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OBJECTIVE: The study was undertaken to identify a monogenic cause of early onset, generalized dystonia. METHODS: Methods consisted of genome-wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients. RESULTS: We identified a heterozygous variant, c.388G>A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR-mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon-inducible double-stranded RNA-dependent protein kinase activator A), the product of another gene causing monogenic dystonia. INTERPRETATION: We identified EIF2AK2 variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia. ANN NEUROL 2021;89:485-497.
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Trastornos Distónicos/genética , Fibroblastos/metabolismo , eIF-2 Quinasa/genética , Adolescente , Adulto , Edad de Inicio , Pueblo Asiatico , Encéfalo/diagnóstico por imagen , Niño , Preescolar , Trastornos Distónicos/metabolismo , Trastornos Distónicos/fisiopatología , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación Missense , Linaje , Población Blanca , Secuenciación del Exoma , Adulto Joven , eIF-2 Quinasa/metabolismoRESUMEN
Genetic mutations in TBC1D24 have been associated with multiple phenotypes, with epilepsy being the main clinical manifestation. The TBC1D24 protein consists of the unique association of a Tre2/Bub2/Cdc16 (TBC) domain and a TBC/lysin motif domain/catalytic (TLDc) domain. More than 50 missense and loss-of-function mutations have been described and are spread over the entire protein. Through whole genome/exome sequencing we identified compound heterozygous mutations, R360H and G501R, within the TLDc domain, in an index family with a Rolandic epilepsy exercise-induced dystonia phenotype (http://omim.org/entry/608105). A 20-year long clinical follow-up revealed that epilepsy was self-limited in all three affected patients, but exercise-induced dystonia persisted into adulthood in two. Furthermore, we identified three additional sporadic paediatric patients with a remarkably similar phenotype, two of whom had compound heterozygous mutations consisting of an in-frame deletion I81_K84 and an A500V mutation, and the third carried T182M and G511R missense mutations, overall revealing that all six patients harbour a missense mutation in the subdomain of TLDc between residues 500 and 511. We solved the crystal structure of the conserved Drosophila TLDc domain. This allowed us to predict destabilizing effects of the G501R and G511R mutations and, to a lesser degree, of R360H and potentially A500V. Next, we characterized the functional consequences of a strong and a weak TLDc mutation (TBC1D24G501R and TBC1D24R360H) using Drosophila, where TBC1D24/Skywalker regulates synaptic vesicle trafficking. In a Drosophila model neuronally expressing human TBC1D24, we demonstrated that the TBC1D24G501R TLDc mutation causes activity-induced locomotion and synaptic vesicle trafficking defects, while TBC1D24R360H is benign. The neuronal phenotypes of the TBC1D24G501R mutation are consistent with exacerbated oxidative stress sensitivity, which is rescued by treating TBC1D24G501R mutant animals with antioxidants N-acetylcysteine amide or α-tocopherol as indicated by restored synaptic vesicle trafficking levels and sustained behavioural activity. Our data thus show that mutations in the TLDc domain of TBC1D24 cause Rolandic-type focal motor epilepsy and exercise-induced dystonia. The humanized TBC1D24G501R fly model exhibits sustained activity and vesicle transport defects. We propose that the TBC1D24/Sky TLDc domain is a reactive oxygen species sensor mediating synaptic vesicle trafficking rates that, when dysfunctional, causes a movement disorder in patients and flies. The TLDc and TBC domain mutations' response to antioxidant treatment we observed in the animal model suggests a potential for combining antioxidant-based therapeutic approaches to TBC1D24-associated disorders with previously described lipid-altering strategies for TBC domain mutations.
