Intrathecal Gene Therapy for Giant Axonal Neuropathy.

BACKGROUND: Giant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic, neurodegenerative disorder caused by biallelic loss-of-function variants in GAN, the gene encoding gigaxonin. METHODS: We conducted an intrathecal dose-escalation study of scAAV9/JeT-GAN (a self-complementary adeno-associated virus-based gene therapy containing the GAN transgene) in children with giant axonal neuropathy. Safety was the primary end point. The key secondary clinical end point was at least a 95% posterior probability of slowing the rate of change (i.e., slope) in the 32-item Motor Function Measure total percent score at 1 year after treatment, as compared with the pretreatment slope. RESULTS: One of four intrathecal doses of scAAV9/JeT-GAN was administered to 14 participants - 3.5×1013 total vector genomes (vg) (in 2 participants), 1.2×1014 vg (in 4), 1.8×1014 vg (in 5), and 3.5×1014 vg (in 3). During a median observation period of 68.7 months (range, 8.6 to 90.5), of 48 serious adverse events that had occurred, 1 (fever) was possibly related to treatment; 129 of 682 adverse events were possibly related to treatment. The mean pretreatment slope in the total cohort was -7.17 percentage points per year (95% credible interval, -8.36 to -5.97). At 1 year after treatment, posterior mean changes in slope were -0.54 percentage points (95% credible interval, -7.48 to 6.28) with the 3.5×1013-vg dose, 3.23 percentage points (95% credible interval, -1.27 to 7.65) with the 1.2×1014-vg dose, 5.32 percentage points (95% credible interval, 1.07 to 9.57) with the 1.8×1014-vg dose, and 3.43 percentage points (95% credible interval, -1.89 to 8.82) with the 3.5×1014-vg dose. The corresponding posterior probabilities for slowing the slope were 44% (95% credible interval, 43 to 44); 92% (95% credible interval, 92 to 93); 99% (95% credible interval, 99 to 99), which was above the efficacy threshold; and 90% (95% credible interval, 89 to 90). Between 6 and 24 months after gene transfer, sensory-nerve action potential amplitudes increased, stopped declining, or became recordable after being absent in 6 participants but remained absent in 8. CONCLUSIONS: Intrathecal gene transfer with scAAV9/JeT-GAN for giant axonal neuropathy was associated with adverse events and resulted in a possible benefit in motor function scores and other measures at some vector doses over a year. Further studies are warranted to determine the safety and efficacy of intrathecal AAV-mediated gene therapy in this disorder. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, NCT02362438.).

The CRL3gigaxonin ubiquitin ligase-USP15 pathway governs the destruction of neurofilament proteins.

Giant axonal neuropathy (GAN) is caused by mutations in the GAN gene encoding for gigaxonin (GIG), which functions as an adaptor of the CUL3-RBX1-GIG (CRL3GIG) E3 ubiquitin ligase complex. The pathological hallmark of GAN is characterized by the accumulation of densely packed neurofilaments (NFs) in the axons. However, there are fundamental knowledge gaps in our understanding of the molecular mechanisms by which the ubiquitin-proteasome system controls the homeostasis of NF proteins. Recently, the deubiquitylating enzyme USP15 was reported to play a crucial role in regulating ubiquitylation and proteasomal degradation of CRL4CRBN substrate proteins. Here, we report that the CRL3GIG-USP15 pathway governs the destruction of NF proteins NEFL and INA. We identified a specific degron called NEFLL12 degron for CRL3GIG. Notably, mutations in the C-terminal Kelch domain of GIG, represented by L309R, R545C, and C570Y, disrupted the binding of GIG to NEFL and INA, leading to the accumulation of these NF proteins. This accounts for the loss-of-function mutations in GAN patients. In addition to regulating NFs, CRL3GIG also controls actin filaments by directly targeting actin-filament-binding regulatory proteins TPM1, TPM2, TAGLN, and CNN2 for proteasomal degradation. Thus, our findings broadly impact the field by providing fundamental mechanistic insights into regulating extremely long-lived NF proteins NEFL and INA by the CRL3GIG-USP15 pathway and offering previously unexplored therapeutic opportunities to treat GAN patients and other neurodegenerative diseases by explicitly targeting downstream substrates of CRL3GIG.

