Enfermedad de Huntington de inicio en la infancia. Una presentación poco frecuente / Childhood-onset Huntignton´s disease. A rare presentation

Introducción La enfermedad de Huntington (EH) es una enfermedad de herencia autosómica dominante caracterizada por la expansión de tripletes de citosina-adenina-guanina (CAG) en el gen que codifica la huntingtina. Los síntomas en la descendencia suelen ser más tempranos por el fenómeno de anticipación. La clínica de inicio en la infancia, antes de los 10 años, difiere de la observada en la adultez. Se manifiesta por afectación motora, dificultades conductuales y retraso o regresión del desarrollo. La corea es infrecuente. El objetivo del caso es describir aspectos clínicos de una paciente con EH de inicio infantil. Caso clínico Niña de 5 años con antecedentes familiares de EH y desarrollo típico hasta los 3 años. Presentó progresivamente afectación del lenguaje con habilidades descendidas para su edad en aspectos expresivos y comprensivos, sin afectación en las habilidades pragmáticas y sociales. En cuanto a la motricidad, la marcha y la bipedestación eran inestables, y mostraba rigidez, distonía y movimientos coreicos. Presentó atrofia de los núcleos lenticulares y caudados en la resonancia magnética, y posteriormente se realizó el diagnóstico molecular con la expansión de tripletes CAG (51 copias). Conclusión La EH de inicio en la infancia presenta manifestaciones clínicas distintas a la forma del adulto. Debe considerarse en pacientes con afectación motora y cognitiva progresiva. Por la herencia familiar, es importante interrogar cuidadosamente sobre los antecedentes familiares y tenerla en cuenta aun sin familiares afectados por el fenómeno de anticipación. (AU)

INTRODUCTIO NHuntington’s disease (HD) is a rare autosomal dominant disease caused by the expansion of CAG triplets in the gene that encodes huntingtin. There are earlier symptoms’ onset in offspring due to the phenomenon of anticipation. The clinical features of childhood-onset HD, before age 10 years, differs from adult-onset form. It is characterized by motor impairment, behavioral difficulties and delay or regression in areas of development; while chorea is rarely seen. In this case we describe clinical aspects of a patient with childhood-onset Huntington’s disease. CASE REPORT A 5-year-old girl with a family history of HD and typical development up to 3 years of age. She progressively acquired language impairment with skills that were below her age in expressive and receptive areas, without deficits in pragmatic and social skills. Regarding motor skills, she manifested instability at walking and standing, with rigidity, dystonia and choreic movements. Atrophy of the basal ganglia was evident on MRI, EEG was normal, and molecular confirmation of CAG triplet revealed repeat length of 51 copies. CONCLUSION. Childhood-onset HD differs from adult-form´s clinical manifestations. It should be considered in patients with progressive motor and cognitive impairment. Due to family inheritance, it is important to carefully examine family history and take it into account even without relatives affected, considering the anticipation phenomenon. (AU)

Hereditary spastic paraplegia type 35 in a Turkish girl with fatty acid hydroxylase-associated neurodegeneration.

OBJECTIVES: The fatty acid 2-hydroxylase gene (FA2H) compound heterozygous or homozygous variants that cause spastic paraplegia type 35 (SPG35) (OMIM # 612319) are autosomal recessive HSPs. FA2H gene variants in humans have been shown to be associated with not only SPG35 but also leukodystrophy and neurodegeneration with brain iron accumulation. CASE PRESENTATION: A patient with a spastic gait since age seven was admitted to the paediatric metabolism department. She was born to consanguineous, healthy Turkish parents and had no family history of neurological disease. She had normal developmental milestones and was able to walk at 11 months. At age seven, she developed a progressive gait disorder with increased muscle tone in her lower limbs, bilateral ankle clonus and dysdiadochokinesis. She had frequent falls and deteriorating school performance. Despite physiotherapy, her spastic paraplegia was progressive. Whole exome sequencing (WES) identified a homozygous NM_024306.5:c.460C>T missense variant in the FA2H gene, of which her parents were heterozygous carriers. A brain MRI showed a slight reduction in the cerebellar volume with no iron deposits. CONCLUSIONS: Pathogenic variants of the FA2H gene have been linked to neurodegeneration with iron accumulation in the brain, leukodystrophy and SPG35. When patients developed progressive gait deterioration since early childhood even if not exhibited hypointensity in the basal ganglia detected by neuroimaging, FA2H-related neurodegeneration with brain iron accumulation should be ruled out. FA2H/SPG35 disease is characterised by notable clinical and imaging variability, as well as phenotypic diversity.

