were normal. Results of cell cultures performed repeatedly, immunological investigations, a polymerase chain reaction (PCR) to detect microorganisms, and cytological investigations of the CSF were all negative. No malignancy was detected by a whole body CT scan with enhancement. Brain MRI with contrast enhancement (Fig. 1a, b) revealed a diffuse meningeal lesion. Secondary hydrocephalus was also observed (Fig.1c). A biopsy of the leptomeninx together with adjacent brain parenchyma from the right frontal lobe revealed foci of necrotic tissue in the subarachnoid space surrounded by chronic inflammatory cells consisting of numerous lymphocytes, plasma cells, a few neutrophils and scattered giant multinucleated cells (Fig. 1e, f). No inflammation was seen in the dura mater and parenchyma per se. These pathological findings associated with the negative laboratory data were consistent with a diagnosis of RM. Y. Hayashi M. Namekawa (&) Department of Neurology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan e-mail: mnamekaw@jichi.ac.jp

Japan Spastic Paraplegia Research Consortium (JASPAC), a nationwide clinical and genetic survey of patients with HSP in Japan, was started from 2006 as a project of the Research Committee for Ataxic Diseases of the Ministry of Health, Labor and Welfare, Japan. To date (October 4, 2010), 321 index patients with HSP have been registered from 40 prefectures in Japan. We are now performing molecular testing for the HSP patients using direct sequencing (SPG4, SPG31, and ARSACS), comparative genomic hybridization (CGH) array (SPG1/2/3A/4/5/6/7/8/10/11/13/15/17/20/21/31/33/39/42/ABCD1/alsin/SACS), and resequencing microarray (SPG1/2/3A/4/5/6/7/8/10/11/13/17/20/21/31/33/ABCD1). In 144 Japanese ADHSP families, SPG4 was the most common form, accounting for 47%, followed by SPG31 (4%), SPG3A (3%), SPG8 (1%), and SPG10 (1%). The results of molecular testing will be applicable to patients in terms of improved positive diagnosis, follow-up, and genetic counseling. Since approximately 40% of ADHSP remain unknown, we will perform high-throughput linkage analyses using SNP HiTLink (SNP High Throughput Linkage analysis system) for the identification of loci for disease-associated genes. Meanwhile, preliminary data showed that SPG11 and ARSACS were common in Japanese ARHSP families. JASPAC will contribute to elucidate the spectrum of clinical features and mutations, genotype/phenotype correlations, pathophisiology in various HSP phenotypes.

We examined the effects of wild-type and mutant atlastin-1 on vesicle transport in the endoplasmic reticulum (ER)-Golgi interface and vesicle budding from ER-derived microsomes using the temperature-sensitive reporter vesicular stomatitis virus glycoprotein (VSV-G), and the ability of purified atlastin-1 to form tubules or vesicles from protein-free phosphatidylserine liposomes. A GTPase domain mutation (T162P) altered the cellular distribution of the ER, but none of the mutations studied significantly affected transport from the ER to the Golgi apparatus. The mutations also had no significant effect on the incorporation of VSV-G into vesicles formed from ER microsomes. Atlastin-1, however, was also incorporated into microsome-derived vesicles, suggesting that it might be implicated in vesicle formation. Purified atlastin-1 transformed phosphatidylserine liposomes into branched tubules and polygonal networks of tubules and vesicles, an action inhibited by GDP and the synthetic dynamin inhibitor dynasore. The GTPase mutations T162P and R217C decreased but did not totally prevent this action; the C-terminal transmembrane domain mutation R495W was as active as the wild-type enzyme. Similar effects were observed in human embryonic kidney cells over-expressing mutant atlastin-1. We concluded that atlastin-1, like dynamin, might be implicated in membrane tubulation and vesiculation and participated in the formation as well as the function of the ER.

