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1.
J Neurogenet ; 38(2): 27-34, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38975939

RESUMEN

Tropical ataxic neuropathy (TAN) is characterised by ataxic polyneuropathy, degeneration of the posterior columns and pyramidal tracts, optic atrophy, and sensorineural hearing loss. It has been attributed to nutritional/toxic etiologies, but evidence for the same has been equivocal. TAN shares common clinical features with inherited neuropathies and mitochondrial disorders, it may be hypothesised that genetic abnormalities may underlie the pathophysiology of TAN. This study aimed to establish evidence for mitochondrial dysfunction by adopting an integrated biochemical and multipronged genetic analysis. Patients (n = 65) with chronic progressive ataxic neuropathy with involvement of visual and/or auditory pathways underwent deep phenotyping, genetic studies including mitochondrial DNA (mtDNA) deletion analysis, mtDNA and clinical exome sequencing (CES), and respiratory chain complex (RCC) assay. The phenotypic characteristics included dysfunction of visual (n = 14), auditory (n = 12) and visual + auditory pathways (n = 29). Reduced RCC activity was present in 13 patients. Mitochondrial DNA deletions were noted in five patients. Sequencing of mtDNA (n = 45) identified a homoplasmic variant (MT-ND6) and a heteroplasmic variant (MT-COI) in one patient each. CES (n = 45) revealed 55 variants in nuclear genes that are associated with neuropathy (n = 27), deafness (n = 7), ataxia (n = 4), and mitochondrial phenotypes (n = 5) in 36 patients. This study provides preliminary evidence that TAN is associated with a spectrum of genetic abnormalities, including those associated with mitochondrial dysfunction, which is in contradistinction from the prevailing hypothesis that TAN is related to dietary toxins. Analysing the functional relevance of these genetic variants may improve the understanding of the pathogenesis of TAN.


Asunto(s)
Ataxia , ADN Mitocondrial , Humanos , Masculino , Femenino , ADN Mitocondrial/genética , Adulto , Persona de Mediana Edad , Ataxia/genética , Adolescente , Enfermedades Mitocondriales/genética , Adulto Joven , Mitocondrias/genética , Niño , Anciano , Secuenciación del Exoma , Fenotipo
2.
J Peripher Nerv Syst ; 29(1): 6-16, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37988274

RESUMEN

Immune checkpoint molecules play pivotal roles in the regulation of immune homeostasis. Disruption of the immune checkpoints causes autoimmune/inflammatory as well as malignant disorders. Over the past few years, the immune checkpoint molecules with inhibitory function emerged as potential therapeutic targets in oncological conditions. The inhibition of the function of these molecules by using immune checkpoint inhibitors (ICIs) has brought paradigmatic changes in cancer therapy due to their remarkable clinical benefits, not only in improving the quality of life but also in prolonging the survival time of cancer patients. Unfortunately, the ICIs soon turned out to be a "double-edged sword" as the use of ICIs caused multiple immune-related adverse effects (irAEs). The development of inflammatory neuropathies such as Guillain-Barré syndrome (GBS) and Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) as the secondary effects of immunotherapy appeared very challenging as these conditions result in significant and often permanent disability. The underlying mechanism(s) through which ICIs trigger inflammatory neuropathies are currently not known. Compelling evidence suggests autoimmune reaction and/or inflammation as the independent risk mechanism of inflammatory neuropathies. There is a lack of understanding as to whether prior exposure to the risk factors of inflammatory neuropathies, the presence of germline genetic variants in immune function-related genes, genetic variations within immune checkpoint molecules, the existence of autoantibodies, and activated/memory T cells act as determining factors for ICI-induced inflammatory neuropathies. Herein, we highlight the available pieces of evidence, discuss the mechanistic basis, and propose a few testable hypotheses on inflammatory neuropathies as irAEs of immunotherapy.


Asunto(s)
Síndrome de Guillain-Barré , Neoplasias , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Humanos , Proteínas de Punto de Control Inmunitario/uso terapéutico , Calidad de Vida , Síndrome de Guillain-Barré/inducido químicamente , Síndrome de Guillain-Barré/tratamiento farmacológico , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/inducido químicamente , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/tratamiento farmacológico , Neoplasias/tratamiento farmacológico
3.
Brain ; 146(12): 5098-5109, 2023 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-37516995

RESUMEN

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% 'solved' and ∼13% 'possibly solved' outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.


