RESUMO
Amyotrophic lateral sclerosis (ALS) is a deadly motor neuron disease (MND) and the most frequent MND in adults. ALS is recognized by degenerative alterations in both upper and lower motor neurons. This disorder is classified to familial and sporadic classes. Disease-causing mutations in SOD1, C9ORF72, FUS, and TARDBP have been recognized in familial ALS cases. However, in spite of conduction of several genetic association studies, heritable genetic risk elements in sporadic have not been identified completely. Several miRNAs have been dysregulated in the serum samples or brain tissues of ALS patients. Moreover, a number of miRNAs have been suggested as putative biomarkers for sporadic ALS. In the current manuscript, we review of miRNAs in the development of ALS.
Assuntos
Neurite do Plexo Braquial/metabolismo , MicroRNAs/metabolismo , Animais , Biomarcadores/metabolismo , Neurite do Plexo Braquial/genética , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , MicroRNAs/genética , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismoRESUMO
Neuromuscular disorders encompass a wide range of conditions often associated with a genetic component. In the present study, we report a patient with severe infantile-onset amyotrophy in whom two compound heterozygous variants in the gene CACNA1H encoding for Cav3.2 T-type calcium channels were identified. Functional analysis of Cav3.2 variants revealed several alterations of the gating properties of the channel that were in general consistent with a loss-of-channel function. Taken together, these findings suggest that severe congenital amyoplasia may be related to CACNA1H and would represent a new phenotype associated with mutations in this gene.
Assuntos
Neurite do Plexo Braquial/genética , Canais de Cálcio Tipo T/genética , Mutação de Sentido Incorreto , Neurite do Plexo Braquial/fisiopatologia , Canais de Cálcio Tipo T/química , Canais de Cálcio Tipo T/fisiologia , Eletrofisiologia , Feminino , Heterozigoto , Humanos , Lactente , Fenótipo , Sequenciamento do ExomaRESUMO
Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder associated with episodic, recurrent, and painful neuropathies affecting the nerves of the brachial plexus. In this study, we report on a family of Lebanese descent with HNA onset in early childhood. The affected family members presented with platelet dysfunction. Platelet aggregation was reduced after stimulation with the agonists ADP and epinephrine in all affected family members. Flow cytometric analyses revealed impaired platelet δ-secretion. The index patient and one brother suffered from kidney cysts. Molecular genetic analysis revealed a heterozygous duplication of exon 2 within the septin 9 (SEPT9) gene in all the affected family members. Such a young child with HNA (aged 2 years) caused by SEPT9 duplication has not been described so far.
Assuntos
Neurite do Plexo Braquial/genética , Septinas/genética , Adolescente , Criança , Pré-Escolar , Éxons/genética , Feminino , Citometria de Fluxo , Duplicação Gênica/genética , Heterozigoto , Humanos , Masculino , Mutação/genética , Agregação Plaquetária/genética , Agregação Plaquetária/fisiologiaRESUMO
Neuralgic amyotrophy (NA) is characterized by sudden onset of severe pain in the shoulder/upper arm and muscle amyotrophy. Up to 60% of patients with NA are misdiagnosed as having shoulder joint pathology or cervical pathology. We report a case of a 13-year-old girl diagnosed with the hereditary form of NA (HNA). Array comparative genomic hybridization showed a maternally inherited duplication of 1.5 Mb including the entire SEPT9-gene. The girl was treated with non-steroidal anti-inflammatory drugs, corticosteroids and physiotherapy. Individuals with HNA should avoid extreme muscle activity and severe cold, as this may trigger attacks.
Assuntos
Neurite do Plexo Braquial/diagnóstico , Adolescente , Neurite do Plexo Braquial/complicações , Neurite do Plexo Braquial/genética , Neurite do Plexo Braquial/terapia , Feminino , Humanos , Dor de Ombro/etiologiaRESUMO
Neuralgic amyotrophy (NA) is a distinct peripheral nervous system (PNS) disorder characterized by sudden attacks of neuropathic pain, usually in a unilateral upper extremity, and patchy paresis with atrophy in the glenohumeral muscles. The lesion sites of NA are commonly considered to be upper brachial plexus (BP) and/or individual branches of the BP. The cause of NA remains unknown. Some evidence suggests a complex pathogenesis in NA that includes predisposition and susceptible PNS structures, and it can be triggered by infection, trauma, and strenuous exercise. NA is considered to be broad and encompasses a spectrum of atypical presentations, including involvement of the lower part of the BP, isolated nerves (anterior interosseous nerve or posterior interosseous nerve), or lumbosacral plexuses. Functional prognosis of NA is less favorable than previously assumed; however, specific therapy for patients with NA remains to be established.
