Wolfram-Like Syndrome, Autosomal Dominant

A number sign (#) is used with this entry because of evidence that autosomal dominant Wolfram-like syndrome (WFSL), involving hearing loss with optic atrophy and/or impaired glucose regulation, is caused by heterozygous mutation in the WFS1 gene (606201) on chromosome 4p16.

Description

Autosomal dominant Wolfram-like syndrome is characterized by the clinical triad of congenital progressive hearing impairment, diabetes mellitus, and optic atrophy. The hearing impairment, which is usually diagnosed in the first decade of life, is relatively constant and alters mainly low- and middle-frequency ranges (summary by Valero et al., 2008).

Wolfram syndrome (WFS1; 222300) is an autosomal recessive allelic disorder characterized by optic atrophy, diabetes mellitus, hearing loss, and diabetes insipidus, and is caused by homozygous or compound heterozygous mutation in the WFS1 gene.

An autosomal dominant syndrome involving optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (125250), is caused by heterozygous mutation in the OPA1 gene (605290).

Clinical Features

Eiberg et al. (2006) reported a 3-generation Danish family in which a Wolfram syndrome (see 222300)-like phenotype segregated in an autosomal dominant fashion. The 4 affected individuals had childhood-onset progressive hearing impairment as well as optic atrophy that began in childhood or middle age. Laboratory evaluation revealed that 3 of the 4 also had impaired glucose regulation: 1 was found to have undiagnosed diabetes, another had impaired glucose tolerance by the oral glucose tolerance test, and the third had poor pancreatic beta-cell function as evaluated by the insulinogenic index. In addition, 1 of the 4 affected individuals had anxiety and a sleeping disorder. Isolated congenital hearing impairment was found in 2 other family members.

Valero et al. (2008) studied a French mother and son with hearing impairment and noninsulin-dependent diabetes mellitus (NIDDM). The index case was the 60-year-old son, who had progressive hearing impairment since childhood, requiring permanent use of a hearing aid, and was diagnosed with NIDDM at 45 years of age. Ophthalmologic examination showed no anomaly, with no optic atrophy or diabetic retinopathy, and no other manifestation classically associated with Wolfram syndrome was observed. His 81-year-old mother, who also had moderate hearing impairment since childhood, did not use a hearing aid but exhibited obvious difficulties with speech comprehension. She was found to have NIDDM at 45 years of age, and insulin was added at 60 years of age due to failure of oral agents. She also had severe visual impairment due to bilateral optic atrophy, which was discovered at age 60 years during an evaluation for diabetes follow-up.

Hogewind et al. (2010) studied a Dutch family in which 2 brothers and their mother had hearing loss and optic neuropathy. No other Wolfram syndrome-related symptoms, such as diabetes mellitus, diabetes insipidus, or renal or psychiatric problems, were reported or discovered on physical examination. Specifically, diabetes mellitus was excluded by confirming normal fasting serum glucose and HbA1c in all 3 affected individuals; insulin and C-peptide were also assessed in the older brother and found to be normal. Hearing in the mother and the older brother was so diminished that they had only minimal speech recognition; the younger brother still had relatively normal maximum speech recognition scores. Ophthalmologic examination in all 3 affected individuals showed an enlarged blind spot on perimetry testing, loss of neuroretinal rim on Heidelberg retinal tomography (HRT), a deviating visual evoked potential (VEP) response, and red-green color vision defect; unaffected family members exhibited none of these findings.

Rendtorff et al. (2011) restudied the Swedish family originally reported by Samuelson (1940), which they stated was the first report of isolated autosomal dominant optic atrophy and sensorineural hearing loss. Vision loss and hearing impairment was reported to have varied in severity among the 4 affected family members originally studied. The deceased proband, who had severe bilateral sensorineural hearing loss from early childhood and optic atrophy from age 9 years, also suffered from depression and hallucinations; 4 other affected family members had regular psychiatric treatment for anxiety, and 1 affected individual had committed suicide. Optic atrophy in this family presented as temporal paleness of the optic nerves, and progressed to low visual acuity after the age of 60 years; in addition, 4 of the 6 affected individuals developed glaucoma which responded well to standard treatment.

