Options in the Treatment of Subacute Sclerosing Panencephalitis: Implications for Low Resource Areas

Purpose of the review Subacute sclerosing panencephalitis (SSPE) is a rare, slowly progressive, and frequently fatal neurodegenerative disorder caused by measles virus. The risk of SSPE remains signifcant globally, with fuctuating incidence noted in in tandem with measles vaccine uptake. This review aims to explore the current global status of SSPE, its treatment, and preventive measures. Recent findings An increase in measles cases have been reported in various parts of the world for different reasons related to the regional context of the outbreak. With reduction in measles vaccine doses since the onset of the COVID-19 pandemic, the future risk of SSPE can only accelerate. In recent years, subsequent cases of SSPE have been reported in the period following documented measles outbreaks in different settings. Concomitantly, there have been efforts to evaluate the effcacy of immunomodulatory, antiviral, and antiseizure therapies that could ameliorate the devastating effects of this disease. This review elucidates on these approaches and their limitations, reasons for poor vaccine coverage in low- and middle-income countries, as well as the possible solutions to the prevention of measles and eventual avoidance of SSPE. Summary Prevention of measles virus infection with the resultant sequelae would be the most effective strategy for the management of SSPE. This approach would be particularly important in low resource setting that currently bears the double burden of widespread communicable diseases and malnutrition

Temporary Efficacy of Pyrimethamine in Juvenile-Onset Tay-Sachs Disease Caused by 2 Unreported HEXA Mutations in the Indian Population

Background: Juvenile Tay-Sachs disease is rarer than other forms of Tay-Sachs disease and is usually seen in children between the age of 2 and 10 years. Pyrimethamine as a pharmacological chaperone was used to increase β-hexosaminidase A activity in this patient. Patient: We describe a patient with Tay-Sachs disease from the Indian population, a juvenile case who presented with developmental regression starting at the age of three, initially with motor followed by language regression. She is currently incapacitated with severe behavioral issues. Conclusion: This brief communication gives an insight into the efficacy of pharmacological chaperones. It also describes two unreported mutations in hexosaminidase A gene from the Indian population. After commencing Pyrimethamine, though initial benefits with increase in levels corresponded with briefly halting the motor regression, the observed increase was only transient and not associated with discernible beneficial neurological or psychiatric effects

Diabetes Mellitus as the Presenting Feature of Friedreich's Ataxia

Patients with Friedreich's ataxia (FA) are at an increased risk of developing diabetes mellitus and glucose intolerance. Diabetes usually develops many years after the initial presentation. We report an 8-year-old girl who initially presented with diabetic ketoacidosis and was treated as a case of insulin-dependent diabetes mellitus. Around a year later, she developed gait problems and ataxia. Cardiac involvement was detected on echocardiography. Genetic testing confirmed the diagnosis of FA. FA should be a diagnostic consideration in children presenting with diabetes and neurological issues, even with early presentation of the former. Early occurrence of diabetes and rapid progression of ataxia in this patient needs a better understanding of underlying genetic mechanisms

Giant axonal neuropathy: Clinical, radiological, and genetic features

Introduction: Giant axonal neuropathy (GAN) is an inherited neurodegenerative disorder caused by mutations in the GAN gene. It affects both the central and peripheral nervous systems. We discuss clinical, electrophysiological, radiological and genetic features in three new unrelated patients with GAN. Methods: Three pediatric patients with suspected GAN were included. The diagnosis was considered in patients with early onset polyneuropathy and characteristic hair with central nervous system involvement or suggestive neuroimaging findings. Biochemical, metabolic and electrophysiological investigations were performed. Diagnosis was confirmed by targeted sequencing of the GAN gene. Results: All the three patients were found to have biallelic mutations in GAN gene. Peripheral neuropathy, characteristic hair, and cerebellar dysfunction were present in all three while bony deformities, cranial nerve involvement and intellectual disability were seen variably. Neuroimaging showed a spectrum of findings which are discussed. Conclusion: GAN is a clinically and radiologically heterogeneous disease where genetic testing is necessary for a definite diagnosis and counselling. With facilities for testing becoming increasingly available, the spectrum is likely to expand further