A Novel Homozygous Deletion Including Exon 1 of FA2H Gene Causes Spastic Paraplegia-35: Genetic and Lipidomics Analysis of the Patients.

BACKGROUND: Fatty acid 2-hydroxylase (FA2H) is encoded by the FA2H gene, with mutations therein leading to the neurodegenerative condition, spastic paraplegia-35 (SPG35). We aim to elucidate the genetic underpinnings of a nonconsanguineous Chinese family diagnosed with SPG35 by examining the clinical manifestations, scrutinizing genetic variants, and establishing the role of FA2H mutation in lipid metabolism. METHODS: Using next-generation sequencing analysis to identify the pathogenic gene in this pedigree and family cosegregation verification. The use of lipidomics of patient pedigree peripheral blood mononuclear cells further substantiated alterations in lipid metabolism attributable to the FA2H exon 1 deletion. RESULTS: The proband exhibited gait disturbance from age 5 years; he developed further clinical manifestations such as scissor gait and dystonia. His younger sister also presented with a spastic gait from the same age. We identified a homozygous deletion in the region of FA2H exon 1, spanning from chr16:74807867 to chr16: 74810391 in the patients. Lipidomic analysis revealed significant differences in 102 metabolites compared with healthy controls, with 62 metabolites increased and 40 metabolites decreased. We specifically zeroed in on 19 different sphingolipid metabolites, which comprised ceramides, ganglioside, etc., with only three of these sphingolipids previously reported. CONCLUSIONS: This is the first study of lipid metabolism in the blood of patients with SPG35. The results broaden our understanding of the SPG35 gene spectrum, offering insights for future molecular mechanism research and laying groundwork for determining metabolic markers.

Dual target deep brain stimulation for complex essential and dystonic tremor - A 5-year follow up.

BACKGROUND: Essential tremor (ET) is characterized by action tremor of the upper limbs, head tremor and voice tremor. Dystonic tremor (DT) is produced by muscle contractions in a body affected by dystonia. Deep brain stimulation (DBS) of ventral intermediate nucleus of the thalamus (VIM) is the most well-known advanced treatment for medication-refractory tremor. However, decline in efficacy overtime has led to explore other targets. This study aimed to measure the efficacy of bilateral dual targeting ViM/caudal Zona Incerta (cZI) stimulation on tremor control. A secondary aim was to evaluate if there was a difference in the efficacy between ET and DT. METHODS: 36 patients were retrospectively recruited at the Walton NHS Foundation Trust, Liverpool, UK. Patients were assessed pre-operatively, and then at 1-year, 3-years, and 5-years post-operatively with the following scales: Fahn-Tolosa-Marin tremor rating (FTMTR) scale, EuroQol-5D, and Hospital Anxiety and Depression Scale. RESULTS: Bilateral ViM-cZI DBS significantly improved overall tremor score by 45.1% from baseline to 3-years post-operatively (p < 0.001). It continued to show improvement in overall FTMTR score by 30.7% at 5-years but this failed to meet significance. However, there was no significant improvement of mood or quality of life (QoL) scores. ET group on average showed a significant better clinical outcome compared to the DT group (p > 0.001). CONCLUSIONS: Our study found that bilateral ViM-cZI DBS treatment had a favourable effect on motor symptoms sustained over the 5-years in tremor patients, especially in ET group. There was limited effect on mood and QoL with similar trends in outcomes for both tremor types.