Mapping

By haplotype and sequence analysis in a 3-generation Danish family segregating an autosomal dominant Wolfram syndrome-like phenotype, Eiberg et al. (2006) excluded linkage to the OPA4 (605293) and OPA5 (610708) loci and excluded mutations in the OPA1 (605290), OPA3 (606580), GJB2 (121011), and GJB6 (604418) genes. A positive lod score of 1.61 was obtained for chromosome 4p16.3.

Molecular Genetics

Domenech et al. (2002) screened the WFS1 gene (606201) in 23 patients with both sensorineural deafness and type 2 diabetes mellitus (NIDDM; 125853) and identified 3 different heterozygous missense mutations in 3 unrelated patients, respectively, but stated that the lack of knowledge about the function of WFS1 made it difficult to explain the possible contribution of these mutations to the diseases.

In a 3-generation Danish family segregating an autosomal dominant Wolfram syndrome-like phenotype, in which affected individuals had deafness, optic atrophy, and impaired glucose regulation mapping to chromosome 4p16.3, Eiberg et al. (2006) analyzed the candidate gene WFS1 and identified a heterozygous missense mutation (E864K; 606201.0020) in affected individuals. The mutation was not found in unaffected family members or in the 2 family members who had isolated congenital hearing impairment.

In a 60-year-old French man with congenital hearing impairment and NIDDM and his 81-year-old mother with deafness, diabetes, and optic atrophy, both of whom were known to be negative for the common mtDNA mutations associated with the maternally inherited diabetes-deafness syndrome (MIDD; 520000), Valero et al. (2008) identified heterozygosity for the E864K mutation in the WSF1 gene. The mutation was not found in 100 French controls. The proband, who also carried an R228Q mutation in WFS1 (606201.0026) that was not found in controls, did not have optic atrophy or any other manifestations of Wolfram syndrome. No DNA was available for study from his deceased father; an unaffected half brother did not carry either WFS1 mutation. Audiogram analysis of his apparently healthy 21-year-old son revealed bilateral mild hearing loss at high frequencies, but the son declined to participate in genetic analysis.

In affected members of a Dutch family with deafness and optic neuropathy, in whom screening of the OPA1 gene (605290) and mtDNA screening for the 3 most frequent Leber optic atrophy (535000) mutations were both negative, Hogewind et al. (2010) identified heterozygosity for a missense mutation in the WSF1 gene (K836N; 606201.0027). The mutation was not found in unaffected family members or in 200 European chromosomes.

Rendtorff et al. (2011) analyzed the WSF1 gene in 15 probands with deafness and optic atrophy who were known to be negative for mutation in the OPA1 and TIMM8A (300356) genes, and identified heterozygosity for the same missense mutation in the WSF1 gene (A684V; 606201.0028) in 6 probands, 1 of whom was from the Swedish family originally described by Samuelson (1940). Two additional probands were heterozygous for 2 different WFS1 missense mutations, respectively (see, e.g., 606201.0031). In 7 of the 8 mutation-positive families, there were spouses with isolated sensorineural hearing loss (SNHL); analysis of the GJB2 gene (121011) revealed that 3 of the probands who were heterozygous for mutation in WFS1 also carried a known SNHL-related mutation in the GJB2 gene (121011.0001 or 121011.0005), inherited from a deaf parent who did not have optic atrophy. Noting that psychiatric disorders, including anxiety, depression, hallucinations, and schizophrenia, were present in affected individuals from 3 of the families with WFS1 mutations, Rendtorff et al. (2011) suggested that additional abnormalities might also be present in other families with Wolfram-like syndrome.