Marked neuropsychiatric involvement and dysmorphic features in nemaline myopathy.

BACKGROUND: Inherited nemaline myopathy is one of the most common congenital myopathies. This genetically heterogeneous disease is defined by the presence of nemaline bodies in muscle biopsy. The phenotypic spectrum is wide and cognitive involvement has been reported, although not extensively evaluated. METHODS: We report two nemaline myopathy patients presenting pronounced central nervous system involvement leading to functional compromise and novel facial and skeletal dysmorphic findings, possibly expanding the disease phenotype. RESULTS: One patient had two likely pathogenic NEB variants, c.2943G > A and c.8889 + 1G > A, and presented cognitive impairment and dysmorphic features, and the other had one pathogenic variant in ACTA1, c.169G > C (p.Gly57Arg), presenting autism spectrum disorder and corpus callosum atrophy. Both patients had severe cognitive involvement despite milder motor dysfunction. CONCLUSION: We raise the need for further studies regarding the role of thin filament proteins in the central nervous system and for a systematic cognitive assessment of congenital myopathy patients.

Aseptic meningitis in Fabry disease due to a novel GLA variant: an expanded phenotype?

BACKGROUND: F abry disease (FD) is an X-linked lysosomal storage disorder with accumulation of globotriosylceramide, causing neurologic involvement mainly as acroparesthesias and cerebrovascular disease. Aseptic meningitis has been reported in 11 patients with FD, but no prior study has correlated alpha-galactosidase (GLA) specific variants with meningitis. We present in this manuscript a family in which a novel GLA pathogenic variant was associated with aseptic meningitis in 2 of 5 family members. METHODS: This study began with identifying the proband, then screening family members for FD symptoms and evaluating symptomatic individuals for genetic and biochemical status. All patients underwent magnetic resonance imaging, and those with headache underwent cerebrospinal fluid (CSF) analysis. RESULTS: Five patients (3 females) from a single family were included in this study. Mean age at diagnosis was 20.6 years. Two patients (40%) had aseptic meningitis; one of them also had cerebrovascular events. C-reactive protein and erythrocyte sedimentation rate were elevated during aseptic meningitis episodes. Both patients responded to intravenous methylprednisolone with resolution of fever, headache, and vomiting. One of them recurred and needed chronic immunosuppression with azathioprine. CONCLUSION: We described aseptic meningitis in a family with a novel GLA variant. Meningitis might be a common phenomenon in FD and not a particularity of this variant. Understanding the mechanisms underlying meningitis and its association with cerebrovascular events may lead to a new paradigm of treatment for stroke in these patients. Further prospective studies with CSF collection in patients with FD and recurrent headache could help to elucidate this question.

Moyamoya associated with Turner syndrome in a patient with type 2 spinocerebellar ataxia-Occam's razor or Hickam's dictum: a case report.

BACKGROUND: Turner syndrome (TS) is a rare condition associated with a completely or partially missing X chromosome that affects 1 in 2500 girls. TS increases the risk of autoimmune diseases, including Graves' disease (GD). Moyamoya disease is a rare cerebral arteriopathy of unknown etiology characterized by progressive bilateral stenosis of the internal carotid artery and its branches. Both TS and GD have been associated with Moyamoya. Type 2 spinocerebellar ataxia (SCA2) is an autosomal dominant cerebellar ataxia caused by a CAG repeat expansion in ATXN2. We present the first case of Moyamoya syndrome in a patient with a previous diagnosis of TS and GD who tested positive for SCA2 and had imaging findings compatible with an overlap of SCA2 and Moyamoya. CASE PRESENTATION: A 43-year-old woman presented with mild gait imbalance for 2 years. Her family history was positive for type 2 spinocerebellar ataxia (SCA2). She had been diagnosed with Turner Syndrome (45,X) and Graves disease three years before. Brain MRI revealed bilateral frontal and parietal cystic encephalomalacia in watershed zones, atrophy of pons, middle cerebellar peduncles and cerebellum. MR angiography showed progressive stenosis of both internal carotid arteries with lenticulostriate collaterals, suggestive of Moya-Moya disease. Molecular analysis confirmed the diagnosis of SCA2. CONCLUSIONS: With increased availability of tools for genetic diagnosis, physicians need to be aware of the possibility of a single patient presenting two or more rare diseases. This report underscores the modern dilemmas created by increasingly accurate imaging techniques and available and extensive genetic testing.

A rare cause of monogenic cerebral small vessel disease and stroke: Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL).

BACKGROUND: Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL) is a rare monogenic cause of cerebral small vessel disease. To date, fewer than 15 patients with CARASAL have been described, all of common European ancestry. METHODS: Clinical and imaging phenotypes of two patients are presented. Genetic variants were identified using targeted Sanger and focused exome sequencing, respectively. RESULTS: Both patients carried the same pathogenic p.Arg325Cys mutation in CTSA. One patient of Chinese ethnicity presented with migraine, tinnitus and slowly progressive cognitive impairment with significant cerebral small vessel disease in the absence of typical cardiovascular risk factors. She later suffered an ischaemic stroke. A second patient from Brazil, of Italian ethnicity developed progressive dysphagia and dysarthria in his 50s, he later developed hearing loss and chronic disequilibrium. Magnetic resonance imaging in both cases demonstrated extensive signal change in the deep cerebral white matter, anterior temporal lobes, thalami, internal and external capsules and brainstem. CONCLUSIONS: CARASAL should be considered in patients with early onset or severe cerebral small vessel disease, particularly where there are prominent symptoms or signs related to brainstem involvement, such as hearing dysfunction, tinnitus or dysphagia or where there is significant thalamic and brainstem involvement on imaging.

