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OBJECTIVE: Prospective studies of encephalitis are rare in regions where encephalitis is prevalent, such as low middle-income Southeast Asian countries. We compared the diagnostic yield of local and advanced tests in cases of pediatric encephalitis in Myanmar. METHODS: Children with suspected subacute or acute encephalitis at Yangon Children's Hospital, Yangon, Myanmar, were prospectively recruited from 2016-2018. Cohort 1 (n = 65) had locally available diagnostic testing, whereas cohort 2 (n = 38) had advanced tests for autoantibodies (ie, cell-based assays, tissue immunostaining, studies with cultured neurons) and infections (ie, BioFire FilmArray multiplex Meningitis/Encephalitis multiplex PCR panel, metagenomic sequencing, and pan-viral serologic testing [VirScan] of cerebrospinal fluid). RESULTS: A total of 20 cases (13 in cohort 1 and 7 in cohort 2) were found to have illnesses other than encephalitis. Of the 52 remaining cases in cohort 1, 43 (83%) had presumed infectious encephalitis, of which 2 cases (4%) had a confirmed infectious etiology. Nine cases (17%) had presumed autoimmune encephalitis. Of the 31 cases in cohort 2, 23 (74%) had presumed infectious encephalitis, of which one (3%) had confirmed infectious etiology using local tests only, whereas 8 (26%) had presumed autoimmune encephalitis. Advanced tests confirmed an additional 10 (32%) infections, 4 (13%) possible infections, and 5 (16%) cases of N-methyl-D-aspartate receptor antibody encephalitis. INTERPRETATION: Pediatric encephalitis is prevalent in Myanmar, and advanced technologies increase identification of treatable infectious and autoimmune causes. Developing affordable advanced tests to use globally represents a high clinical and research priority to improve the diagnosis and prognosis of encephalitis. ANN NEUROL 2023;93:615-628.
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Doenças Autoimunes do Sistema Nervoso , Doenças Transmissíveis , Encefalite , Encefalite Infecciosa , Meningite , Criança , Humanos , Meningite/líquido cefalorraquidiano , Meningite/diagnóstico , Estudos Prospectivos , Mianmar , Encefalite/líquido cefalorraquidianoRESUMO
INTRODUCTION: X-linked myopathy with excessive autophagy (XMEA) is characterized by autophagic vacuoles with sarcolemmal features. Mutations in VMA21 result in insufficient lysosome acidification, causing progressive proximal weakness with onset before age 20 years and loss of ambulation by middle age. METHODS: We describe a patient with onset of slowly progressive proximal weakness of the lower limbs after age 50, who maintains ambulation with the assistance of a cane at age 71. RESULTS: Muscle biopsy at age 66 showed complex muscle fiber splitting, internalized capillaries, and vacuolar changes characteristic of autophagic vacuolar myopathy. Vacuoles stained positive for sarcolemmal proteins, LAMP2, and complement C5b-9. Ultrastructural evaluation further revealed basal lamina reduplication and extensive autophagosome extrusion. Sanger sequencing identified a known pathologic splice site mutation in VMA21 (c.164-7T>G). CONCLUSIONS: This case expands the clinical phenotype of XMEA and suggests VMA21 sequencing be considered in evaluating men with LAMP2-positive autophagic vacuolar myopathy.
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Autofagia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Doenças Musculares/patologia , Idoso , Autofagia/fisiologia , Biópsia , Análise Mutacional de DNA , Progressão da Doença , Eletromiografia , Éxons/genética , Imunofluorescência , Humanos , Imuno-Histoquímica , Íntrons/genética , Masculino , Fibras Musculares Esqueléticas/patologia , Debilidade Muscular/etiologia , Debilidade Muscular/fisiopatologia , Doenças Musculares/genética , Mutação/genética , Mutação/fisiologia , ATPases Vacuolares Próton-Translocadoras/genéticaRESUMO
In the United States (U.S.), newborn screening (NBS) for spinal muscular atrophy (SMA) is implemented by individual states. There is likely variation in the practice patterns of state NBS programs and among the providers caring for newborns with SMA. This is a prospective, descriptive, observational study that seeks to quantify and describe practice patterns and heterogeneities in state NBS programs and provider practices in the U.S. We surveyed U.S. state NBS programs and care providers of newborns with SMA. Thirty states and 41 practitioners responded. NBS program practices vary by state. Most (74%) state programs provide results to both primary care and specialist providers and also defer confirmatory SMA testing to those providers. Two states had relatively high rates of false-positive or inclusive results. The total birth prevalence of SMA was 1:13,862. Most providers were in tertiary care centers (90%) and were child neurologists (81%) and/or had fellowship training in Neuromuscular Medicine or Electromyography (76%). All providers see new referrals in less than a week, but many do not initiate treatment until >3 weeks of age (39%), with most commonly reported delays related to insurance processes. Most (81%) prefer onasemnogene abeparvovec-xioi (OA) as the treatment of choice, mainly due to perceived efficacy and the route/frequency of administration. NBS practice patterns in the U.S. vary by state but overall yielded the predicted birth prevalence of positive results. Providers evaluate these newborns urgently, but many do not initiate therapy until after 3 weeks of age. Treatment delays are mainly related to insurance processes.