Deep Brain Stimulation for GNAO1-Associated Dystonia: A Systematic Review and Meta-Analysis.

OBJECTIVES: Guanine nucleotide-binding protein alpha-activating activity polypeptide O (GNAO1) syndrome, a rare congenital monogenetic disorder, is characterized by a neurodevelopmental syndrome and the presence of dystonia. Dystonia can be very pronounced and even lead to a life-threatening status dystonicus. In a small number of pharmaco-refractory cases, deep brain stimulation (DBS) has been attempted to reduce dystonia. In this study, we summarize the current literature on outcome, safety, and outcome predictors of DBS for GNAO1-associated dystonia. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis on individual patient data. We included 18 studies describing 28 unique patients. RESULTS: The mean age of onset of symptoms was 2.4 years (SD 3.8); 16 of 28 patients were male, and dystonia was nearly always generalized (20/22 patients). Symptoms were present before DBS for a median duration of 19.5 months, although highly variable, occurring between 3 and 168 months. The exact phenotype, genotype, and radiologic abnormalities varied and seemed to be of little importance in terms of DBS outcome. All studies described an improvement in dystonia. Our meta-analysis focused on pallidal DBS and found an absolute and relative improvement in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) of 32.5 points (37.9%; motor part; p = 0.001) and 5.8 points (21.5%; disability part; p = 0.043) at last follow-up compared with preoperative state; 80% of patients were considered responders (BFMDRS-M reduction by ≥25%). Although worsening over time does occur, an improvement was still observed in patients after >10 years. All reported cases of status dystonicus resolved after DBS surgery. Skin erosion and infection were observed in 18% of patients. CONCLUSION: Pallidal DBS can be efficacious and safe in GNAO1-associated dystonia.

Clinical outcomes after MRI connectivity-guided radiofrequency thalamotomy for tremor.

OBJECTIVE: Radiofrequency thalamotomy (RF-T) is an established treatment for refractory tremor. It is unclear whether connectivity-guided targeting strategies could further augment outcomes. The aim of this study was to evaluate the efficacy and safety of MRI connectivity-guided RF-T in severe tremor. METHODS: Twenty-one consecutive patients with severe tremor (14 with essential tremor [ET], 7 with Parkinson's disease [PD]) underwent unilateral RF-T at a single institution between 2017 and 2020. Connectivity-derived thalamic segmentation was used to guide targeting. Changes in the Fahn-Tolosa-Marin Rating Scale (FTMRS) were recorded in treated and nontreated hands as well as procedure-related side effects. RESULTS: Twenty-three thalamotomies were performed (with 2 patients receiving a repeated intervention). The mean postoperative assessment time point was 14.1 months. Treated-hand tremor scores improved by 63.8%, whereas nontreated-hand scores deteriorated by 10.1% (p < 0.01). Total FTMRS scores were significantly better at follow-up compared with baseline (mean 34.7 vs 51.7, p = 0.016). Baseline treated-hand tremor severity (rho = 0.786, p < 0.01) and total FTMRS score (rho = 0.64, p < 0.01) best correlated with tremor improvement. The most reported side effect was mild gait ataxia (n = 11 patients). CONCLUSIONS: RF-T guided by connectivity-derived segmentation is a safe and effective option for severe tremor in both PD and ET.