Asunto(s)
Distrofia Muscular de Cinturas , Distrofias Musculares , Enfermedades Neuromusculares , Enfermedades del Sistema Nervioso Periférico , Humanos , Enfermedades Neuromusculares/genética , Distrofia Muscular de Cinturas/diagnóstico , ADN
4.
J Neurogenet ; 36(1): 21-31, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35499206

RESUMEN

The Hereditary Spastic Paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders characterized by length dependent degeneration of the corticospinal tracts. Genetic data related to HSPs are limited from India. We aimed to comprehensively analyse the phenotypic characteristics and genetic basis of a large cohort of HSP from India. Patients with HSP phenotype were evaluated for their clinical features, electrophysiological and radiological abnormalities. Genetic analyses were carried out by clinical exome sequencing (n = 52) and targeted sequencing (n = 5). The cohort comprised of 57 probands (M:F 40:17, age: 3.5-49 years). Based on the phenotype, the cohort could be categorized as 'pure' (n = 15, 26.3%) and 'complicated' (n = 42, 73.7%) HSP. Brain MRI showed thin corpus callosum (n = 10), periventricular hyperintensities (n = 20), cerebral atrophy (n = 3), cerebellar atrophy (n = 3) and diffuse atrophy (n = 4). Sixty-seven variants representing 40 genes were identified including 47 novel variants. Forty-eight patients (84.2%) had variants in genes previously implicated in HSP and other spastic paraplegia syndromes (SPG genes = 24, non-SPG genes = 24); among these 13 had variations in more than one gene and 12 patients (21.0%) had variations in genes implicated in potentially treatable/modifiable metabolic disorders (MTHFR = 8, MTRR = 1, ARG1 = 2 and ABCD1 = 1). In nine patients, no genetic variants implicated in spastic paraplegia phenotype were identified. Thus, the present study from India highlights the phenotypic complexities and spectrum of genetic variations in patients with HSP including those implicated in metabolically modifiable disorders. It sets a platform for carrying out functional studies to validate the causal role of the novel variants and variants of uncertain significance.


Asunto(s)
Paraplejía Espástica Hereditaria , Atrofia , Perfil Genético , Humanos , Mutación , Paraplejía , Fenotipo , Paraplejía Espástica Hereditaria/genética
5.
J Neurol Neurosurg Psychiatry ; 93(12): 1299-1305, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36376023

RESUMEN

BACKGROUND: High-level evidence for using steroids in epileptic encephalopathy (EE), other than West syndrome (WS), is lacking. This study investigated the efficacy and safety of pulse intravenous methylprednisolone (IVMP) in EE other than WS. METHODS: This is an open-label evaluator-blinded randomised controlled study. Children aged 6 months or more with EE other than WS were included. Eighty children were randomised into intervention and non-intervention groups with 40 in each group. At the first visit (T1) seizure frequency, electroencephalographic (EEG) and Vineland Social Maturity Scale (VSMS) were obtained, and antiseizure medication (ASM) were optimised. After 1 month (T2), subjects were randomised to intervention (ASM+3 months IVMP pulse) or non-intervention group (only ASM) with 40 subjects in each group. They were followed up for 4 months (T3) and assessed. RESULTS: After 4 months of follow-up, 75% of patients receiving IVMP had >50% seizure reduction versus 15.4% in control group (χ2=28.29, p<0.001) (RR 4.88, 95% CI 2.29 to 10.40), median percentage change in seizure frequency (91.41% vs 10%, p<0.001), improvement in EEG (45.5% vs 9.4%, χ2=10.866, p=0.001) and social age domain of VSMS scores (Z=-3.62, p<0.001) compared with baseline. None of the patients in the intervention group had any serious side-effects. DISCUSSION: Three-month pulse IVMP therapy showed significant improvement in seizure frequency, EEG parameters and VSMS scores, with no steroid-related serious adverse effects. It can be considered as a safe and effective add on treatment in children with EE other than WS. TRIAL REGISTRATION NUMBER: CTRI/2019/02/017807.


