RESUMO
Ataxia with oculo-motor apraxia type 2 (AOA2) is a recently described autosomal recessive cerebellar ataxia (ARCA) caused by mutations in the senataxin gene (SETX). We analysed the phenotypic spectrum of 19 AOA2 patients with mutations in SETX, which seems to be the third most frequent form of ARCA in Algeria after Freidreich ataxia and Ataxia with vitamin E deficiency. In AOA2 patients, the mean age at onset for all families was in the second decade. Cerebellar ataxia was progressive, slowly leading to disability which was aggravated by axonal polyneuropathy present in almost all the patients. Mean disease duration until wheelchair was around 20 years. Oculo-motor apraxia (OMA) was present in 32% of the patients while convergent strabismus was present in 37%. Strabismus is therefore also very suggestive of AOA2 when associated with ataxia and polyneuropathy even in the absence of OMA. Cerebellar atrophy was more severe in the eldest patients; however it may also be an early sign since it was present in the youngest and paucisymptomatic patients. The initial sign was gait ataxia in all but two patients who presented with head tremor and writer cramp, respectively. Serum alpha-fetoprotein, which was elevated in all tested patients, was a good marker to suggest molecular studies of the SETX gene.
Assuntos
Apraxias/genética , Ataxia Cerebelar/complicações , Ataxia Cerebelar/genética , Transtornos da Motilidade Ocular/complicações , Transtornos da Motilidade Ocular/genética , RNA Helicases/genética , Adolescente , Adulto , Idade de Início , Apraxias/complicações , Apraxias/patologia , Apraxias/fisiopatologia , Atrofia , Ataxia Cerebelar/patologia , Ataxia Cerebelar/fisiopatologia , Cerebelo/patologia , Cerebelo/fisiopatologia , DNA Helicases , Análise Mutacional de DNA , Progressão da Doença , Feminino , Humanos , Masculino , Enzimas Multifuncionais , Mutação , Fibras Nervosas Mielinizadas/patologia , Condução Nervosa , Transtornos da Motilidade Ocular/patologia , Transtornos da Motilidade Ocular/fisiopatologia , Linhagem , Fenótipo , Adulto Jovem , alfa-Fetoproteínas/análiseRESUMO
Autosomal-recessive forms of Charcot-Marie-Tooth (ARCMT) account for less than 10% of the families in the European CMT population but are more frequent in the Mediterranean basin and the Middle East because of more widespread consanguinity. Until now, demyelinating ARCMT was more extensively studied at the genetic level than the axonal form. Since 1999, the number of localized or identified genes responsible for demyelinating ARCMT has greatly increased. Eight genes, EGR2, GDAP1, KIAA1985, MTMR2, MTMR13, NDRG1, PRX, and CTDP1, have been identified and two new loci mapped to chromosomes 10q23 and 12p11-q13. In this review, we will focus on the particular clinical and/or neuropathological features of the phenotype caused by mutations in each of these genes, which might guide molecular diagnosis.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Transtornos Cromossômicos/genética , Doenças Desmielinizantes/genética , Genes Recessivos/genética , Catarata/genética , Catarata/fisiopatologia , Doença de Charcot-Marie-Tooth/classificação , Doença de Charcot-Marie-Tooth/fisiopatologia , Transtornos Cromossômicos/fisiopatologia , Anormalidades Congênitas , Doenças Desmielinizantes/fisiopatologia , Face/anormalidades , Humanos , SíndromeRESUMO
Charcot-Marie-Tooth disease is an heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked and autosomal recessive. By homozygosity mapping, we have identified, in the 5q23-q33 region, a third locus responsible for an autosomal recessive form of demyelinating CMT. Haplotype reconstruction and determination of the minimal region of homozygosity restricted the candidate region to a 4 cM interval. A physical map of the candidate region was established by screening YACs for microsatellites used for genetic analysis. Combined genetic, cytogenetic and physical mapping restricted the locus to a less than 2 Mb interval on chromosome 5q32. Seventeen consanguineous families with demyelinating ARCMT of various origins were screened for linkage to 5q31-q33. Three of these seventeen families are probably linked to this locus, indicating that the 5q locus accounts for about 20% of demyelinating ARCMT. Several candidate genes in the region were excluded by their position on the contig and/or by sequence analysis. The most obvious candidate gene, EGR1, expressed specifically in Schwann cells, mapped outside of the candidate region and no base changes were detected in two families by sequencing of the entire coding sequence.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Cromossomos Humanos Par 5 , Proteínas de Ligação a DNA/genética , Proteínas Imediatamente Precoces/genética , Fatores de Transcrição/genética , Dedos de Zinco/genética , Sequência de Bases , Mapeamento Cromossômico , Proteína 1 de Resposta de Crescimento Precoce , Ligação Genética , Homozigoto , Humanos , Repetições de Microssatélites , Dados de Sequência Molecular , LinhagemRESUMO
