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F abry disease (FD) is an X-linked lysosomal storage disorder with accumulation of globotriosylceramide, causing neurologic involvement mainly as acroparesthesias and cerebrovascular disease. Aseptic meningitis has been reported in 11 patients with FD, but no prior study has correlated alpha-galactosidase (GLA) specific variants with meningitis. We present in this manuscript a family in which a novel GLA pathogenic variant was associated with aseptic meningitis in 2 of 5 family members.This study began with identifying the proband, then screening family members for FD symptoms and evaluating symptomatic individuals for genetic and biochemical status. All patients underwent magnetic resonance imaging, and those with headache underwent cerebrospinal fluid (CSF) analysis.Five patients (3 females) from a single family were included in this study. Mean age at diagnosis was 20.6 years. Two patients (40%) had aseptic meningitis; one of them also had cerebrovascular events. C-reactive protein and erythrocyte sedimentation rate were elevated during aseptic meningitis episodes. Both patients responded to intravenous methylprednisolone with resolution of fever, headache, and vomiting. One of them recurred and needed chronic immunosuppression with azathioprine.We described aseptic meningitis in a family with a novel GLA variant. Meningitis might be a common phenomenon in FD and not a particularity of this variant. Understanding the mechanisms underlying meningitis and its association with cerebrovascular events may lead to a new paradigm of treatment for stroke in these patients. Further prospective studies with CSF collection in patients with FD and recurrent headache could help to elucidate this question.

The blood–brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood–brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype–phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood–brain barrier and impaired neuronal function.

Neuronal ceroid lipofuscinosis type 2 (CLN2) is a rare neurodegenerative genetic disease that affects children in early life. Its classic form is rapidly progressive, leading to death within the first 10 years. The urge for earlier diagnosis increases with the availability of enzyme replacement therapy. A panel of nine Brazilian child neurologists combined their expertise in CLN2 with evidence from the medical literature to establish a consensus to manage this disease in Brazil. They voted 92 questions including diagnosis, clinical manifestations, and treatment of the disease, considering the access to healthcare in this country. Clinicians should suspect CLN2 disease in any child, from 2 to 4 years old, with language delay and epilepsy. Even though the classic form is the most prevalent, atypical cases with different phenotypes can be found. Electroencephalogram, magnetic resonance imaging, molecular and biochemical testing are the main tools to investigateand confirm the diagnosis. However, we have limited access to molecular testing in Brazil, and rely on the support from the pharmaceutical industry. The management of CLN2 should involve a multidisciplinary team and focus on the quality of life of patients and on family support. Enzyme replacement therapy with Cerliponase α is an innovative treatment approved in Brazil since 2018; it delays functional decline and provides quality of life. Given the difficulties for the diagnosis and treatment of rare diseases in our public health system, the early diagnosis of CLN2 needs improvement as enzyme replacement therapy is available and modifies the prognosis of patients. Resumo Lipofuscinose ceróide neuronal (CLN2) é uma doença genética neurodegenerativa rara que afeta crianças nos primeiros anos de vida. A sua forma clássica é rapidamente progressiva, levando à morte nos primeiros 10 anos. A necessidade de um diagnóstico precoce aumenta com a disponibilidade do tratamento de terapia enzimática. Um painel de nove neurologistas infantis brasileiros combinou sua experiência em CLN2 com evidências da literatura médica para estabelecer um consenso no manejo desta doença no Brasil. Eles votaram 92 questões abordando diagnóstico, manifestações clínicas e tratamento, considerando o acesso à saúde no Brasil. Deve-se suspeitar de CLN2 em qualquer criança de 2 a 4 anos de idade que apresente atraso de linguagem e epilepsia. Apesar da forma clássica ser a mais prevalente, podem ser encontrados casos atípicos com diferentes fenótipos. Eletroencefalograma, ressonância magnética, testes moleculares e bioquímicos são as principais ferramentas para investigar e confirmar o diagnóstico. No entanto, o acesso aos testes moleculares é limitado no Brasil, necessitando contar com o apoio da indústria farmacêutica. O manejo da CLN2 deve envolver uma equipe multidisciplinar e focar na qualidade de vida dos pacientes e no apoio familiar. A terapia de reposição enzimática com Cerliponase alfa é um tratamento inovador aprovado no Brasil desde 2018; ele retarda o declínio funcional e proporciona qualidade de vida. Diante das dificuldades para o diagnóstico e tratamento de doenças raras em nosso sistema público de saúde, o diagnóstico precoce de CLN2 precisa de melhorias pois a terapia de reposição enzimática está disponível e modifica o prognóstico dos pacientes.

Krabbe disease (KD), or globoid cell leukodystrophy (Online Mendelian Inheritance in Man #245200), is an autosomal recessive lysosomal storage disease caused by mutations in GALC leading to galactocerebrosidase deficiency. Age at onset can vary from early infancy (3-6 months of age) to adulthood, which has rarely been reported. Little is known about the natural history and early manifestations of adult onset KD (AOKD).Here, we report a patient with an incidental diagnosis of AOKD and discuss management options in this scenario.A 32-year-old woman came to medical attention because of headache and had brain magnetic resonance imaging findings compatible with AOKD, two pathogenic variants in GALC, and reduced activity of galactocerebrosidase. The jury is still out about the best management of such cases, and clinicians should be aware of this diagnosis, as AOKD is a potentially treatable condition.AOKD is a rare and potentially treatable condition. More studies on natural history of AOKD are urgently needed to guide the best management of this disease.

