A new mutation in a patient with Wolfram syndrome

Dear Editor:

Wolfram syndrome is a neurodegenerative disease characterised by the appearance of diabetes mellitus and optic atrophy in young patients. In the years following onset, patients also usually present such other symptoms as sensorineural hypoacusia, diabetes insipidus, progressive neurological anomalies (cerebellar ataxia, peripheral neuropathy, dementia), psychiatric disorders, and atonia of the urinary tract. The syndrome was described in 1938 by Donald J. Wolfram, who reported 4 cases of diabetes mellitus and optic atrophy in members of the same family, who subsequently developed hearing loss, incontinence, and ataxia.¹ Prevalence is estimated at one case per 770 000 population.²

Wolfram syndrome is caused by a mutation of the WFS1 gene, located in chromosome region 4p16.1, which codes for the transmembrane protein wolframin. This protein is located in the endoplasmic reticulum and is expressed in practically all tissues of the body, although at higher concentrations in the beta cells of pancreatic islets and the brain. The function of the protein is not well understood; wolframin is believed to be involved in cellular transport and calcium homeostasis in the endoplasmic reticulum.³ Given the disease's rareness and its considerable genetic and clinical heterogeneity, the term “Wolfram syndrome spectrum” is frequently used. Disorders associated with the WFS1 gene include Wolfram syndrome,⁴ which follows an autosomal recessive inheritance pattern, and Wolfram-like syndrome and low-frequency sensorineural hearing loss (LFSNHL), which follow an autosomal dominant inheritance pattern. Wolfram-like syndrome is characterised by the combination of sensorineural hearing loss, diabetes mellitus, psychiatric disorders, and variable optic atrophy. LFSNHL is characterised by congenital, nonsyndromic, slowly progressive, low-frequency sensorineural hearing loss.⁵

Treatment is symptomatic and depends on the clinical manifestation. Mean age at death is 30 years; death is usually due to disease complications (hypoglycaemic coma, status epilepticus, advanced renal failure, suicide, central respiratory failure, etc.).²

Our patient was a 14-year-old girl with a history of a year and a half of progressively decreasing visual acuity. She had been diagnosed with type 1 diabetes mellitus the previous year and had been receiving treatment with insulin since that time. Her psychomotor development was normal and she performed well academically. The patient presented tics, and reported dry eyes and lips despite drinking 4 litres of water daily. She had no other history of interest. Her 4-year-old brother was healthy; no family history of consanguinity was known. However, history of adult-onset type 1 diabetes mellitus was reported in cousins on the mother's side of the family. In the preceding 18 months, she began experiencing progressively decreasing visual acuity and presented bilateral optic atrophy. Physical examination revealed no abnormalities. The ophthalmological examination showed decreased visual acuity in both eyes (0.3 to 0.5 in the right eye and 0.4 to 0.5 in the left eye) with a preserved visual field; direct ophthalmoscopy revealed pallor and atrophy in both optic discs. The neurological examination, including eye movements, motor system, sensitivity, coordination, and gait, yielded normal results. An optical coherence tomography study confirmed bilateral optic atrophy. Visual evoked potentials with checkerboard stimulation showed a signal of forked and asynchronous morphology, decreased amplitude, and normal latencies. Flash visual evoked potentials yielded normal results. Full field electroretinography showed no alterations. Suspecting Wolfram syndrome, we requested a genetic study of the WFS1 gene; the patient was heterozygous for variants c.2643_2646del and c.1703_1704del in exon 8. Variant c.1703_1704del has not previously been described as a mutation or a polymorphism in the most commonly used genetic variant databases.^6–10 This deletion causes synthesis of a truncated protein; we therefore consider that this variant is probably pathogenic.

Wolfram syndrome is a rare disease which should be suspected in young patients with progressive bilateral optic atrophy and diabetes mellitus. It is a clinically and genetically heterogeneous neurodegenerative disease whose pathophysiological mechanism is not well understood. More than 200 mutations of the WFS1 gene in chromosome region 4p16.1 have been described as causing the disease,⁶ which follows an autosomal recessive inheritance pattern. One of the variants identified in our patient has not previously been described in this syndrome; therefore, we consider the c.1703_1704del variant in exon 8 of the WFS1 gene to be a probably pathogenic mutation. Early diagnosis of Wolfram syndrome is important in order to provide adequate genetic counselling.