BACKGROUND: A large family with autosomal dominant nocturnal frontal lobe epilepsy from the south of Spain was studied. The clinical appearance of the disease in this family, which included 28 members, of whom 11 were affected and 2 were obligate carriers, was identical to that previously described in an Australian family and a Norwegian family, in which mutations in exon 5 of the CHRNA4 gene were found. METHODS: Following DNA extraction, the family was genotyped with 4 fluorescent markers flanking the locus to the CHRNA4 gene on chromosome 20q13.3, and lod score computations were performed. The exon 5 of the CHRNA4 gene was amplified between nucleotides 535 and 825 and polymerase chain reaction products were purified and sequenced directly. RESULTS: The same missense mutation as that found in the Australian family, C-->T, which causes the replacement of a serine with phenylalanine in amino acid 252 in exon 5, was detected. This mutation segregated with the disorder in all 11 affected members, in the 2 obligate carriers, and in 1 asymptomatic sibling, and was not found in 1 spouse and 1 daughter. Neither of the 2 polymorphisms found in a series of families with epilepsy were found in our sample [corrected]. CONCLUSIONS: These data confirm the clinical homogeneity in the phenotypic expression of autosomal dominant nocturnal frontal lobe epilepsy caused by mutation in the CHRNA4 gene, and the pathogenic role of the Ser252Phe mutation in this disorder.
Assuntos
Epilepsia do Lobo Frontal/genética , Fenilalanina/genética , Mutação Puntual/genética , Receptores Nicotínicos/genética , Serina/genética , Adulto , Alelos , Criança , Pré-Escolar , Análise Mutacional de DNA , Eletroencefalografia , Epilepsia do Lobo Frontal/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , EspanhaRESUMO
BACKGROUND: Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders characterized by progressive and predominant spasticity of the lower limbs, in which dominant, recessive, and X-linked forms have been described. While autosomal dominant HSP has been extensively studied, autosomal recessive HSP is less well known and is considered a rare condition. OBJECTIVE: To analyze the clinical presentation in a large group of patients with autosomal recessive HSP from Portugal and Algeria to define homogeneous groups that could serve as a guide for future molecular studies. RESULTS: Clinical features in 106 patients belonging to 46 Portuguese and Algerian families with autosomal recessive HSP are presented, as well as the results of molecular studies in 23 of these families. Five phenotypes are defined: (1) pure early-onset families, (2) pure lateonset families, (3) complex families with mental retardation, (4) complex families with mental retardation and peripheral neuropathy, and (5) complex families with cerebellar ataxia. Six additional families have specific complex presentations, each of which is unique in the present series. Pyramidal signs in the upper limbs and pes cavus are frequent findings, while pseudobulbar signs, including dysarthria, dysphagia, and brisk jaw jerks, are more frequent in the complex forms. The complex forms have a poorer prognosis, while pure forms, particularly those with early onset, are more benign. One Algerian pure early-onset kindred was linked to the locus on chromosome 8, previously reported in 4 Tunisian families. Two of the Portuguese kindreds with complex forms (one with mental retardation and the other associated with hypoplasia of the corpus callosum) showed linkage to the locus recently identified on chromosome 16. CONCLUSIONS: Although autosomal recessive HSP represents a heterogeneous group of diseases, some phenotypes can be defined by analyzing a large group of patients. The fact that only one Algerian family was linked to chromosome 8 suggests that this is a rare localization even in kindreds with the same ethnic background. Linkage to chromosome 16 was found in 2 clinically diverse Portuguese kindreds, illustrating that this locus is also rare and may correspond to different phenotypes.