Objective Protein misfolding plays a central role not only in amyotrophic lateral sclerosis (ALS), but also in other conditions, such as frontemporal dementia (FTD), inclusion body myopathy (hIBM) or Paget's disease of bone. The concept of multisystem proteinopathies (MSP) was created to account for those rare families that segregate at least 2 out of these 4 conditions in the same pedigree. The calcium-dependent phospholipid-binding protein annexin A11 was recently associated to ALS in European pedigrees. Herein, we describe in detail 3 Brazilian families presenting hIBM (isolated or in combination with ALS/FTD) caused by the novel p.D40Y change in the gene encoding annexin A11 (ANXA11). Methods We collected clinical, genetic, pathological and skeletal muscle imaging from 11 affected subjects. Neuroimaging was also obtained from 8 patients and 8 matched controls. Results Clinico-radiological phenotype of this novel hIBM reveals a slowly progressive predominant limb-girdle syndrome, but with frequent axial (ptosis/dropped head) and distal (medial gastrocnemius) involvement as well. Muscle pathology identified numerous rimmed vacuoles with positive annexin A11, TDP-43 and p62 inclusions, but no inflammation. Central nervous system was also involved: two patients had FTD, but diffusion tensor imaging uncovered multiple areas of cerebral white matter damage in the whole group (including the corticospinal tracts and frontal subcortical regions). Interpretation These findings expand the phenotypic spectrum related to ANXA11. This gene should be considered the cause of a novel multisystem proteinopathy (MSP type 6), rather than just ALS. This article is protected by copyright. All rights reserved.

ATP6V1B2 encodes a subunit of the lysosomal transmembrane proton pump necessary for adequate functioning of several acid hydrolases. De novo monoallelic variants of this gene have been associated with two distinct phenotypes: Zimmermann-Laband syndrome 2 (ZLS2), an intellectual deficiency/multiple malformation syndrome, and dominant deafness onychodystrophy (DDOD), a multiple malformation syndrome without cognitive involvement. Epilepsy is not observed in DDOD, is variably present in ZLS2, but is a common feature in Zimmermann-Laband syndrome 1 (ZLS1) (caused by monoallelic pathogenic variants in KCNH1) and Zimmermann-Laband syndrome-like (ZLSL) (associated with KCNK4 variants). Herein, we report a case of an infant with severe epileptic encephalopathy with microcephaly and profound developmental delay, associated with a novel de novo loss-of-function variant in ATP6V1B2, diagnosed by whole-exome sequencing. This finding expands the spectrum of ATP6V1B2-associated disorders and adds ATP6V1B2 as a new member for the growing list of early-onset epileptic encephalopathy genes. [Published with video sequence].

Chatron et al. describe a novel syndrome caused by bi-allelic loss-of-function mutations in GAD1, the gene encoding the GABA synthetic enzyme GAD67. The syndrome is characterized by the unique association of developmental and epileptic encephalopathy, cleft palate, joint contractures and/or omphalocele., Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1−/− mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.

Background: The knowledge about the molecular basis of epilepsies has increased enormously with the advent of next-generation sequencing (NGS) technology, and CYFIP2 is one of the many genes recently recognized and associated with epilepsy. Pathogenic variants in CYFIP2 cause Developmental and Epileptic Encephalopathy 65 (DEE65), which is characterized by hypotonia, profound developmental delay, and epilepsy. Case Presentation: Herein, we report a 3-year-old male with an early onset epileptic encephalopathy (Ohtahara syndrome) evolving to Lennox-Gastaut syndrome refractory to several antiseizure medications. Whole exome sequencing (WES) disclosed a heterozygous pathogenic variant p.(Arg87Cys) in CYFIP2, which occurred as a de novo event. After the introduction of cannabidiol, the patient remained seizure-free for 16 months and had a marked electroencephalographic improvement. Conclusion: Cannabidiol might be a therapeutic option for CYFIP2-related epilepsy

Ataxia with oculomotor apraxia (AOA) is characterized by early-onset cerebellar ataxia associated with oculomotor apraxia. AOA1, AOA2, AOA3, and AOA4 subtypes may present pathogenic variants in APTX, SETX, PIK3R5, and PNKP genes, respectively. Mutations in XRCC1 have been found to cause autosomal recessive spinocerebellar ataxia-26 (SCAR26) now considered AOA5.To examine a cohort of Brazilians with autosomal recessive cerebellar ataxia plus oculomotor apraxia and determine the frequencies of AOA subtypes through genetic investigation.We evaluated clinical, biomarkers, electrophysiological, and radiological findings of 52 patients with AOA phenotype and performed a genetic panel including APTX, SETX, PIK3R5, PNKP, and XRCC1.We found pathogenic variants in SETX (15 patients), PNKP (12), and APTX (5). No mutations in PIK3R5 or XRCC1 were identified.AOA2 and AOA4 were the most common forms of AOA in Brazil. Mutations in PIK3R5 and XRCC1 were not part of this genetic spectrum. © 2022 International Parkinson and Movement Disorder Society.

