RESUMO
In this report, we describe a kindred consisting of five affected males presenting with many of the well-recognized features of Aarskog-Scott syndrome. The diagnosis, which was confirmed by the identification of a novel nonsense mutation of FGD1, was associated with the presence of a symmetric distal arthropathy with electromyographic signs of myopathy. These features should be considered in the evaluation of future patients.
Assuntos
Códon sem Sentido/genética , Nanismo/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Deformidades Congênitas da Mão/genética , Cardiopatias Congênitas/genética , Artropatias/genética , Doenças Musculares/genética , Adolescente , Blefaroptose/genética , Pré-Escolar , Análise Mutacional de DNA , Nanismo/diagnóstico , Eletromiografia , Face/anormalidades , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Genitália Masculina/anormalidades , Deformidades Congênitas da Mão/diagnóstico , Cardiopatias Congênitas/diagnóstico , Humanos , Lactente , Masculino , Adulto JovemRESUMO
OBJECTIVE: To assess the mutational and clinical spectrum of spatacsin associated with autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC). METHODS: A retrospective study was carried out at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia from February 2008 until March 2011. Four unrelated Saudi Arabian families with ARHSP-TCC were studied, totaling 13 affected individuals. Clinical presentations included gait disturbance at variable ages (2-18 years), spastic paraplegia with mild to moderate cognitive impairment and evidence of peripheral neuropathy in 2 families. Brain MRI showed TCC accompanied by periventricular white matter changes and cortical atrophy. RESULTS: A genome wide scan demonstrated linkage to the SPG11 locus. Sequencing revealed 4 mutations. The first is an insertion/deletion (indel) consisting of a 3 base pair (bp) deletion and 23 bp insertion (L1268L fsX), the second is a one bp deletion (S1923R fsX), and the third and the fourth are nonsense mutations (Q341X and R651X). All mutations predict premature truncation of the spatacsin protein. CONCLUSION: We report 2 novel mutations in this gene, including an indel considerably larger than any other identified to date. The identification of these mutations further confirms the causative link between SPG11 and ARHSP-TCC in these families.
Assuntos
Sequência de Aminoácidos/genética , Códon sem Sentido/genética , Corpo Caloso/patologia , Proteínas/genética , Deleção de Sequência/genética , Paraplegia Espástica Hereditária/genética , Adolescente , Adulto , Árabes , Cromossomos Humanos Par 15/genética , Transtornos Cognitivos/genética , Análise Mutacional de DNA , Ligação Genética , Humanos , Imageamento por Ressonância Magnética , Linhagem , Estudos Retrospectivos , Arábia Saudita , Paraplegia Espástica Hereditária/sangueRESUMO
PURPOSE: Nephrogenic Diabetes Insipidus (NDI) is genetically heterogeneous and may be inherited in an X-linked or autosomal recessive manner. We aimed to investigate the molecular basis of NDI among Arab families. METHODS: Direct sequencing of coding regions for AQP2 and AVPR2 was used to identify underlying mutations. One large deletion required Southern blot analysis and a PCR-based strategy to identify deletion junctions. RESULTS: We identified two novel missense mutations (AQP2:p.Gly100Arg and p.Gly180Ser) in AQP2 and one novel missense mutation (AVPR2:p.Gly122Asp), one previously reported missense mutation (AVPR2:p.Arg137His) and one novel contiguous deletion (AVPR2:c.25 + 273_ARHGAP4o:2650-420del) affecting AVPR2. We also describe evidence of lyonization associated with the novel deletion. CONCLUSIONS: Two novel mutations were identified in each of AVPR2 and AQP2 underlying CNDI in Arab families. Identification of these mutations will facilitate early diagnosis of CNDI, counseling of families and provide opportunities for early intervention aimed at reducing morbidity. The presence of affected females and consanguinity, as is often observed in Arab communities should not be used to rule out AVPR2 as a candidate when considering diagnostic testing. Careful observation of phenotypic heterogeneity should be used in referring such families for both AQP2 and AVPR2 molecular genetic testing.