Adult Leukodystrophies: A Step-by-Step Diagnostic Approach.

Leukodystrophies usually affect children, but in the last several decades, many instances of adult leukodystrophies have been reported in the medical literature. Because the clinical manifestation of these diseases can be nonspecific, MRI can help with establishing a diagnosis. A step-by-step approach to assist in the diagnosis of adult leukodystrophies is proposed in this article. The first step is to identify symmetric white matter involvement, which is more commonly observed in these patients. The next step is to fit the symmetric white matter involvement into one of the proposed patterns. However, a patient may present with more than one pattern of white matter involvement. Thus, the third step is to evaluate for five distinct characteristics-including enhancement, lesions with signal intensity similar to that of cerebrospinal fluid, susceptibility-weighted MRI signal intensity abnormalities, abnormal peaks at MR spectroscopy, and spinal cord involvement-to further narrow the differential diagnosis. ©RSNA, 2019.

Multiple endocrine neoplasia type 1 presenting as refractory epilepsy and polyneuropathy--a case report.

Hypoglycemia is a well recognized cause of acute symptomatic seizures. The fact that hypoglycemia can cause peripheral neuropathy is less appreciated. We describe a case of insulinoma associated peripheral neuropathy. A 17 year-old previously healthy man was referred for investigation of refractory epilepsy. A history of recurrent seizures, slowly progressive weakness of his feet and hands, and weight gain was obtained. Physical examination showed signs of a chronic sensory-motor polyneuropathy. He was diagnosed with insulinoma and primary hyperparathyroidism, characterizing multiple endocrine neoplasia, type 1 syndrome. Cases of insulinoma associated peripheral neuropathy are very rare. The more characteristic clinical picture appears to be distal weakness, worse in the intrinsic hand and feet muscles, and no or mild sensory signs. Peripheral nervous system symptoms may not completely resolve, despite removal of the cause of hyperinsulinism/hypoglycemia and full reversion of central nervous system symptoms. Mechanisms underlying hypoglycemic neuropathy are still poorly understood.

Did you rule out neurosyphilis?

Neurosyphilis, formerly a frequent cause of dementia, is now a rare condition in developed countries. However, syphilis remains common in many developing countries, where adequate diagnosis and treatment of early syphilis may be lacking, increasing the chances of neurosyphilis and prevalence of syphilitic dementia. OBJECTIVES: To present cases of syphilitic dementia seen in a cognitive and behavioral neurology unit in Brazil, emphasizing their first symptoms and the challenges they posed in diagnosis. METHODS: At our unit of the Hospital das Clínicas of the University of São Paulo, all patients are submitted to blood treponemal tests. When the test is positive, a lumbar puncture is performed. We retrospectivelly reviewed all cases of neurosyphilis seen in our unit from January 1991 to November 2009. RESULTS: Nine cases of neurosyphilis (0.77% of the 1160 cases in our files) were identified over the period. Patients with neurosyphilis were all men, had a mean age of 47.8 (±13.0) years (median of 43 years), and presented with various neuropsychiatric syndromes and elusive diagnoses. The median time from onset of symptoms to diagnosis was 24 months and only one patient made a full recovery after treatment. CONCLUSIONS: Neurosyphilis is not frequent but remains present, causing several types of neuropsychiatric syndromes. As it is very simple to rule out neurosyphilis by performing a blood treponemal test, this test should be performed in all patients with neuropsychiatric symptoms, particularly in regions of the world where syphilis is still a commonly occurring disease.

Neurossífilis, anteriormente uma causa freqüente de demência, é atualmente rara nos países desenvolvidos. A sífilis é ainda uma doença comum em muitos países em desenvolvimento, onde o diagnóstico e tratamento da sífilis precoce podem não ser adequados, o que aumenta a possibilidade de ocorrência de neurossífilis e de demência. OBJETIVOS: apresentar casos de demência sifilítica atendidos em uma unidade de neurologia cognitiva e do comportamento no Brasil, enfatizando os primeiros sintomas e os desafios que impuseram ao diagnóstico. MÉTODOS: Em nossa unidade do Hospital das Clínicas da Universidade de São Paulo, todos os pacientes são submetidos a teste treponêmico no sangue. Quando o teste é positivo, é realizada punção lombar. Avaliamos retrospectivamente todos os casos de neurossífilis atendidos em nossa unidade de janeiro de 1991 a novembro de 2009. RESULTADOS: Nove casos de neurossífilis (0,77% dos 1.160 casos de nossos arquivos) foram identificados neste período. Os pacientes com neurossífilis eram todos homens, com idade média de 47,8 (±13,0) anos (mediana de 43 anos), e apresentaram-se com vários tipos de síndromes neuropsiquiátricas, de difícil diagnóstico. O tempo médio entre o início dos sintomas e o diagnóstico foi de 24 meses e apenas um paciente teve recuperação completa após o tratamento. CONCLUSÕES: Neurossífilis não é frequente, mas ainda está presente causando vários tipos de síndromes neuropsiquiátricas. Como é muito simples excluir o diagnóstico de neurossífilis mediante teste treponêmico no sangue, este teste deve ser realizado em todo paciente com sintomas neuropsiquiátricos, particularmente nas regiões do mundo onde a sífilis é ainda uma doença comum.