Background Turner syndrome (TS) is a rare condition associated with a completely or partially missing X chromosome that affects 1 in 2500 girls. TS increases the risk of autoimmune diseases, including Graves’ disease (GD). Moyamoya disease is a rare cerebral arteriopathy of unknown etiology characterized by progressive bilateral stenosis of the internal carotid artery and its branches. Both TS and GD have been associated with Moyamoya. Type 2 spinocerebellar ataxia (SCA2) is an autosomal dominant cerebellar ataxia caused by a CAG repeat expansion in ATXN2. We present the first case of Moyamoya syndrome in a patient with a previous diagnosis of TS and GD who tested positive for SCA2 and had imaging findings compatible with an overlap of SCA2 and Moyamoya. Case presentation A 43-year-old woman presented with mild gait imbalance for 2 years. Her family history was positive for type 2 spinocerebellar ataxia (SCA2). She had been diagnosed with Turner Syndrome (45,X) and Graves disease three years before. Brain MRI revealed bilateral frontal and parietal cystic encephalomalacia in watershed zones, atrophy of pons, middle cerebellar peduncles and cerebellum. MR angiography showed progressive stenosis of both internal carotid arteries with lenticulostriate collaterals, suggestive of Moya-Moya disease. Molecular analysis confirmed the diagnosis of SCA2. Conclusions With increased availability of tools for genetic diagnosis, physicians need to be aware of the possibility of a single patient presenting two or more rare diseases. This report underscores the modern dilemmas created by increasingly accurate imaging techniques and available and extensive genetic testing.

Background Biallelic loss-of-function NDUFA12 variants have hitherto been linked to mitochondrial complex I deficiency presenting with heterogeneous clinical and radiological features in nine cases only. Objectives To fully characterize, both phenotypically and genotypically, NDUFA12-related mitochondrial disease. Methods We collected data from cases identified by screening genetic databases of several laboratories worldwide and systematically reviewed the literature. Results Nine unreported NDUFA12 cases from six pedigrees were identified, with presentation ranging from movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. MRI showed basal ganglia abnormalities (n = 6), optic atrophy (n = 2), or was unremarkable (n = 1). All carried homozygous truncating NDUFA12 variants, three of which are novel. Conclusions Our case series expands phenotype-genotype correlations in NDUFA12-associated mitochondrial disease, providing evidence of intra- and inter-familial clinical heterogeneity for the same variant. It confirms NDUFA12 variants should be included in the diagnostic workup of Leigh/Leigh-like syndromes - particularly with dystonia - as well as isolated optic atrophy.

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS. Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS. We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS. These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products. Notably, this is in contrast with SPTLC1 variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy. We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro. The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease.

Background Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) causes unique retinal abnormalities, which have not been systematically investigated. Objective To deeply phenotype the retina in ARSACS in order to better understand its pathogenesis and identify potential biomarkers. Methods We evaluated 29 patients with ARSACS, 66 with spinocerebellar ataxia (SCA), 38 with autosomal recessive cerebellar ataxia (ATX), 22 with hereditary spastic paraplegia (SPG), 21 cases of papilledema, and 20 healthy controls (total n = 196 subjects). Participants underwent visual acuity assessment, intraocular pressure measurement, fundoscopy, and macular and peripapillary optical coherence tomography (OCT). Macular layers thicknesses in ARSACS were compared with those of age-matched healthy controls. Ophthalmologists analyzed the scans for abnormal signs in the different patient groups. Linear regression analysis was conducted to look for associations between retinal changes and age, age at onset, disease duration, and Scale for the Assessment and Rating of Ataxia (SARA) scores in ARSACS. Results Only patients with ARSACS exhibited peripapillary retinal striations (82%) on fundoscopy, and their OCT scans revealed foveal hypoplasia (100%), sawtooth appearance (89%), papillomacular fold (86%), and macular microcysts (18%). Average peripapillary retinal nerve fiber layer (pRNFL) was thicker in ARSACS than in SCA, ATX, SPG, and controls; a cut-off of 121 μm was 100% accurate in diagnosing ARSACS. All macular layers were thicker in ARSACS when compared to healthy controls. RNFL thickness in the inferior sector of the macula positively correlated with SARA scores. Conclusions Retinal abnormalities are highly specific for ARSACS, and suggest retinal hyperplasia due to abnormal retinal development. OCT may provide potential biomarkers for future clinical trials. © 2021 International Parkinson and Movement Disorder Society.

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Objective To present a cohort of 8 males and perform a systematic review of all published cases with a single copy of MECP2 carrying a pathogenic variant. Methods We reviewed medical records of males with a single copy of MECP2 carrying a pathogenic variant. We searched in Medline (Pubmed) and Embase to collect all articles which included well-characterized males with a single copy of MECP2 carrying a pathogenic or likely pathogenic variant in MECP2 (1999–2020). Results The literature search yielded a total of 3,185 publications, of which 58 were included in our systematic review. We were able to collect information on 27 published patients with severe neonatal encephalopathy, 47 individuals with isolated or familial mental retardation X-linked 13 (XLMR13), as well as 24 individuals with isolated or familial Pyramidal signs, parkinsonism, and macroorchidism (PPM-X). In our cohort, we met eight individuals aged 4 to 19-year-old at the last evaluation. Three MECP2-associated phenotypes were seen in male carriers of a single copy of the gene: severe neonatal encephalopathy (n = 5); X-linked intellectual deficiency 13 (n = 2); and pyramidal signs, parkinsonism, and macroorchidism (PPM-X) (n = 1). Two novel de novo variants [p.(Gly252Argfs∗7) and p.(Tyr132Cys)] were detected. Conclusion In males, the MECP2 pathogenic variants can be associated with different phenotypes, including neonatal severe encephalopathy, intellectual deficiency, or late-onset parkinsonism and spasticity. The typical RS phenotype is not expected in males, except in those with Klinefelter syndrome or somatic mosaicism for MECP2.