Asunto(s)
Encefalopatías , Metilprednisolona , Niño , Humanos , Metilprednisolona/efectos adversos , Convulsiones/terapia , Resultado del Tratamiento , Administración Intravenosa
6.
Eur J Neurol ; 29(7): 2074-2083, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35322935

RESUMEN

BACKGROUND: The IL-33/ST2 immune axis plays crucial roles in infection and immunity. A dysregulated IL-33/ST2 axis can induce autoimmune reaction and inflammatory responses. Guillain-Barré syndrome (GBS) is an acute peripheral neuropathy, mostly caused by post-infection autoimmunity. The role of IL-33/ST2 axis is not known in GBS. This study aimed to explore the role of IL-33/ST2 axis in GBS. METHODS: Three single nucleotide polymorphisms (SNPs) of Il33 gene (rs16924159, rs7044343, rs1342336) and three SNPs of Il1rl1 gene (rs10192157, rs1041973, rs10206753) coding for suppressor of tumorigenicity 2 (ST2) were genotyped in 179 GBS patients and 186 healthy controls by TaqMan Allelic Discrimination Assay. Plasma levels of IL-33 and sST2 were measured in a subset of GBS patients (n = 80) and healthy controls (n = 80) by ELISA. RESULTS: The frequencies of CC genotype of rs10192157 (p = 0.043) and TT genotype of rs10206753 (p = 0.036) SNPs of Il1rl1 gene differed significantly between GBS patients and healthy controls. Gene-gene interaction between Il33 and Il1rl1 genes also conferred significant risk for GBS. In addition, the plasma sST2 levels were significantly elevated in GBS patients compared to healthy subjects (24,934.31 ± 1.81 pg/ml vs. 12,518.97 ± 1.51 pg/ml, p < 0.001). Plasma sST2 levels showed a significant correlation with the disability scores at the peak of neurological deficit in GBS patients. CONCLUSIONS: The IL-33/ST2 axis is suggested to influence the immunopathogenesis of GBS. Genetic variants of Il1rl1 gene might serve as a risk determinant of GBS and plasma sST2 levels might emerge as a biomarker of severity of GBS, if replicated further by other studies.


Asunto(s)
Síndrome de Guillain-Barré , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Genotipo , Síndrome de Guillain-Barré/inmunología , Humanos , Proteína 1 Similar al Receptor de Interleucina-1/genética , Interleucina-33/genética , Polimorfismo de Nucleótido Simple
7.
J Peripher Nerv Syst ; 27(2): 131-143, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35138004

RESUMEN

Guillain-Barré syndrome (GBS) is the commonest post-infectious polyradiculopathy. Although genetic background of the host seems to play an important role in the susceptibility to GBS, genes conferring major risk are not yet known. Dysregulation of Toll-like receptor (TLR) molecules exacerbates immune-inflammatory responses and the genetic variations within TLR pathway-related genes contribute to differential risk to infection. The aim of this study was to delineate the impact of genetic variations within TLR2, TLR3, and TLR4 genes as well as TLR signaling pathway-related genes such as MyD88, TRIF, TRAF3, TRAF6, IRF3, NFκß1, and IκBα on risk of developing GBS. Fourteen polymorphisms located within TLR2 (rs3804099, rs111200466), TLR3 (rs3775290, rs3775291), TLR4 (rs1927911, rs11536891), MyD88 (rs7744, rs4988453), TRIF (rs8120), TRAF3 (rs12147254), TRAF6 (rs4755453), IRF3 (rs2304204), NFκß1 (rs28362491), and IκBα (rs696) genes were genotyped in 150 GBS patients and 150 healthy subjects either by PCR-RFLP or TaqMan Allelic Discrimination Assay. Genotypes of two polymorphic variants, Del/Del of rs111200466 insertion and deletion (INDEL) polymorphism of TLR2 gene and TT of rs3775290 single nucleotide polymorphism (SNP) of TLR3 gene had significantly higher frequencies among GBS patients, while the frequencies of TT genotype of rs3804099 SNP of TLR2 gene and TT genotype of rs11536891 SNP of TLR4 gene were significantly higher in controls. Gene-gene interaction study by Multifactor Dimensionality Reduction analysis also suggested a significant combined effect of TLR2, and NFκß1 genes on the risk of GBS. The SNPs in the IκBα and IRF3 genes correlated with severity of GBS. The genes encoding TLRs and TLR signaling pathway-related molecules could serve as crucial genetic markers of susceptibility and severity of GBS.


