CANVAS-related RFC1 mutations in patients with immune-mediated neuropathy.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy.

Identification of a novel mutation and genotype-phenotype relationship in MEGF10 myopathy.

Mutations in MEGF10 are associated with early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD). Recently, a mild variant phenotype of EMARDD has been reported in patients with multiple minicores in the myofibers. However, some reported patients had no clear cores. We present a patient who had progressive weakness since his 30 s and then developed severe respiratory failure at the age of 66 years and found that he had a novel mutation, p.G739R, in MEGF10. He had no clear core in the biopsied muscle. We summarize the clinical and genetic characteristics of the current and reported patients with MEGF10 and statistically evaluate the genotype-phenotype correlation. Results show that patients with missense mutations in at least one allele had significantly later onset than those with biallelic truncation mutations.

Hemiplegic migraine type 2 with new mutation of the ATP1A2 gene in Japanese cases.

We analyzed the clinical symptoms of hemiplegic migraine (HM) and their relevance in four Japanese patients considered to have ATP1A2 mutations as a cause. Sequencing of ATP1A2 was performed using the Sanger method in 43 blood samples from clinically suspected patients with familial HM. Subsequently, algorithm analysis, allele frequency determination, and three-dimensional structure analysis of the recognized variants were performed, and the recognized variants were evaluated. We found four heterozygous missense mutations in ATP1A2 (Case 1: p.R51C; Case 2: p.R65L; Case 3: p.A269P; Case 4: p.D999H), three of which had not been reported to date. These four mutations may also affect the structure of the protein products, as assessed using a three-dimensional structural analysis. In all four cases, the clinical symptoms included visual, sensory, motor, and verbal symptoms and the frequency and duration of headache attacks varied. Additionally, oral administration of a combination of lomerizine hydrochloride and topiramate had a partial effect in three cases. We report four missense mutations in ATP1A2. This report will be useful for the future analysis of mutations and clinical types in Asians, as well as Westerners, with migraine.

Phenotypic and molecular diversities of spinocerebellar ataxia type 2 in Japan.

BACKGROUND: We intended to clarify the phenotypic and molecular diversities of spinocerebellar ataxia type 2 (SCA2) in Japan. METHODS: DNA was extracted from the peripheral blood of 436 patients, including 126 patients with chronic neuropathy, 108 with amyotrophic lateral sclerosis, and 202 with cerebellar ataxia. We then PCR-amplified and sequenced the ATXN2 gene. The biopsied sural nerves of mutation-positive patients were subjected to light-microscopic and electron-microscopic analyses. Transfection analyses were performed using a Schwann cell line, IMS32. RESULTS: We found PCR-amplified products potentially corresponding to expanded CAG repeats in four patients. Two patients in the chronic neuropathy group had a full repeat expansion or an intermediate expansion (39 or 32 repeats), without limb ataxia. The sural nerve biopsy findings of the two patients included axonal neuropathy and mixed neuropathy (axonal changes with demyelination). Schwann cells harbored either cytoplasmic or nuclear inclusions on electron microscopic examination. Both patients recently exhibited pyramidal signs. In the third patient in the cerebellar ataxia group, we identified a novel 21-base duplication mutation near 22 CAG repeats (c.432_452dup). The transfection study revealed that the 21-base-duplication mutant Ataxin-2 proteins aggregated in IMS32 and rendered cells susceptible to oxidative stress, similar to a CAG-expanded mutant. The fourth patient, with 41 repeats, had ataxia and spasticity. The two patients with cerebellar ataxia also had peripheral neuropathy. CONCLUSIONS: Patients with expanded CAG repeats can exhibit a neuropathy-dominant phenotype not described previously. The novel 21-base-duplication mutant seems to share the aggregation properties of polyglutamine-expanded mutants.

Neutral Lipid Storage Disease Associated with the PNPLA2 Gene: Case Report and Literature Review.