Background Spastic paraplegia, optic atrophy and neuropathy (Spoan syndrome) is an autosomal recessive disease with approximately 70 cases recorded in Brazil and Egypt. Methods This is a prospective longitudinal study performed with 47 patients affected with Spoan syndrome of seven communities of Rio Grande do Norte (Brazil) to investigate changes in motor function based on comparative data obtained from a 10-year follow-up. Results The mean age of the participants was 47.21 ± 12.42 years old, and the mean age at loss of ambulation and hand function were 10.78 ± 5.55 and 33.58 ± 17.47 years old, respectively. Spearman’s correlation analysis between the score on the Modified Barthel Index and the investigated variables evidenced statistical significance for age (p p = 0.042 and p = 0.021, respectively). Statistical significance was not evidenced for the remainder of the variables, including age at onset of symptoms (p = 0.634), age at loss of ambulation (p = 0.664) and age at loss of hand function (p = 0.118). Conclusions Our analysis allows asserting that the participants exhibited slight dependence until age 35. The greatest losses occurred from ages 35 to 41, and starting at 50, practically all patients become completely dependent. These findings are relevant for determining the prognosis as well as suitable treatment, rehabilitation and assistive technology for these individuals.

SCN3A was recently recognized as a gene associated with neurodevelopmental disorder and epilepsy. We present two additional patients with a novel de novo SCN3A pathogenic variant, and a review of all published cases of de novo variants. In one of our patients brain magnetic resonance imaging (MRI) disclosed a severe polymicrogyria and in the other it was normal. The clinical phenotype was characterized by a severe developmental delay and refractory epilepsy in the patient with polymicrogyria and intellectual disability with autistic features and pharmacoresponsive epilepsy in the subject with normal MRI. Polymicrogyria, a disorder of progenitor cells proliferation and migration, is an unanticipated finding for an ion channel dysfunction.

ObjectiveThe aim of the study was to report the proportion of homozygous and compound heterozygous variants in the survival motor neuron 1 (SMN1) gene in a large population of patients with spinal muscular atrophy (SMA) and to correlate the severity of the disease with the presence of specific intragenic variants in SMN1 and with the SMN2 copy number.MethodsFour hundred fifty Brazilian patients with SMA were included in a retrospective study, and clinical data were analyzed compared with genetic data; the SMN2 copy number was obtained by multiplex ligation-dependent probe amplification and pathogenic variants in SMN1 by next-generation sequencing.ResultsFour hundred two patients (89.3%) presented homozygous exon 7-SMN1 deletion, and 48 (10.7%) were compound heterozygous for the common deletion in one allele and a point mutation in the other allele. Recurrent variants in exons 3 and 6 (c.460C>T, c.770_780dup and c.734_735insC) accounted for almost 80% of compound heterozygous patients. Another recurrent pathogenic variant was c.5C>G at exon 1. Patients with c.770_780dup and c.734_735insC had a clinical phenotype correlated with SMN2 copy number, whereas the variants c.460C>T and c.5C>G determined a milder phenotype independently of the SMN2 copies.ConclusionsPatients with specific pathogenic variants (c.460C>T and c.5C>G) presented a milder phenotype, and the SMN2 copy number did not correlate with disease severity in this group.

International audience; Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.

Background Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an important form of inherited ataxia with a varied clinical spectrum. Detailed studies of phenotype and genotype are necessary to improve diagnosis and elucidate this disorder pathogenesis. OBJECTIVE AND METHODS: To investigate the clinical phenotype, retinal architecture, neuroimaging features and genetic profile of Brazilian patients with ARSACS, we performed neurological and ophthalmological evaluation in thirteen Brazilian patients with molecularly confirmed ARSACS, and examined their mutation profiles. Optical coherence tomography protocol (OCT) consisted in peripapillary retinal nerve fiber layer (RNFL) measurement and qualitative analysis of perifoveal scans. Neuroimaging protocol accessed the frequency of atrophy in cerebellum, corpus callosum and parietal lobe, brainstem signal abnormalities, and posterior fossa arachnoid cysts. We reviewed the literature to delineate the ARSACS phenotype in the largest series worldwide. RESULTS: All patients had ataxia and spasticity, and 11/13 had peripheral neuropathy. Macular microcysts were present in two patients. Peripapillary striations, dentate appearance of inner retina and papillomacular fold were found in eleven cases. All individuals exhibited thickening of RNFL in OCT. The most frequent radiological signs were cerebellar atrophy (13/13), biparietal atrophy (12/13), and linear pontine hypointensities (13/13). Genetic analysis revealed 14 different SACS variants, of which two are novel. CONCLUSION: Macular microcysts, inner retina dentate appearance and papillomacular fold are novel retinal imaging signs of ARSACS. Ophthalmological and neuroimaging changes are common findings in Brazilian patients. The core clinical features of ARSACS are ataxia, spasticity and peripheral neuropathy with onset predominantly in the first decade of life.

