Prevalence of Fragile X-Associated Tremor/Ataxia Syndrome in Patients with Cerebellar Ataxia in Japan.

The presence of fragile X mental retardation 1 (FMR1) premutation has been linked to patients with a certain type of cerebellar ataxia, the fragile X-associated tremor/ataxia syndrome (FXTAS). However, its prevalence in Japan has yet to be clarified. The aim of the present study is to determine the prevalence of FXTAS in Japanese patients with cerebellar ataxia and to describe their clinical characteristics. DNA samples were collected from 1328 Japanese patients with cerebellar ataxia, referred for genetic diagnosis. Among them, 995 patients with negative results for the most common spinocerebellar ataxia subtypes were screened for FMR1 premutation. Comprehensive clinical and radiological analyses were performed for the patients harbouring FMR1 premutation. We herein identified FMR1 premutation from one female and two male patients, who satisfied both clinical and radiological criteria of FXTAS (0.3%; 3/995) as well. Both male patients presented with high signal intensity of corticomedullary junction on diffusion-weighted magnetic resonance imaging, a finding comparable to that of neuronal intranuclear inclusion disease. The female patient mimicked multiple system atrophy in the early stages of her disease and developed aseptic meningitis with a suspected immune-mediated mechanism after the onset of FXTAS, which made her unique. Despite the lower prevalence rate in Japan than the previous reports in other countries, the present study emphasises the necessity to consider FXTAS with undiagnosed ataxia, regardless of men or women, particularly for those cases presenting with similar clinical and radiological findings with multiple system atrophy or neuronal intranuclear inclusion disease.

Peripheral neuropathy in a case with CADASIL: a case report.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized clinically by central nervous system dysfunctions. It is unclear whether CADASIL is involved in peripheral neuropathy. CASE PRESENTATION: A 67-year-old Japanese man with stepwise progression of sensory and motor neuropathy was admitted to our hospital. Peripheral neuropathy of the extremities was detected through electrophysiological and pathological studies, and brain magnetic resonance imaging revealed bilateral periventricular ischemic and thalamic hemorrhagic lesions. We diagnosed CADASIL after detecting granular osmiophilic material in the walls of the endoneurial vessels morphologically and identifying a heterozygous NOTCH3 mutation p.Arg75Pro. CONCLUSIONS: CADASIL is to be included in the work-up of not classified peripheral neuropathies.

Myopathy in a patient with systemic AA amyloidosis possibly induced by psoriasis vulgaris: An autopsy case.

INTRODUCTION: Amyloid myopathy is a rare manifestation of primary systemic amyloid light-chain (AL) amyloidosis, but it has not been reported to occur in secondary amyloid A (AA) amyloidosis. METHODS: We describe a 46-year-old man with psoriasis vulgaris who presented with idiopathic upper and lower limb weakness and was eventually diagnosed with hypertrophic cardiomyopathy. Muscle biopsy findings were compatible with mild inflammatory myopathy. He died of cardiopulmonary arrest, and an autopsy was performed. RESULTS: The autopsy revealed amyloid plaques immunopositive for AA (but not AL or transthyretin) in the perimysial, perivascular, and endomysial regions of the iliopsoas muscle. The final diagnosis was systemic AA amyloidosis with muscle amyloid angiopathy, possibly induced by psoriasis vulgaris. CONCLUSION: This is an extremely rare autopsy case of myopathy in a patient with systemic AA amyloidosis. The reason for the unusually large amount of amyloid deposition in muscle blood vessel walls remains unclear.

Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan.

BACKGROUND AND OBJECTIVES: The GAA repeat expansion within the fibroblast growth factor 14 (FGF14) gene has been found to be associated with late-onset cerebellar ataxia. This study aimed to investigate the genetic causes of cerebellar ataxia in patients in Japan. METHODS: We collected a case series of 940 index patients who presented with chronic cerebellar ataxia and remained genetically undiagnosed after our preliminary genetic screening. To investigate the FGF14 repeat locus, we employed an integrated diagnostic strategy that involved fluorescence amplicon length analysis polymerase chain reaction (PCR), repeat-primed PCR, and long-read sequencing. RESULTS: Pathogenic FGF14 GAA repeat expansions were detected in 12 patients from 11 unrelated families. The median size of the pathogenic GAA repeat was 309 repeats (range: 270-316 repeats). In these patients, the mean age of onset was 66.9 ± 9.6 years, with episodic symptoms observed in 56% of patients and parkinsonism in 30% of patients. We also detected FGF14 repeat expansions in a patient with a phenotype of multiple system atrophy, including cerebellar ataxia, parkinsonism, autonomic ataxia, and bilateral vocal cord paralysis. Brain magnetic resonance imaging (MRI) showed normal to mild cerebellar atrophy, and a follow-up study conducted after a mean period of 6 years did not reveal any significant progression. DISCUSSION: This study highlights the importance of FGF14 GAA repeat analysis in patients with late-onset cerebellar ataxia, particularly when they exhibit episodic symptoms, or their brain MRI shows no apparent cerebellar atrophy. Our findings contribute to a better understanding of the clinical variability of GAA-FGF14-related diseases.

Neuromyelitis optica spectrum disorder safely and successfully treated with satralizumab during pregnancy and breastfeeding: a case report.

