Wolfram syndrome type 1 in siblings – A case report

INTRODUCTION

Wolfram syndrome (WS) type 1 is a neurodegenerative genetic disorder caused by mutations in the WFS1 gene, inherited in an autosomal recessive manner. However, severe cases with autosomal dominant inheritance have also been reported.^[1] The WFS1 gene encodes the protein wolframin, which is involved in protein folding in the endoplasmic reticulum and calcium homeostasis. Disruption of this protein leads to cellular death, particularly affecting pancreatic beta cells and neurons.^[2,3] This gene was described in 1998 and is located on the short arm of chromosome 4. It contains eight exons, and pathogenic and likely pathogenic variants are found in exon 8 in 88% of patients.^[4] The syndrome was first described in 1938 by Wolfram and Wagener as an association of juvenile onset diabetes mellitus (DM) and bilateral optic atrophy (AO). Subsequently, the association with diabetes insipidus (DI) and sensorineural deafness was described, leading to the acronym DIDMOAD, by which the syndrome is also known today.^[5]

The combination of DM and AO is present in almost 100% of patients and is a diagnostic criterion.^[6] Both are early-onset symptoms, typically presenting during the first decade of life. Other symptoms not encompassed within the acronym have also been reported. These include urinary tract abnormalities such as hydronephrosis, urinary incontinence, bladder atony, and recurrent urinary tract infections, occurring in the third decade of life. Neurological manifestations, including cerebellar ataxia, cognitive impairment, peripheral neuropathy, and bulbar dysfunction, occur in the fourth decade. Psychiatric manifestations such as depression and behavioral disturbances have also been described. Furthermore, additional findings such as cataracts and hypogonadism due to pituitary atrophy have been documented.^[7] The estimated prevalence of the disease is 1 in 770,000 inhabitants, and the carrier frequency is 1 in 354.^[1,8] The diagnosis is based on the clinical symptom association and genetic testing.

CASE REPORT

The index case was a 14-year-old adolescent girl, born in the third pregnancy of non-consanguineous healthy parents, who was first admitted at the age of 8 years for evaluation of progressive vision loss over the past 2 years. Visual acuity (VA) was found to be 6/60 bilaterally, and visual evoked potentials were bilaterally altered, suggesting axonal and demyelinating neuropathy. Initially, optic neuritis was suspected, and empirical treatment with high doses of corticosteroids (three doses of methylprednisolone 30 mg/kg/day intravenously, followed by oral prednisone 1 mg/kg/day for 20 days with tapering doses) was initiated; but further investigations, including autoimmune studies and imaging were normal. No blood glucose (BG) measurement was performed before the first 4 days of steroid therapy.

Five days after completing the above treatment, the patient returned with complaints of polyuria, polydipsia, and nocturnal enuresis. A BG level of 730 mg/dL, ketonemia of 0.9 mmol/L, and normal capillary blood gas analysis (pH 7.35 and serum bicarbonate 23.7 mmol/L) were observed. Further studies during hospitalization revealed negative pancreatic autoantibody titers, and treatment with multiple doses of insulin was started with glargine and aspart insulin before meals, with a daily insulin dose of 0.7 U/kg.

Given the association of visual pathway involvement and early-onset DM, WS was suspected, and genetic testing was requested. Whole-exome sequencing revealed a homozygous c.1582T>G variant in the WSF1 gene, resulting in a missense mutation leading to a tryptophan-to-aspartic acid substitution at position 528 of the wolframin protein. The variant was classified as likely pathogenic.

Polyuria, polydipsia, and enuresis persisted despite correction of hyperglycemia, and DI was suspected. A diuresis of 4–5 L/day was recorded, with a urine osmolality of 53 mOsm/kg and plasma osmolality of 297 mOsm/kg. The desmopressin challenge test was positive, showing an increase in urine osmolality to 634 mOsm/kg. Magnetic resonance imaging of the brain revealed the absence of the neurohypophysis signal. She was started on sublingual desmopressin treatment, at a dose of 120 µg/day in three divided doses, with improvement in polydipsia and polyuria.

