Wolfram syndrome is a rare, autosomal recessive neurodegenerative disorder that begins in childhood. The initial symptom, usually appearing in the first decade of life, is often insulin-dependent diabetes mellitus. This is typically followed by visual loss due to optic atrophy and progressive neurodegeneration. Other variable symptoms may include progressive hearing loss, central diabetes insipidus, ataxia, areflexia, dyspraxia, epilepsy, autonomic dysfunction, and endocrine disorders such as delayed onset of puberty, hypogonadism in boys, growth retardation, and non-autoimmune hypothyroidism. Psychiatric symptoms may also occur. Life expectancy is significantly reduced, averaging 30 years, with respiratory failure due to brainstem atrophy being the most common cause of death. No causal therapy currently exists. The incidence of Wolfram syndrome is reported to be between 1:160,000 and 1:770,000.
Wolfram syndrome is caused by homozygous or compound heterozygous pathogenic variants in the WFS1 gene. This gene encodes a hydrophobic, 890 amino acid-long glycoprotein (also known as wolframin) that contains nine transmembrane segments and is localized in the endoplasmic reticulum membrane. It is primarily expressed in the brain and pancreatic beta cells, but is also found in the lung and placenta. Currently, over 200 variants have been described, primarily in the region of the gene encoding the transmembrane and C-terminal domains of wolframin. The protein is significant for endoplasmic reticulum homeostasis, although its exact mechanism of action is not yet fully understood.
Rarely, dominant pathogenic variants in WFS1 have been reported, causing isolated hearing impairment and diabetes, or in combination with hearing loss, optic atrophy (a condition known as Wolfram-like syndrome), or autosomal dominant congenital cataracts.
Another autosomal dominant form, Wolfram syndrome type 2, caused by variants in the CISD2 gene, has also been described.
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