Assuntos
Neurite do Plexo Braquial/diagnóstico , Neurite do Plexo Braquial/genética , Predisposição Genética para Doença , Neuralgia/etiologia , Neuralgia/genética , Neurite do Plexo Braquial/complicações , Neurite do Plexo Braquial/terapia , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia/terapia , Linhagem , PrognósticoRESUMO
Septin 9 (SEPT9) interacts with microtubules (MTs) and is mutated in hereditary neuralgic amyotrophy (HNA), an autosomal-dominant neuropathy. The mechanism of SEPT9 interaction with MTs and the molecular basis of HNA are unknown. Here, we show that the N-terminal domain of SEPT9 contains the novel repeat motifs K/R-x-x-E/D and R/K-R-x-E, which bind and bundle MTs by interacting with the acidic C-terminal tails of ß-tubulin. Alanine scanning mutagenesis revealed that the K/R-R/x-x-E/D motifs pair electrostatically with one another and the tails of ß-tubulin, enabling septinseptin interactions that link MTs together. SEPT9 isoforms lacking repeat motifs or containing the HNA-linked mutation R88W, which maps to the R/K-R-x-E motif, diminished intracellular MT bundling and impaired asymmetric neurite growth in PC-12 cells. Thus, the SEPT9 repeat motifs bind and bundle MTs, and thereby promote asymmetric neurite growth. These results provide the first insight into the mechanism of septin interaction with MTs and the molecular and cellular basis of HNA.
Assuntos
Neurite do Plexo Braquial/genética , Microtúbulos/metabolismo , Septinas/química , Motivos de Aminoácidos , Animais , Cães , Humanos , Células Madin Darby de Rim Canino , Células PC12 , Isoformas de Proteínas , Ratos , Tubulina (Proteína)/metabolismoRESUMO
Hereditary spastic paraplegia(HSP or SPG) is a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by progressive spasticity, weakness of lower limbs, and pathologically by retrograde axonal degeneration of corticospinal tracts and posterior spinal tracts. Presence of additional features allows differentiation between simple and complex forms of the disease. Genetically, 16 loci for HSP accompanied by distal amyotrophy have been mapped, for which 13 genes have been identified. With the identification of causative genes, the molecular mechanism of this disease is gradually elucidated.
Assuntos
Neurite do Plexo Braquial/genética , Paraplegia Espástica Hereditária/genética , Neurite do Plexo Braquial/complicações , Heterogeneidade Genética , Humanos , Paraplegia Espástica Hereditária/complicaçõesRESUMO
Hereditary neuralgic amyotrophy is a rare autosomal dominant disorder involving recurrent episodes of painful brachial plexus neuropathies. Involvement of other nerves has been described in some families. The age of onset is from infancy to adulthood. Mutations in the SEPT9 gene were identified in approximately half of the hereditary neuralgic amyotrophy families. We evaluated a family with six affected members from three generations with a point mutation in the SEPT9 gene. One of the patients presented in the neonatal period with vocal cord paralysis necessitating intubation and prolonged ventilation. The neonatal presentation of vocal cord paralysis broadens the phenotypic spectrum of hereditary neuralgic amyotrophy. The identification of a SEPT9 mutation in a neonate with respiratory distress due to vocal cord paralysis expands the differential diagnosis in these patients.