Mutations in the PNPLA2 gene cause neutral lipid storage disease with myopathy (NLSDM) or triglyceride deposit cardiomyovasculopathy. We report a detailed case study of a 53-year-old man with NLSDM. The PNPLA2 gene was analyzed according to the reported method. We summarized the clinical, laboratory, and genetic information of 56 patients, including our patient and 55 other reported patients with homozygous or compound heterozygous mutations in the PNPLA2 gene. We found a novel homozygous mutation (c.194delC) in the PNPLA2 gene that resulted in frameshift. The patient suffered from normal-tension glaucoma and pulmonary cysts, symptoms that are relatively common in the elderly but were not previously reported for this disease. Our summary confirmed that Jordan's anomaly, polymorphonuclear leukocytes with lipid accumulation, was the most consistent finding of this disease. Because this disease is potentially treatable, our results may help rapid and correct diagnosis.

Pathological Findings in Male Patients With Anti-N-methyl-d-Aspartate Receptor Encephalitis.

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is the most common type of autoimmune encephalitis. The disease predominantly affects women (1:5-1:10), with only 3 reports of autopsy findings in women being published to date. The present study reports findings from the first autopsy performed on a man with anti-NMDAR encephalitis. The patient had some scattered lesions in the limbic system with neuronal loss, gliosis, and microglial activation. The temporal and frontal cortices showed additional patchy demyelination. T-lymphocyte infiltration was detectable in the fusiform gyrus lesion. These findings were partly similar to those reported in female patients. Although clinical differences based on the sex of the patient are reported for this disease, the observed pathological similarities potentially help to establish common therapeutic strategies for all patients. Severe testicular damage was additionally observed in the male patient in this study. Biopsy-proven severe testicular damage was also confirmed in another, previously fertile man who became azoospermic. Moreover, serum follicle-stimulating hormone levels, which often increased in response to disturbed spermatogenesis, were elevated, and testosterone/luteinizing hormone ratio reflecting Leydig cell function was low in all 5 male patients in this study. Overall, these findings suggest similar brain pathology in patients of both sexes and severe testicular damage in male patients.

Histopathological features of a patient with Charcot-Marie-Tooth disease type 2U/AD-CMTax-MARS.

Charcot-Marie-Tooth (CMT) disease is a complex of peripheral nervous system disorders. CMT type 2U (CMT2U) is an autosomal dominant (AD) disease caused by mutations in the MARS gene encoding methionyl-tRNA synthetase; this disease has thus been newly called AD-CMTax-MARS. A few families with mutations in the MARS gene have been reported, without detailed histopathological findings. We describe a 70-year-old woman who had bilateral dysesthesia of the soles since the age of 66 years. Sural nerve biopsy showed a decrease in the density of large myelinated nerve fibers. Increased clusters of regenerating myelinated nerve fibers were noted. Electron microscopic analyses revealed degeneration of unmyelinated nerves. There was no vasculitis or inflammatory cell infiltration. Genetic analysis identified a heterozygous p.P800T mutation, a reported mutation in the MARS gene. We report the detailed histopathological findings in a patient with CMT2U/AD-CMTax-MARS. The findings are similar to those found in CMT2D caused by mutations in the GARS gene, encoding glycyl-tRNA synthetase.

Treatable Leukoencephalopathy in a Patient with Hypophosphatemia.

We report the first patient with pathologically proven leukoencephalopathy associated with hypophosphatemia. A 61-year-old woman had repetitive episodes of decreased consciousness with pontine and pallidal lesions and extensive leukoencephalopathy on MRI, later found to be associated with hypophosphatemia. Although hypophosphatemia has been linked to central pontine and extrapontine myelinolysis (osmotic myelinolysis), lesions in the deep white matter have not been reported. Brain biopsy performed during the first diagnosis process revealed nonspecific demyelination with gliosis, a finding similar to that of chronic osmotic myelinolysis. After normalization of phosphate levels, her consciousness completely improved and MRI abnormalities partly resolved. We should consider that leukoencephalopathy can be associated with hypophosphatemia, which is often treatable.

Differential Progression of Dysphagia in Heredity and Sporadic Ataxias Involving Multiple Systems.