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Acetilcisteína/análogos & derivados , Antioxidantes/uso terapéutico , Modelos Animales de Enfermedad , Drosophila melanogaster/fisiología , Distonía/tratamiento farmacológico , Epilepsia Rolándica/genética , Proteínas Activadoras de GTPasa/genética , Esfuerzo Físico , alfa-Tocoferol/uso terapéutico , Acetilcisteína/uso terapéutico , Adolescente , Secuencias de Aminoácidos/genética , Secuencia de Aminoácidos , Animales , Animales Modificados Genéticamente , Transporte Biológico/efectos de los fármacos , Dominio Catalítico/genética , Niño , Preescolar , Cristalografía por Rayos X , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Distonía/etiología , Epilepsia Rolándica/tratamiento farmacológico , Femenino , Proteínas Activadoras de GTPasa/química , Proteínas Activadoras de GTPasa/fisiología , Humanos , Lactante , Locomoción/genética , Locomoción/fisiología , Masculino , Modelos Moleculares , Mutación Missense , Neuronas/fisiología , Estrés Oxidativo , Linaje , Conformación Proteica , Especies Reactivas de Oxígeno/metabolismo , Proteínas Recombinantes/metabolismo , Alineación de Secuencia , Eliminación de Secuencia , Homología de Secuencia de Aminoácido , Vesículas Sinápticas/metabolismo , Proteínas de Unión al GTP rab/química , Proteínas de Unión al GTP rab/genéticaRESUMEN
VPS13 protein family members VPS13A through VPS13C have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants including frameshift, missense, and partial duplication mutations with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia, or tremor), and progressive spastic ataxia or paraparesis. Characteristic brain magnetic resonance imaging shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and choreoacanthocytosis. Muscle biopsy in 1 case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological diseases and a possible role in mitochondrial function. Ann Neurol 2018;83:1089-1095.
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Discapacidad Intelectual/genética , Trastornos del Movimiento/genética , Espasticidad Muscular/genética , Mutación/genética , Atrofia Óptica/genética , Proteínas/genética , Ataxias Espinocerebelosas/genética , Ganglios Basales/patología , Encéfalo/patología , Niño , Humanos , Enfermedad de Leigh/patología , Imagen por Resonancia Magnética/métodos , Espasticidad Muscular/patología , LinajeRESUMEN
PURPOSE: FDG PET/CT is emerging as a new tool for the evaluation of acute encephalitis (AE). However, to date, there are no exclusively pediatric studies on the use of FDG PET for suspected AE. The objective of this study was to compare qualitative and quantitative brain PET to conventional brain imaging in a cohort of children, and to identify patterns of metabolic abnormalities characteristic of AE. METHODS: This retrospective study included 34 children imaged with PET/CT, CT and magnetic resonance imaging (MRI). The positivity rate of all three imaging modalities was measured. Besides visual assessment, quantification of relative regional brain metabolism (RRBM) was performed and compared to a database of normal pediatric brains. RESULTS: Fourteen subjects had a clinical diagnosis of autoimmune encephalitis (AIE) or encephalitis of unknown origin (EX), six of anti-N-methyl-D-aspartate receptor (anti-NMDAr) encephalitis, three of Hashimoto's encephalopathy, three of neurolupus and eight had other subtypes of encephalitis. Quantitative PET was abnormal in 100% of cases, visually assessed PET in 94.1% of subjects, MRI in 41.2% and CT in 6.9%. RRBM quantification demonstrated multiple hyper and hypo metabolic cortical regions in 82.3% of subjects, exclusively hypermetabolic abnormalities in 3%, and exclusively hypometabolic abnormalities in 14.7%. The basal ganglia were hypermetabolic in 26.5% of cases on visual assessment and in 58.8% of subjects using quantification. CONCLUSION: In our pediatric population FDG PET was more sensitive than conventional imaging for the detection of AE, and basal ganglia hypermetabolism was frequently encountered.
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Encéfalo/diagnóstico por imagen , Encefalitis/diagnóstico por imagen , Fluorodesoxiglucosa F18/análisis , Enfermedad de Hashimoto/diagnóstico por imagen , Adolescente , Ganglios Basales/diagnóstico por imagen , Niño , Preescolar , Femenino , Humanos , Inflamación , Imagen por Resonancia Magnética , Masculino , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos/análisis , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
INTRODUCTION: Disturbances of eye movements are infrequently encountered in motor neuron diseases (MNDs) or motor neuropathies, and there is no known syndrome that combines progressive muscle weakness with downbeat nystagmus. METHODS: To describe the core clinical features of a syndrome of MND associated with downbeat nystagmus, clinical features were collected from 6 patients. RESULTS: All patients had slowly progressive muscle weakness and wasting in combination with downbeat nystagmus, which was clinically most obvious in downward and lateral gaze. Onset was in the second to fourth decade with finger extension weakness, progressing to other distal and sometimes more proximal muscles. Visual complaints were not always present. Electrodiagnostic testing showed signs of regional motor axonal loss in all patients. DISCUSSION: The etiology of this syndrome remains elusive. Because finger extension weakness and downbeat nystagmus are the discriminating clinical features of this MND, we propose the name FEWDON-MND syndrome. Muscle Nerve 56: 1164-1168, 2017.
