RESUMO
OBJECTIVES: The hereditary spastic paraplegias (HSP) are a genetically and clinically heterogeneous group of neurodegenerative disorders, mainly characterized by a progressive spasticity and weakness of the lower limbs. Mutations in the SPG4 and SPG3A genes are responsible for approximately 50% of autosomal dominant HSP. To genetically diagnose the Portuguese families with HSP, mutation analysis was performed for the SPG4 and SPG3A genes. PATIENTS AND METHODS: Analysis was performed by polymerase chain reaction, followed by denaturing high performance liquid chromatography (DHPLC), in 61 autosomal dominant (AD)-HSP families and 19 unrelated patients without family history. RESULTS: Ten novel mutations were identified: one in the SPG3A and nine in the SPG4 genes; three known mutations in the SPG4 were also found. Most of the novel mutations were frameshift or nonsense (80%), resulting in a dysfunctional protein. CONCLUSIONS: The SPG4 and SPG3A analysis allowed the identification of 10 novel mutations and the genetic diagnosis of approximately a quarter of our AD-HSP families.
Assuntos
Adenosina Trifosfatases/genética , GTP Fosfo-Hidrolases/genética , Paraplegia/genética , Idade de Início , Sequência de Aminoácidos , Cromatografia Líquida de Alta Pressão , Família , Feminino , Proteínas de Ligação ao GTP , Genes Dominantes , Humanos , Masculino , Proteínas de Membrana , Dados de Sequência Molecular , Mutação , Paraplegia/epidemiologia , Linhagem , Reação em Cadeia da Polimerase , Análise de Sequência de Proteína , EspastinaRESUMO
Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders characterized by progressive spasticity of the lower limbs. Here, we performed a genome-wide linkage analysis on a consanguineous family presenting an autosomal recessive form of HSP associated with mild mental retardation, brainstem dysraphia, and clinically asymptomatic cerebellar atrophy. We have mapped the disease locus SPG32 to chromosome 14q12-q21 within a 30-cM interval, which excludes the atlastin gene.
Assuntos
Cromossomos Humanos Par 14/genética , Predisposição Genética para Doença/genética , Mutação/genética , Paraplegia Espástica Hereditária/genética , Adulto , Tronco Encefálico/anormalidades , Tronco Encefálico/metabolismo , Tronco Encefálico/fisiopatologia , Cerebelo/anormalidades , Cerebelo/metabolismo , Cerebelo/fisiopatologia , Mapeamento Cromossômico , Consanguinidade , Análise Mutacional de DNA , Feminino , GTP Fosfo-Hidrolases/genética , Proteínas de Ligação ao GTP , Marcadores Genéticos/genética , Testes Genéticos , Genótipo , Humanos , Padrões de Herança/genética , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Deficiência Intelectual/fisiopatologia , Masculino , Proteínas de Membrana , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Malformações do Sistema Nervoso/fisiopatologia , Linhagem , Paraplegia Espástica Hereditária/metabolismo , Paraplegia Espástica Hereditária/fisiopatologiaRESUMO
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.