Narcolepsia multirresistente / Multidrug resistant narcolepsy

Introducción: La narcolepsia de tipo 1 es una enfermedad degenerativa focal del hipotálamo que afecta selectivamente a las neuronas productoras de orexina (hipocretina). Presenta múltiples manifestaciones clínicas, tanto en vigilia como en sueño. Con frecuencia, los síntomas son tan disruptivos que ocasionan enorme sufrimiento y deterioro de la calidad de vida de los pacientes. Aunque en ocasiones es suficiente con un abordaje no farmacológico, la gran mayoría de los enfermos necesita medicación para un adecuado control clínico. Caso clínico: Varón que a los 43 años comenzó a presentar de forma aguda excesiva somnolencia diurna y episodios de cataplejía. Tras un exhaustivo estudio se le diagnosticó narcolepsia de tipo 1. A lo largo de la evolución de la enfermedad se le prescribieron antidepresivos, neuroestimulantes y oxibato sódico, en monoterapia o en combinación. La respuesta al tratamiento farmacológico fue insuficiente y se acompañó de numerosos efectos secundarios. Tras la introducción de pitolisant se objetivó una franca mejoría de los síntomas, y se consiguió reducir la dosis de los otros fármacos y de sus efectos adversos. Conclusión: Son numerosas las medidas disponibles en la actualidad para abordar los síntomas cardinales de la enfermedad, aunque siguen existiendo casos resistentes al tratamiento antinarcoléptico. Los fármacos con mecanismos de acción sobre receptores del sistema histaminérgico pueden resultar de gran utilidad en estos casos.(AU)

Introduction: Narcolepsy type 1 is a focal degenerative disease of the hypothalamus that selectively affects orexin (hypocretin)-producing neurons. It presents multiple clinical manifestations, both in wakefulness and in sleep. The symptoms are often so disruptive that they cause enormous suffering and impair patients’ quality of life. Although a non-pharmacological approach is sometimes sufficient, the vast majority of patients need medication for adequate clinical management. Case report: A male who, at 43 years of age, began to present acutely with excessive daytime sleepiness and episodes of cataplexy. After a thorough examination, he was diagnosed with narcolepsy type 1. Throughout the course of the disease, he was prescribed antidepressants, neurostimulants and sodium oxybate, in monotherapy or in combination. The response to pharmacological treatment was insufficient and accompanied by numerous side effects. Following the introduction of pitolisant, there was a marked improvement in his symptoms and a reduction in the dose of the other drugs and their adverse effects was achieved. Conclusion: A number of measures are now available to address the cardinal symptoms of the disease, although there are still cases that are resistant to anti-narcoleptic treatment. Drugs with mechanisms of action that act upon receptors in the histaminergic system can be very useful in these cases.(AU)

Beyond Motor Deficits: Environmental Enrichment Mitigates Huntington's Disease Effects in YAC128 Mice.

Huntington's disease (HD) is a neurodegenerative genetic disorder characterized by motor, psychiatric, cognitive, and peripheral symptoms without effective therapy. Evidence suggests that lifestyle factors can modulate disease onset and progression, and environmental enrichment (EE) has emerged as a potential approach to mitigate the progression and severity of neurodegenerative processes. Wild-type (WT) and yeast artificial chromosome (YAC) 128 mice were exposed to different EE conditions. Animals from cohort 1 were exposed to EE between postnatal days 21 and 60, and animals from cohort 2 were exposed to EE between postnatal days 60 and 120. Motor and non-motor behavioral tests were employed to evaluate the effects of EE on HD progression. Monoamine levels, hippocampal cell proliferation, neuronal differentiation, and dendritic arborization were also assessed. Here we show that EE had an antidepressant-like effect and slowed the progression of motor deficits in HD mice. It also reduced monoamine levels, which correlated with better motor performance, particularly in the striatum. EE also modulated neuronal differentiation in the YAC128 hippocampus. These results confirm that EE can impact behavior, hippocampal neuroplasticity, and monoamine levels in YAC128 mice, suggesting this could be a therapeutic strategy to modulate neuroplasticity deficits in HD. However, further research is needed to fully understand EE's mechanisms and long-term effects as an adjuvant therapy for this debilitating condition.

From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington's Disease Research.