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Enfermedad de la Neurona Motora/diagnóstico por imagen , Enfermedad de la Neurona Motora/fisiopatología , Debilidad Muscular/diagnóstico por imagen , Debilidad Muscular/fisiopatología , Nistagmo Patológico/diagnóstico por imagen , Nistagmo Patológico/fisiopatología , Adolescente , Adulto , Electrodiagnóstico/métodos , Femenino , Dedos/fisiopatología , Humanos , Masculino , Enfermedad de la Neurona Motora/complicaciones , Debilidad Muscular/complicaciones , Nistagmo Patológico/complicaciones , Estudios Retrospectivos , Adulto JovenRESUMEN
Infantile spasms (IS) is an early-onset epileptic encephalopathy of unknown etiology in â¼40% of patients. We hypothesized that unexplained IS cases represent a large collection of rare single-gene disorders. We investigated 44 children with unexplained IS using comparative genomic hybridisation arrays (aCGH) (n = 44) followed by targeted sequencing of 35 known epilepsy genes (n = 8) or whole-exome sequencing (WES) of familial trios (n = 18) to search for rare inherited or de novo mutations. aCGH analysis revealed de novo variants in 7% of patients (n = 3/44), including a distal 16p11.2 duplication, a 15q11.1q13.1 tetrasomy and a 2q21.3-q22.2 deletion. Furthermore, it identified a pathogenic maternally inherited Xp11.2 duplication. Targeted sequencing was informative for ARX (n = 1/14) and STXBP1 (n = 1/8). In contrast, sequencing of a panel of 35 known epileptic encephalopathy genes (n = 8) did not identify further mutations. Finally, WES (n = 18) was very informative, with an excess of de novo mutations identified in genes predicted to be involved in neurodevelopmental processes and/or known to be intolerant to functional variations. Several pathogenic mutations were identified, including de novo mutations in STXBP1, CASK and ALG13, as well as recessive mutations in PNPO and ADSL, together explaining 28% of cases (5/18). In addition, WES identified 1-3 de novo variants in 64% of remaining probands, pointing to several interesting candidate genes. Our results indicate that IS are genetically heterogeneous with a major contribution of de novo mutations and that WES is significantly superior to targeted re-sequencing in identifying detrimental genetic variants involved in IS.
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Cromosomas Humanos/genética , Mutación , Espasmos Infantiles/genética , Preescolar , Deleción Cromosómica , Duplicación Cromosómica , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Lactante , Recién Nacido , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Análisis de Secuencia de ADN , Espasmos Infantiles/patología , TetrasomíaRESUMEN
Our group previously described and mapped to chromosomal region 12p13 a form of dominantly inherited hereditary spastic ataxia (HSA) in three large Newfoundland (Canada) families. This report identifies vesicle-associated membrane protein 1 (VAMP1), which encodes a critical protein for synaptic exocytosis, as the responsible gene. In total, 50 affected individuals from these families and three independent probands from Ontario (Canada) share the disease phenotype together with a disruptive VAMP1 mutation that affects a critical donor site for the splicing of VAMP1 isoforms. This mutation leads to the loss of the only VAMP1 isoform (VAMP1A) expressed in the nervous system, thus highlighting an association between the well-studied VAMP1 and a neurological disorder. Given the variable phenotype seen in the affected individuals examined here, we believe that VAMP1 should be tested for mutations in patients with either ataxia or spastic paraplegia.
