General description

Wolfram syndrome is predominantly an autosomal recessive disorder associated with mutations in the WFS1 gene, which encodes the transmembrane endoplasmic reticulum (ER) protein wolframin. The disease has been classified into two types: Wolfram syndrome type 1 (WS-1), which is the most prevalent form, and Wolfram syndrome type 2 (WS-2). While most affected individuals carry recessive WFS1 mutations, a subgroup of patients with dominant WFS1 mutations typically present with milder phenotypes, often characterized by optic atrophy and sensorineural hearing loss.

The hallmark clinical features of Wolfram syndrome include juvenile-onset diabetes mellitus and progressive optic atrophy, which are considered the minimum criteria for clinical diagnosis. Diabetes mellitus is typically the first symptom to appear, usually diagnosed around age 6, and nearly all patients require insulin replacement therapy. Optic atrophy generally follows, appearing around age 11, with initial manifestations including loss of color vision and peripheral vision, ultimately progressing to blindness within approximately 8 years after the first signs appear.

Beyond these defining characteristics, Wolfram syndrome presents with a constellation of additional symptoms. Diabetes insipidus, resulting from pituitary gland dysfunction that disrupts vasopressin release, affects approximately 70% of patients. Sensorineural hearing loss occurs in about 65% of cases, ranging from congenital deafness to mild hearing loss beginning in adolescence and worsening over time. Males may experience hypogonadism due to reduced testosterone levels, affecting growth and sexual development.

Neurological complications may include bladder dysfunction, cerebellar ataxia, cognitive impairment, and psychiatric disorders. The disease follows a progressive course, with central diabetes insipidus and sensorineural deafness typically occurring in the second decade of life, dilated renal outflow tracts in the third decade, and neurological symptoms appearing in the fourth decade. The life expectancy of patients is generally between 30-40 years, with death often resulting from respiratory failure caused by brainstem atrophy.