Asunto(s)
Síndrome de Guillain-Barré , Receptor Toll-Like 2 , Receptores Toll-Like , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/farmacología , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad/genética , Síndrome de Guillain-Barré/genética , Humanos , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/farmacología , Inhibidor NF-kappaB alfa/genética , Polimorfismo de Nucleótido Simple , Transducción de Señal/genética , Factor 3 Asociado a Receptor de TNF/genética , Factor 3 Asociado a Receptor de TNF/farmacología , Factor 6 Asociado a Receptor de TNF/genética , Factor 6 Asociado a Receptor de TNF/farmacología , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 3/genética , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Receptores Toll-Like/genética
8.
Can J Neurol Sci ; 49(5): 708-712, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-34663487

RESUMEN

Vanishing white matter disease (VWMD) due to eIF2B mutations is a common leukodystrophy characterised by childhood onset, autosomal recessive inheritance, and progressive clinical course with episodic worsening. There are no reports of genetically confirmed adult patients from India. We describe the phenotype of two adults with genetically confirmed VWMD and typical radiological findings. Both had spastic ataxia and cognitive and behavioural disturbances. Other neurological features included myoclonic jerks and parkinsonism. At the last follow-up (duration: 2-9 years), one patient was wheelchair-bound. VWMD is rare in adults but should be suspected based on radiological findings and confirmed by eIF2B mutation.


Asunto(s)
Enfermedades Desmielinizantes , Factor 2B Eucariótico de Iniciación , Leucoencefalopatías , Enfermedades Neurodegenerativas , Factor 2B Eucariótico de Iniciación/genética , Humanos , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/genética , Mutación/genética , Fenotipo
9.
Metab Brain Dis ; 37(3): 743-760, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34997870

RESUMEN

BACKGROUND: Disorders of tetrahydrobiopterin metabolism represent a rare group of inherited neurotransmitter disorders that manifests mainly in infancy or childhood with developmental delay, neuroregression, epilepsy, movement disorders, and autonomic symptoms. METHODOLOGY: A retrospective review of genetically confirmed cases of disorders of tetrahydrobiopterin metabolism over a period of three years (Jan 2018 to Jan 2021) was performed across two paediatric neurology centres from South India. RESULTS: A total of nine patients(M:F=4:5) fulfilled the eligibility criteria. The genetic variants detected include homozygous mutations in the QDPR(n=6), GCH1(n=2), and PTS(n=1) genes. The median age at onset of symptoms was 6-months(range 3-78 months), while that at diagnosis was 15-months (8-120 months), resulting in a median delay in diagnosis of 9-months. The main clinical manifestations included neuroregression (89%), developmental delay(78%), dystonia(78%) and seizures(55%). Management strategies included a phenylalanine restricted diet, levodopa/carbidopa, 5-Hydroxytryphtophan, and folinic acid. Only, Patient-2 afforded and received BH4 supplementation at a sub-optimal dose later in the disease course. We had a median duration of follow up of 15 months (range 2-48 months). Though the biochemical response has been marked; except for patients with GTPCH deficiency, only mild clinical improvement was noted with regards to developmental milestones, seizures, or dystonia in others. CONCLUSION: Tetrahydrobiopterin deficiencies represent a rare yet potentially treatable cause for non-phenylketonuria hyperphenylalaninemia with better outcomes when treated early in life. Screening for disorders of biopterin metabolism in patients with hyperphenylalaninemia prevents delayed diagnosis. This study expands the genotype-phenotype spectrum of patients with disorders of tetrahydrobiopterin metabolism from South India.


Asunto(s)
Distonía , Fenilcetonurias , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Biopterinas/uso terapéutico , Niño , Preescolar , Distonía/genética , Femenino , Humanos , Lactante , Masculino , Fenilalanina , Fenilcetonurias/diagnóstico , Fenilcetonurias/tratamiento farmacológico , Fenilcetonurias/genética
10.
J Peripher Nerv Syst ; 26(3): 298-306, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34254392

RESUMEN

Guillain-Barré syndrome (GBS) is the commonest post-infectious inflammatory peripheral neuropathy with undiscerned aetiology. The commonly reported antecedent infections implicated in India include Campylobacter jejuni, chikungunya, dengue, and Japanese encephalitis (JE). In this study from south India, we investigated the role of these four agents in triggering GBS. This case-control study was performed on 150 treatment-naive patients with GBS and 150 age and sex-matched controls from the same community. IgM immunoreactivity for C. jejuni, chikungunya, and dengue was detected by enzyme-linked immunosorbent assay (ELISA) in serum of patients with GBS and control subjects. Immunoreactivity against JE was detected in serum as well as cerebrospinal fluid (CSF) from patients (n = 150) and orthopaedic control (n = 45) subjects. The immunoreactivity against infections was compared between demyelinating and axonal subtypes of GBS. Overall, 119/150 patients with GBS had serological evidence of antecedent infection. Amongst those with evidence of antecedent infection, 24 (16%), 8 (5%), and 9 (6%) patients were exclusively immunoreactive to chikungunya, JE, and C. jejuni, respectively. In the remaining patients (78/119), immunoreactivity to multiple pathogens was noted. Immunoreactivity to C. jejuni infection was found in 32% of GBS patients compared to 2.7% controls (P < .001), whereas to chikungunya virus was reported in 66.7% of patients with GBS compared to 44.7% controls (P = .006). Anti-dengue immunoreactivity was significantly associated with the demyelinating subtype of GBS. Patients positive for JE IgM (CSF) manifested demyelinating electrophysiology. In this large case-control study, immunoreactivity against multiple infectious agents was observed in a subset of patients. Chikungunya was the commonest antecedent infection, followed by C. jejuni.