Diagnosis of multiple sclerosis (MS) is often difficult because of the wide range of clinical presentations and the absence of biomarkers or specific test to confirm the disease. The condition can therefore be confounded with other inflammatory or genetic conditions that affect the CNS, like inherited leukoencephalopathies. Among inherited leukoencephalopathies, X-linked adrenoleukodystrophy (X-ALD) figures out as one of the most commom.1,2

Purpose Cerebrospinal fluid (CSF) or brain parenchyma lactate detection is important for the diagnosis of some diseases with aerobic cellular metabolism compromise. Our purpose is to correlate intraventricular magnetic resonance spectroscopy (MRS) lactate detection and quantification to CSF and blood lactate concentration. Methods Twenty-one patients (13 females; mean age 5 years) suspected of having mitochondrial disorders underwent proton MRS with point-resolved spectroscopy (TE = 144 ms). The volume of interest was positioned in the lateral ventricles, and LCModel was used for the MRS lactate peak detection and quantification. CSF and venous blood samples were obtained for lactate quantification immediately after MRS. Comparisons between MRS, CSF, and blood lactate detection and quantification were performed. p Results In our series, CSF lactate levels were high in 11 patients (52%) and blood serum lactate levels were high in 3 patients (14%). MRS was able to detect a lactate peak in all patients. A positive correlation between MRS lactate quantification and CSF lactate was observed (Pearson correlation coefficient = 0.750; p Conclusion If MRS shows increased lactate levels in the ventricles, CSF puncture is not needed for lactate increase confirmation.

Defects in iron–sulphur [Fe-S] cluster biogenesis are increasingly recognized as causing neurological disease. Mutations in a number of genes that encode proteins involved in mitochondrial [Fe-S] protein assembly lead to complex neurological phenotypes. One class of proteins essential in the early cluster assembly are ferredoxins. FDX2 is ubiquitously expressed and is essential in the de novo formation of [2Fe-2S] clusters in humans. We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2. Patients were clinically evaluated, underwent MRI, nerve conduction studies, EMG and muscle biopsy. To define the genetic aetiology, a combination of homozygosity mapping and whole exome sequencing was performed. We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life. Sensory-motor axonal neuropathy led to progressive distal weakness. MRI disclosed a reversible or partially reversible leukoencephalopathy. Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation. The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C > T, p.P144L). The deleterious effect of the mutation was validated by real-time reverse transcription polymerase chain reaction and western blot analysis, which demonstrated normal expression of FDX2 mRNA but severely reduced expression of FDX2 protein in muscle tissue. This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2, which encodes a ubiquitously expressed mitochondrial ferredoxin essential for early [Fe-S] cluster biogenesis. Defeitos na biogênese do cluster ferro-enxofre [Fe-S] são cada vez mais reconhecidos como causadores de doenças neurológicas. Mutações em vários genes que codificam proteínas envolvidas na montagem da proteína mitocondrial [Fe-S] levam a fenótipos neurológicos complexos. Uma classe de proteínas essenciais na montagem inicial do cluster são as ferredoxinas. FDX2 é expresso de forma ubíqua e é essencial na formação de novo de aglomerados de [2Fe-2S] em humanos. Descrevemos e definimos geneticamente uma nova síndrome neurológica complexa identificada em duas famílias brasileiras, com uma nova mutação homozigótica em FDX2. Os pacientes foram avaliados clinicamente, submetidos a ressonância magnética, estudos de condução nervosa, EMG e biópsia muscular. Para definir a etiologia genética, foi realizada uma combinação de mapeamento de homozigose e sequenciamento de todo o exoma. Identificamos seis pacientes de duas famílias aparentemente não aparentadas com herança autossômica recessiva de um fenótipo neurológico complexo envolvendo atrofia óptica e nistagmo desenvolvendo-se aos 3 anos de idade, seguidos de miopatia e episódios recorrentes de cãibras, mialgia e fraqueza muscular na primeira ou segunda década de vida. A neuropatia axonal sensório-motora levou à fraqueza distal progressiva. A ressonância magnética revelou uma leucoencefalopatia reversível ou parcialmente reversível. A biópsia muscular demonstrou um padrão incomum de succinato desidrogenase regional e deficiência de citocromo c oxidase com acúmulo de ferro. O fenótipo foi mapeado em ambas as famílias para a mesma mutação homozigótica missense em FDX2 (c.431C > T, p.P144L). O efeito deletério da mutação foi validado por reação em cadeia da polimerase de transcrição reversa em tempo real e análise de Western blot, que demonstrou expressão normal de mRNA de FDX2, mas expressão severamente reduzida da proteína FDX2 no tecido muscular. Este estudo descreve um novo fenótipo neurológico complexo com características incomuns de ressonância magnética e biópsia muscular, mapeado conclusivamente para uma mutação em FDX2, que codifica uma ferredoxina mitocondrial ubíqua expressa essencial para a biogênese inicial do cluster [Fe-S].

Objective:To perform functional characterization of a potentially pathogenic KCNB1 variant identified by clinical exome sequencing of a proband with a neurodevelopmental disorder that included epilepsy and centrotemporal spikes on EEG.Methods:Whole-exome sequencing identified the KCNB1 variant c.595A>T (p.Ile199Phe). Biochemical and electrophysiologic experiments were performed to determine whether this variant affected protein expression, trafficking, and channel functional properties.Results:Biochemical characterization of the variant suggested normal protein expression and trafficking. Functional characterization revealed biophysical channel defects in assembled homotetrameric and heterotetrameric channels.Conclusions:The identification of the KCNB1 variant c.595A>T (p.Ile199Phe) in a neurodevelopmental disorder that included epilepsy with centrotemporal spikes expands the phenotypic spectrum of epilepsies associated with KCNB1 variants. The KCNB1-I199F variant exhibited partial loss of function relative to the wild-type channel. This defect is arguably less severe than previously reported KCNB1 variants, suggesting the possibility that the degree of KCNB1 protein dysfunction may influence disease severity.