Huntington's disease (HD) is a debilitating neurodegenerative genetic disorder caused by an expanded polyglutamine-coding (CAG) trinucleotide repeat in the huntingtin (HTT) gene. HD behaves as a highly penetrant dominant disorder likely acting through a toxic gain of function by the mutant huntingtin protein. Widespread cellular degeneration of the medium spiny neurons of the caudate nucleus and putamen are responsible for the onset of symptomology that encompasses motor, cognitive, and behavioural abnormalities. Over the past 150 years of HD research since George Huntington published his description, a plethora of pathogenic mechanisms have been proposed with key themes including excitotoxicity, dopaminergic imbalance, mitochondrial dysfunction, metabolic defects, disruption of proteostasis, transcriptional dysregulation, and neuroinflammation. Despite the identification and characterisation of the causative gene and mutation and significant advances in our understanding of the cellular pathology in recent years, a disease-modifying intervention has not yet been clinically approved. This review includes an overview of Huntington's disease, from its genetic aetiology to clinical presentation and its pathogenic manifestation. An updated view of molecular mechanisms and the latest therapeutic developments will also be discussed.

Generation of the human iPSC lines AKOSi011-A carrying the mutation p.Pro65Ser/p.Asp35T and AKOSi012-A, carrying the mutation p.Tyr231His, derived from FAHN patient fibroblasts.

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a hereditary neurodegenerative disease caused by mutations in the FA2H gene. Patients show a wide range of neurological symptoms and an abnormal myelination. Here we describe the generation of the human induced pluripotent stem cell (hiPSC) lines AKOSi011-A and AKOSi012-A, derived from FAHN-patient fibroblasts, carrying the compound heterozygous mutation p.Pro65Ser/p.Asp35Tyr and the homozygous mutation p.Tyr231His, respectively. The hiPSC lines were generated using a non-integrating Sendai virus. The obtained hiPSCs show an unobtrusive karyotype, carry the mutations of the original fibroblasts, express pluripotency markers and can differentiate into cells of the three germ layers.

The first reports of FA2H-associated neurodegeneration from two unrelated Iranian families.

BACKGROUND: NBIA (neurodegeneration with brain iron accumulation) is a diverse collection of neurodegenerative illnesses defined by iron accumulation in the basal ganglia. The fatty acid hydroxylase-associated neurodegeneration, or FAHN, is one of the uncommon subtypes of NBIAs, associated with inherited autosomal recessive mutations in gene coding the membrane-bound fatty acid 2 hydroxylase (FA2H) enzyme. CASES: Here, we report two cases with FAHN from two unrelated families from Iran confirmed by whole exome sequencing. CONCLUSION: FAHN is an uncommon variant of NBIA that may manifest as spastic paraparesis without signs of iron buildup on brain imaging. As a result, it should be taken into account while making a differential diagnosis of the hereditary spastic paraplegia (HSP) syndrome, especially in individuals who lack iron deposits.

What the Gut Tells the Brain-Is There a Link between Microbiota and Huntington's Disease?

The human intestinal microbiota is a diverse and dynamic microenvironment that forms a complex, bi-directional relationship with the host. The microbiome takes part in the digestion of food and the generation of crucial nutrients such as short chain fatty acids (SCFA), but is also impacts the host's metabolism, immune system, and even brain functions. Due to its indispensable role, microbiota has been implicated in both the maintenance of health and the pathogenesis of many diseases. Dysbiosis in the gut microbiota has already been implicated in many neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). However, not much is known about the microbiome composition and its interactions in Huntington's disease (HD). This dominantly heritable, incurable neurodegenerative disease is caused by the expansion of CAG trinucleotide repeats in the huntingtin gene (HTT). As a result, toxic RNA and mutant protein (mHTT), rich in polyglutamine (polyQ), accumulate particularly in the brain, leading to its impaired functions. Interestingly, recent studies indicated that mHTT is also widely expressed in the intestines and could possibly interact with the microbiota, affecting the progression of HD. Several studies have aimed so far to screen the microbiota composition in mouse models of HD and find out whether observed microbiome dysbiosis could affect the functions of the HD brain. This review summarizes ongoing research in the HD field and highlights the essential role of the intestine-brain axis in HD pathogenesis and progression. The review also puts a strong emphasis on indicating microbiome composition as a future target in the urgently needed therapy for this still incurable disease.