[Involvement of autonomic nervous system since middle age in elderly patient with giant axonal neuropathy caused by novel genetic mutation].

A 69-year-old man began to experience difficulty with walking at the age of 5 years and started use of a cane at around 13 years, then finally started using a wheelchair at 17 years old. A diagnosis of Charcot-Marie-Tooth disease was previously determined at another hospital, though neither peripheral nerve biopsy nor gene analysis was conducted. He visited our institution at the age of 54 years and irregular outpatient examinations were started, which indicated slowly progressive muscle weakness and sensory disturbance of the limbs, leading to a decline in activities of daily living. Gene analysis at 60 years old identified a novel homozygous missense mutation in the gigaxonin gene, c.1478A>C, p.E493A. Intellectual capacity was preserved and kinky hair was not present, though complications such as vocal cord paralysis, paralytic ileus, and dysarthria were noted starting at age 61. Based on these findings, the patient was diagnosed with a mild form of giant axonal neuropathy.

Axonal Transport Defect in Gigaxonin Deficiency Rescued by Tubastatin A.

Giant axonal neuropathy (GAN) is a disease caused by a deficiency of gigaxonin, a mediator of the degradation of intermediate filament (IF) proteins. A lack of gigaxonin alters the turnover of IF proteins, provoking accumulation and disorganization of neurofilaments (NFs) in neurons, a hallmark of the disease. However, the effects of IF disorganization on neuronal function remain unknown. Here, we report that cultured embryonic dorsal root ganglia (DRG) neurons derived from Gan-/- mice exhibit accumulations of IF proteins and defects in fast axonal transport of organelles. Kymographs generated by time-lapse microscopy revealed substantial reduction of anterograde movements of mitochondria and lysosomes in axons of Gan-/- DRG neurons. Treatment of Gan-/- DRG neurons with Tubastatin A (TubA) increased the levels of acetylated tubulin and it restored the normal axonal transport of these organelles. Furthermore, we tested the effects of TubA in a new mouse model of GAN consisting of Gan-/- mice with overexpression of peripherin (Prph) transgene. Treatment of 12-month-old Gan-/-;TgPer mice with TubA led to a slight amelioration of motor function, especially a significant improvement of gait performance as measured by footprint analyses. Moreover, TubA treatment reduced the abnormal accumulations of Prph and NF proteins in spinal neurons and it boosted the levels of Prph transported into peripheral nerve axons. These results suggest that drug inhibitors of histone deacetylase aiming to enhance axonal transport should be considered as a potential treatment for GAN disease.

A multilevel screening pipeline in zebrafish identifies therapeutic drugs for GAN.

Giant axonal neuropathy (GAN) is a fatal neurodegenerative disorder for which there is currently no treatment. Affecting the nervous system, GAN starts in infancy with motor deficits that rapidly evolve toward total loss of ambulation. Using the gan zebrafish model that reproduces the loss of motility as seen in patients, we conducted the first pharmacological screening for the GAN pathology. Here, we established a multilevel pipeline to identify small molecules restoring both the physiological and the cellular deficits in GAN. We combined behavioral, in silico, and high-content imaging analyses to refine our Hits to five drugs restoring locomotion, axonal outgrowth, and stabilizing neuromuscular junctions in the gan zebrafish. The postsynaptic nature of the drug's cellular targets provides direct evidence for the pivotal role the neuromuscular junction holds in the restoration of motility. Our results identify the first drug candidates that can now be integrated in a repositioning approach to fasten therapy for the GAN disease. Moreover, we anticipate both our methodological development and the identified hits to be of benefit to other neuromuscular diseases.