Mutations in SPG3A causing autosomal dominant pure spastic paraplegia led to identification of atlastin, a new dynamin-like large GTPase. Atlastin is localized in the endoplasmic reticulum, the Golgi, neurites and growth cones and has been implicated in neurite outgrowth. To investigate whether it exerts its activity in the early secretory system, we expressed normal and mutant atlastin in cell culture. Pathogenic mutations in the GTPase domain interfered with the maturation of Golgi complexes by preventing the budding of vesicles from the endoplasmic reticulum, whereas mutations in other regions of the protein disrupted fission of endoplasmic reticulum-derived vesicles or their migration to their Golgi target. Atlastin, therefore, plays a role in vesicle trafficking in the ER/Golgi interface. Furthermore, atlastin partially co-localized with proteins of the p24/emp/gp25L family that regulate vesicle budding and trafficking in the early secretory pathway, and co-immunoprecipitated p24, suggesting a functional relationship that should be further explored.

Namekawa M, Takiyama Y, Sakoe K, Nagaki H, Shimazaki H, Yoshimura M, Ikeguchi K, Nakano I, Nishizawa M. A Japanese SPG4 family with a novel missense mutation of the SPG4 gene: intrafamilial variability in age at onset and clinical severity. Acta Neurol Scand 2002: 106: 387–391. © Blackwell Munksgaard 2002. Objectives– We report the results of clinical and genetic studies on a Japanese SPG4 family. Material and methods– Family N included eight patients in four generations with autosomal dominant transmission. We performed neurological and molecular analyses on the SPG4 gene in the family members comprising three patients, 12 at-risk individuals, and three normal spouses. Results– The three patients showed pure spastic paraplegia, two of them exhibiting a decrease in vibration sense. There was marked intrafamilial variability in age at onset and clinical severity in the present family. On molecular analysis, a novel missense mutation (nt1579 CT) in exon 12 of the SPG4 gene was found in the three patients, three probably affected, and an asymptomatic carrier. Conclusion– The present SPG4 family, which was shown to have a novel SPG4 mutation, exhibited marked variability in the clinical features, indicating the participation of additional factors in the phenotypic appearance of this family.

Alexander's disease, a leukodystrophy characterized by Rosenthal fibers (RFs) in the brain, is categorized into three subtypes: infantile, juvenile, and adult. Although most are sporadic, occasional familial Alexander's disease cases have been reported for each subtype. Hereditary adult-onset Alexander's disease shows progressive spastic paresis, bulbar or pseudobulbar palsy, palatal myoclonus symptomatologically, and prominent atrophy of the medulla oblongata and upper spinal cord on magnetic resonance imaging. Recent identification of GFAP gene mutations in the sporadic infantile- and juvenile-onset Alexander's disease prompted us to examine the GFAP gene in two Japanese hereditary adult-onset Alexander's disease brothers with autopsy in one case. Both had spastic paresis without palatal myoclonus, and magnetic resonance imaging showed marked atrophy of the medulla oblongata and cervicothoracic cord. The autopsy showed severely involved shrunken pyramids, but scarce Rosenthal fibers (RFs). Moderate numbers of Rosenthal fibers (RFs) were observed in the stratum subcallosum and hippocampal fimbria. In both cases, we found a novel missense mutation of a G-to-T transition at nucleotide 841 in the GFAP gene that results in the substitution of arginine for leucine at amino acid residue 276 (R276L). This is the first report of identification of the causative mutation of the GFAP gene for neuropathologically proven hereditary adult-onset Alexander's disease, suggesting a common molecular mechanism underlies the three Alexander's disease subtypes.

Background Autosomal-recessive hereditary spastic paraplegias (AR-HSP) consist of a genetically diverse group of neurodegenerative diseases characterised by pyramidal tracts dysfunction. The causative genes for many types of AR-HSP remain elusive. We tried to identify the gene mutation for AR-HSP with cerebellar ataxia and neuropathy. Methods This study included two patients in a Japanese family with their parents who are first cousins. Neurological examination and gene analysis were conducted in the two patients and two normal family members. We undertook genome-wide linkage analysis employing single nucleotide polymorphism arrays using the two patients’ DNAs and exome sequencing using one patient9s sample. Results We detected a homozygous missense mutation (c.4189T>G, p.F1397V) in the lysosomal trafficking regulator ( LYST ) gene, which is described as the causative gene for Chediak–Higashi syndrome (CHS). CHS is a rare autosomal-recessive syndrome characterised by hypopigmentation, severe immune deficiency, a bleeding tendency and progressive neurological dysfunction. This mutation was co-segregated with the disease in the family and was located at well-conserved amino acid. This LYST mutation was not found in 200 Japanese control DNAs. Microscopic observation of peripheral blood in the two patients disclosed large peroxidase-positive granules in both patients’ granulocytes, although they had no symptoms of immune deficiency or bleeding tendency. Conclusions We diagnosed these patients as having adult CHS presenting spastic paraplegia with cerebellar ataxia and neuropathy. The clinical spectrum of CHS is broader than previously recognised. Adult CHS must be considered in the differential diagnosis of AR-HSP.