Assuntos
Paraplegia Espástica Hereditária/diagnóstico , Adolescente , Adulto , Idoso , Argélia , Axônios/patologia , Criança , Pré-Escolar , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 8/genética , Avaliação da Deficiência , Progressão da Doença , Feminino , Ligação Genética , Marcadores Genéticos , Humanos , Masculino , Fenótipo , Portugal , Fatores de Risco , Índice de Gravidade de Doença , Paraplegia Espástica Hereditária/genética , Cromossomo X/genéticaRESUMO
The hereditary sensory and motor neuropathies form a clinically heterogenous group of disorders, the most frequent of which is Charcot-Marie-Tooth disease (CMT). The autosomal dominant forms of CMT are well characterized, but the nosology of autosomal recessive CMT is still controversial. We report two large consanguineous Algerian families with an autosomal recessive demyelinating CMT and similar clinical manifestations. The clinical, electrophysiologic, and neuropathologic features resemble those of autosomal dominant CMT1, but the early onset and rapid progression of deformities are specific. We excluded by linkage analysis the three loci CMT1A (17p11.2), CMT1B (1q22-23), and CMT4A (8q11-21.1) responsible for demyelinating forms of CMT. These findings suggest a subtype of autosomal recessive neuropathy, the locus of which is undetermined.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/patologia , Genes Recessivos , Nervos Periféricos/patologia , Nervos Periféricos/fisiopatologia , Adolescente , Adulto , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Doenças Desmielinizantes/fisiopatologia , Eletrofisiologia , Feminino , Ligação Genética , Humanos , Masculino , Microscopia Eletrônica , Condução Nervosa , LinhagemRESUMO
Giant axonal neuropathy is a rare severe autosomal recessive childhood disorder affecting both the peripheral nerves and the central nervous system. Peripheral nerves characteristically show giant axonal swellings filled with neurofilaments. The giant axonal neuropathy gene was localised by homozygosity mapping to chromosome 16q24.1 and identified as encoding a novel, ubiquitously expressed cytoskeletal protein named gigaxonin.We describe a consanguineous Algerian family with three affected sibs aged 16, 14 and 12 years who present a mild demyelinating sensory motor neuropathy, hypoacousia and kyphoscoliosis which was moderate in the two elder patients, severe in the third one, with no sign of central nervous system involvement and normal cerebral magnetic resonance imaging. This clinical picture is different from the classical severe form, with kinky hairs and early onset of central nervous system involvement and from the less severe form, with protracted course and late involvement of central nervous system. Nerve biopsy showed a moderate loss of myelinated fibers and several giant axons with thin or absent myelin, filled with neurofilaments. This neuropathological aspect is similar to the previously described families linked to the gigaxonin gene. Genetic study in this family showed absence of linkage to chromosome 16q24.1, indicating for the first time, a genetic heterogeneity in giant axonal neuropathy. We propose to call this form of giant axonal neuropathy giant axonal neuropathy 2, and to use the name of giant axonal neuropathy 1 for the form linked to 16q24.1.
Assuntos
Axônios/patologia , Cromossomos Humanos Par 16 , Doenças do Sistema Nervoso/genética , Adolescente , Argélia , Axônios/ultraestrutura , Criança , Mapeamento Cromossômico , Cromossomos Humanos Par 16/genética , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/fisiopatologia , Eletrofisiologia , Família , Feminino , Heterogeneidade Genética , Ligação Genética , Humanos , Masculino , Microscopia Eletrônica , Neurofibrilas/ultraestrutura , LinhagemRESUMO
Giant axonal neuropathy is a rare autosomal recessive childhood disorder characterized by a peripheral neuropathy and features of central nervous system involvement. We describe four patients belonging to a consanguineous Algerian family with late onset (6-10 years) slowly progressive autosomal recessive giant axonal neuropathy. The propositus presented with a Charcot-Marie-Tooth 2-like phenotype with foot deformity, distal amyotrophy of lower limbs, areflexia and distal lower limb hypoesthesia. Central nervous system involvement occurred 10 years later with mild cerebellar dysarthria and nystagmus in the propositus and 16 years after onset, a spastic paraplegia in the oldest patient. The two youngest patients (13 and 8 years old) do not present any signs of central nervous involvement. Magnetic resonance imaging showed cerebellar atrophy in the two older. Nerve biopsy showed moderate axonal loss with several giant axons filled with neurofilaments. Genetic study established a linkage to chromosome 16q locus. This clinical presentation differs from the classical form of giant axonal neuropathy.