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Genes Dominantes , Paraplejía Espástica Hereditaria/genética , Degeneraciones Espinocerebelosas/genética , Proteína 1 de Membrana Asociada a Vesículas/genética , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , Mutación , Terranova y LabradorRESUMEN
INTRODUCTION: Erythromelalgia due to heterozygous gain-of-function SCN9A mutations usually presents as a pure sensory-autonomic disorder characterized by recurrent episodes of burning pain and redness of the extremities. METHODS: We describe a patient with an unusual phenotypic presentation of gross motor delay, childhood-onset erythromelalgia, extreme visceral pain episodes, hypesthesia, and self-mutilation. The investigation of the patient's motor delay included various biochemical analyses, a comparative genomic hybridization array (CGH), electromyogram (EMG), and muscle biopsy. Once erythromelalgia was suspected clinically, the SCN9A gene was sequenced. RESULTS: The EMG, CGH, and biochemical tests were negative. The biopsy showed an axonal neuropathy and neurogenic atrophy. Sequencing of SCN9A revealed a heterozygous missense mutation in exon 7; p.I234T. CONCLUSIONS: This is a case of global motor delay and erythromelalgia associated with SCN9A. The motor delay may be attributed to the extreme pain episodes or to a developmental perturbation of proprioceptive inputs.
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Trastornos de la Destreza Motora/genética , Mutación Missense/genética , Canal de Sodio Activado por Voltaje NAV1.7/genética , Índice de Severidad de la Enfermedad , Trastornos Somatomorfos/genética , Carbamazepina/uso terapéutico , Preescolar , Comorbilidad , Eritromelalgia/tratamiento farmacológico , Eritromelalgia/epidemiología , Eritromelalgia/genética , Femenino , Humanos , Hipoestesia/tratamiento farmacológico , Hipoestesia/epidemiología , Hipoestesia/genética , Mexiletine/uso terapéutico , Trastornos de la Destreza Motora/tratamiento farmacológico , Trastornos de la Destreza Motora/epidemiología , Trastornos Somatomorfos/tratamiento farmacológico , Trastornos Somatomorfos/epidemiología , Resultado del TratamientoRESUMEN
Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication-based mechanisms such fork stalling and template switching or microhomology-mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients' fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele-specific LMNB1 expression levels.
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Duplicación de Gen , Lamina Tipo B/genética , Enfermedad de Pelizaeus-Merzbacher/genética , Adulto , Secuencia de Bases , Puntos de Rotura del Cromosoma , Hibridación Genómica Comparativa , ADN/química , ADN/genética , Humanos , Lamina Tipo B/metabolismo , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Enfermedad de Pelizaeus-Merzbacher/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described neuroinflammatory demyelinating disease. OBJECTIVE: To better understand the clinical spectrum, risk factors and outcomes in MOGAD. METHODS: Retrospective cohort study including all subjects harboring anti-MOG antibodies identified in major academic hospitals across the province of Quebec. RESULTS: We identified 45 MOGAD cases. The minimal estimated point-prevalence was 0.52/100 000 in Quebec. Median age at presentation was 32 years (range 1-71) with equal sex ratio. Most frequent ethnic groups were Caucasians and Asians. The most frequent clinical manifestations at onset were optic neuritis (ON), affecting 56% of adults, and acute disseminated encephalomyelitis (ADEM), affecting 33% of children. First MRI was abnormal in 84% of cases. Most CSF samples showed pleocytosis without oligoclonal bands. Two brain biopsies revealed lipid-laden macrophages and reactive astrocytes. Despite steroids, only 38% had fully recovered at 4 weeks after onset. Half of pediatric and two thirds of adult-onset MOGAD subjects experienced relapses. At last follow-up, 69% showed residual deficits, which were moderate to severe in 17% of adults. CONCLUSION: MOGAD has heterogeneous disease course, and it is not a benign disease for a substantial proportion of adults. Best disease-modifying therapies remain to be determined.