Background: Satralizumab, a monoclonal antibody that recognizes interleukin-6 receptors, is known to reduce the relapse rate in neuromyelitis optica spectrum disorder (NMOSD), but its safety during pregnancy has not been established. We present the case of an NMOSD patient who safely completed pregnancy, parturition, and breastfeeding under satralizumab treatment. Importantly, satralizumab transfer to umbilical cord blood, infant serum, or breast milk was not observed. Case presentation: A 37-year-old Japanese female developed anti-aquaporin 4 antibody-positive NMOSD with left optic neuritis. Despite responding to steroid and azathioprine therapy, she experienced moon face and weight gain and desired the prompt reduction of the steroid dosage. She also wanted to conceive a child with a safe and preferably early pregnancy and parturition. Because pregnancy and parturition after the onset of NMOSD elevate the risk of relapse and miscarriage, treatment with satralizumab was initiated with the patient's consent. She experienced normal parturition and continued with satralizumab, steroid, and azathioprine treatments while breastfeeding without experiencing any relapses. Concentrations of satralizumab in the umbilical cord blood, infant serum, and breast milk were below the detection sensitivity. Conclusion: These findings suggest that satralizumab may be safe and effective for the perinatal management of NMOSD, especially when there are concerns about continuing pregnancy and the risk of relapse after parturition.

Clinical and genetic characterization of 16q-linked autosomal dominant spinocerebellar ataxia in South Kyushu, Japan.

16q-ADCA (OMIM no. 117210) is an autosomal dominant spinocerebellar ataxia (AD-SCA) characterized by late-onset pure cerebellar ataxia and -16C>T substitution of the puratrophin-1 gene. Recently, a series of single-nucleotide polymorphisms (haplotype block) were found to be specific to 16q-ADCA. We screened patients with ataxia and found 62 patients, including four homozygotes who carry the C-T substitution of the puratrophin-1 gene. By further analysis of the patients with the haplotype block, we observed a single-founder effect for 16q-ADCA, even in patients who are supposed to be sporadic late cortical cerebellar atrophy (LCCA). We also observed slippage mutations of microsatellite markers, GATA01 and 17 msm, in the pedigrees. We compared the clinical course of 16q-ADCA in heterozygotes and homozygotes with the haplotype block and observed no apparent gene dosage effect. 16q-ADCA accounts for 27% of AD-SCAs and is the most frequent AD-SCA in South Kyushu, Japan.

[Differential Diagnosis of Immune-Mediated Encephalopathies: "Neurological Symptoms of Diffuse Brain Damage": A New Concept].

In recent years, incidence of autoimmune encephalopathies has increased. The diagnosis of the severe form of autoimmune encephalopathy is not difficult; however, milder forms can be misdiagnosed as general encephalopathies. We often treat Hashimoto's encephalopathy, which has diverse clinical symptoms and is often misdiagnosed as a psychosomatic disease. We have found that the neurological findings and symptoms of patients with Hashimoto's encephalopathy are similar to those of psychogenic diseases, such as giveway weakness and atypical sensory disorder. To understand the mechanism underlying these symptoms, we propose a new concept: neurological symptoms of diffuse brain damage. This theory is based on the premise that etiologically, symptoms observed were caused by diffuse, spotty, and shaded brain damage due to autoimmune encephalopathies. We also found similar neurological conditions in patients with anti-ganglionic acetylcholine receptor antibody-related encephalopathy, encephalopathies that developed after injection of the cervical cancer vaccine, and encephalopathies associated with Stiff person syndrome. In conclusion, the clinical features of autoimmune encephalopathy include the "neurological symptoms of diffuse brain damage" as well as the presence of antibodies. We could diagnose autoimmune encephalopathy more easily, using this new diagnostic concept.

[Clinical Features and Treatment of Hashimoto Encephalopathy].

Hashimoto encephalopathy (HE) is characterized by heterogeneous neurological symptoms. HE is diagnosed based on three criteria-the presence of antithyroid antibodies, neurological symptoms from the cerebrum and/or cerebellum, and a positive response to immunotherapy. We clinically analyzed 18 patients (3 men, 15 women; age range, 38-81years) diagnosed with HE in our hospital from May 2013 to January 2016. Eleven patients showed sensory abnormalities such as strong pain, deep muscle pain, dysesthesia, paresthesia, or neuralgia. Surprisingly, the majority of the pain was distributed in a manner that was not explainable anatomically. Seventeen patients showed motor disturbances, such as weakness, paresis of extremities, or dexterity movement disorder, and eight patients showed give-way weakness, which is disruption of continuous muscle contraction. Other symptoms indicative of brain-related anomalies such as tremor, dystonia, involuntary movements, cerebellar ataxia, parkinsonism, memory loss, and chronic fatigue were also seen. In most patients, such motor, sensory, or higher brain functions were markedly improved with immunosuppressive therapies such as prednisolone, azathioprine, or immunoadsorption therapy. Although give-way weakness and anatomically unexplainable pain are typically considered as being psychogenic in origin, the presence of these symptoms is indicative of HE. HE exhibits diffuse involvement of the entire brain and thus, these symptoms are explainable. We propose that physicians should not diagnose somatoform disorders without first excluding autoimmune encephalopathy.

[Pure trigeminal motor neuropathy with an antecedent infection: a case report].

Pure trigeminal motor neuropathy is a rare clinical manifestation, and its etiology remains obscure. Here, we report the case of a 67-year-old woman who presented with jaw deviation to the right. Neurological examination revealed atrophy of the right temporal and masseter muscles and jaw deviation to the right. Absence of other cranial nerve abnormalities, such as loss of sensation in the trigeminal nerve territory, suggested involvement of only the motor component of the right mandibular nerve. Results of laboratory tests, including hematologic, serologic, and biochemical analysis, were unremarkable, except for the finding of lymphocytic pleocytosis in the cerebrospinal fluid on symptom onset. Brain MRI revealed no abnormality in the brainstem or trigeminal nerve. Electromyography indicated chronic denervation in the right temporal muscle. A few days before the occurrence of the neurological signs, the patient had experienced flu-like symptoms; this suggests that post-infection neuropathy may be a possible cause of the right motor trigeminal neuropathy observed in our case.