Assuntos
Neurite do Plexo Braquial/genética , Mutação , Septinas/genética , Paralisia das Pregas Vocais/genética , Neurite do Plexo Braquial/complicações , Pré-Escolar , Feminino , Humanos , Recém-Nascido , Masculino , LinhagemRESUMO
The septins are a family of GTP-binding proteins, evolutionarily conserved from yeast through to mammals, with roles in multiple core cellular functions. Here we provide an overview of our current knowledge of septin structure and function and focus mainly on mammalian septins, but gain much insight by drawing on knowledge of septins in other organisms. We describe their genomic and transcriptional complexity: a complexity manifest also in the diversity of scaffold structures that septins can form. Septin complexes can act to localize interacting proteins at specific intracellular locales and can also define membrane compartments by defining diffusion barriers. By such activities, septins can contribute to the definition of spatial asymmetry and cell polarity and we suggest a potential role in stem cell biology. Finally, we review the evidence that septins contribute to various disease states and argue that it is a breakdown in the tight regulation of their expression (particularly of individual isoforms), and also their inherent ability to oligomerize, which is pathogenic. Study of the perturbation of septin complex formation in disease will provide valuable insights into septin biology and will be a fertile ground for study.
Assuntos
Morfogênese/genética , Septinas/fisiologia , Animais , Infecções Bacterianas/genética , Neurite do Plexo Braquial/genética , Citoesqueleto/genética , Expressão Gênica/genética , Humanos , Mamíferos , Neoplasias/genética , Fagocitose/genética , Isoformas de Proteínas/genética , Septinas/genética , Septinas/metabolismoRESUMO
INTRODUCTION: Hereditary neuralgic amyotrophy (HNA) is a rare condition characterized by recurrent episodes of painful paralysis preferentially affecting the brachial plexus. It is often linked to a mutation in the SEPT9 gene. CASE REPORT: A 69-year-old female patient experienced a dozen episodes of severe neurological deficit mainly affecting the brachial plexus and the phrenic and recurrent nerves. The diagnosis of HNA without SEPT9 gene mutation was retained. DISCUSSION: HNA can have significant sequelae. A genetic heterogeneity exists and mutations in the SEPT9 gene may not be found. Immunomodulatory and corticosteroid treatments have sometimes proved to be effective.
Assuntos
Neurite do Plexo Braquial/etiologia , Neurite do Plexo Braquial/genética , Septinas/genética , Idoso , Anti-Inflamatórios/uso terapêutico , Neurite do Plexo Braquial/patologia , Disfonia/etiologia , Dispneia/etiologia , Humanos , Imunossupressores/uso terapêutico , Masculino , Metilprednisolona/uso terapêutico , Mutação/genética , Paralisia/etiologia , Nervo Frênico/patologiaRESUMO
We identified a family in Mali with two sisters affected by spastic paraplegia. In addition to spasticity and weakness of the lower limbs, the patients had marked atrophy of the distal upper extremities. Homozygosity mapping using single nucleotide polymorphism arrays showed that the sisters shared a region of extended homozygosity at chromosome 19p13.11-q12 that was not shared by controls. These findings indicate a clinically and genetically distinct form of hereditary spastic paraplegia with amyotrophy, designated SPG43.
Assuntos
Neurite do Plexo Braquial/genética , Cromossomos Humanos Par 19/genética , Loci Gênicos , Paraplegia Espástica Hereditária/genética , Adolescente , Idade de Início , Feminino , Homozigoto , Humanos , Mali , Linhagem , Polimorfismo de Nucleotídeo Único , Irmãos , Adulto JovemRESUMO
BACKGROUND: Hereditary neuralgic amyotrophy (HNA), also known as hereditary brachial plexus neuropathy, has phenotypic and genetic heterogeneity. Mutations in the septin 9 (SEPT9) gene were recently identified in some HNA patients. The phenotypic spectrum of HNA caused by SEPT9 mutations is not well known. OBJECTIVE: To characterise the phenotype of a large family of HNA patients with the SEPT9 R88W mutation. METHODS: We report clinical, electrophysiological, neuroimaging and genetic findings of six HNA patients from a Japanese family. RESULTS: All 17 neuropathic episodes identified were selectively and asymmetrically distributed in the upper-limb nerves. Severe pain was an initial symptom in 16 episodes (94%). Motor weakness occurred in 15 (88%) and sensory signs in 10 (59%). A minor dysmorphism, hypotelorism, was seen in all. Nerve conduction studies revealed focal demyelination as well as prominent axonal degeneration changes. Needle electromyography revealed chronic neurogenic patterns only in the upper limbs. An MRI study showed a gadolinium-enhanced brachial plexus. The missense mutation c.262C>T; p.R88W was found in exon 2 of SEPT9 in all patients. CONCLUSIONS: The SEPT9 R88W mutation in this family causes selective involvement of the brachial plexus and upper-limb nerves. Wider and more universal recognition of clinical hallmarks and genetic counselling are of diagnostic importance for HNA caused by the SEPT9 mutation.