Asunto(s)
Síndrome de Guillain-Barré , Estudios de Casos y Controles , Fiebre Chikungunya/complicaciones , Fiebre Chikungunya/epidemiología , Dengue/complicaciones , Dengue/epidemiología , Síndrome de Guillain-Barré/epidemiología , Humanos , Inmunoglobulina M
11.
Acta Neurol Scand ; 144(2): 155-160, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33899225

RESUMEN

OBJECTIVES: Median nerve enlargement in leprosy seems to be more proximal than in carpal tunnel syndrome (CTS), but this feature has not been studied systematically. The aim of the study was to compare the sites of median nerve enlargement in patients with leprosy with that of patients with CTS. MATERIALS AND METHODS: Transverse sections of the median nerve were recorded from wrist to the mid-forearm (at distal wrist crease and at 2-cm: M1, 4-cm: M2, 6-cm: M3, 8-cm: M4 and 10-cm: M5, proximal to the distal wrist crease in the forearm) in patients with leprosy, CTS and healthy subjects using high-resolution ultrasound. RESULTS: Twenty-six patients each with leprosy and CTS were compared with healthy controls. Patients with leprosy included 6 (23.1%), 7 (26.9%), 7 (26.9%) and 6 (23.1%) patients with borderline tuberculoid, borderline-borderline, borderline lepromatous and lepromatous leprosy, respectively. Cross-sectional area (CSA) of median nerve was increased in all patients with leprosy as compared to healthy controls at all points of measurement. CSA was higher among patients with leprosy as compared to CTS at all points except at the wrist. In patients with leprosy, the maximal enlargement was noted 2-cm (M1) proximal to the wrist crease with gradual tapering of the CSA proximally (p < .05). In contrast, in patients with CTS the median nerve was maximally enlarged at the distal wrist crease (p<.05). CONCLUSIONS: Median nerve enlargement 2-cm proximal to the distal wrist crease distinguishes leprosy from CTS. This important discriminating sign can be used at point-of-care to identify patients with leprosy.


Asunto(s)
Síndrome del Túnel Carpiano/diagnóstico por imagen , Síndrome del Túnel Carpiano/patología , Lepra/patología , Nervio Mediano/diagnóstico por imagen , Nervio Mediano/patología , Adulto , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ultrasonografía
12.
Hum Genomics ; 13(1): 53, 2019 10 22.
Artículo en Inglés | MEDLINE | ID: mdl-31640787

RESUMEN

BACKGROUND: Dysfunction in inwardly rectifying potassium channel Kir4.1 has been implicated in SeSAME syndrome, an autosomal-recessive (AR), rare, multi-systemic disorder. However, not all neurological, intellectual disability, and comorbid phenotypes in SeSAME syndrome can be mechanistically linked solely to Kir4.1 dysfunction. METHODS: We therefore performed whole-exome sequencing and identified additional genetic risk-elements that might exert causative effects either alone or in concert with Kir4.1 in a family diagnosed with SeSAME syndrome. RESULTS: Two variant prioritization pipelines based on AR inheritance and runs of homozygosity (ROH), identified two novel homozygous variants in KCNJ10 and PI4KB and five rare homozygous variants in PVRL4, RORC, FLG2, FCRL1, NIT1 and one common homozygous variant in HSPA6 segregating in all four patients. The novel mutation in KCNJ10 resides in the cytoplasmic domain of Kir4.1, a seat of phosphatidylinositol bisphosphate (PIP2) binding. The mutation altered the subcellular localization and stability of Kir4.1 in patient-specific lymphoblastoid cells (LCLs) compared to parental controls. Barium-sensitive endogenous K+ currents in patient-specific LCLs using whole-cell patch-clamp electrophysiology revealed membrane depolarization and defects in inward K+ ion conductance across the membrane, thereby suggesting a loss-of-function effect of KCNJ10 variant. CONCLUSION: Altogether, our findings implicate the role of new genes in SeSAME syndrome without electrolyte imbalance and thereby speculate the regulation of Kir4.1 channel activity by PIP2 and integrin-mediated adhesion signaling mechanisms.