Novel Homozygous FA2H Variant Causing the Full Spectrum of Fatty Acid Hydroxylase-Associated Neurodegeneration (SPG35).

Fatty acid hydroxylase-associated neurodegeneration (FAHN/SPG35) is caused by pathogenic variants in FA2H and has been linked to a continuum of specific motor and non-motor neurological symptoms, leading to progressive disability. As an ultra-rare disease, its mutational spectrum has not been fully elucidated. Here, we present the prototypical workup of a novel FA2H variant, including clinical and in silico validation. An 18-year-old male patient presented with a history of childhood-onset progressive cognitive impairment, as well as progressive gait disturbance and lower extremity muscle cramps from the age of 15. Additional symptoms included exotropia, dystonia, and limb ataxia. Trio exome sequencing revealed a novel homozygous c.75C>G (p.Cys25Trp) missense variant in the FA2H gene, which was located in the cytochrome b5 heme-binding domain. Evolutionary conservation, prediction models, and structural protein modeling indicated a pathogenic loss of function. Brain imaging showed characteristic features, thus fulfilling the complete multisystem neurodegenerative phenotype of FAHN/SPG35. In summary, we here present a novel FA2H variant and provide prototypical clinical findings and structural analyses underpinning its pathogenicity.

Obsessive-compulsive symptoms are negatively correlated with motor severity in patients with generalized dystonia.

We aimed to clarify the correlations between motor symptoms and obsessive-compulsive symptoms and between the volumes of basal ganglia components and obsessive-compulsive symptoms. We retrospectively included 14 patients with medically intractable, moderate and severe generalized dystonia. The Burke-Fahn-Marsden Dystonia Rating Scale and Maudsley Obsessional Compulsive Inventory were used to evaluate the severity of dystonia and obsessive-compulsive symptoms, respectively. Patients with generalized dystonia were divided into two groups; patients whose Maudsley Obsessional Compulsive Inventory score was lower than 13 (Group 1) and 13 or more (Group 2). Additionally, the total Maudsley Obsessional Compulsive Inventory scores in patients with dystonia were significantly higher than normal volunteers' scores (p = 0.025). Unexpectedly, Group 2 (high Maudsley Obsessional Compulsive Inventory scores) showed milder motor symptoms than Group 1 (low Maudsley Obsessional Compulsive Inventory scores) (p = 0.016). "Checking" rituals had a strong and significant negative correlation with the Burke-Fahn-Marsden Dystonia Rating Scale (ρ = - 0.71, p = 0.024) and a strong positive correlation with the volumes of both sides of the nucleus accumbens (right: ρ = 0.72, p = 0.023; left: ρ = 0.70, p = 0.034). Our results may provide insights into the pathogenesis of obsessive-compulsive disorder and dystonia.

Juvenile Huntington's disease in northern Brazil: a case series report / Doença de Huntington juvenil no norte do Brasil: relato de uma série de casos

Introduction: Huntington's disease (HD) is a neurodegenerative disorder caused by CAG expansion repeats in the HTT gene. Usually, the symptoms start to manifest in mid-adulthood. In about 5% of cases, however, the signs begin before the age of 20 years. These cases are known as juvenile HD (JHD). Objective: here we report a case series of JHD from Amazonas, a state where data are scarce due to the restricted access to specialized medical assistance for diagnosis and care. Case series: the patients were attended by neurologists specialized in movement disorders at Manaus. Two cases manifested the disease in childhood (6 and 7 years old) and two cases, in adolescence (12 and 16 years old). All cases showed dystonia and parkinsonism as predominant motor disorders. Moreover, signs of cognitive decline, depression, and psychosis were observed in all patients. Conversely, cerebellar signs, gait disturbances, seizures, and some psychiatric symptoms were variable among the cases. Expansion size varied from 66 to 84 to CAG repeats and the difference in age at onset between parent and child varied from 23 to 43 years. Conclusion: to our knowledge, these are the first clinical reports of JHD in northern Brazil. These cases illustrate the variability in clinical phenotypes and genetic features of JHD cases. Furthermore, they can contribute to the awareness of HD here, both by professionals and the public in general.