Assuntos
Axônios/patologia , Doença de Charcot-Marie-Tooth/patologia , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/patologia , Adolescente , Adulto , Argélia , Atrofia/genética , Atrofia/patologia , Atrofia/fisiopatologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Mapeamento Cromossômico , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Linhagem , Doenças do Sistema Nervoso Periférico/fisiopatologiaRESUMO
Charcot-Marie-Tooth disease constitutes a genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. The axonal type of Charcot-Marie-Tooth is designated type 2. Six loci for autosomal dominant and three for recessive Charcot-Marie-Tooth type 2 have been reported so far. In this study we report the phenotype of autosomal recessive axonal Charcot-Marie-Tooth type 2 due to a recently-described mutation (c.892C>T-p.R298C) in a gene encoding Lamin A/C nuclear envelope proteins and the first gene in which a mutation leads to autosomal recessive Charcot-Marie-Tooth type 2. We have explored eight patients from four Algerian families. The onset is usually in the second decade and the course is rapid, involving upper limbs and proximal muscles, leading to a severe condition in less than 4 years. Many different mutations in Lamin A/C have been identified as causing variable phenotypes, such as limb girdle muscular dystrophy type 1B, autosomal dominant and recessive Emery-Dreyfuss muscular dystrophy, dilated cardiomyopathy with atrioventricular conduction defect, and Dunnigan-type familial partial lipodystrophy should prompt us to fully investigate the skeletal and cardiac muscles in patients affected with autosomal recessive Charcot-Marie-Tooth type 2 carrying a mutation in LMNA.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Lamina Tipo A/genética , Mutação , Argélia , Axônios/patologia , Cromossomos Humanos Par 1 , Análise Mutacional de DNA , Eletrofisiologia , Saúde da Família , Genes Recessivos , Predisposição Genética para Doença , Homozigoto , Humanos , Imuno-Histoquímica , Mutação de Sentido Incorreto , Membrana Nuclear/genética , Linhagem , Nervos Periféricos/diagnóstico por imagem , Nervos Periféricos/patologia , Fenótipo , UltrassonografiaRESUMO
We describe a six generation Saudi kindred, with a recessive hereditary motor and sensory neuropathy (HMSN). Four individuals were affected including two children (a boy and a girl) and a 23-year-old man. The fourth (a female) died at the age of 14 years. Onset of the disease was early (< 2 years) and the clinical and neurophysiological features were, generally, quite similar to those of an Italian family linked to chromosome 11q23. The peculiar pathologic pattern was irregular and redundant loops associated with folding of the myelin sheaths. The genetic study confirmed linkage to chromosome 11q23 and refined the location of the gene between D11S1311 and D11S917, a 3.3 cM region. These findings support the existence of a homogeneous and distinct entity within the form of HMSN associated with focally folded myelin sheaths.
Assuntos
Cromossomos Humanos Par 11 , Genes Recessivos , Ligação Genética , Neuropatia Hereditária Motora e Sensorial/genética , Neuropatia Hereditária Motora e Sensorial/patologia , Bainha de Mielina/patologia , Adulto , Pré-Escolar , Feminino , Genótipo , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Humanos , Masculino , Microscopia Eletrônica , Sistema Nervoso/patologia , Sistema Nervoso/fisiopatologia , Linhagem , Nervo Sural/patologiaRESUMO
Disruption of the function of the mouse jerky gene by transgene insertion causes generalized recurrent seizures reminiscent of human idiopathic generalized epilepsy (IGE). A human homologue, JRK/JH8, has been cloned, which maps to 8q24, a chromosomal region associated with several forms of IGE. JRK/JH8 is, therefore, a candidate locus for at least some forms of IGE. We report corrected cDNA sequences and extended open reading frames for the mouse jerky and human JRK/JH8 genes, which add 48 amino acids to the N-terminus of the Jerky protein and which extends the region of homology with the N-terminal DNA-binding domain of the centromere-binding protein, CENP-B. Systematic sequencing of the coding region of the extended JRK/JH8 gene identified single nucleotide polymorphisms that define three haplotypes, which were used for association studies in patients with idiopathic generalized epilepsy. We report one subject with childhood absence epilepsy (CAE) that evolved to juvenile myoclonic epilepsy (JME) that has a unique de novo mutation that results in a non-conservative amino acid change at a potential protein glycosylation site. Familial analysis supports a causal role for this mutation in the disease.