Sporadic ataxia affecting multiple systems, such as cerebellar, extrapyramidal, and autonomic systems, is known as multiple system atrophy cerebellar type (MSA-C), while similar multisystem involvements are seen in certain types of hereditary ataxia, such as spinocerebellar ataxia type 3 (SCA3). Dysphagia is a common symptom that can predispose to aspiration pneumonia, a major cause of death in patients with these diseases. Although the progressions of dysphagia in patients with MSA-C have been reported sporadically, those in SCA3 have not been reported. We retrospectively compared the results of repetitive videofluoroscopic examinations in patients with SCA3 (n = 6) and in those with MSA-C (n = 7). The result showed that the gross progression of dysphagia was significantly slower in patients with SCA3 than in those with MSA-C, but the maximum progression speeds were not significantly different. The dysphagia severities were not associated with impaired activity of daily living evaluated by the Barthel index in MSA-C, but were associated in SCA3. Despite the small number of patients enrolled, these data suggest that physicians should monitor swallowing functions in patients with SCA3 after mild dysphagia develops because it may progress as rapidly as it does in MSA-C.

VCP gene analyses in Japanese patients with sporadic amyotrophic lateral sclerosis identify a new mutation.

Accumulating evidence has proven that mutations in the VCP gene encoding valosin-containing protein (VCP) cause inclusion body myopathy with Paget disease of the bone and frontotemporal dementia. This gene was later found to be causative for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, occurring typically in elderly persons. We thus sequenced the VCP gene in 75 Japanese patients with sporadic ALS negative for mutations in other genes causative for ALS and found a novel mutation, p.Arg487His, in 1 patient. The newly identified mutant as well as known mutants rendered neuronal cells susceptible to oxidative stress. The presence of the mutation in the Japanese population extends the geographic region for involvement of the VCP gene in sporadic ALS to East Asia.

Eyelid tremor in a patient with anti-caspr2 antibody-related encephalitis.

We describe the first case of a patient with eyelid tremor probably associated with anti-contactin-associated protein-like 2 (Caspr2) antibody. Encephalitis associated with anti-voltage-gated potassium channel antibody is now attributed to autoantibodies against leucine-rich glioma inactivated 1 (Lgi1) and less frequently against Caspr2. Eyelid tremor or blepharoclonus is a rare or underdiagnosed involuntary movement that has been found in patients with infarction in the thalamus or drug-induced or idiopathic parkinsonism. Since patients with anti-Caspr2 antibody-related encephalitis occasionally have extrapyramidal signs, we speculate that the eyelid tremor was also caused by anti-Caspr2 antibody in our patient. Partial resolution of his symptoms by plasmapheresis also supported the involvement in immunological processes.

Overlapping demyelinating syndromes and anti­N-methyl-D-aspartate receptor encephalitis.

OBJECTIVE: To report the clinical, radiological, and immunological association of demyelinating disorders with anti­Nmethyl- D-aspartate receptor (NMDAR) encephalitis. METHODS: Clinical and radiological analysis was done of a cohort of 691 patients with anti-NMDAR encephalitis. Determination of antibodies to NMDAR, aquaporin-4 (AQP4), and myelin oligodendrocyte glycoprotein (MOG) was performed using brain immunohistochemistry and cell-based assays. RESULTS: Twenty-three of 691 patients with anti-NMDAR encephalitis had prominent magnetic resonance imaging (MRI) and/or clinical features of demyelination. Group 1 included 12 patients in whom anti-NMDAR encephalitis was preceded or followed by independent episodes of neuromyelitis optica (NMO) spectrum disorder (5 cases, 4 anti-AQP4 positive) or brainstem or multifocal demyelinating syndromes (7 cases, all anti-MOG positive). Group 2 included 11 patients in whom anti-NMDAR encephalitis occurred simultaneously with MRI and symptoms compatible with demyelination (5 AQ4 positive, 2 MOG positive). Group 3 (136 controls) included 50 randomly selected patients with typical anti-NMDAR encephalitis, 56 with NMO, and 30 with multiple sclerosis; NMDAR antibodies were detected only in the 50 anti-NMDAR patients, MOG antibodies in 3 of 50 anti-NMDAR and 1 of 56 NMO patients, and AQP4 antibodies in 48 of 56 NMO and 1 of 50 anti-NMDAR patients (p<0.0001 for all comparisons with Groups 1 and 2). Most patients improved with immunotherapy, but compared with anti-NMDAR encephalitis the demyelinating episodes required more intensive therapy and resulted in more residual deficits. Only 1 of 23 NMDAR patients with signs of demyelination had ovarian teratoma compared with 18 of 50 anti-NMDAR controls (p50.011). INTERPRETATION: Patients with anti-NMDAR encephalitis may develop concurrent or separate episodes of demyelinating disorders, and conversely patients with NMO or demyelinating disorders with atypical symptoms (eg, dyskinesias, psychosis) may have anti-NMDAR encephalitis.