After the diagnosis, the patient underwent periodic screening for associated abnormalities, including cardiac evaluation by echocardiography, renal dimensions on ultrasound abdomen, and hearing assessment by formal audiometry, which were normal.

Following the molecular diagnosis, genetic testing was conducted on family members. A targeted Sanger sequencing analysis revealed that both parents were heterozygous carriers of the mutation. Among the patient’s three siblings, the youngest was homozygous for the mutation, while the other two siblings tested negative. The 8-year-old affected brother was kept under follow-up in outpatient consultations for endocrinology and pediatric ophthalmology. He had a VA of 12/60 bilaterally, optic disc pallor on fundus examination, and loss of ganglion cells on optical coherence tomography. No endocrinological abnormalities were present till the last follow-up.

DISCUSSION

WS type 1 is a rare disorder, but it should be suspected when there is an association between insulin-dependent DM and bilateral AO.^[8] Typically, DM is the first manifestation, with onset in early childhood, around the age of 6 years. It presents with negative autoantibodies and is not associated with high-risk human leukocyte antigen (HLA) haplotypes. Metabolic decompensations, such as diabetic ketoacidosis, are infrequent, and insulin requirements are generally lower than those required for type 1 DM.^[9] Long-term complications are rare and tend to be less severe. This less aggressive disease course compared to type 1 DM is due to greater residual activity in the pancreatic beta cells.^[9] When beta cell death is not caused by autoimmune mechanisms, there is more residual activity, as seen in WS.

Neurodegeneration, which initially presents as AO, is the second complication to appear, with an average onset around 11 years of age.^[9] It progresses to blindness in approximately 8 years due to bilateral optic disc atrophy.^[9] Although the onset is typically with DM followed by AO, in our patient, the most precocious symptom was vision loss due to AO, followed by the onset of DM. AO was also the first symptom in her brother.

Central DI results from the loss of vasopressin-secreting neurons and typically manifests in the second decade of life, with an average age of diagnosis of 12 years. Its prevalence is between 60% and 87%,^[9] and in our case, DI debuted at the age of 14 years.

Sensorineural hearing loss usually develops in the second decade of life and is present in 50–70% of cases.

Currently, no curative treatment is available for WS. However, there are several treatments in the research phase, focusing on restoring calcium homeostasis in the endoplasmic reticulum, optimizing the structure of wolframin using chemical chaperones, modulating endoplasmic reticulum stress, regenerative drugs, and gene therapy.^[10] Since this is a degenerative disease, in addition to symptomatic treatment for each condition (insulin for DM, desmopressin for DI, and hearing aids for sensorineural hearing loss), the administration of coenzyme Q and B-vitamin complexes can be considered for neurological issues.

Early diagnosis and multidisciplinary follow-up from the beginning are crucial for the early treatment of the various conditions that constitute the syndrome, aiming to provide the best possible quality of life and prevent complications. Improved follow-up has led to a decrease in mortality due to renal failure, with central respiratory failure secondary to brainstem atrophy now being the leading cause of death, and life expectancy is <50 years.^[11]

Genetic testing of family members is essential, with recommendations to initiate follow-up for asymptomatic carriers of the mutation, to anticipate the first manifestations and prevent complications.

Given that neurodegeneration is the underlying pathophysiological process of WS, it is important to consider future research focused on halting the neurological progression of this disorder.

CONCLUSION

This case highlights the importance of considering WS type I in patients with early-onset, insulin-dependent DM and negative autoimmunity, particularly when DM is associated with AO. Given the progressive and multisystemic nature of the disorder, coordinated multidisciplinary follow-up is fundamental. Furthermore, due to its hereditary nature, genetic testing of all family members is crucial to enable early diagnosis, appropriate monitoring, and preventive care.