We describe the unusual case of a 51-year-old woman with spinocerebellar ataxia type 1 (SCA1) who showed choreiform movements in addition to cerebellar ataxia. To date, extrapyramidal signs including involuntary movements have been rarely reported in SCA1. Surface electromyogram in our patient revealed grouped discharges whose duration was longer than that of chorea observed in HD, indicating that the involuntary movements represented choreoathetosis rather than pure chorea. These choreiform movements have not been seen in non-hereditary spinocerebellar ataxia. Therefore, if "sporadic" cases of cerebellar ataxia show such movements, the possibility of genetic origin of the ataxia is high and a surveillance of various forms of hereditary spinocerebellar ataxia including SCA1 is required.

We describe a Japanese family which includes 13 patients in five generations who have dominantly inherited ataxia. Molecular testing revealed that in these patients the SCA6/CACNL1A4 gene carries the smallest known expanded CAG repeat (21 repeat units). The clinical features of these patients exhibited predominantly cerebellar ataxia with onset late in adult life and a very slowly progressive disease course. In addition, this SCA6 family showed some characteristic clinical and genetic features, including (1) apparent lack of genetic anticipation, with an intergenerationally stable CAG repeat size and (2) down-beat nystagmus and diabetes mellitus in some of the SCA6 patients. We identified three individuals homozygous for an expanded CAG repeat (21/21) in the SCA6/CACNL1A4 gene, two of whom were symptomatic. There were no apparent differences in clinical phenotype between the individuals homozygous and those heterozygous for an expanded CAG repeat in the SCA6/CACNL1A4 gene.

Seven families with six different SPG3A mutations were identified among 106 with autosomal dominant hereditary spastic paraplegia (HSP). Two mutations were novel (T162P, C375R). SPG3A was twice as frequent as SPG4 in patients with onset before age 10 years (31.8%). Later onset was not observed. The phenotype was pure HSP, but disease duration was longer than in non-SPG3A/SPG4 patients, leading ultimately to greater handicap.

Marchiafava-Bignami disease (MBD) is a rare alcohol-associated disorder characterized by demyelination and necrosis of the corpus callosum. We herein present the case of a 56-year-old man with chronic alcoholism who was admitted to our hospital in a coma without focal or lateralizing neurological signs. MRI revealed a callosal lesion consistent with MBD and additional bifrontal linear cortical lesions. The callosal lesion completely disappeared with intravenous administration of high-dose multivitamins and corticosteroids, although the patient remained in a vegetative state. This case further supports the notion that cortical involvement in patients with MBD is a predictor of a poor prognosis.

Onconeural immunity, a cancer-stimulated immune reaction that cross-reacts with neural tissues, is considered to be the principal pathological mechanism for paraneoplastic neurological syndromes (PNS). A common PNS is paraneoplastic cerebellar degeneration (PCD). We had encountered a PCD patient with urothelial carcinomas (UC) of the urinary bladder who was negative for the well-characterized PNS-related onconeural antibodies. In the present study, we aimed to identify a new PCD-related onconeural antibody, capable of recognizing both cerebellar neurons and cancer tissues from the patient, and applied a proteomic approach using mass spectrometry. We identified anti-creatine kinase, brain-type (CKB) antibody as a new autoantibody in the serum and cerebrospinal fluid from the patient. Immunohistochemistry indicated that anti-CKB antibody reacted with both cerebellar neurons and UC of the urinary bladder tissues. However, anti-CKB antibody was not detected in sera from over 30 donors, including bladder cancer patients without PCD, indicating that anti-CKB antibody is required for onset of PCD. We also detected anti-CKB antibody in sera from three other PCD patients. Our study demonstrated that anti-CKB antibody may be added to the list of PCD-related autoantibodies and may be useful for diagnosis of PCD.