Assuntos
Proteínas de Ligação a DNA/genética , Epilepsia Tipo Ausência/genética , Mutação , Epilepsia Mioclônica Juvenil/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo Genético , Proteínas/genética , Alelos , Sequência de Aminoácidos/genética , Sequência de Bases/genética , Progressão da Doença , Frequência do Gene , Genótipo , Humanos , Dados de Sequência Molecular , Mutação/genética , Proteínas Nucleares , Fases de Leitura Aberta/genética , Linhagem , Proteínas de Ligação a RNA , Valores de ReferênciaRESUMO
The authors report the results of an electroclinical and tomographic study of 145 cases of partial epilepsy in children. Without advancing any views on etiology or symptomatologic classification, they analyse the various prognoses on the basis of case history, clinical aspects, symptomatology of seizures, EEG and tomographic signs. None of these factors in isolation appears to determine the prognosis of epilepsy. A significant percentage of apparently idiopathic epilepsies may develop adversely whereas half of the cases show a good prognosis.
Assuntos
Eletroencefalografia , Epilepsias Parciais/patologia , Tomografia Computadorizada por Raios X , Adolescente , Argélia , Criança , Pré-Escolar , Epilepsias Parciais/diagnóstico por imagem , Epilepsias Parciais/fisiopatologia , Feminino , Humanos , Lactente , Masculino , Estudos RetrospectivosRESUMO
We describe clinical, electrophysiological and genetic features in 44 patients with Unverricht-Lündborg disease from 19 families living in North African countries (Tunisia, Algeria and Morocco). The mean age of patients was 25.3 years; mean age was at onset 11.3 years. The disease began more frequently with seizures (91 per cent) or myoclonus (80 p. 100) than ataxia (16 p. 100). Subsequently myoclonus and generalized seizures were present in all patients, cerebellar signs were absent in four cases. EEG findings included normal background activity (90 p. 100), spontaneous fast generalized spikes (93 p. 100) and photosensitivity (70 p. 100). Antiepileptic polytherapy (clonazepam and/or phenobarbital and/or valporic acid) was used in 84 per cent of cases. Antiepileptic drugs were more effective in controlling epileptic seizures (less than one seizure/month in 60 p. 100) than myocloni which persisted daily in 64 p. 100 of cases. Mean duration of the disease was 13.5 years. One patient died of status epilepticus. Consanguinity was noted in 17 families (first degree in 15 families). Linkage to chromosome 21q 22.3 was confirmed in 11 families. We noted an inter and intrafamilial variability of clinical signs and disease course.
Assuntos
Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/fisiopatologia , Adolescente , Adulto , Idade de Início , Argélia , Biópsia , Cerebelo/fisiopatologia , Eletroencefalografia , Eletromiografia , Eletrofisiologia , Epilepsias Mioclônicas/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Marrocos , Músculo Esquelético/patologia , Linhagem , Estudos Retrospectivos , TunísiaAssuntos
Doença de Charcot-Marie-Tooth/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 13/genética , Doenças Desmielinizantes/genética , Homozigoto , Adulto , Argélia/etnologia , Doença de Charcot-Marie-Tooth/etnologia , Doença de Charcot-Marie-Tooth/patologia , Mapeamento Cromossômico , Doenças Desmielinizantes/etnologia , Doenças Desmielinizantes/patologia , Feminino , Genes Recessivos , Testes Genéticos , Humanos , Líbano/etnologia , Masculino , Linhagem , Nervo Sural/patologiaAssuntos
Doenças Desmielinizantes/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Doenças do Sistema Nervoso Periférico/genética , Processamento Alternativo/genética , Axônios/fisiologia , Sequência de Bases , Criança , Códon sem Sentido , Consanguinidade , DNA/química , DNA/genética , Análise Mutacional de DNA , DNA Complementar/química , DNA Complementar/genética , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/fisiopatologia , Eletrofisiologia , Saúde da Família , Feminino , Genótipo , Humanos , Masculino , Microscopia Eletrônica , Linhagem , Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Nervo Fibular/patologia , Nervo Fibular/ultraestrutura , FenótipoRESUMO
CMT2B1, an axonal subtype (MIM 605588) of the Charcot-Marie-Tooth disease, is an autosomal recessive motor and sensory neuropathy characterized by progressive muscular and sensory loss in the distal extremities with chronic distal weakness. The genetic defect associated with the disease is, to date, a unique homozygous missense mutation, p.Arg298Cys (c.892C>T), in the LMNA gene. So far, this mutation has only been found in affected individuals originating from a restricted region of North Western Africa (northwest of Algeria and east of Morocco), strongly suggesting a founder effect. In order to address this hypothesis, genotyping of both STRs and intragenic SNPs was performed at the LMNA locus, at chromosome 1q21.2-q21.3, in 42 individuals affected with CMT2B1 from 25 Algerian families. Our results indicate that the affected individuals share a common ancestral haplotype in a region of about 1.0 Mb (1 cM) and that the most recent common ancestor would have lived about 800-900 years ago (95% confidence interval: 550 to 1300 years).