Assuntos
Neurite do Plexo Braquial/genética , Proteínas do Citoesqueleto/genética , Proteínas de Ligação ao GTP/genética , Mutação de Sentido Incorreto/genética , Adolescente , Adulto , Idoso , Braço/inervação , Plexo Braquial/patologia , Criança , Família , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/genética , Linhagem , Fenótipo , Septinas , Adulto JovemRESUMO
BACKGROUND: Genomic copy number variants have been shown to be responsible for multiple genetic diseases. Recently, a duplication in septin 9 (SEPT9) was shown to be causal for hereditary neuralgic amyotrophy (HNA), an episodic peripheral neuropathy with autosomal dominant inheritance. This duplication was identified in 12 pedigrees that all shared a common founder haplotype. METHODS AND RESULTS: Based on array comparative genomic hybridisation, we identified six additional heterogeneous tandem SEPT9 duplications in patients with HNA that did not possess the founder haplotype. Five of these novel duplications are intragenic and result in larger transcript and protein products, as demonstrated through reverse transcription-PCR and western blotting. One duplication spans the entire SEPT9 gene and does not generate aberrant transcripts and proteins. The breakpoints of all the duplications are unique and contain regions of microhomology ranging from 2 to 9 bp in size. The duplicated regions contain a conserved 645 bp exon within SEPT9 in which HNA-linked missense mutations have been previously identified, suggesting that the region encoded by this exon is important to the pathogenesis of HNA. CONCLUSIONS: Together with the previously identified founder duplication, a total of seven heterogeneous SEPT9 duplications have been identified in this study as a causative factor of HNA. These duplications account for one third of the patients in our cohort, suggesting that duplications of various sizes within the SEPT9 gene are a common cause of HNA.
Assuntos
Neurite do Plexo Braquial/enzimologia , Neurite do Plexo Braquial/genética , Duplicação Cromossômica/genética , Septinas/genética , Pareamento de Bases/genética , Sequência de Bases , Análise Mutacional de DNA , Éxons/genética , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , RecidivaRESUMO
BACKGROUND: Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder that manifests as recurrent, episodic, painful brachial neuropathies. A gene for HNA maps to chromosome 17q25.3 where mutations in SEPT9, encoding the septin-9 protein, have been identified. OBJECTIVE: To determine the frequency and type of mutations in the SEPT9 gene in a new cohort of 42 unrelated HNA pedigrees. METHODS: DNA sequencing of all exons and intron-exon boundaries for SEPT9 was carried out in an affected individual in each pedigree from our HNA cohort. Genotyping using microsatellite markers spanning the SEPT9 gene was also used to identify pedigrees with a previously reported founder haplotype. RESULTS: Two missense mutations were found: c.262C>T (p.Arg88Trp) in seven HNA pedigrees and c.278C>T (p.Ser93Phe) in one HNA pedigree. Sequencing of other known exons in SEPT9 detected no additional disease-associated mutations. A founder haplotype, without defined mutations in SEPT9, was present in seven pedigrees. CONCLUSIONS: We provide further evidence that mutation of the SEPT9 gene is the molecular basis of some cases of hereditary neuralgic amyotrophy (HNA). DNA sequencing of SEPT9 demonstrates a restricted set of mutations in this cohort of HNA pedigrees. Nonetheless, sequence analysis will have an important role in mutation detection in HNA. Additional techniques will be required to find SEPT9 mutations in an HNA founder haplotype and other pedigrees.
Assuntos
Sequência de Bases , Neurite do Plexo Braquial/genética , Análise Mutacional de DNA , GTP Fosfo-Hidrolases/genética , Mutação de Sentido Incorreto , Análise de Sequência , Mapeamento Cromossômico , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , SeptinasRESUMO
Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder associated with recurrent episodes of focal neuropathy primarily affecting the brachial plexus. Point mutations in the SEPT9 gene have been previously identified as the molecular basis of HNA in some pedigrees. However in many families, including those from North America demonstrating a genetic founder haplotype, no sequence mutations have been detected. We report an intragenic 38 Kb SEPT9 duplication that is linked to HNA in 12 North American families that share the common founder haplotype. Analysis of the breakpoints showed that the duplication is identical in all pedigrees, and molecular analysis revealed that the duplication includes the 645 bp exon in which previous HNA mutations were found. The SEPT9 transcript variants that span this duplication contain two in-frame repeats of this exon, and immunoblotting demonstrates larger molecular weight SEPT9 protein isoforms. This exon also encodes for a majority of the SEPT9 N-terminal proline rich region suggesting that this region plays a role in the pathogenesis of HNA.