Asunto(s)
Pérdida Auditiva Sensorineural/genética , Discapacidad Intelectual/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Canales de Potasio de Rectificación Interna/genética , Convulsiones/genética , Adolescente , Adulto , Niño , Femenino , Proteínas Filagrina , Pérdida Auditiva Sensorineural/patología , Homocigoto , Humanos , Discapacidad Intelectual/patología , Masculino , Mutación/genética , Fenotipo , Convulsiones/patología , Secuenciación del Exoma , Adulto Joven
13.
Muscle Nerve ; 62(6): 728-734, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32939766

RESUMEN

BACKGROUND: Antibodies against ganglioside complexes (GSCs) are associated with various clinical features and subtypes of Guillain-Barré syndrome (GBS). METHODS: One-hundred patients were evaluated for antibodies to GSCs formed by combination of GM1, GM2, GD1a, GD1b, GT1b, and GQ1b using manual enzyme linked immuno-sorbent assay (ELISA). RESULTS: Twenty-six patients were GSC antibody-positive, most frequent being against GM1-containing GSC (76.9%). Gender distribution, mean age, symptom-duration, antecedent events, electrophysiological subtypes, requirement for mechanical ventilation, and median duration of hospital stay were comparable between the GSC antibody-positive and negative groups. There was no association between specific GSC antibody and electrophysiological subtypes or clinical variants. After controlling for false discovery rate (FDR) using the Benjamini-Hochberg method, the number of subjects who improved in overall disability sum score, modified Erasmus GBS outcome score, and neuropathy symptom score at discharge was significantly higher in the GSC antibody-positive group. Improvements in Medical Research Council sum scores and Hughes Disability Scale during the hospital stay between the GSC antibody-positive and negative groups were not significantly different after controlling for FDR. CONCLUSIONS: The GSC antibody-positive group had better outcome at hospital discharge in some of the disability scores. Pathophysiological pathways among patients without GSC antibodies may be different and this requires further evaluation.


Asunto(s)
Autoanticuerpos/inmunología , Gangliósidos/inmunología , Síndrome de Guillain-Barré/inmunología , Adolescente , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Femenino , Gangliósido G(M1)/inmunología , Gangliósido G(M2)/inmunología , Síndrome de Guillain-Barré/fisiopatología , Síndrome de Guillain-Barré/terapia , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , India , Masculino , Persona de Mediana Edad , Plasmaféresis , Respiración Artificial , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
14.
Acta Neurol Scand ; 139(5): 428-437, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30693486

RESUMEN

BACKGROUND: Data on antibody profile in myasthenia gravis (MG) from India are limited. OBJECTIVES: To investigate antibody profile in patients with MG and their clinical correlates. PATIENTS AND METHODS: Patients of MG (n = 85, M:F::1.1:1, mean age: 39.29 ± 17.3 years, mean symptom duration: 72.94 ± 91.8 months) were evaluated for clinical features, MG foundation of America (MGFA) score, response to treatment, and outcome at last follow-up. Antibodies to acetylcholine receptor (AChR), muscle-specific kinase (MUSK), titin and ryanodine receptor (RYR) were analysed using ELISA. RESULTS: Based on the regional distribution of weakness, the cohort could be categorized as: generalized: 60, ocular: 16 and oculo-bulbar: 9. Sixty patients were followed up for a mean duration of 26.74 ± 13.8 months. Outcome at last follow-up was as follows: remission-22, no remission-33 and dead-5. AChR and MUSK antibodies were detected in 58 and 8 patients, respectively. Frequency of generalized MG, worse MGFA score during the disease course and thymomatous histology significantly correlated with presence of AChR-antibodies, though outcome at last follow-up was comparable between AChR-antibody positive and negative groups. Patients with MUSK antibodies had oculo-bulbar or generalized MG and frequent respiratory crisis, but majority improved or remitted with treatment. Titin antibodies were detected in 31.8% and RYR antibodies in 32.9%. Their presence did not correlate with age at onset of MG, severity or presence of thymoma. CONCLUSION: This report highlights the spectrum of antibodies in MG in an Indian cohort. AChR-antibody positivity correlated with clinical severity. Outcome was good in majority of MUSK antibody-positive MG. The role of other antibodies, complementary vs epiphenomenon, remains open.


