Wolfram Syndrome 2

A number sign (#) is used with this entry because of evidence that Wolfram syndrome-2 (WFS2) is caused by homozygous mutation in the CISD2 gene (611507) on chromosome 4q24.

Description

Wolfram syndrome-2 is an autosomal recessive neurodegenerative disorder characterized by diabetes mellitus, high frequency sensorineural hearing loss, optic atrophy or neuropathy, and defective platelet aggregation resulting in peptic ulcer bleeding (summary by Mozzillo et al., 2014).

For a discussion of genetic heterogeneity of Wolfram syndrome, see WFS1 (222300).

Clinical Features

El-Shanti et al. (2000) reported 16 individuals from 4 consanguineous Jordanian families with a phenotype consistent with Wolfram syndrome. The patients developed diabetes mellitus in the first or second decade, followed by visual loss due to optic atrophy in all patients, and high frequency sensorineural hearing loss in all except 2 patients. Eight patients had urinary tract dilatation. Several patients had profound upper gastrointestinal ulceration and bleeding. None of the patients developed diabetes insipidus. In a follow-up of 3 of the families reported by El-Shanti et al. (2000), Amr et al. (2007) noted that 1 of the patients had depression resulting in suicide and that several additional patients had developed symptomatic hearing loss.

Mozzillo et al. (2014) reported a 17-year-old Caucasian girl, born of unrelated Italian parents, with WFS2. She presented with recurrent bleeding upper intestinal ulcers at age 5 years. At age 16, she had reduced visual acuity associated with optic neuropathy, but not optic atrophy. At age 17, she developed diabetes mellitus, and was also found to have bilateral sensorineural hearing loss affecting high frequencies. Laboratory studies showed defective platelet aggregation in response to ADP. Mozzillo et al. (2014) suggested that the patients reported by El-Shanti et al. (2000) may have had optic neuropathy rather than optic atrophy.

Rondinelli et al. (2015) studied 2 Italian sisters, ages 19 and 22 years, who both developed severe duodenal ulcers and anemia in the first months of life. Mild hearing loss limited to high frequencies was detected at ages 10 and 13 years. Both were diagnosed with nonautoimmune insulin-requiring diabetes mellitus at age 12, followed by the diagnosis of mild optic atrophy a few years later. The older sister developed neurogenic bladder requiring intermittent self-catheterization, whereas the younger experienced mild polyuria starting at age 9 with no progression. Both sisters exhibited other endocrine findings, including hypogonadism and/or menstrual alteration. Other features included hypogammaglobulinemia as well as rheumatologic disease, manifested as HLA B27-positive spondyloarthritis in the older sib and Lofgren syndrome (a form of sarcoidosis) in the younger.

Inheritance

The transmission pattern of Wolfram syndrome-2 in the families reported by El-Shanti et al. (2000) was consistent with autosomal recessive inheritance.

Mapping

With the use of 3 microsatellite markers reported to be linked to the 4p16.1 locus, El-Shanti et al. (2000) excluded linkage in 3 of 4 families with Wolfram syndrome. Two affected individuals in 1 family showed homozygosity for all 3 markers from the region of linkage on 4p16.1. For the other 3 families, genetic heterogeneity for Wolfram syndrome was verified with demonstration of linkage to 4q22-q24.

Molecular Genetics

In affected members of 3 consanguineous families of Jordanian descent with Wolfram syndrome studied by El-Shanti et al. (2000), Amr et al. (2007) identified a homozygous truncating mutation in the CISD2 gene (611507.0001). The CISD2-encoded protein, ERIS (endoplasmic reticulum intermembrane small protein), localizes to the endoplasmic reticulum.

In a 17-year-old Caucasian girl, born of unrelated Italian parents, with WFS2, Mozzillo et al. (2014) identified a homozygous intragenic deletion in the CISD2 gene (611507.0002).

In 2 Italian sisters with Wolfram syndrome, who were negative for mutation in the WFS1 gene, Rondinelli et al. (2015) sequenced the CISD2 gene and identified homozygosity for a splicing mutation (611507.0003) for which their unaffected parents were heterozygous.

Animal Model

Chen et al. (2009) provided evidence that the Cisd2 gene is involved in mammalian life span control. In mice, Cisd2 was primarily localized to the mitochondria and associated with the outer mitochondrial membrane. Cisd2-null mice showed early senescence and shortened life span compared to wildtype mice. Features included prominent eyes, protruding ears, corneal opacities and degeneration, thinner bones and hair, and decreased muscle mass, which are all consistent with premature aging. Tissue from mutant mice showed progressive mitochondrial breakdown and dysfunction accompanied by autophagic cell death, which preceded nerve and muscle degeneration. Mitochondria isolated from the mutant mice showed a defect in respiration. Together, the phenotype was suggestive of premature aging with some features of Wolfram syndrome. The findings suggested that Wolfram syndrome-2 is in part a mitochondria-mediated disorder. Chen et al. (2009) also noted that the human CISD2 gene maps to chromosome 4q22-q24, close to a region implicated in human longevity (152430).