Assuntos
Neurite do Plexo Braquial/genética , Efeito Fundador , GTP Fosfo-Hidrolases/genética , Duplicação Gênica , Predisposição Genética para Doença , Pareamento de Bases/genética , Sequência de Bases , Segregação de Cromossomos , Análise Mutacional de DNA , Éxons/genética , Família , Feminino , Regulação da Expressão Gênica , Haplótipos , Humanos , Masculino , Dados de Sequência Molecular , Mutação/genética , América do Norte , Linhagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fases de Leitura/genética , SeptinasRESUMO
Hereditary neuralgic amyotrophy (HNA), an autosomal dominant disorder associated with SEPT9 mutation located on chromosome 17q25, causes recurrent painful weakness with sensory disturbances in a brachial distribution. We present electrophysiological, clinical phenotype, and molecular genetic data of three members from a family with HNA with the C262T SEPT9 mutation. The degree of motor weakness and recovery is variable within this family. Severity and recovery from motor deficits may have been a function of comorbid medical conditions. To our knowledge, this is the first report to confirm SEPT9 mutation in a family with suspected HNA.
Assuntos
Neurite do Plexo Braquial/genética , GTP Fosfo-Hidrolases/genética , Neuropatia Hereditária Motora e Sensorial/genética , Fenótipo , Recuperação de Função Fisiológica/genética , Plexo Braquial/fisiopatologia , Neurite do Plexo Braquial/complicações , Criança , Pré-Escolar , Feminino , Variação Genética , Neuropatia Hereditária Motora e Sensorial/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Remissão Espontânea , SeptinasRESUMO
We report a family in which two siblings presented with an apparent dysmorphic syndrome, including hypotelorism, blepharophimosis, slight ptosis, epicanthal folds, microstomia and dysmorphic ears. One sibling had a cleft palate. Initially, blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) was suspected; however, mutation of the FOXL2 gene was not detected. Moreover, the patients' father and paternal grandmother had experienced recurrent episodes of unilateral brachial neuritis and were diagnosed to have hereditary neuralgic amyotrophy (HNA). HNA is a rare, inherited form of brachial neuritis whose phenotypic spectrum may include hypotelorism, cleft palate and other minor dysmorphisms. HNA maps to chromosome 17q25 and is associated with mutations in the SEPT9 gene. After confirming a heterozygous SEPT9 mutation (R88W) in the father and his mother, it became apparent that the dysmorphic features in the children were part of HNA and that previous complaints of the daughter, erroneously diagnosed as pronatio dolorosa and then epiphysiolysis of the capitellum humeri, were in fact a first neuralgic pain attack. Both children were shown to have inherited the paternal SEPT9 mutation. Wider recognition of HNA as a syndromic disorder may facilitate its diagnosis in affected young persons who may not yet have manifested episodes of brachial neuritis.
Assuntos
Neurite do Plexo Braquial/genética , GTP Fosfo-Hidrolases/genética , Mutação , Adolescente , Adulto , Blefarofimose/genética , Blefaroptose/genética , Pré-Escolar , Família , Feminino , Humanos , Lactente , Masculino , Fenótipo , Septinas , SíndromeRESUMO
SEPT9 is a member of the cytoskeleton-related septin family, which is highly expressed in glia cells in neuronal tissues. Sequence alterations in SEPT9 are known to cause hereditary neuralgic amyotrophy (HNA) but precise cellular consequences have yet to be determined. Since SEPT9 is thought to function through interaction with other septins and small GTPase Rho-mediated signaling, we analyzed the properties of HNA-associated SEPT9 missense variants, SEPT9F (c.278C>T/p.Ser93Phe in SEPT9_v3; NM_006640.3) and SEPT9W (c.262C>T/p.Arg88Trp in SEPT9_v3). We found both sequence variants, but not the wild type, to form filaments with SEPT4 along stress fibers in mesenchymal mouse mammary gland NMuMG cells. In the epithelial cells, the variants, but not the wild type, were colocalized with SEPT11 at cell-cell junctions. In addition, although septin filaments containing SEPT9_v3 were disrupted by Rho/Rhotekin signaling, this was not the case with SEPT9F and SEPT9W. Sequence variations in SEPT9 causing HNA are thus likely to alter modes of interaction with partner molecules in cells, and consequently contribute to the pathogenesis of HNA.