A New Mouse Model of Giant Axonal Neuropathy with Overt Phenotypes and Neurodegeneration Driven by Neurofilament Disorganization.

Research on pathogenic mechanisms underlying giant axonal neuropathy (GAN), a disease caused by a deficiency of gigaxonin, has been hindered by the lack of appropriate animal models exhibiting substantial symptoms and large neurofilament (NF) swellings, a hallmark of the human disease. It is well established that intermediate filament (IF) proteins are substrates for gigaxonin-mediated degradation. However, it has remained unknown to what extent NF accumulations contribute to GAN pathogenesis. Here, we report the generation of a new mouse model of GAN that is based on crossing transgenic mice overexpressing peripherin (Prph) with mice knockout for Gan The Gan-/-;TgPer mice developed early onset sensory-motor deficits along with IF accumulations made up of NF proteins and of Prph, causing swelling of spinal neurons at a young age. Abundant inclusion bodies composed of disorganized IFs were also detected in the brain of Gan-/-;TgPer mice. At 12 months of age, the Gan-/-;TgPer mice exhibited cognitive deficits as well as severe sensory and motor defects. The disease was associated with neuroinflammation and substantial loss of cortical neurons and spinal neurons. Giant axons (≥160 µm2) enlarged by disorganized IFs, a hallmark of GAN disease, were also detected in dorsal and ventral roots of the Gan-/-;TgPer mice. These results, obtained with both sexes, support the view that the disorganization of IFs can drive some neurodegenerative changes caused by gigaxonin deficiency. This new mouse model should be useful to investigate the pathogenic changes associated with GAN disease and for drug testing.SIGNIFICANCE STATEMENT Research on pathogenic mechanism and treatment of GAN has been hampered by the lack of animal models exhibiting overt phenotypes and substantial neurofilament disorganization, a hallmark of the disease. Moreover, it remains unknown whether neurologic defects associated with gigaxonin deficiency in GAN are because of neurofilament disorganization as gigaxonin may also act on other protein substrates to mediate their degradation. This study reports the generation of a new mouse model of GAN based on overexpression of Prph in the context of targeted disruption of gigaxonin gene. The results support the view that neurofilament disorganization may contribute to neurodegenerative changes in GAN disease. The Gan-/-;TgPer mice provide a unique animal model of GAN for drug testing.

Gigaxonin is required for intermediate filament transport.

Gigaxonin is an adaptor protein for E3 ubiquitin ligase substrates. It is necessary for ubiquitination and degradation of intermediate filament (IF) proteins. Giant axonal neuropathy is a pathological condition caused by mutations in the GAN gene that encodes gigaxonin. This condition is characterized by abnormal accumulation of IFs in both neuronal and non-neuronal cells; however, it is unclear what causes IF aggregation. In this work, we studied the dynamics of IFs using their subunits tagged with a photoconvertible protein mEOS 3.2. We have demonstrated that the loss of gigaxonin dramatically inhibited transport of IFs along microtubules by the microtubule motor kinesin-1. This inhibition was specific for IFs, as other kinesin-1 cargoes, with the exception of mitochondria, were transported normally. Abnormal distribution of IFs in the cytoplasm can be rescued by direct binding of kinesin-1 to IFs, demonstrating that transport inhibition is the primary cause for the abnormal IF distribution. Another effect of gigaxonin loss was a more than 20-fold increase in the amount of soluble vimentin oligomers in the cytosol of gigaxonin knock-out cells. We speculate that these oligomers saturate a yet unidentified adapter that is required for kinesin-1 binding to IFs, which might inhibit IF transport along microtubules causing their abnormal accumulation.

Expanding the genetic spectrum of giant axonal neuropathy: Two novel variants in Iranian families.

