RESUMO
Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS-affected family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define HS as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6.
Assuntos
Adenosina Trifosfatases/genética , Amelogênese Imperfeita/genética , Fibroblastos/patologia , Perda Auditiva Neurossensorial/genética , Proteínas de Membrana/genética , Mutação/genética , Unhas Malformadas/genética , Peroxissomos/patologia , ATPases Associadas a Diversas Atividades Celulares , Adolescente , Adulto , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Peroxissomos/metabolismo , Fenótipo , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
When a candidate for predictive testing for the Huntington disease gene is a monozygotic twin, confidentiality of the co-twin's diagnosis and autonomy of participation are among the critical genetic counseling issues. Predictive testing can proceed when twins voluntarily and simultaneously request counseling and evaluation in an HD testing program. This case describes a young man referred for predictive testing to an HD testing site on the East Coast of the United States. Family history revealed a twin brother of unknown zygosity who resided on the West Coast of the United States. The genetic counselors on opposite coasts collaborated to provide genetic counseling and evaluation for voluntary, informed predictive testing of the twins, protecting their rights while observing national protocol guidelines