Background and Purpose— The present study determines associations between early blood pressure (BP) variability and stroke outcomes after intravenous thrombolysis. Methods— In 527 stroke patients receiving intravenous alteplase (0.6 mg/kg), BP was measured 8 times within the first 25 hours. BP variability was determined as ΔBP (maximum-minimum), standard deviation (SD), coefficient of variation, and successive variation. Results— The systolic BP course was lower among patients with modified Rankin Scale (mRS) 0 to 1 than those without ( P Conclusions— Early systolic BP variability was positively associated with symptomatic intracerebral hemorrhage and death after intravenous thrombolysis.

The authors describe two patients in a Japanese family with autosomal recessive spastic ataxia of Charlevoix-Saguenay. They presented early onset spastic ataxia, sensorimotor neuropathy, nystagmus, slurred speech, and hypermyelinated retinal nerve fibers. The authors identified a homozygous missense mutation (T7492C) in the SACS gene, which resulted in the substitution of arginine for tryptophan at amino acid residue 2498 (W2498R).

Intravascular lymphomatosis (IVL) is a rare subtype of diffuse large B cell lymphoma, characterized by the presence of tumor cells only in the lumina of small vessels. Antemortem diagnosis of IVL is extremely difficult because of its varied clinical presentation and absence of lymphadenopathy.A 57-year-old man was hospitalized for fever of unknown origin, weight loss, and general fatigue, all of which were progressive and had appeared in a span of 6 months. Physical examination revealed spiked fever and splenomegaly, but no lymphadenopathy or skin lesions. Neurological examination revealed spastic paraparesis with sensory and urinary disturbances. The levels of serum lactate dehydrogenase and soluble interleukin-2 receptor were 527 IU/L and 8,220 U/mL (normal range: 220-530, respectival), respectively. Although IVL was strongly suggested, repeated bone marrow and muscle biopsies were negative. Despite the presence of splenomegaly, his poor physical status did not allow a diagnostic splenectomy. Six random biopsy specimens of healthy-appearing skin showed obliteration of small vessels in the subcutaneous fat tissue by lymphoma cells. Chemotherapy, including rituximab, was successful, and the patient has survived with complete remission until now.Random skin biopsy is an extreme useful tool for the diagnosis of IVL. The rate of positive diagnoses is high, since sufficient specimens can be obtained easily with little invasion. To yield positive results, the biopsy should (i) target a visible skin lesion, if possible; (ii) include not only the dermis but also deeper layers, including the hypodermic adipose tissue; (iii) be relatively large; and (iv) should be performed at, at least, 3 different locations such as the upper arm, thigh, and abdomen.

We report a 58-year-old woman with adult onset Alexander disease. At the age of 54 she noticed numbness in bilateral legs and at 57 she developed left sided spastic gait. Her walking difficulty was gradually worsened and followed by the development of weakness in left arm, dysarthria and dysphagia. Her mother and elder brother also had similar clinical presentations which suggested an autosomal dominant neurological disorder. With MRI findings showing localized atrophy of medulla oblongata and upper cervical cord with hyperintensities on T2-weighted image, diagnosis of adult onset Alexander disease was made. We performed genetic analysis and found novel variant (S398F) in the glial fibrillary acidic protein gene. In case of slowly progressive myelopathy with bulbar palsy of unknown origin, especially those with atrophy limited to medulla oblongata and upper cervical cord, adult onset Alexander disease should be taken into consideration.

The autosomal dominant cerebellar ataxias (ADCAs) comprise a genetically and clinically heterogenous group of neurodegenerative disorders. Very recently, a C-to-T single nucleotide substitution in the puratrophin-1 gene was found to be strongly associated with a form of ADCA linked to chromosome 16q22.1 (16q-linked ADCA; OMIM 600223). We found the C-to-T substitution in the puratrophin-1 gene in 20 patients with ataxia (16 heterozygotes and four homozygotes) and four asymptomatic carriers in 9 of 24 families with an unknown type of ADCA. We also found two cases with 16q-linked ADCA among 43 sporadic patients with late-onset cortical cerebellar atrophy (LCCA). The mean age at onset in the 22 patients was 61.8 years, and that of homozygous patients was lower than that of heterozygous ones in one family. Neurological examination revealed that the majority of our patients showed exaggerated deep tendon reflexes in addition to the cardinal symptom of cerebellar ataxia (100%), and 37.5% of them had sensorineural hearing impairment, whereas sensory axonal neuropathy was absent. The frequency of 16q-linked ADCA was about 1/10 of our series of 110 ADCA families, making it the third most frequent ADCA in Japan.