BACKGROUND: Giant axonal neuropathy (GAN) is a progressive childhood hereditary polyneuropathy that affects both the peripheral and central nervous systems. Disease-causing variants in the gigaxonin gene (GAN) cause autosomal recessive giant axonal neuropathy. Facial weakness, nystagmus, scoliosis, kinky or curly hair, pyramidal and cerebellar signs, and sensory and motor axonal neuropathy are the main symptoms of this disorder. Here, we report two novel variants in the GAN gene from two unrelated Iranian families. METHODS: Clinical and imaging data of patients were recorded and evaluated, retrospectively. Whole-exome sequencing (WES) was undertaken in order to detect disease-causing variants in participants. Confirmation of a causative variant in all three patients and their parents was carried out using Sanger sequencing and segregation analysis. In addition, for comparing to our cases, we reviewed all relevant clinical data of previously published cases of GAN between the years 2013-2020. RESULTS: Three patients from two unrelated families were included. Using WES, we identified a novel nonsense variant [NM_022041.3:c.1162del (p.Leu388Ter)], in a 7-year-old boy of family 1, and a likely pathogenic missense variant [NM_022041.3:c.370T>A (p.Phe124Ile)], in two affected siblings of the family 2. Clinical examination revealed typical features of GAN-1 in all three patients, including walking difficulties, ataxic gait, kinky hair, sensory-motor polyneuropathy, and nonspecific neuroimaging abnormalities. Review of 63 previously reported cases of GAN indicated unique kinky hair, gait problem, hyporeflexia/areflexia, and sensory impairment were the most commonly reported clinical features. CONCLUSIONS: One homozygous nonsense variant and one homozygous missense variant in the GAN gene were discovered for the first time in two unrelated Iranian families that expand the mutation spectrum of GAN. Imaging findings are nonspecific, but the electrophysiological study in addition to history is helpful to achieve the diagnosis. The molecular test confirms the diagnosis.

Ataxia y neuropatía sensitiva de inicio en la edad adulta como manifestación clínica de mutaciones en el gen POLG / Adult-onset sensory neuropathy and ataxia as a clinical manifestation of POLG gene mutations

Introducción: La ataxia sensitiva es un síntoma frecuente en numerosas patologías neurológicas con causas múltiples y es una manifestación clínica frecuente en enfermedades relacionadas con genes que influyen en el metabolismo mitocondrial, como POLG. El objetivo del presente trabajo es describir las características diferenciales de cuatro pacientes con variantes patógenas en el gen POLG y expresión clínica común en forma de ataxia y neuropatía sensitiva de inicio en la edad adulta. Pacientes y métodos: Se realizó una revisión de las características clínicas de los pacientes portadores de variantes patógenas en el gen POLG de una consulta de enfermedades neuromusculares en un hospital de tercer nivel. Resultados: Se estudió a tres varones y una mujer de edad adulta (edad media: 40 años; 27-46) sin antecedentes familiares reseñables, con una duración de los síntomas de en torno a 10 años. El síntoma que motivó la consulta fue una alteración de la marcha en relación con ataxia sensitiva. Todos los pacientes presentaban anomalías oculomotoras. El estudio neurofisiológico evidenció una neuropatía sensitiva de predominio axonal. La resonancia magnética cerebral mostró atrofia y lesión de la sustancia blanca cerebelosa. La resonancia magnética muscular mostró sustitución grasa en músculos de muslos y gemelos sin un patrón específico. Todos ellos fueron portadores (homocigotos o heterocigotos compuestos) de variantes patógenas en el gen POLG. Conclusiones: El análisis molecular del gen POLG es una posibilidad diagnóstica prioritaria que se debe considerar en casos de ataxia sensitiva de inicio en la edad adulta, especialmente si se asocia a neuropatía sensitiva u oftalmoparesia.(AU)