Multiple system involvement in a Japanese patient with a V31A mutation in the SOD1 gene.

The superoxide dismutase-1 (SOD1) gene is the first gene for familial amyotrophic lateral sclerosis (ALS) with autosomal dominant inheritance. We describe a Japanese patient who had slowly progressive motor neuron disease with autonomic and sensory disturbances, urine incontinence and sensory neuropathy. This patient was found to have V31A mutation in the SOD1 gene. Although slow progression has been previously observed in patients with ALS caused by several mutations in the SOD1 gene, symptoms unrelated with motor systems are very rare. In addition, MRI showed cerebellar and brainstem atrophy, a finding previously unreported in SOD1-related ALS. The COQ2 gene, a gene very recently reported to be associated with multiple system atrophy, as well as genes for spinocerebellar ataxias was analyzed, the result of which showed no mutation in this patient. The V31A mutation is thus likely to be associated with atypical ALS affecting multiple systems.

A case of anti-N-methyl-d-aspartate receptor encephalitis with multiple sclerosis-like demyelinated lesions.

OBJECTIVE: To describe an unusual case of a male patient with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis who presented with multiple white matter lesions. Brain biopsy of the patient was performed, and follow-up evaluation of the cerebrospinal fluid (CSF) NMDAR antibody titer was implemented. DESIGN: Case report. SETTING: University hospital. PATIENT: A 35-year-old man with anti-NMDAR encephalitis initially presented with fever and psychiatric symptoms. After an initial attack of anti-NMDAR encephalitis, 2 atypical relapses occurred, which presented with myelitis and multifocal white matter lesions; the lesions were open-ring-shaped and partially enhanced. INTERVENTION: Analysis of the brain biopsy specimen revealed the presence of demyelinated lesions with discrete borders. Subsequent intravenous methylprednisolone therapy resulted in improvement in the brain lesions. Prednisolone and cyclophosphamide were orally administered thereafter. Clinical progression of the disease paralleled observed changes in the CSF NMDAR antibody titer. CONCLUSION: The demyelinated lesions observed in this case were similar to lesions found in multiple sclerosis. On the basis of our finding that the clinical progression of the disease and the associated symptoms paralleled changes in the CSF NMDAR antibody titer, we speculate that the lesions formed as a result of anti-NMDAR encephalitis.

Details of treatment-related difficulties in men with anti-N-methyl-D-aspartate receptor encephalitis.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibody-associated encephalitis is an immunologic disease characterized by a female preponderance. Males are infrequently affected. The clinical symptoms of affected boys as well as girls have been summarized, and they have some clinical features distinct from those of adults. However, the characteristics of men have been described in only a few reports. We describe in detail four men with anti-NMDAR encephalitis who presented with several clinical features that complicated disease management and recovery, including venous thrombosis, bilateral hippocampal involvement, hypersexuality, and joint contracture. We also report the first detailed clinical information about a male patient who died of this disease. In addition, we summarize the clinical characteristics of five patients previously reported by others.

Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia.