CLIPPERS Spectrum Disorder: A Rare Pediatric Neuroinflammatory Condition

CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) is a recently described, rare neuroinflammatory disorder diagnosed by clinical symptoms involving the brain stem with a distinct pattern on neuroimaging and a perivascular T-lymphocyte infiltrate on brain biopsy. It is a condition usually described in adults in the fourth to fifth decade. We report a case of 13-year-old Indian boy who presented with recurrent episodes of ataxia and diplopia with onset at 7 years of age. He was investigated extensively to rule out infective, neoplastic, autoimmune, and demyelinating conditions over a span of 6 years. The diagnosis of CLIPPERS was entertained on the basis of clinico-radio-pathological correlation. Treatment with steroids and steroid-sparing agents, particularly methotrexate, seems to provide a promising outcome. With very few cases in literature so far, reporting of a larger case series with pediatric onset may expand it to CLIPPERS spectrum disorder

Development of global rating instruments for pediatric patients with ataxia telangiectasia

NTRODUCTION: Ataxia telangiectasia (AT) is a neurodegenerative disorder with cerebellar and extrapyramidal features. Interventional and epidemiological studies in AT should rely on specific scales which encompass the specific neurological features, as well the early progressive course and the subsequent plateau. The aim of this study was to build a scale of the CGI type (Clinical Global Impression) which is disease specific, as well as to check the feasibility of the ICARS scale for ataxia in this population. METHODS: We recruited 63 patients with ataxia, aged 10.76 ± 3.2 years, followed at 6 international AT centers, 49 of them (77.8%) with classical AT. All patients were evaluated for ataxia with ICARS scale. In patients with AT, two CGI scales were scored, unstructured as structured for which separate anchors were provided. RESULTS: Mean ICARS score was 44.7 ± 20.52, and it's severity positively correlated with age (Spearman correlation, r = 0.46, p < 0.01). Mean CGI score was 2 (moderately involved). There was a high correlation between the structured and unstructured CGIs (Spearman correlation, r = 0.87, p < 0.01). Both CGI scales showed positive correlation between severity and increasing age (Spearman correlation r = 0.59, p < 0.01 for structured CGI and r = 0.61, p < 0.01 for unstructured). DISCUSSION: We succeeded to build two CGI scales: structured and unstructured, which are disease specific for AT. The unstructured scale showed better connection to disease course; the sensitivity of the unstructured scale could be improved by adding anchors related to extrapyramidal features. In addition we showed that ataxia can be reliably measured in children with AT by using ICAR

Multi-gene testing in neurological disorders showed an improved diagnostic yield: data from over 1000 Indian patients

Background Neurological disorders are clinically heterogeneous group of disorders and are major causes of disability and death. Several of these disorders are caused due to genetic aberration. A precise and confirmatory diagnosis in the patients in a timely manner is essential for appropriate therapeutic and management strategies. Due to the complexity of the clinical presentations across various neurological disorders, arriving at an accurate diagnosis remains a challenge. Methods We sequenced 1012 unrelated patients from India with suspected neurological disorders, using TruSight One panel. Genetic variations were identified using the Strand NGS software and interpreted using the StrandOmics platform. Results We were able to detect mutations in 197 genes in 405 (40%) cases and 178 mutations were novel. The highest diagnostic rate was observed among patients with muscular dystrophy (64%) followed by leukodystrophy and ataxia (43%, each). In our cohort, 26% of the patients who received definitive diagnosis were primarily referred with complex neurological phenotypes with no suggestive diagnosis. In terms of mutations types, 62.8% were truncating and in addition, 13.4% were structural variants, which are also likely to cause loss of function. Conclusion In our study, we observed an improved performance of multi-gene panel testing, with an overall diagnostic yield of 40%. Furthermore, we show that NGS (next-generation sequencing)-based testing is comprehensive and can detect all types of variants including structural variants. It can be considered as a single-platform genetic test for neurological disorders that can provide a swift and definitive diagnosis in a cost-effective manner

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia

Abstract Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0–49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2–5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1–46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an ‘AP-4 deficiency syndrome’. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.</jats:p