Introduction: Sensory ataxia is a frequent symptom in numerous neurological pathologies, being a frequent clinical manifestation in diseases related to genes influencing mitochondrial metabolism, such as POLG. The aim is to describe the differential characteristics of four patients with pathogenic variants in the POLG gene with clinical expression in the form of adult-onset ataxia and sensory neuropathy. Patients and methods: We reviewed the clinical features of patients diagnosed with POLG pathogenic variants from a tertiary hospital. Results: Three men and one woman (mean age: 40 years; 27-46) with no family history were studied with symptoms for 10 years. All patients developed a gait disturbance related to sensory ataxia. All patients had oculomotor abnormalities. The neurophysiological study showed a sensory axonal neuropathy. Brain magnetic resonance imaging studies showed atrophy and cerebellar white matter lesion and muscle magnetic resonance imaging showed fatty substitution in thigh and calf muscles without a specific pattern. A molecular study revealed pathogenic variants in the POLG gene. Conclusions: In cases of adult-onset sensory ataxia, the molecular analysis of the POLG gene should be considered, especially if associated with sensory neuropathy or ophthalmoparesis.(AU)

Evaluation of hair structural abnormalities in children with different neurological diseases.

BACKGROUND: Hair microscopy is a fast and effortless diagnostic method for many diseases affecting hair in daily practice. Many diseases can present with hair shaft disorders in pediatric neurology practice. METHODS: Children with pathological hair findings were included in our study. Microscopic evaluation of the hair was performed under light microscopy. The clinical findings, pathological hair shaft findings, laboratory tests, and final diagnosis of the patients were evaluated. RESULTS: In our study, 16 patients with rare pathological hair findings were identified. Of these 16 patients, nine were diagnosed with giant axonal neuropathy, three with Griscelli syndrome, two with Menkes disease, and two with autosomal recessive woolly hair disease. In hair inspection, curly and tangled hair in patients with giant axonal neuropathy; silvery blond hair in patients with Griscelli syndrome; sparse, coarse, and light-colored hair in patients with Menkes disease; and hypotrichosis in patients with autosomal recessive woolly hair were remarkable findings. Dystrophic hair was detected in most of the patients on light microscopy. In addition, signs of trichorrhexis nodosa, tricoptylosis, and pili torti were found. In particular, pigment deposition in the hair shaft of two patients diagnosed with Griscelli syndrome and pili torti findings in two patients with Menkes disease were the most important findings suggestingthe diagnosis. CONCLUSIONS: Detection of hair findings in the physical examination and performing light microscopic evaluation facilitates the diagnosis of rare diseases accompanied by hair findings. A hair examination should be performed as a part of physical and neurological examinationson eachpatient regardless of thecomplaint.

Two novel pathogenic mutations of GAN gene identified in a chinese family with giant axonal neuropathy: a case report.

BACKGROUND: Giant axonal neuropathy (GAN) is a rare autosomal recessive, early-onset and fatal neurodegenerative disorder which develops into severe impairments in both peripheral and central nervous systems. METHODS AND RESULTS: Trio-WES analysis was used to detect genetic mutations associated with disorders, and Sanger sequencing was used to confirm the mutations in the patient. We identified two novel variations in GAN gene (c.809G > T(p.G270V); c.1182 C > A(p.Y394X)) within a Chinese family. Meanwhile, we propose a hypothesis of the molecular mechanism leading to GAN. CONCLUSIONS: This study extend the number of GAN mutations associated with GAN disease and would provide reference for clinical diagnosis in the future.

Giant axonal neuropathy (GAN) in an 8-year-old girl caused by a homozygous pathogenic splicing variant in GAN gene.