Introdução: a doença de Huntington (DH) é um distúrbio neurodegenerativo causado pela expansão de repetições CAG no gene HTT. Geralmente, os sintomas começam a se manifestar na vida adulta tardia. Em cerca de 5% dos casos, no entanto, os sinais começam antes da idade de 20 anos. Esses casos são conhecidos como DH juvenil (DHJ). Objetivo: neste estudo, nós reportamos uma série de casos de DHJ do Amazonas, um estado onde os dados ainda são escassos devido ao acesso restrito à assistência médica especializada para o diagnóstico e cuidado. Série de casos: os pacientes foram atendidos por neurologistas especializados em transtornos do movimento em Manaus. Dois casos manifestaram a doença na infância (6 e 7 anos) e dois casos, na adolescência (12 e 16 anos). Todos os casos apresentaram distonia e parkinsonismo como sintomas motores predominantes. Sinais de declínio cognitivo, depressão e psicose também foram observados em todos os pacientes. Por outro lado, sinais cerebelares, distúrbios da marcha, convulsões e alguns sintomas psiquiátricos foram variáveis entre os casos. O tamanho da expansão CAG variou de 66 a 84 repetições e a diferença na idade de início dos sintomas entre pais e filhos variou de 23 a 43 anos. Conclusão: ao nosso conhecimento, estes são os primeiros relatos clínicos da DHJ na região Norte. Esses casos ilustram a variabilidade nos fenótipos clínicos e nas características genéticas dos casos de DHJ. Além disso, eles podem contribuir para a conscientização da DH na região, tanto pelos profissionais quanto pelo público geral.

Polymerogenic neuroserpin causes mitochondrial alterations and activates NFκB but not the UPR in a neuronal model of neurodegeneration FENIB.

The neurodegenerative condition FENIB (familiar encephalopathy with neuroserpin inclusion bodies) is caused by heterozygous expression of polymerogenic mutant neuroserpin (NS), with polymer deposition within the endoplasmic reticulum (ER) of neurons. We generated transgenic neural progenitor cells (NPCs) from mouse fetal cerebral cortex stably expressing either the control protein GFP or human wild type, polymerogenic G392E or truncated (delta) NS. This cellular model makes it possible to study the toxicity of polymerogenic NS in the appropriated cell type by in vitro differentiation to neurons. Our previous work showed that expression of G392E NS in differentiated NPCs induced an adaptive response through the upregulation of several genes involved in the defence against oxidative stress, and that pharmacological reduction of the antioxidant defences by drug treatments rendered G392E NS neurons more susceptible to apoptosis than control neurons. In this study, we assessed mitochondrial distribution and found a higher percentage of perinuclear localisation in G392E NS neurons, particularly in those containing polymers, a phenotype that was enhanced by glutathione chelation and rescued by antioxidant molecules. Mitochondrial membrane potential and contact sites between mitochondria and the ER were reduced in neurons expressing the G392E mutation. These alterations were associated with a pattern of ER stress that involved the ER overload response but not the unfolded protein response. Our results suggest that intracellular accumulation of NS polymers affects the interaction between the ER and mitochondria, causing mitochondrial alterations that contribute to the neuronal degeneration seen in FENIB patients.

Generation of the human iPSC line AKOSi010-A from fibroblasts of a female FAHN patient, carrying the compound heterozygous mutation p.Gly45Arg/p.His319Arg.

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a rare childhood onset neurodegenerative disease caused by mutations in the FA2H gene. Patients display abnormal myelination, cerebellar atrophy and some have iron deposition in the central nervous system. Here we describe the generation of AKOSi010-A, a human induced pluripotent stem cell (hiPSC) line derived from fibroblasts of a female patient carrying the compound heterozygous p.Gly45Arg/p.His319Arg, using non-integrating Sendai virus. The generated iPSCs express pluripotency markers, can differentiate into cell types of the three germ layers and show a normal karyotype. This cell line displays a unique source to study the pathophysiology of FAHN.