Pure hereditary spastic paraplegias are characterized by isolated and progressive spasticity in the lower limbs. We mapped the spastic paraplegia 28 (SPG28) locus to chromosome 14q21.3-q22.3 in a Moroccan family with autosomal recessive hereditary spastic paraplegia. Affected patients experienced development of progressive spastic gait during childhood and required help walking in their early 40s. Nine additional hereditary spastic paraplegia families were not linked to this locus, demonstrating further genetic heterogeneity. No mutations were found in exons of GCH1 and SPG3A, two genes from the candidate region involved in movement disorders.

A 62-year-old man with well-controlled diabetes mellitus developed numbness of the bilateral feet and hands, followed by subacutely progressive weakness and amyotrophy of extremities. He became bed-ridden state, and dyspnea also appeared, so he was referred to our hospital. Physical examination revealed a lean man, with dark-reddish skin pigmentation, crabbed fingers, bilateral pretibial pitting edema, and bristles in extremities. Thoracoabdominal paradoxical respiration was observed and pulmonary vesicular sounds was decreased markedly in the both lungs. Laboratory data revealed hypoproteinemia, abnormalities of endocrine system, but M-protein was not detected. Serum vascular endothelial growth factor level was quite high. Chest radiography revealed elevation of the bilateral diaphragm, the % vital capacity (%VC) was 24%, and arterial blood gas analysis showed marked hypoxia with hypercapnia. These findings suggested that his respiratory failure was induced by bilateral diaphragmatic paralysis caused by bilateral phrenic nerve palsy due to Crow-Fukase syndrome. He became somnolent because of hypercapnic narcosis, so non-invasive positive pressure ventilation (NIPPV) was started. We treated him with intravenous immunoglobulin and oral corticosteroids therapies, and after these therapies, his symptoms were remarkably recovered and NIPPV became unnecessary soon. The most frequent causes of respiratory failure in Crow-Fukase syndrome are pleural effusion and pulmonary hypertension, and only two cases of this syndrome with respiratory failure caused by bilateral diaphragmatic paralysis were reported until now. When the patients with Crow-Fukase syndrome complain of dyspnea, we should take the diaphragmatic paralysis into consideration, which may be improved by appropriate therapies.