Giant axonal neuropathy (GAN) is a progressive disease that involves the peripheral and central nervous systems. This neurodegenerative disease is caused by variants in the GAN gene encoding gigaxonin, and is inherited in an autosomal recessive manner. Herein, we performed whole-exome sequencing on a 8-year-old child with dense, curly hair, weakness in both lower limbs, and abnormal MRI. The child was born to consanguineous parents. Our results revealed that the child carried the c.1373+1G>A homozygous pathogenic variant of the GAN gene, while both parents were heterozygous carriers. According to the validation at the cDNA levels, the splicing variant led to the skipping of exon 8 and affected the Kelch domain's formation. Unlike the previously reported cases of GAN, the child's clinical manifestations revealed peripheral nervous system involvement, no vertebral signs, cerebellar signs, and spasticity, but only MRI abnormalities. These results suggested that the patient's central nervous system was mildly involved, which may be related to the genotype. In order to further clarify the correlation between GAN genotype and phenotype, combined with this patient, 54 cases of reported homozygous variants of the GAN gene were merged for the analysis of genotype and phenotype. The results revealed a certain correlation between the GAN gene variant domain and the patient's clinical phenotype, such as central nervous system involvement and age of onset.

Anesthetic Management of Children and Adolescents With Giant Axonal Neuropathy: A Large Case Series.

Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the GAN gene, which encodes for gigaxonin, a protein involved in intermediate filament processing in neural cells and fibroblasts. We report on 14 GAN patients who underwent 77 anesthetics during the conduct of an intrathecal gene transfer clinical trial from April 2015 to August 2020. We observed only a few nonsignificant perianesthetic complications. Our data expand the knowledge regarding safety of anesthesia for patients with this rare and potentially fatal disease and highlights the tolerability of shorter procedural sedation and anesthesia.

Giant axonal neuropathy: cross-sectional analysis of a large natural history cohort.

Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease with early childhood onset that presents as a prominent sensorimotor neuropathy and commonly progresses to affect both the PNS and CNS. The disease is caused by biallelic mutations in the GAN gene located on 16q23.2, leading to loss of functional gigaxonin, a substrate specific ubiquitin ligase adapter protein necessary for the regulation of intermediate filament turnover. Here, we report on cross-sectional data from the first study visit of a prospectively collected natural history study of 45 individuals, age range 3-21 years with genetically confirmed GAN to describe and cross-correlate baseline clinical and functional cohort characteristics. We review causative variants distributed throughout the GAN gene in this cohort and identify a recurrent founder mutation in individuals with GAN of Mexican descent as well as cases of recurrent uniparental isodisomy. Through cross-correlational analysis of measures of strength, motor function and electrophysiological markers of disease severity, we identified the Motor Function Measure 32 to have the strongest correlation across measures and age in individuals with GAN. We analysed the Motor Function Measure 32 scores as they correspond to age and ambulatory status. Importantly, we identified and characterized a subcohort of individuals with a milder form of GAN and with a presentation similar to Charcot-Marie-Tooth disease. Such a clinical presentation is distinct from the classic presentation of GAN, and we demonstrate how the two groups diverge in performance on the Motor Function Measure 32 and other functional motor scales. We further present data on the first systematic clinical analysis of autonomic impairment in GAN as performed on a subset of the natural history cohort. Our cohort of individuals with genetically confirmed GAN is the largest reported to date and highlights the clinical heterogeneity and the unique phenotypic and functional characteristics of GAN in relation to disease state. The present work is designed to serve as a foundation for a prospective natural history study and functions in concert with the ongoing gene therapy trial for children with GAN.

Extensive rod and cone photoreceptor-cell degeneration in rat models of giant axonal neuropathy: implications for gene therapy of human disease.

Background: Giant axonal neuropathy (GAN; ORPHA: 643; OMIM# 256850) is a rare, hereditary, pediatric neurodegenerative disorder associated with intracellular accumulations of intermediate filaments (IFs). Validation of therapeutic efficacy and viral vector delivery systems with GAN knockout (KO) mouse models has provided the springboard for the development of a viral vector being delivered intrathecally in an ongoing Phase I gene therapy clinical trial for the treatment of children with GAN (https://clinicaltrials.gov/ct2/show/NCT02362438).Purpose: To characterize the ocular pathologic phenotype of newly developed GAN rat models.Materials and Methods: Microscopic examination of eyes at various timepoints.Results: We noted the unexpected finding of progressive and extensive degeneration of rod and cone photoreceptor (PR) cells in the retinas of GAN rat models.Conclusion: This PR-cell loss in rat models of GAN raises the possibility that PR-cell loss may contribute to the visual impairment observed in human GAN. The intrathecal viral vector employed in the ongoing Phase I gene therapy clinical trial for the treatment of children with GAN was not specifically designed to address PR-cell degeneration. If GAN-associated PR-cell loss is present and clinically significant in humans, then future treatment protocols for GAN may need to include a gene transfer approach or combinatorial treatment strategy that also targets retinal PR cells.