Leucodistrofia metacromática del adulto: reporte de caso / Adult-onset metachromatic leukodystrophy

RESUMEN INTRODUCCIÓN: La leucodistrofia metacromática (LDM) es una enfermedad poco frecuente que se caracteriza por desmielinización progresiva a nivel del sistema nervioso central y periférico. En la mayoría de los casos, es causada por una actividad deficiente de la enzima arilsulfatasa-A. Pertenece al grupo de las leucodistrofias, que son trastornos hereditarios de la sustancia blanca asociados con una variabilidad fenotípica y una heterogeneidad genética importante. El fenotipo de la LDM suele relacionarse con la edad de presentación, que puede variar desde la infancia hasta la adultez. Cuando se presenta en la edad adulta, puede debutar con manifestaciones neuropsiquiátricas, lo que lleva con frecuencia a diagnósticos erróneos. REPORTE DE CASO: Se presenta el caso de una paciente adulta que debutó con un cuadro clínico caracterizado por cambios comportamentales progresivos, con posterior inicio de manifestaciones clínicas motoras. El diagnóstico de LDM se sospechó a partir de la clínica y los hallazgos típicos en la resonancia magnética (RM) cerebral, y se confirmó con la detección de actividad deficiente de la arilsulfatasa-A (ARSA) y la secuenciación del gen ARSA que confirmó la mutación en estado homocigoto, compatible con este diagnóstico. DISCUSIÓN: Destacamos en este caso la importancia de la sospecha clínica, el reconocimiento temprano y el manejo multidisciplinario como factores pronósticos del curso de la enfermedad, ya que en la actualidad no hay tratamiento definitivo para la enfermedad.

ABSTRACT INTRODUCTION: Metachromatic leukodystrophy (MLD) is an infrequent disease characterized by progressive demyelination of the central and peripheral nervous system. In most cases, it is caused by deficient activity of arylsulfatase-A. It belongs to the group of leukodystrophies, which are inherited white matter disorders that can be associated with significant phenotypic variability and genetic heterogeneity. The phenotype in MLD is usually related to the age of onset, which can vary from childhood to adulthood. Adult-onset MLD can debut with neuropsychiatry symptoms, which can often lead to misdiagnosis. CASE REPORT: We report the case of an adult female patient who presented with progressive behavioral changes, followed by motor manifestations. MLD was initially suspected based on the clinical presentation and the characteristic findings on brain magnetic resonance imaging (MRI), with subsequent confirmation by detection of deficient arylsulfatase-A (ARSA) activity and ARSA gene sequencing, which demonstrated homozygosity, compatible with this diagnosis. DISCUSSION: We highlight the importance of clinical suspicion, early recognition and multidisciplinary management as a prognostic factor for the course of the disease, since there is currently no definitive treatment for the disease.

Outcomes after liver transplantation in MPV17 deficiency (Navajo neurohepatopathy): A single-center case series.

BACKGROUND: MPV17-related mitochondrial DNA maintenance defect (MPV17 deficiency) is a rare, autosomal recessive mitochondrial DNA depletion syndrome with a high mortality rate in infancy and early childhood due to progression to liver failure. Liver transplantation for children with MPV17 deficiency has been considered controversial due to uncertainty about the potential progression of extrahepatic manifestations following liver transplantation. METHODS: We describe our institution's experience for two infants diagnosed with infantile MPV17 deficiency who presented in acute on chronic liver failure, but with normal development and normal neurological status who successfully underwent liver transplantation. RESULTS: Both patients underwent successful liver transplantation with normal development and neurological status at 3 years and 16 months post-transplant, respectively. CONCLUSIONS: In this rare disease population, we describe two infants with MPV17 deficiency who underwent liver transplantation for acute on chronic liver failure who continue to have normal development, without progression of neurological disease. MPV17 deficiency should not be considered a contraindication to liver transplantation.