Assuntos
Doença de Charcot-Marie-Tooth/genética , Efeito Fundador , Lamina Tipo A/genética , Mutação de Sentido Incorreto , Argélia , Substituição de Aminoácidos , Feminino , Homozigoto , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Sequências de Repetição em Tandem , Fatores de TempoRESUMO
OBJECTIVE: Mutations in various genes of the neuromuscular junction cause congenital myasthenic syndrome (CMS). A single truncating mutation (epsilon1293insG) in the acetylcholine receptor epsilon subunit gene (CHRNE) was most often identified in CMS families originating from North Africa and was possibly a founder mutation. METHODS: Twenty-three families were studied with an early onset form of CMS and originating from Tunisia, Algeria, Morocco, and Libya. Screening for the mutation epsilon1293insG was performed by direct sequencing. Haplotype analysis was done with 9 (CA)n repeat microsatellite markers and 6 SNPs flanking epsilon1293insG on chromosome 17p13-p12. Dating was calculated using the ESTIAGE method for rare genetic diseases. RESULTS: The epsilon1293insG mutation was identified in 14 families (about 60% of the initial 23). The expression of the CMS in affected members of these families was relatively homogeneous, without fetal involvement or being life-threatening, with moderate hypotonia and oculobulbar involvement, mild and stable disease course, and good response to cholinesterase inhibitors. Haplotype analysis revealed a common conserved haplotype encompassing a distance of 63 kb. The estimated age of the founder event was at least 700 years. CONCLUSIONS: These results strongly support the hypothesis that epsilon1293insG derives from an ancient single founder event in the North African population. Identification of founder mutations in isolated or inbred populations may have important implications in the context of molecular diagnosis and genetic counseling of patients and families by detection of heterozygous carriers.
Assuntos
Predisposição Genética para Doença/genética , Mutação/genética , Síndromes Miastênicas Congênitas/genética , Receptores Nicotínicos/genética , África do Norte/etnologia , Inibidores da Colinesterase/farmacologia , Análise Mutacional de DNA , Feminino , Efeito Fundador , Frequência do Gene , Aconselhamento Genético/normas , Marcadores Genéticos/genética , Testes Genéticos , Genótipo , Haplótipos , Heterozigoto , Humanos , Masculino , Biologia Molecular/normas , Síndromes Miastênicas Congênitas/etnologia , Síndromes Miastênicas Congênitas/fisiopatologiaRESUMO
BACKGROUND: Mutations in the SPG7 gene, which encodes paraplegin, are responsible for an autosomal recessive hereditary spastic paraplegia (HSP). OBJECTIVE: To screen the SPG7 gene in a large population of HSP families compatible with autosomal recessive transmission. METHODS: The authors analyzed 136 probands with pure or complex HSP for mutations in the SPG7 using denaturation high-performance liquid chromatography and direct sequencing. RESULTS: The authors identified 47 variants including 6 mutations, 27 polymorphisms, and 14 changes with unknown effects. In one family from Morocco, compound c.850_851delTTinsC and c.1742_1744delTGG heterozygous mutations were shown to be causative. This family had complex HSP with cerebellar impairment. Progression of the disease was rapid, resulting in a severe disease after 8 years of duration. Also detected were 20 families with one heterozygous mutation that was not found in a large control population. The mutations produced highly defective proteins in four of these families, suggesting that they were probably causative. Direct sequencing of all exons and reverse transcription PCR experiments demonstrated the absence of a second mutation. However, the p.Ala510Val missense substitution previously described as a polymorphism was shown to be significantly associated with HSP, suggesting that it had a functional effect. CONCLUSION: SPG7 mutations account for less than 5% of hereditary spastic paraplegia (HSP) families compatible with autosomal recessive inheritance. Cerebellar signs or cerebellar atrophy on brain imaging were the most frequent additional features in patients with SPG7 HSP. Rare nucleotide variants in SPG7 are frequent, complicating routine diagnosis.