Giant axonal neuropathy with novel GAN pathogenic variant in a patient of consanguineous origin from Poonch Jammu and Kashmir-India.

Giant axonal neuropathy (GAN) is a severe and rare autosomal recessive neurodegenerative disorder of childhood affecting both the peripheral and central nervous systems (CNS). It is caused by mutations in the GAN (gigaxonin) gene linked to chromosome 16q24. Here, we present a 15-year-old male patient with GAN from a consanguineous family of Poonch, Jammu and Kashmir (J&K)-India. Whole-exome sequencing (WES) was employed to unravel the genetic cause of GAN in the proband. Pathogenic variant identified with WES was confirmed in other affected sibling using Sanger sequencing. Magnetic resonance imaging (MRI) and detailed clinical investigation was also carried out on proband. WES revealed a novel homozygous stopgain GAN mutation (NM_022041, c.C1028G, p.S343X) in the patient. MRI of brain displayed bilateral symmetrical confluent areas of deep white matter signal changes affecting periventricular regions (with sparing of subcortical U-fibers), posterior limbs of internal capsules, thalami, external capsules, and semioval centers. The patient was initially suspected to be a case of metachromatic leukodystrophy. However, WES analysis revealed a pathogenic variant in GAN gene as causative. No other pathogenic variant relevant to any other type of dystrophy was reported in WES. Our findings extend the geographical distribution of GAN to even a very remote region in India, extend the mutational and imaging spectrum of GAN and substantiate the need for introducing genetic testing and counselling in primary referral centers/district hospitals in India.

Características clínicas y respuesta al recambio plasmático terapéutico en los pacientes con síndrome de Guillain Barré / Clinical characteristics and plasma exchange response in Guillain-Barré patients

RESUMEN El objetivo del estudio fue describir las características clínicas, la respuesta al tratamiento y posibles factores asociados de los pacientes con síndrome de Guillain Barré en el Instituto Nacional de Ciencias Neurológicas. Se realizó un estudio descriptivo sobre egresos hospitalarios durante el periodo 2017-2019. La respuesta al tratamiento se evaluó mediante la escala de discapacidad de Hughes. De los 31 pacientes el 61,3% eran varones, y la edad promedio fue de 50 años. Al ingreso, el 87,1% de pacientes se encontraban en el grado 3 o 4 de la escala de Hughes, la mayoría con compromiso axonal, el cual estuvo asociado a discapacidad. Solo 22 pacientes recibieron recambio plasmático; luego de seis meses el 90,9% disminuyó al menos en un grado en la escala de Hughes y el 42,8% quedaron sin discapacidad. En conclusión, se encontró un predominio del sexo masculino y del compromiso axonal, este último asociado a discapacidad.

ABSTRACT The objective of the study was to describe the clinical characteristics, treatment response and possible associated factors of patients with Guillain-Barré syndrome at the National Institute of Neurological Sciences. A descriptive study on hospital discharges was conducted during the period 2017-2019. Treatment response was evaluated based on Hughes' disability scale. From 31 patients 61.3% were males and the mean age was 50 years. At admission, 87.1% of patients were on grade 3 or 4 of Hughes scale, most of them with axonal compromise which was associated to disability. Only 22 patients received plasma exchange; 6 months thereafter, 90.9% of patients decreased by at least one degree in Hughes scale and 42.8% were left without disability. In conclusion, a male and axonal subtype predominance was found, been the latter associated to disability.

