Abstract
Wolfram syndrome (WFS) is inherited as an autosomal recessive disease with main clinical features of diabetes mellitus, optic atrophy, diabetes insipidus and deafness. However, various neurological defects may also be detected. The aim of this study was to evaluate aspects of brain structure and function using PET-CT (positron emission tomography and computed tomography) and MRI (magnetic resonance imaging) in pediatric patients with WFS. Regional changes in brain glucose metabolism were measured using standardized uptake values (SUVs) based on images of (18F) fluorodeoxyglucose (FDG) uptake in 7 WFS patients aged 10.1–16.0 years (mean 12.9±2.4) and in 20 healthy children aged 3–17.9 years (mean 12.8±4.1). In all patients the diagnosis of WFS was confirmed by DNA sequencing of the WFS1 gene. Hierarchical clustering showed remarkable similarities of glucose uptake patterns among WFS patients and their differences from the control group. SUV data were subsequently standardized for age groups <13 years old and>13 years old to account for developmental differences. Reduced SUVs in WFS patients as compared to the control group for the bilateral brain regions such as occipital lobe (−1.24±1.20 vs. −0.13±1.05; p = 0.028) and cerebellum (−1.11±0.69 vs. −0.204±1.00; p = 0.036) were observed and the same tendency for cingulate (−1.13±1.05 vs. −0.15±1.12; p = 0.056), temporal lobe (−1.10±0.98 vs. −0.15±1.10; p = 0.057), parietal lobe (−1.06±1.20 vs. −0.08±1.08; p = 0.058), central region (−1.01±1.04 vs. −0.09±1.06; p = 0.060), basal ganglia (−1.05±0.74 vs. −0.20±1.07; p = 0.066) and mesial temporal lobe (−1.06±0.82 vs. −0.26±1.08; p = 0.087) was also noticed. After adjusting for multiple hypothesis testing, the differences in glucose uptake were non-significant. For the first time, regional differences in brain glucose metabolism among patients with WFS were shown using PET-CT imaging.
Highlights
Wolfram syndrome (WFS) (OMIM 222300) is inherited as an autosomal recessive trait
Diabetes and optic atrophy were present in all WFS patients except one (WFS7) with diabetes only
Neurological signs were observed in all but one patient (WFS7), and included the following: ataxia/gait disturbances (WFS1, WFS2, WFS3, WFS4, WFS6), nystagmus (WFS1, WFS3, WFS6), lack of tendon reflexes in the extremities or hyporeflexia (WFS3, WFS4, WFS5), cognitive disorders (WFS2, WFS4, WFS5), dysphagia (WFS3), and polyneuropathy (WFS1) (Table 2)
Summary
The product of the WFS1 gene, is an integral component of the endoplasmic reticulum (ER) and protects cells from ER stress, which occurs due to accumulation of endogenously synthesized protein products. The clinical criteria for WFS are diabetes mellitus and optic atrophy coexisting with other disorders, especially neurodegenerative ones. Neurological complications are the most common cause of death in WFS patients, who have an average life expectancy of about 30 years [5, 6, 7]. Discrepancies between the degree of clinical manifestation of neurological disorders and the results of imaging studies of the central nervous system have been noted in some WFS patients [8, 9]. Attempts to find a genotype-phenotype correlation between the severity of neurological defects and the type of WFS1 mutation have been unsuccessful
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