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A K Annamalai, S Ellard, M Shanmugam, T P Jai Juganya, E De Franco, Juvenile diabetes and visual impairment: Wolfram syndrome, QJM: An International Journal of Medicine, Volume 112, Issue 10, October 2019, Pages 803–804, https://doi.org/10.1093/qjmed/hcz066
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The presence of diabetes and visual impairment in a young individual is a good diagnostic criterion to suspect Wolfram syndrome (WS) or Diabetes insipidus, Diabetes mellitus, optic atrophy and deafness.1,2 WS is a rare autosomal recessive disease due to mutations in the Wolframin (WFS1) gene. These mutations lead to endoplasmic reticulum stress-related decline of pancreatic beta-cell number and a decrease in endogenous insulin secretion. Affected individuals are therefore usually insulin-dependent, with a few rare exceptions reported.3–5 Here we describe a 9-year-old boy who presented with visual impairment and diabetes, with a novel homozygous WFS1 frameshift mutation p.(Ala671fs) confirming WS. This patient has a normal endogenous insulin level necessitating a very low total daily insulin requirement for good glycaemic control.
A 9-year-old boy presented to our endocrine clinic with decreased vision for 6 months and polyuria for 4 months. His parents were non-consanguineous and there was no family history of diabetes. His visual acuity was 1/6 on both eyes and retinal examination revealed bilateral optic atrophy without diabetic retinopathy (Figure 1A and B). His fasting blood glucose levels were elevated at 14.43 mmol/l with no ketonuria and HbA1C of 9.2%. Anti-glutamic acid decarboxylase antibody levels were normal with a normal c-peptide. An audiogram and an abdomen ultrasound were normal and there were no learning difficulties. An overnight water deprivation test was normal. In view of the optic atrophy and juvenile diabetes a genetic analysis was done to confirm WS. Sanger sequencing analysis of the WFS1 gene (NM_006005.3) detected a homozygous frameshift mutation p.(Ala671fs), c.2010dup, in the last exon. This variant is predicted to result in insertion of a premature termination codon after 41 amino acids, resulting in possible translation of a truncated protein and loss of >10% of the normal WFS1 protein. The patient’s parents were both heterozygous for the mutation. The patient was treated with small doses of insulin with remarkable glycaemic and visual improvement. He is currently requiring five units of biphasic insulin daily for the past 24 months with an HbA1c of 6% and no further neuro-degenerative progression.