Características clínicas y respuesta al recambio plasmático terapéutico en los pacientes con síndrome de Guillain Barré / Clinical characteristics and plasma exchange response in Guillain-Barré patients

RESUMEN El objetivo del estudio fue describir las características clínicas, la respuesta al tratamiento y posibles factores asociados de los pacientes con síndrome de Guillain Barré en el Instituto Nacional de Ciencias Neurológicas. Se realizó un estudio descriptivo sobre egresos hospitalarios durante el periodo 2017-2019. La respuesta al tratamiento se evaluó mediante la escala de discapacidad de Hughes. De los 31 pacientes el 61,3% eran varones, y la edad promedio fue de 50 años. Al ingreso, el 87,1% de pacientes se encontraban en el grado 3 o 4 de la escala de Hughes, la mayoría con compromiso axonal, el cual estuvo asociado a discapacidad. Solo 22 pacientes recibieron recambio plasmático; luego de seis meses el 90,9% disminuyó al menos en un grado en la escala de Hughes y el 42,8% quedaron sin discapacidad. En conclusión, se encontró un predominio del sexo masculino y del compromiso axonal, este último asociado a discapacidad.

ABSTRACT The objective of the study was to describe the clinical characteristics, treatment response and possible associated factors of patients with Guillain-Barré syndrome at the National Institute of Neurological Sciences. A descriptive study on hospital discharges was conducted during the period 2017-2019. Treatment response was evaluated based on Hughes' disability scale. From 31 patients 61.3% were males and the mean age was 50 years. At admission, 87.1% of patients were on grade 3 or 4 of Hughes scale, most of them with axonal compromise which was associated to disability. Only 22 patients received plasma exchange; 6 months thereafter, 90.9% of patients decreased by at least one degree in Hughes scale and 42.8% were left without disability. In conclusion, a male and axonal subtype predominance was found, been the latter associated to disability.

Síndrome de Sjögren primario que debuta con polimiositis mitocondrial, neuropatía axonal y parálisis hipopotasémica: reporte de caso / Onset of primary Sjögren syndrome with mitochondrial polymyositis, axonal neuropathy, and hypokalaemic paralysis: Case report

RESUMEN El síndrome de Sjögren es una entidad multisistémica de naturaleza autoinmune, clásicamente considerada una exocrinopatía debido a la alta frecuencia de síntomas secos (queratoconjuntivitis seca, xerostomía) como resultado de infiltración poliglandular por linfocitos autorreactivos. Sin embargo, menos del 10% de estos pacientes puede iniciar con manifestaciones extraglandulares severas, traducidas en peores desenlaces a largo plazo. Se presenta el caso de una gestante que inició con síndrome de debilidad aguda proximal relacionada con miositis con enfermedad mitocondrial e hipopotasemia severa, en el contexto de acidosis tubular renal distal, como manifestación extraglandular de síndrome de Sjögren primario. Se discuten brevemente manifestaciones neurológicas de esta entidad, incluyendo aquellas secundarias a trastornos metabólicos precipitados por compromiso autoinmune.

ABSTRACT Sjögren's syndrome is a multisystemic autoimmune disorder. It is classically considered as an exocrine disease, given the high frequency of dry symptoms (keratoconjunctivitis sicca, xerostomia) as a result of poly-glandular infiltration by autoreactive lymphocytes. However, less than 10% of these patients can onset with severe extra-glandular manifestations, resulting in worse long-term outcomes. The case of a pregnant woman is presented, who debuted with acute proximal weakness syndrome related to myositis with mitochondrial pathology and severe hypokalaemia in the context of distal renal tubular acidosis, as an extra-glandular manifestation of primary Sjögren's syndrome. Neurological manifestations of this condition are briefly discussed, including those secondary to metabolic disorders precipitated by autoimmune compromise.