Summary Objectives Deletion of the chromosome 15q11-q13, the most common genetic mechanism associated with Angelman syndrome (AS), is highly associated with a severe phenotype. However, deletion is not a genetically homogeneous group as it is composed by two main groups: Class I with breakpoints at BP1 (proximal) and BP3 (distal) and Class II present breakpoints at BP2 (proximal) and BP3 (distal). In this study, we aimed to evaluate the impact of the breakpoint on the electroclinical profile. Methods We evaluated 16 patients with AS caused by 15q11-13 deletion (6 were Class I; 10 were Class II). We characterized epilepsy features by clinical history obtained from parents and caretakers with a pre-standard questionnaire. These data were corroborated by medical records, contact with previous physicians, and video-EEG monitoring. Suggestive EEG patterns for AS were classified according to the classical description of Boyd et al. (1988). Results AS patients with BP1–BP3 deletion had significantly more daily and disabling seizures than AS patients with BP1–BP2 deletion. They also presented a significant higher frequency of status epilepticus and epilepsy aggravated by fever. Need for polytherapy was significantly more frequent in BP1–BP3 patients. EEG features were similar in both groups. Conclusion This study shows a significant correlation between the two deletion classes and AS clinical, but not the electrographic phenotype. Epilepsy is more severe and refractory to treatment in patients with larger deletions. Deletion is not a homogeneous group and knowledge on the breakpoint may have a clinical implication and represent an important factor in parental counseling.

Gerstmann-Sträussler-Scheinker is a genetic prion disease and the most common mutation is p.Pro102Leu. We report clinical, molecular and neuropathological data of seven individuals, belonging to two unrelated Brazilian kindreds, carrying the p.Pro102Leu. Marked differences among patients were observed regarding age at onset, disease duration and clinical presentation. In the first kindred, two patients had rapidly progressive dementia and three exhibited predominantly ataxic phenotypes with variable ages of onset and disease duration. In this family, age at disease onset in the mother and daughter differed by 39 years. In the second kindred, different phenotypes were also reported and earlier ages of onset were associated with 129 heterozygosis. No differences were associated with apoE genotype. In these kindreds, the codon 129 polymorphism could not explain the clinical variability and 129 heterozygosis was associated with earlier disease onset. Neuropathological examination in two patients confirmed the presence of typical plaques and PrPsc immunopositivity. RESUMO A doença de Gerstmann-Sträussler-Scheinker é uma doença priônica genética, cuja mutação mais frequente é p.Pro102Leu. Descrevem-se dados clínicos, moleculares e neuropatológicos de sete indivíduos em duas famílias não relacionadas com p.Pro102Leu. Diferenças notáveis entre os pacientes em relação à idade de início, duração da doença e apresentação clínica foram encontradas. Na primeira família, dois pacientes apresentaram demência rapidamente progressiva e três apresentaram fenótipo de ataxia com idade variáveis de início e duração da doença. Nesta família, a idade de início entre mãe e filha diferiu em 39 anos. Na segunda família, fenótipos diferentes foram observados e idades precoces de início dos sintomas foram associadas à heterozigose no códon 129. Não houve diferença em relação ao genótipo do gene da apoE. O genótipo do códon 129 não foi responsável pela variabilidade clínica; heterozigose no códon 129 esteve associada ao início precoce da doença. O exame neuropatológico em dois pacientes confirmou presença de placas típicas e imunohistoquímica para PrPsc.

A 22-year-old woman presented with a 4-year history of progressive gait disturbance and slurred speech. Examination disclosed ataxia, nystagmus, pyramidal signs, bradykinesia, and feet dystonia with a cock-walk gait pattern (video at [Neurology.org][1]). There was no weakness of ankle dorsiflexion or plantar flexion. Family history was remarkable for ataxia. MRI showed mild pontocerebellar atrophy (figure). Genetic testing confirmed spinocerebellar ataxia type 3 (SCA3; 34/77 alleles). There were poor responses to levodopa, anticholinergic drugs, and botulinum toxin. [1]: http://neurology.org/lookup/doi/10.1212/WNL.0000000000004497

Background VCP (valosin-containing protein gene) variants have been associated with peripheral and central neurodegenerative processes, including inclusion body myopathy (IBM), Paget disease of bone (PDB), frontotemporal dementia (FTD), and familial amyotrophic lateral sclerosis (ALS) type 14. The combination of IBM, PDB (IBMPFD1) can presented in one individual. However, the association of IBMPFD1 and ALS in the same family is rare. Methods We reported three individuals from a Brazilian kindred with intrafamilial phenotype variability. Whole exome sequencing (WES) of the proband was performed and revealed a novel VCP variant. VCP Sanger sequencing was performed in the proband and his family members to confirm WES finding and segregation. We performed a systematic review of the literature regarding the genotypic-phenotypic VCP correlations. Results Each individual presented with either myopathy with rimmed vacuoles, ALS, or FTD. There was no PDB. WES of the proband identified the heterozygous variant c.271A>T (p.Asn91Tyr) in the exon 3 of VCP. Sanger sequencing confirmed the segregation of this variant in an autosomal-dominant pattern. Conclusion This study expands the genotypic spectrum of the missense mutations of the VCP gene with a novel p.Asn91Tyr variant found in a Brazilian family presenting with the unusual intrafamiliar association of myopathy with rimmed vacuoles, ALS and FTD.