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OBJECTIVE: To test the hypothesis that we will be able to detect change in motor outcome measures over time in a cohort with mutations in FKRP. METHODS: Individuals with documented FKRP mutations were evaluated annually with a battery of established motor outcome measures including limited quantitative myometry and timed function measures. Results were analyzed using random coefficient regression to determine annual change in each measure. Due to the nonlinear progression through the lifespan of the study participants, pediatric (<19 years) and adult (≥19 years) cohorts were analyzed separately. Effect of genotype was evaluated in each cohort. RESULTS: Sixty-nine participants (30 pediatric, 44 adult) with at least 2 evaluations were included. There was a small but statistically significant decline in timed motor function measures in both pediatric and adult cohorts. Genotype significantly affected rate of decline in the pediatric but not the adult cohort. Some pediatric patients who are homozygous for the c.826C>A mutation showed improving motor performance in adolescence. Performance on the 10-meter walk/run was highly correlated with other timed function tests. CONCLUSIONS: There is a slow annual decline in motor function in adults with FKRP mutations that can be detected with standard motor outcome measures, while the results in the pediatric population were more variable and affected by genotype. Overall, these analyses provide a framework for development of future clinical trials. The dystroglycanopathies natural history study (Clinical Trial Readiness for the Dystroglycanopathies) may be found on clinicaltrials.gov (NCT00313677).
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Progressão da Doença , Transtornos Motores/genética , Mutação , Pentosiltransferases/genética , Adolescente , Adulto , Criança , Avaliação da Deficiência , Feminino , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: To determine the frequency of urologic and gastrointestinal (GI) symptoms in a cohort of individuals with dystroglycanopathy compared with healthy household controls. METHODS: Participants in a North American dystroglycanopathy natural history study (NCT00313677) and other members of their households completed a questionnaire modified from validated instruments and clinical criteria. Urologic and GI symptom frequency, effect on patient life, and medications taken for these symptoms were assessed. Those younger than 4 years or not toilet trained were excluded. Healthy human bladder, esophagus, and duodenum from surgical specimens were immunostained for glycosylated α-dystroglycan. RESULTS: Thirty of 58 potential participants with dystroglycanopathy (51.7%) and 16 household controls participated. Subjects were aged 6 to 51 years (mean 26.7); 60.0% were female. Controls were aged 7 to 55 years (mean 34.6); 56.3% were female. The dystroglycanopathy cohort had higher frequency of urinary voiding symptoms (p = 0.02), higher urologic symptom scores (p = 0.05), and higher dysphagia symptom scores (p = 0.04). A correlation existed between urologic symptom score and effect on life (r = 0.71; 95% confidence interval 0.46, 0.85; p < 0.0001) and between dysphagia symptom score and effect on life (r = 0.72; 95% confidence interval 0.48, 0.86; p < 0.0001). Glycosylated α-dystroglycan was present in visceral smooth muscle of all normal tissues analyzed. CONCLUSIONS: Urologic symptoms and dysphagia are reported more frequently by individuals with dystroglycanopathies than by household controls. These symptoms can cause a perceived negative effect on patient life. Our results suggest urologic and GI dysfunction may be part of the dystroglycanopathy phenotype, and that questions about these symptoms should be incorporated into routine care because they may influence medical management.
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Transtornos de Deglutição/diagnóstico , Distroglicanas , Gastroenteropatias/diagnóstico , Doenças Urológicas/diagnóstico , Adolescente , Adulto , Criança , Estudos de Coortes , Transtornos de Deglutição/psicologia , Distroglicanas/análise , Feminino , Gastroenteropatias/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida/psicologia , Inquéritos e Questionários , Doenças Urológicas/psicologia , Adulto JovemRESUMO
Introduction. The valosin-containing protein (VCP) regulates several distinct cellular processes. Consistent with this, VCP mutations manifest variable clinical phenotypes among and within families and are a diagnostic challenge. Methods. A 60-year-old man who played ice hockey into his 50's was evaluated by electrodiagnostics, muscle biopsy, and molecular genetics. Results. With long-standing pes cavus and toe walking, our patient developed progressive weakness, cramps, memory loss, and paresthesias at age 52. An axonal sensorimotor neuropathy was found upon repeated testing at age 58. Neuropathic histopathology was present in the quadriceps, and exome sequencing revealed the VCP mutation c.290 C>T, p.Gly97Glu. Conclusions. Our patient reflects the clinical heterogeneity of VCP mutations, as his neurological localization is a spectrum between a lower motor neuron disorder and a hereditary axonal peripheral neuropathy such as CMT2. Our case demonstrates a rare manifestation of the c.290 C>T, pGly97Glu VCP mutation.