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Encefalomielitis Aguda Diseminada , Neuritis Óptica , Humanos , Glicoproteína Mielina-Oligodendrócito , Estudios Retrospectivos , Encefalomielitis Aguda Diseminada/diagnóstico por imagen , Progresión de la Enfermedad , AutoanticuerposRESUMEN
Tourette's Syndrome (TS) is a neurodevelopmental disorder that is characterized by motor and phonic tics. A recent TS genome-wide association study (GWAS) identified a genome-wide significant locus. However, determining the biological mechanism of GWAS signals remains difficult. To characterize effects of expression quantitative trait loci (eQTLs) in TS and understand biological underpinnings of the disease. Here, we conduct a TS transcriptome-wide association study (TWAS) consisting of 4819 cases and 9488 controls. We demonstrate that increased expression of FLT3 in the dorsolateral prefrontal cortex (DLPFC) is associated with TS. We further show that there is global dysregulation of FLT3 across several brain regions and probabilistic causal fine-mapping of the TWAS signal prioritizes FLT3 with a posterior inclusion probability of 0.849. After, we proxy the expression with 100 lymphoblastoid cell lines, and demonstrate that TS cells has a 1.72 increased fold change compared to controls. A phenome-wide association study also points toward FLT3 having links with immune-related pathways such as monocyte count. We further identify several splicing events in MPHOSPH9, CSGALNACT2 and FIP1L1 associated with TS, which are also implicated in immune function. This analysis of expression and splicing begins to explore the biology of TS GWAS signals.
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Síndrome de Tourette , Estudios de Casos y Controles , Estudio de Asociación del Genoma Completo , Humanos , Sitios de Carácter Cuantitativo , Síndrome de Tourette/genética , Transcriptoma , Tirosina Quinasa 3 Similar a fmsRESUMEN
Importance: Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified. Objective: To identify common genetic factors associated with risk of ET. Design, Setting, and Participants: Case-control genome-wide association study. Inverse-variance meta-analysis was used to combine cohorts. Multicenter samples collected from European populations were collected from January 2010 to September 2019 as part of an ongoing study. Included patients were clinically diagnosed with or reported having ET. Control individuals were not diagnosed with or reported to have ET. Of 485â¯250 individuals, data for 483â¯054 passed data quality control and were used. Main Outcomes and Measures: Genotypes of common variants associated with risk of ET. Results: Of the 483â¯054 individuals included, there were 7177 with ET (3693 [51.46%] female; mean [SD] age, 62.66 [15.12] years), and 475â¯877 control individuals (253â¯785 [53.33%] female; mean [SD] age, 56.40 [17.6] years). Five independent genome-wide significant loci and were identified and were associated with approximately 18% of ET heritability. Functional analyses found significant enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis pathways. Genetic correlation (r), which measures the degree of genetic overlap, revealed significant common variant overlap with Parkinson disease (r, 0.28; P = 2.38 × 10-8) and depression (r, 0.12; P = 9.78 × 10-4). A separate fine-mapping of transcriptome-wide association hits identified genes such as BACE2, LRRN2, DHRS13, and LINC00323 in disease-relevant brain regions, such as the cerebellum. Conclusions and Relevance: The results of this genome-wide association study suggest that a portion of ET heritability can be explained by common genetic variation and can help identify new common genetic risk factors for ET.
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Temblor Esencial/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad/genética , Variación Genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , TranscriptomaRESUMEN
This article aims to provide a practical review of pediatric dystonia from a clinician's perspective. The focus is on the underlying genetic causes, recent findings, and treatable conditions. Dystonia can occur in an isolated fashion or accompanied by other neurological or systemic features. The clinical presentation is often a complex overlap of neurological findings with a large differential diagnosis. We recommend an approach guided by thorough clinical evaluation, brain magnetic resonance imaging (MRI), biochemical analysis, and genetic testing to hone in on the diagnosis. This article highlights the clinical and genetic complexity of pediatric dystonia and underlines the importance of a genetic diagnosis for therapeutic considerations.
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Distonía/diagnóstico , Distonía/terapia , Trastornos Distónicos/diagnóstico , Trastornos Distónicos/terapia , Niño , Distonía/genética , Trastornos Distónicos/genética , HumanosRESUMEN
BACKGROUND: The most common cause of autosomal dominant Hereditary Spastic Paraplegia (HSP) is mutations in the SPG4 gene. We have previously identified novel SPG4 mutations in a collection of North American families including the c.G1801A mutation present in two families from Quebec. The aim of this study is to estimate the frequency of the c.G1801A mutation in the French Canadian (FC) population and to determine whether this mutation originates from a common ancestor. METHODS: We collected and sequenced exon 15 in probands of 37 families. Genotypes of markers flanking the SPG4 gene were used to construct haplotypes in five families. Clinical information was reviewed by a neurologist with expertise in HSP. RESULTS: We have identified three additional unrelated families with the c.G1801A mutation and haplotype analysis revealed that all five families share a common ancestor. The mutation is present in 7% of all our FC families and explains half of our spastin linked FC families. The phenotype associated with the c.G1801A genotype is pure HSP with bladder involvement. CONCLUSION: In this study we have determined that the relative frequency of the c.G1801A mutation in our FC collection is 7%, and approximately 50% in the spastin positive FC group. This mutation is the most common HSP mutation identified in this population to date and is suggestive of a founder effect in Quebec.
