RESUMO
OBJECTIVES: To evaluate the auditory, vestibular, and retinal characteristics of a large American DFNA11 pedigree with autosomal dominant progressive sensorineural hearing loss that first impacts the low- and mid-frequency auditory range. The pedigree (referred to as the HL2 family) segregates a myosin VIIA (MYO7A) mutation in exon 17 at DNA residue G2164C (MYO7A) that seems to be influenced by a genetic modifier that either rescues or exacerbates the MYO7A alteration. DNA analysis to examine single-nucleotide polymorphisms in 2 candidate modifier genes (ATP2B2 and Wolfram syndrome 1 [WFS1]) is summarized in this report. STUDY DESIGN: Family study. RESULTS: The degree of low- and mid-frequency hearing loss in HL2 family members segregating the MYO7A mutation varies from mild to more severe, with approximately the same number of HL2 family members falling at each end of the severity spectrum. The extent of hearing loss in HL2 individuals can vary between family generations. Differences in the degree of hearing loss in MYO7A HL2 family members may be mirrored by vestibular function in at least 2 of these same individuals. The single-nucleotide polymorphisms examined within ATP2B2 and WFS1 did not segregate with the mild versus more severe auditory phenotype. CONCLUSION: The severity of the auditory and vestibular phenotypes in MYO7A HL2 family members may run in parallel, suggesting a common modifier gene within the inner ear. The putative MYO7A genetic modifier is likely to represent a common polymorphism that is not linked tightly to the MYO7A mutation on the MYO7A allele.
Assuntos
Perda Auditiva Neurossensorial/genética , Miosinas/genética , Síndromes de Usher/genética , Testes Calóricos , Transferência Genética Horizontal/genética , Perda Auditiva Neurossensorial/diagnóstico , Humanos , Masculino , Proteínas de Membrana/genética , Miosina VIIa , Linhagem , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Mutação Puntual/genética , Polimorfismo de Nucleotídeo Único/genética , Índice de Gravidade de Doença , Fatores Sexuais , Síndromes de Usher/diagnóstico , Síndrome de Wolfram/genéticaRESUMO
BACKGROUND: The hallmark of Wolfram syndrome -- an extremely rare autosomal recessive disorder -- is the association of juvenile onset diabetes mellitus with optic atrophy. Additional symptoms such as deafness and diabetes insipidus may develop. HISTORY AND SIGNS: An 18-year-old man suffered progressive visual loss over the last seven years. Severe optic atrophy with extensive cupping and slightly elevated intraocular pressure in both eyes were found. Perimetry revealed peripheral defects with paracentral scotomas. ERG results excluded tapetoretinal degeneration; visual evoked responses were delayed. At the age of nine the patient had been diagnosed with diabetes mellitus type I and neurosensory deafness, seven years later a beginning hypogonadism was found. THERAPY AND OUTCOME: Wolfram syndrome is a progressive degenerative disorder with reduced life expectancy. Treatment is symptomatic. CONCLUSIONS: Wolfram syndrome should be considered in every patient who presents with optic atrophy and juvenile onset diabetes mellitus.