Amyotrophic lateral sclerosis (ALS) is a paralytic and usually fatal disorder caused by motor-neuron degeneration in the brain and spinal cord. Most cases of ALS are sporadic but about 5-10% are familial. Mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP, also known as TDP43) and fused in sarcoma (FUS, also known as translocated in liposarcoma (TLS)) account for approximately 30% of classic familial ALS. Mutations in several other genes have also been reported as rare causes of ALS or ALS-like syndromes. The causes of the remaining cases of familial ALS and of the vast majority of sporadic ALS are unknown. Despite extensive studies of previously identified ALS-causing genes, the pathogenic mechanism underlying motor-neuron degeneration in ALS remains largely obscure. Dementia, usually of the frontotemporal lobar type, may occur in some ALS cases. It is unclear whether ALS and dementia share common aetiology and pathogenesis in ALS/dementia. Here we show that mutations in UBQLN2, which encodes the ubiquitin-like protein ubiquilin 2, cause dominantly inherited, chromosome-X-linked ALS and ALS/dementia. We describe novel ubiquilin 2 pathology in the spinal cords of ALS cases and in the brains of ALS/dementia cases with or without UBQLN2 mutations. Ubiquilin 2 is a member of the ubiquilin family, which regulates the degradation of ubiquitinated proteins. Functional analysis showed that mutations in UBQLN2 lead to an impairment of protein degradation. Therefore, our findings link abnormalities in ubiquilin 2 to defects in the protein degradation pathway, abnormal protein aggregation and neurodegeneration, indicating a common pathogenic mechanism that can be exploited for therapeutic intervention.

Abnormal cystatin C levels in two patients with bardet-biedl syndrome.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by central obesity, mental impairment, rod-cone dystrophy, polydactyly, hypogonadism in males, and renal abnormalities. The causative genes have been identified as BBS1-14. In the Western countries, the prevalence of this disease ranges from 1/13,500 to 1/160,000, while only a few Japanese patients have been reported in the English-language literature. The incidence of renal dysfunction or anomalies in previous reports varies considerably ranging from ∼20% to universal occurrence. We here report that two Japanese patients who had BBS with normal BUN and creatinine levels had elevated levels of cystatin C, a sensitive marker of glomerular filtration rate. A urine albumin level increased only in the elder patient. Thus, cystatin C may be useful for detecting renal abnormalities in patients with an apparent normal renal function. Because this disease is diagnosed by accumulation of symptoms, such a sensitive marker might help early diagnosis of BBS.

Serial neuroimaging in tolosa-hunt syndrome with acute bilateral complete ophthalmoplegia.

Tolosa-Hunt syndrome (THS) is a very rare, relapsing, and remitting painful ophthalmoplegia caused by nonspecific granulomatous inflammation in the cavernous sinus. To our knowledge, bilateral complete, simultaneous palsies of all 3 cranial nerves associated with extraocular movement have not been reported. We describe the first such patient with bilateral THS that responded quickly to corticosteroid therapy. A 54-year-old man presented with a periorbital and frontal headache with acute bilateral severe blepharoptosis and fixed eyes, which dramatically responded to corticosteroid therapy. He had diabetes mellitus type II. Brain MRI showed granulomatous inflammation in both cavernous sinuses and thickening of the surrounding dura mater of the cranial base, suggesting the coexistence of focal hypertrophic cranial pachymeningitis. Our experience indicates that steroid therapy with strict control of blood sugar should be considered in patients with THS complicated by diabetes. MRI is a valuable tool for serially monitoring the response of lesions to treatment in THS.

Treatable fluctuating mental impairment in a patient with Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by rod-cone dystrophy, polydactyly, central obesity, mental retardation, and hypogonadism. Although many organs are involved in BBS, hyperammonemia caused by portal hypertension has been reported previously in only a single patient. We describe the second such patient with BBS and hyperammonemia, associated with fluctuating mental impairment. The patient was a 17-year-old boy with BBS. Esophageal, gastric, and rectal varices and mild hepatic dysfunction started to develop at 5 years of age. A liver biopsy showed dilated portal veins with mild fibrosis in portal tract. From the age of 17 years, he often had forced laughter with apparently normal consciousness. Laboratory examinations revealed hyperammonemia (112.2mg/ml). Oral medication lowered the blood ammonia level to 69.9 mg/ml, reduced the frequency of forced laughter, and improved his IQ. Patients with BBS may have additional diseases or conditions that affect mental status, such as hyperammonemia. Physicians should explore the underlying causes of these conditions and treat such patients, who already have a compromised quality of life.