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Adenosina Trifosfatasas/genética , Efecto Fundador , Paraplejía Espástica Hereditaria/genética , Población Blanca/genética , Adolescente , Adulto , Anciano , Niño , Francia/etnología , Frecuencia de los Genes , Haplotipos , Humanos , Persona de Mediana Edad , Mutación/genética , Linaje , Quebec , Paraplejía Espástica Hereditaria/etnología , EspastinaRESUMEN
BACKGROUND: Hereditary spastic paraplegia (HSP) is a neurodegenerative disease characterized by progressive spasticity and weakness of the lower limbs. The most common form of HSP is caused by mutations in the SPG4 gene, which codes for spastin, an adenosine triphosphatase with various cellular activities (AAA) protein family member. OBJECTIVE: To investigate a large collection of predominantly North American patients with HSP for mutations in the spastin encoding gene, SPG4. METHODS: DNA from 76 unrelated affected individuals was studied for mutations by single-stranded conformational polymorphism analysis and direct sequencing. Each new variant identified was then analyzed in 80 control subjects to determine whether the variant is a common polymorphism or a rare mutation. All DNA samples were amplified by polymerase chain reaction, followed by electrophoresis and autoradiography. RESULTS: We identified 8 novel mutations and 5 previously reported mutations in 15 affected individuals. The novel mutations are 4 missense, 1 nonsense, 1 frameshift, and 2 splice mutations. Two polymorphisms (one in an affected individual) were also identified. CONCLUSIONS: Our collection of families with HSP is different on a genetic level from those previously described. The percentage of our families with a SPG4 mutation is 10% lower than the 40% estimate of families with autosomal dominant HSP noted to be linked to this locus, and splice mutations are not predominant in our collection. Interestingly, we also identified 2 recurring mutations in specific populations (R562Q and G559D), which may facilitate the development of future spastin diagnostic testing in these populations.
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Adenosina Trifosfatasas/genética , Paraplejía Espástica Hereditaria/genética , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Polimorfismo Conformacional Retorcido-Simple , EspastinaRESUMEN
OBJECTIVE: To identify the underlying locus and disease-causing mutation for adult-onset autosomal dominant leukodystrophy (ADLD). DESIGN: Previously, an adult-onset ADLD locus on chromosome 5q23 was mapped between markers D5S1495 and CTT/CCT15. This region contains 13 known and putative candidate genes. A 2-point linkage analysis confirmed linkage of a large multigenerational French Canadian family to chromosome 5q23. In addition, screening of the 13 genes within the candidate interval as well as 5 neighboring genes was completed, followed by comparative genomic hybridization. SUBJECTS: A multigenerational French Canadian family with ADLD mimicking progressive multiple sclerosis was identified and studied. Eight affected family members were available for the study and presented with autonomic dysfunction as well as upper motorneuron signs affecting gait. RESULTS: The thorough candidate gene approach did not identify any mutation. Consequently, a whole-chromosome comparative genomic hybridization for chromosome 5 identified a 280-kilobase duplication within the chromosomal band 5q23.2 in 2 affected individuals. This duplication contains 3 genes: LMNB1, FLJ36242, and MARCH3. CONCLUSION: We have identified a novel duplication on chromosomal band 5q23.2 in a French Canadian family with ADLD that supports the implication of duplicated LMNB1 as the disease-causing mutation. However, additional functional studies of lamin B1 overexpression are necessary to elucidate the involvement of lamin B1 in myelination and in degenerative disorders such as ADLD and multiple sclerosis.