Orthopnea is a preference for breathing in an upright rather than a supine position, usually associated with congestive heart failure and/or pulmonary edema, lung diseases, neurological disorders, and other conditions. In patients with ALS, orthopnea in the supine position, which is predictive of poor prognosis [1], is mainly caused by upward displacement of the paretic diaphragms by abdominal organs, preventing adequate air intake [2, 3]. We present here an ALS patient who developed marked dyspnea in the supine position, presumably due to different mechanism. A 67-year-old ex-carpenter first noticed weakness in his right arm 2 years prior. The weakness extended to the right hand within 6 months. Neurological examination at that time revealed right spastic hemiplegia with intact sensation, atrophy of the right upper limb, and bilaterally increased tendon reflexes with positive Babinski signs. Both brain and cervical MRIs were unremarkable. A needle electromyography showed active neurogenic changes in all the examined muscles of the four limbs, confirming the diagnosis of ALS. The symptoms gradually worsened, and 16 months after onset, dysphagia and shortness of breath at night required him to avoid the supine position when sleeping. A neurological examination, 20 months after onset, revealed bilateral flail-arms and slight tongue atrophy with fasciculation. His speech was slurred and he had dysphagia, but was still able to walk without aid. All tendon reflexes were increased, with bilateral positive Babinski signs. His breathing was normal when sitting or lying on the right or left side, but he choked so severely when supine that he could not remain in that position for even a second; neither protrusion of the tongue nor respiratory support with a non-invasive ventilator prevented suffocation. The choking stopped immediately, however, with his head tilted and his jaw thrust forward. Blood gas analysis revealed no hypercapnia or hypoxia, although spirometry showed a slight reduction of his vital capacity (2.73 l; 79% of the predicted value). No organic lesions were found by laryngoscopy when sitting. X-ray examination (Fig. 1) showed the oropharyngeal airway to be normal when the patient was upright (Fig. 1a) but when supine with choking, the mandible slipped down, occluding the airway at the base of the tongue (Fig. 1b). Tilting the head and thrusting the jaw forward, in the supine position, restored the upper airway (Fig. 1c). The respiratory distress observed in this patient is a form of orthopnea, although it was not caused by weakness of the diaphragm. It seems rather to be caused by a dynamic collapse of the upper airway, presumably due to gravitational pull on the mandible. Mandibuloptosis, a term unfamiliar to neurologists, is a drop of the mandible caused by gravity. It is occasionally encountered in ALS patients, who keep their mouths open, with sialorrhea, because of weakness of the jaw-closure muscles (temporal and masseter muscles); this is mandibuloptosis in the upright position. Mandibuloptosis can also occur in the supine position, causing a collapse of the upper airway accompanied by glossoptosis, due to weakness of the lateral pterygoid muscle, responsible for jaw protraction. Indeed, our patient could not place his lower teeth in front of his upper teeth even when upright. The failure of M. Namekawa (&) T. Kameda I. Nakano Department of Neurology, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan e-mail: mnamekaw@jichi.ac.jp

We studied a large Japanese family with autosomal dominant pure hereditary spastic paraplegia (ADPHSP) clinically and genetically. To date, seven loci causing ADPHSP have been mapped to chromosomes 14q, 2p, 15q, 8q, 12q, 2q, and 19q. Among these loci, the SPG4 locus on chromosome 2p21–p22 has been shown to account for approximately 40% of all autosomal dominant hereditary spastic paraplegia (ADHSP) families. Very recently, Hazan et al. identified the SPG4 gene encoding a new member of the AAA (ATPases associated with diverse cellular activities) protein family, named spastin. We found a novel insertion mutation (nt1272–1273insA) in exon 8 of the SPG4 gene in the present family. Our study is the first to confirm the causative mutation of the SPG4 gene in Japanese. Clinically, it is noteworthy that the disease progression in the patients of this family was slow in spite of the late onset, and more than half of the patients showed severe constipation in addition to pure spastic paraplegia.

Adult Alexander disease is a rare leucodystrophy with severe atrophy of the lower brainstem and upper cervical cord.1 The pathological character is the presence of Rosenthal fibres that contain aggregates of intermediate protein, GFAP, associated with mutations in GFAP gene.2 Because pathogenesis is degenerative, the most typical clinical course is slowly progressive; the intermittent course has not been sufficiently described so far.2 We show a case of genetically confirmed adult Alexander's disease with acute exaggeration and remission, and relapse. A 33-year-old woman had been well until she suddenly fell down and lost consciousness in 2002. She had left-sided paresis and dysarthria, and was admitted to a hospital. Her medical history was unremarkable except for mild diabetes mellitus. There was no family history of neurological diseases or consanguineous marriage. Her father died of heart disease (in his 40s), her mother died of diabetes mellitus and angina pectoris (in her 50s), and her two daughters were healthy. Brain MRI showed atrophy of the upper cervical cord and T2-hyperintensity in the bilateral periventricular areas and the medulla. The patient was treated for acute ischaemic stroke with medical therapy and rehabilitation (figure 1A). She gradually improved, with the ability to walk with an aid 6 months after the onset and was discharged home 1 year after the onset with left-sided weakness and slight dysarthria. There was no exacerbation or improvement of …

Chronic inflammatory demyelinating polyradiculoneuropathy is an autoimmune disease characterized by recurrent demyelination and remyelination with resultant thickening of the peripheral nerves. We report a case in which sonography was instrumental in demonstrating diffuse peripheral nerve hypertrophy. On sonography, both brachial plexuses were found to be diffusely hypertrophic and hypoechoic. Similar findings were noted for the median, sciatic, and femoral nerves. The brachial plexus findings were confirmed by MRI.