Charcot-Marie-Tooth (CMT) disease is a hereditary neuropathy of motor and sensory impairment with distal predominance. Atrophy and weakness of lower limbs are the first signs of the disease. It can be classified, with the aid of electromyography and nerve conduction studies, as demyelinating (CMT1) or axonal (CMT2). OBJECTIVE: Clinical and neurophysiological investigation of a large multigenerational family with CMT2 with autosomal dominant mode of transmission. METHOD: Fifty individuals were evaluated and neurophysiological studies performed in 22 patients. RESULTS: Thirty individuals had clinical signs of motor-sensory neuropathy. Babinski sign was present in 14 individuals. Neurophysiological study showed motor-sensory axonal polyneuropathy. CONCLUSION: The clinical and neurophysiological characteristics of this family does not differ from those observed with other forms of CMT, except for the high prevalence of Babinski sign. A doença de Charcot-Marie-Tooth (CMT) é uma neuropatia hereditária de acometimento sensitivo e motor de predomínio distal. Atrofia e fraqueza em membros inferiores são os primeiros sinais da doença. Pode ser classificada, com auxílio da eletroneuromiografia, em desmielinizante (CMT1) ou axonal (CMT2). OBJETIVO: Investigação clínica e neurofisiológica de família com portadores de CMT2 de herança dominante. MÉTODO: Foi feita avaliação neurológica de 50 indivíduos e eletroneuromiografia em 22 pacientes. RESULTADOS: Trinta indivíduos tinham sinais clínicos de neuropatia sensitivo-motora. Sinal de Babinski estava presente em 14 indivíduos. A eletroneuromiografia demonstrou polineuropatia axonal sensitiva e motora. CONCLUSÃO: As características clínicas e neurofisiológicas desta família não se diferem das observadas em outras formas de CMT, exceto pela alta prevalência de sinal de Babinski.

Mutations in PUS3 , which encodes a highly conserved enzyme responsible for posttranscriptional modification of tRNA, have been shown in a single family to be a cause of nonsyndromic intellectual disability (ID).1 In this study, we used whole-exome sequencing (WES) to identify biallelic mutations in PUS3 associated with syndromic ID with dysmorphic features, white matter disease (WMD), and renal abnormalities in a nonconsanguineous family from Brazil. The authors thank the patients and their family for participating in this study.

Approximately 50% of all carriers of 2q21-q31 deletions present epileptic seizures. The band 2q24 constitutes the smallest commonly deleted segment in these patients, and contains the voltage-gated sodium channel genes SCN1A and SCN2A, associated with Dravet syndrome and benign familial neonatal-infantile seizures, respectively. A further putative locus involving epilepsy in the region was previously identified through disruption of the SLC4A10 gene by translocation. In the course of performing high-resolution DNA copy number analyses on syndromic mentally impaired individuals, we encountered three patients with overlapping deletions in chromosome region 2q24. Two of these patients exhibited epileptic seizures in addition to mental deficiency. The deletion in one of the epileptic patients did not include the SCN cluster, demonstrating that a less severe form of epilepsy maps to an adjacent genomic region. This second region comprises about 3 Mb and contains the candidate gene SLC4A10, providing further support for the potential role of this gene in epilepsy.

Introduction Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder leading to neonatal intractable seizures and epileptic encephalopathy. Clinical seizures usually begin in the first hours of life, with poor response to anticonvulsants, evolving to refractory status epilepticus. Diagnostic assessment includes cerebrospinal fluid analysis, gene testing and clinical response to parenteral pyridoxine. Early recognition and treatment is highly desired to avoid unfavorable neurodevelopmental outcome. Electroencephalographic monitoring commonly reveals pretreatment multifocal epileptiform activity and burst suppression pattern; after pyridoxine injection, the incidence of sharp waves decreases and periods of suppression can occur. Methods Case report of a 11-month-old girl with first seizure with 4 h after birth and delayed genetic confirmation of pyridoxine-dependent epilepsy due to the gene ALDH7A1. EEG monitoring was performed during pyridoxine infusion. Results A 11 month-old girl, with unremarkable gestational and delivery history, started seizures 4 h after birth. Initially treated with phenobarbital, she evolved to convulsive status epilepticus (CSE), leading to orotracheal intubation and continuous sedation for 5 days. At 3 months, she had a new CSE, being hospitalized for 4 months and started on sodium valproate, vigabatrin, clobazam and levetiracetam. Epileptic seizures remained weekly. Phenobarbital and cannabidiol were added, with no further benefit. At 9 months, seizures became daily and she had a new CSE. In the ICU, it was started midazolam, ketamine, topiramate and ketogenic diet. After 1 month, she was discharged and referred to a tertiary hospital. An exome sequencing revealed 2 copies in homozygosis in the gene ALDH7A1, variant Chr5:125.894.936 C > T, previously associated with PDE. While being admitted for pyridoxin treatment, she started a new CSE. EEG showed diffuse spikes, polyspikes and sharp waves at intervals of 1–2 s. Immediately after intravenous injection of pyridoxine 200 mg, epileptiform activity became progressively less frequent, alternating with periods of attenuattion lasting from 2 to 8 s, with no longer SE after 3 min. After 3 days, EEG showed moderate diffuse disorganization, with no epileptiform activity. Discharge was after 10 days. Outpatient EEG monitoring showed left centrotemporal sharp waves and mild disorganization of background activity. Conclusion This case illustrates a clinical scenario of seizures starting in the neonatal period, with recurrent convulsive status epilepticus and little response to anticonvulsants and ketogenic diet. The delayed diagnosis can be explained by rarity of the condition and limited availability of gene testing in public health system in medium and low-income countries. It remarks the importance of empirical pyridoxine treatment in neonates with early beginning of refractory seizures and status epilepticus (SE). EEG evolution and SE cessation documents pyridoxine responsiveness.

