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Cochleosaccular dysplasia or degeneration (Scheibe degeneration) is considered the most common cause of profound congenital hearing impairment, and accounts for approximately 70% of cases 2 with hereditary deafness. A five-generation family with hereditary hearing impairment associated with cochleosaccular degeneration has recently been identified. The diagnosis of classical Scheibe degeneration was based on histopathological findings in the temporal bones of the proband, a 61-year-old profoundly deaf male. Auditory structures in the brainstem of the proband were also studied. Twenty-two members of the family were contacted for surveys and blood samples. Of these, 6 males and 2 females have hearing impairment. Complete audiological evaluation was done on 12 family members, and prior audiologic records of the proband and affected family members were available for study. Affected family members suffer a mild bilateral high-frequency hearing loss during childhood and adolescence, and progress to moderate-to-profound deafness in the second and third decades of life. The family is suitable for linkage analysis and does not map to previously reported loci harboring autosomal dominant, nonsyndromic hereditary hearing impairment genes. The genetic study of this family will be helpful in identifying the genes which, when mutated, result in Scheibe degeneration.

Mutations within three genes, SDHB, SDHC, and SDHD, encoding distinct subunits of a hetero-oligomeric protein known as the mitochondrial complex II, a component of the mitochondrial electron transport chain and the Krebs cycle have been implicated in the pathogenesis of hereditary paraganglioma (PGL). This study describes a mutation screen of SDHB, SDHC, and SDHD in blood and tumor samples of 14 sporadic and three familial cases of head and neck PGL (HNP). Germline mutations in SDHB and SDHD were identified in two of the three affected individuals with familial HNP. The SDHB mutation was a novel 3 base pair, in-frame deletion of AGC at nucleotide 583-585 encoding serine (delS195). The SDHD mutation was a C to T transition within codon 81 causing substitution of proline with leucine (P81L). In contrast to familial cases, no germline or somatic mutations were identified in the 14 sporadic cases of HNP. The presence of mutations within SDHB and SDHD in two of the three samples of familial PGLs and absence of mutations in sporadic cases is consistent with the significant contribution of these genes to familial but not sporadic PGL. The etiology of sporadic PGL remains to be elucidated.

Mutations in GJB3, the gene encoding the gap junction protein Connexin 31 (CX31), have been pathogenically linked to erythrokeratodermia and non-syndromic autosomal dominant (DFNA2) or recessive hereditary hearing impairment (HHI). To determine the contribution of CX31 to sporadic deafness, we assessed 63 individuals with non-syndromic hearing impairment for CX31 mutations. Single coding exon of CX31 was amplified from genomic DNA and then sequenced. Single nucleotide sequence alteration was present in 15 out of 63 patients (24%), all of the positives being heterozygous for the four different single base pair changes that were detected: C94T, C201T, C357T and C798T. Of these, only C94T transition, identified in two patients, results in amino acid change, R32W, while the other three changes are single nucleotide polymorphisms (SNPs). The R32W substitution in CX31 has been previously documented and is speculated to manifest variable penetrance, similar to the polymorphic allele encoding CX26M34T. Over one-third of all samples were also screened with denaturing high-performance liquid chromatography (dHPLC). Seven out of 25 individuals screened were determined to be positive for CX31 sequence variation. Sequence analysis of the 25 individuals screened identified nucleotide alterations in all of the 7 'positives' and in none of the 16 'negatives' yielding a specificity and sensitivity of 100%. Thus, dHPLC represents a highly efficient CX31 screening technique. This study suggests that while sequence alterations are common, pathogenic mutations of CX31 are infrequent in sporadic non-syndromic hearing impairment.

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