Assuntos
Neurite do Plexo Braquial/genética , Proteínas do Citoesqueleto/genética , GTP Fosfo-Hidrolases/química , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/fisiologia , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mutação , Transdução de Sinais , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Proteínas Reguladoras de Apoptose , Proteínas de Ligação ao GTP , Humanos , Glândulas Mamárias Animais/metabolismo , Mesoderma/metabolismo , Camundongos , Neurônios/metabolismo , Ratos , SeptinasRESUMO
A common feature of the mammalian septin gene family is complex genomic architecture with multiple alternate splice variants. Septin 9 has 18 distinct transcripts encoding 15 polypeptides, with two transcripts (SEPT9_v4 and v4*) encoding the same polypeptide. We have previously reported that the ratio of these distinct transcripts is altered in neoplasia, with the v4 transcript being the usual form in normal cells but v4* becoming predominant in tumours. This led us to ask what the functional differences between these two transcripts might be. The 5'-UTRs of v4 and v4* have distinct 5' ends encoded by exons 1beta (v4) and 1zeta and 2 (v4*) and a common 3' region and initiating ATG encoded within exon 3. Here we show that the two mRNAs are translated with different efficiencies and that cellular stress can alter this. A putative internal ribosome entry site can be identified in the common region of the v4 and v4* 5'-UTRs and translation is modulated by an upstream open-reading frame in the unique region of the v4 5'-UTR. Germline mutations in hereditary neuralgic amyotrophy (HNA) map to the region which is common to the two UTRs. These mutations dramatically enhance the translational efficiency of the v4 5'-UTR, leading to elevated SEPT9_v4 protein under hypoxic conditions. Our data provide a mechanistic insight into how the HNA mutations can alter the fine control of SEPT9_v4 protein and its regulation under physiologically relevant conditions and are consistent with the episodic and stress-induced nature of the clinical features of HNA.
Assuntos
Neurite do Plexo Braquial/genética , GTP Fosfo-Hidrolases/genética , Biossíntese de Proteínas/genética , Regiões 5' não Traduzidas , Processamento Alternativo , Animais , Northern Blotting , Western Blotting , Neurite do Plexo Braquial/patologia , Células COS , Linhagem Celular Tumoral , Chlorocebus aethiops , Éxons/genética , GTP Fosfo-Hidrolases/metabolismo , Regulação da Expressão Gênica , Células HeLa , Humanos , Luciferases/genética , Luciferases/metabolismo , Mutação , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Septinas , Transcrição GênicaRESUMO
Familial spastic paraplegia (FSP) with severe muscular atrophy of hands and feet is exceptional. Autosomal dominant forms were initially described by Silver in 1966. We report two cases, from the same Tunisian family, presenting FSP with severe amyotrophy of the hands. A brother and his sister, aged respectively 37 and 36 years old, presented practically the same clinical picture. Their parents were cousins. The female patient was hospitalized. Both patients developed gait disorders around the age of three years. Muscular atrophy of the hands arose much later, around the age of 20 years. The neurological examination disclosed a spastic gait with distal amyotrophy, severe in the hands and moderate in the feet. Sensitivity was preserved and there was no fasciculation. The spinal cord and cerebral MRI was normal. Electromyography (EMG) showed a neurogenic pattern in the distal muscles. Stimulation of the median, ulnar and sciatica nerves was ineffective. The somatosensory evoked potentials (EP) were delayed (upper limb) or desynchronised (lower limb). The auditory and visual EP were normal. The cerebrospinal fluid contained 1 mononuclear cell/mm3 and 10 mg protein/100 ml. Abnormalities of the cranio-vertebral junction, Arnold-Chiari malformation, syringomyelia and familial juvenile amyotrophic lateral sclerosis (ALS) were excluded and the diagnosis of Silver's syndrome was evoked.