Contains fulltext : 87597.pdf (Publisher’s version ) (Closed access) Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype-phenotype correlations do not exist for the common c.698G>A and c.707T>C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dopa. 01 juni 2010

Mitochondriopathies are a heterogeneous group of diseases with variable phenotypic presentation, which can range from subclinical to lethal forms. They are related either to DNA mutations or nuclear-encoded mitochondrial genes that affect the integrity and function of these organelles, compromising adenosine triphosphate (ATP) synthesis. Magnetic resonance (MR) is the most important imaging technique to detect structural and metabolic brain abnormalities in mitochondriopathies, although in some cases these studies may present normal results, or the identified brain abnormalities may be nonspecific. Magnetic resonance spectroscopy (MRS) enables the detection of high cerebral lactate levels, even when the brain has normal appearance by conventional MR scans. MRS is a useful tool for the diagnosis of mitochondriopathies, but must be correlated with clinical, neurophysiological, biochemical, histological, and molecular data to corroborate the diagnosis. Our aim is to clarify the most relevant issues related to the use of MRS in order to optimize its technical parameters, improving its use in the diagnosis of mitochondriopathies, which is often a challenge.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurological progressive disorder associated with the FMR1 gene premutation. We report on variable presentation of findings associated with FXTAS in 3 brothers aged 68, 74, and 73 years, carrying premutation alleles of (CGG)(123,) (CGG)(109), and (CGG)(91) triplets, respectively. Based on previously proposed diagnostic criteria for the syndrome, clinical and radiological data allowed establishing a "definite" diagnosis of FXTAS in the two carriers of the longest (CGG)(n). The carrier of the (CGG)(91) allele, although presenting a major radiological sign of the syndrome (symmetrical white-matter lesions in the middle cerebellar peduncles), did not have any significant neurological manifestation at 73 years of age.

Benign hereditary chorea (BHC) was originally described in 1967, but it was not until 2002 that linkage analysis and positional cloning identified the causative gene, NKX2-1 (also known as TTF-1).(1,2) The range of manifestations spans from isolated chorea, pulmonary disease, or thyroid dysfunction, with one-third of patients having the full brain-lung-thyroid syndrome.(3) Recent reports have expanded the NKX2-1 phenotype, as patients may present with additional movement disorders such as dystonia and myoclonus.(3) We present a case with early-onset chorea, ataxia, and dystonia.

Molecular analysis of five Brazilian families, including eight patients presenting with nonclassic Tay-Sachs disease, was performed to identify frequent causative mutations and their correlation with clinical course. Three patients were affected by the B1 subacute variant and were shown to carry the R178H mutation (the DN allele), which is also common among Portuguese patients. Two of them were compound heterozygotes, whereas the third presented with the mutation in both alleles. Since Brazil was a Portuguese colony for over two centuries, common ancestry might be the probable explanation. The fourth patient presented with a juvenile phenotype and carries the R499H mutation, which has been reported only once worldwide and is associated with residual enzyme activity, responsible for a slower clinical course. The fifth family, of an Ashkenazi Jewish background, showed an extensive intrafamilial clinical variability among three affected sibs presenting with muscle atrophy, ataxia, and psychiatric symptoms. They were first diagnosed as having atypical spinal muscular atrophy and, subsequently, spinocerebellar ataxia, but, recently, the diagnosis of late-onset Tay-Sachs disease was confirmed based on reduced plasma hexosaminidase A activity and the G269S/InsTATC1278 genotype. It is therefore highly recommended to test patients with a similar clinical history for Tay-Sachs disease. In the same family, one first cousin committed suicide at the age of 24 years, presenting with a clinical phenotype that suggested an undiagnosed case and highlighting the effect of the intrafamilial clinical variability in delaying a prompt diagnosis. It is now recognized that his parents are, in fact, a carrier couple. Additionally, another relative had been previously identified as a heterozygote in a Tay-Sachs disease screening program, but the information was not shared among the family. Since this information might anticipate diagnosis and genetic counseling, it is advisable that heterozygote screening programs encourage families to share genetic information. ( J Child Neurol 2006;21:540—544; DOI 10.2310/7010.2006.00102).

The authors describe the electroclinical phenotype of four patients with Angelman syndrome (AS) determined by its rarest genetic mechanism-uniparental disomy (UPD). The analysis of ours and published patients showed that in UPD, when epilepsy occurred, it was milder compared to patients with deletion, although a suggestive EEG was observed in most patients. We found that UPD patients do not completely fit the scenario delineated for AS, suggesting that patients determined by different mechanisms should be distinctly addressed, for a better understanding of this syndrome.