Asunto(s)
Autoanticuerpos/inmunología , Miastenia Gravis/inmunología , Adulto , Pueblo Asiatico , Autoantígenos/inmunología , Estudios de Cohortes , Conectina/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , India , Masculino , Persona de Mediana Edad , Fenotipo , Proteínas Tirosina Quinasas Receptoras/inmunología , Receptores Colinérgicos/inmunología , Canal Liberador de Calcio Receptor de Rianodina/inmunología , Adulto Joven
15.
Cytokine ; 103: 77-82, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29331587

RESUMEN

Guillain Barré Syndrome (GBS) is a severe disorder of the peripheral nervous system with an inadequately known etiopathology. It is a post infectious immune mediated disorder, characterized by autoantibody production, complement activation as well as T reactivity against gangliosides. However, the precise etiopathogenesis remains poorly understood in a majority of the patients. Th17 cells, a recently identified lineage of Th cells have emerged as a predominant inducer of autoimmunity and inflammation in various immunological disorders. Pathobiological role of Th17 pathway is also becoming increasingly apparent in the nervous system disorders. Two cytokines, such as IL-23, known to determine the pathogenic potential of Th17 cells and IL-17, a prototype effector cytokine of Th17 pathway can form IL-23/IL-17 immune axis. Aberrant functioning of this immune axis has been implicated in many autoimmune diseases. Therapeutic strategies that potentially target this immune axis have shown encouraging results in diseases with immunological underpinnings. Preliminary data obtained both from animal and clinical studies indicate a possible role of this immune axis in GBS. Herein, we explore and highlight the relevance and functional implications of IL-23/IL-17 immune axis in GBS. Understanding this immune axis may shed important insights into the etiology and treatment of GBS.


Asunto(s)
Síndrome de Guillain-Barré/inmunología , Síndrome de Guillain-Barré/patología , Síndrome de Guillain-Barré/terapia , Interleucina-17/inmunología , Interleucina-23/inmunología , Células Th17/inmunología , Humanos , Células Th17/patología
16.
Cytokine ; 110: 58-62, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29704819

RESUMEN

Guillain Barré Syndrome (GBS) is one of the commonest acquired immune-mediated neuropathies, often preceded by infections. Although cellular immune responses are shown to substantially account for the pathophysiology of GBS, the precise mechanistic basis of risk and disease course remains enigmatic till date. Cytokines are best known for their abilities to drive cellular immunity and inflammation through their co-ordinated actions. Data obtained from clinical and animal model studies suggest important implications of some of the cytokines in the progression and recovery of GBS. However, these studies were performed on few cytokines and small set of GBS patients, thereby lacking a complete understanding of the patterns of association of cytokines representing Th1, Th2, and Th17 responses with GBS. We studied 65 well-characterized GBS patients and 73 age- and sex-matched healthy controls. A panel of 15 cytokines representing Th1, Th2 and Th17 pathways was assayed using Multiplex Suspension Array platform. Plasma levels of five cytokines were found to be altered in GBS patients compared to healthy control subjects: (i) IL-1ß exhibited reduced levels, and (ii) IFN-γ, IL-4, IL-21 and IL-33 were elevated in GBS patients. The most important finding of this study was up-regulated expression of IL-21 and IL-33 in patients with GBS. Given the role of IL-33 as an alarmin, the elevated level of this cytokine provides important indication about a much broader role of cytokines in GBS. This study also provides evidence towards a multi-lineage Th cells (Th1, Th2 and Th17) associated cytokine responses in the pathophysiology of GBS.


Asunto(s)
Citocinas/inmunología , Síndrome de Guillain-Barré/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
17.
Can J Neurol Sci ; 45(2): 243-247, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29249217

RESUMEN

This case series aimed to describe clinicoradiological, electromyographic, and etiological spectra in palatal tremor (essential=1; symptomatic=26). Patients with symptomatic palatal tremor had 2 to 10 Hz arrhythmic electromyographic bursts, a spectrum of changes in inferior olivary nucleus, with/without lesions in Guillain Mollaret triangle, and varied etiologies (genetic=9, vascular=6, trauma=3, infections=3). Exome sequencing showed variations in POLG, WDR81, NDUFS8, TENM4, and EEF2. Clinical phenotypes of patients with POLG, WDR81, and NDUFS8 variations were consistent with that described in literature. We highlight salient magnetic resonance imaging features, electrophysiological observations, and diverse etiologies in a large cohort of palatal tremor.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Mutación/genética , Hueso Paladar/fisiopatología , Temblor/genética , Temblor/patología , Adolescente , Adulto , Encéfalo/diagnóstico por imagen , Estudios de Cohortes , ADN Polimerasa gamma/genética , Electromiografía , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , NADH Deshidrogenasa/genética , Proteínas del Tejido Nervioso/genética , Temblor/diagnóstico por imagen , Temblor/fisiopatología , Adulto Joven
18.
Arch Womens Ment Health ; 21(4): 465-469, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29417305