In this report, we describe the case of a new Japanese family (32 to 64years old; 2 females and 1 male) affected by adult-onset Alexander disease. Clinically, one member (age at onset, 56years old) developed cerebellar ataxia, another (age at onset, 55years old) showed cerebellar ataxia and pseudobulbar signs, and one member (32years old) was asymptomatic. Marked atrophy of the medulla oblongata and spinal cord was detected in the two symptomatic patients by magnetic resonance imaging (MRI). However, in the asymptomatic patient, cervicomedullary atrophy was mild. Hyperintensity signals in the medulla oblongata were detected in the two symptomatic patients, but not in the asymptomatic patient. In addition, there are symmetrical hyperintensity signals in the posterior part of the globus pallidus on T2-weighted images in the two symptomatic patients, which are rarely observed in adult-onset Alexander disease. Molecular genetic analysis revealed a novel missense mutation (p. D78N) in the glial fibrillary acidic protein (GFAP) gene in this family. The typical atrophy of the medulla oblongata and upper cervical cord detected by MRI is the diagnostic feature of adult-onset Alexander disease. Genetic analysis of the GFAP gene is recommended for all patients with late-onset progressive ataxia and suspected of having adult-onset Alexander disease on the basis of MRI findings. Additionally, these characteristic MRI patterns might even lead to the identification of asymptomatic cases, as in one of our cases.

We present here a 25-year-old woman with genetically confirmed (p.R276L mutation in the GFAP gene) juvenile-onset AxD. Episodic vomiting appeared at age nine, causing anorexia and insufficient growth. Brain MRI at age 11 showed a small nodular lesion with contrast enhancement in the left dorsal portion of the cervicomedullary junction. Her episodic vomiting improved spontaneously at age 13, and she became neurologically asymptomatic. The enhancement of the lesion disappeared simultaneously, although the plaque remained. Longitudinal MRI observations, however, revealed insidiously progressive cervicomedullary atrophy without a signal change. This case broadens our knowledge of AxD: (1) molecular analysis of the GFAP gene is warranted in patients with MRI evidence of tumor-like lesions in the brainstem, particularly if they present with isolated episodic vomiting and/or anorexia; (2) the disease can be self-remitting for at least 12 years; (3) cervicomedullary atrophy, characteristic of the adult form, can be insidiously progressive without a signal change before the clinical symptoms appear.

Background Alexander disease (ALX) is a rare neurological disorder characterized by white matter degeneration and cytoplasmic inclusions in astrocytes called Rosenthal fibers, labeled by antibodies against glial fibrillary acidic protein (GFAP). Three subtypes are distinguished according to age at onset: infantile (under age 2), juvenile (age 2 to 12) and adult (over age 12). Following the identification of heterozygous mutations in GFAP that cause this disease, cases of adult-onset ALX have been increasingly reported. Case Presentation We present a 60-year-old Japanese man with an unremarkable past and no family history of ALX. After head trauma in a traffic accident at the age of 46, his character changed, and dementia and dysarthria developed, but he remained independent. Spastic paresis and dysphagia were observed at age 57 and 59, respectively, and worsened progressively. Neurological examination at the age of 60 revealed dementia, pseudobulbar palsy, left-side predominant spastic tetraparesis, axial rigidity, bradykinesia and gaze-evoked nystagmus. Brain MRI showed tadpole-like atrophy of the brainstem, caused by marked atrophy of the medulla oblongata, cervical spinal cord and midbrain tegmentum, with an intact pontine base. Analysis of the GFAP gene revealed a heterozygous missense mutation, c.827G>T, p.R276L, which was already shown to be pathogenic in a case of pathologically proven hereditary adult-onset ALX. Conclusion The typical tadpole-like appearance of the brainstem is strongly suggestive of adult-onset ALX, and should lead to a genetic investigation of the GFAP gene. The unusual feature of this patient is the symmetrical involvement of the basal ganglia, which is rarely observed in the adult form of the disease. More patients must be examined to confirm, clinically and neuroradiologically, extrapyramidal involvement of the basal ganglia in adult-onset ALX.