RESUMEN

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is increasingly being recognised to be associated with protean neuropsychiatric manifestations. Anti-NMDAR encephalitis is considered to be the most common amongst the autoimmune-mediated encephalitic disorders. It is caused by the autoantibodies against GluN1 subunits of N-methyl-D-aspartate (NMDA) receptor and manifests with prominent psychiatric symptoms, especially during the initial phase of illness. Literature anti-NMDAR encephalitis presenting with postpartum psychosis is scant. In this report, we present a 28-year-old lady with postpartum psychosis as presenting manifestation of anti-NMDAR encephalitis and discuss the neuropsychiatric manifestations of this emerging entity.


Asunto(s)
Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico , Encéfalo/diagnóstico por imagen , Catatonia/etiología , Periodo Posparto , Trastornos Psicóticos/etiología , Convulsiones/etiología , Adulto , Encefalitis Antirreceptor N-Metil-D-Aspartato/líquido cefalorraquídeo , Encefalitis Antirreceptor N-Metil-D-Aspartato/tratamiento farmacológico , Autoanticuerpos/inmunología , Diagnóstico Diferencial , Femenino , Humanos , Imagen por Resonancia Magnética , Embarazo , Trastornos Psicóticos/diagnóstico , Receptores de N-Metil-D-Aspartato/inmunología , Esteroides/uso terapéutico
19.
Neurol India ; 66(5): 1332-1337, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30232999

RESUMEN

BACKGROUND: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare disorder; there is limited experience regarding its clinical course and therapeutic response. AIMS AND OBJECTIVES: To describe the clinical profile, investigations, and therapeutic outcome in pediatric OMAS. PATIENTS AND METHODS: Fourteen children (age: 27.1 ± 7 months; male: female = 1:2.3) suffering from OMAS seen over a period of 10 years (2006-2015) were included in the study. Their clinicodemographic profile, investigations, therapeutic outcome at follow-up, and relapses were reviewed. RESULTS: Ten children reported antecedent events (respiratory infection: 7; gastrointestinal infection: 1; vaccination: 2). The most common referral diagnosis was acute cerebellitis (n = 8). Hypotonia (n = 9), abnormal behavior (n = 10), and neuroregression (n = 6) were also the frequent manifestations. Brain magnetic resonance imaging, cerebrospinal fluid, and urinary vanillylmandelic acid were normal in all the patients. Seven patients had an underlying tumor (abdomen: 4; thorax: 2; neck: 1) detected by ultrasound (n = 2/14), computed tomography (CT) (n = 6/12), and fluorodeoxyglucose - positron emission tomography (n = 2/2). CT scan identified the tumor in 2 patients where metaiodobenzylguanidine scintigraphy was negative. All patients received steroids for 22.3 ± 20 months (3 months to 5 years). Eight required prolonged immunomodulation (>12 months). Complete remission after follow-up of 31.3 ± 19 months (7 months to 5 years) was noted in 5 patients, whereas the rest had persisting behavioral and cognitive abnormalities. Relapses were noted in 6 patients related to intercurrent infections (n = 5) and discontinuation of steroids (n = 1). The patients presented with isolated symptoms of the full-blown syndrome during their relapses. CONCLUSION: OMAS in children runs an indolent course requiring careful monitoring and long-term immunomodulation. An abnormal behavior is common and the outcome is variable.


Asunto(s)
Síndrome de Opsoclonía-Mioclonía/diagnóstico por imagen , Síndromes Paraneoplásicos/diagnóstico por imagen , Preescolar , Femenino , Glucocorticoides/uso terapéutico , Hospitales Universitarios , Humanos , Lactante , Masculino , Metilprednisolona/uso terapéutico , Síndrome de Opsoclonía-Mioclonía/tratamiento farmacológico , Síndromes Paraneoplásicos/tratamiento farmacológico , Prednisolona/uso terapéutico , Atención Terciaria de Salud , Resultado del Tratamiento
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