The Leukodystrophy Spectrum in Saudi Arabia: Epidemiological, Clinical, Radiological, and Genetic Data

Abstract

Background: Leukodystrophies (LDs) are inherited heterogeneous conditions that affect the central nervous system with or without peripheral nerve involvement. They are individually rare, but collectively, they are common. Thirty disorders were included by the Global Leukodystrophy Initiative Consortium (GLIA) as LDs. Methods: We conducted a retrospective chart review of a consecutive series of patients diagnosed with different types of LD from four large tertiary referral centers in Riyadh, Saudi Arabia. Only those 30 disorders defined by GLIA as LDs were included. Results: In total, 83 children from 61 families were identified and recruited for this study. The male-to-female ratio was 1.5:1, and a consanguinity rate of 58.5% was observed. An estimated prevalence of 1:48,780 or 2.05/100,000 was observed based on the clinical cohort, whereas a minimum of 1:32,857 or 3.04/100,000 was observed based on the local genetic database. The central region of the country exhibited the highest prevalence of LDs (48.5%). The most common LD was metachromatic leukodystrophy (MLD), and it accounted for 25.3%. The most common disorder based on carrier frequency was AGS. Novel variants were discovered in 51% of the cases, but 49% possessed previously reported variants. Missense variants were high in number and accounted for 73% of all cases. Compared with other disorders, MLD due to saposin b deficiency was more common than expected, Pelizaeus-Merzbacher-like disease was more prevalent than Pelizaeus-Merzbacher disease, and X-linked adrenoleukodystrophy was less common than expected. The mortality rate among our patients with LD was 24%. Conclusion: To the best of our knowledge, this is the largest cohort of patients with LD from Saudi Arabia. We present epidemiological, clinical, radiological, and genetic data. Furthermore, we report 18 variants that have not been reported previously. These findings are of great clinical and molecular utility for diagnosing and managing patients with LD.

Keywords: Saudi Arabia; leukodystrophy; metachromatic leukodystrophy; neurometabolic; novel mutations.

Figure 1

(A) A representation of the different LD disorders included in our cohort and their percentages. (B) The genes reported in the LD disorder cohort in the present study. (C) Representation of novel and previously reported variants identified in the present study and the type of mutations identified. (D) Represent the type of variants identified in the present study.

Figure 2

Geographical distribution of LD in Saudi Arabia.

Figure 3

(A–H) MRI/CT brain of patients included in this study. (A) Brain MRI of a 30-month-old boy with metachromatic leukodystrophy. (a) Axial T2WI demonstrates bilateral symmetrical confluent areas of periventricular deep white matter signal change (thin arrow) with sparing of subcortical U-fibers (star). Note the classic tigroid pattern. (b) Axial T2WI exhibits bilateral involvement of the cerebellar white matter (thick arrow) and the pons. (B) Brain MRI of a 10-day-old boy with Zellweger syndrome. (a) Axial T2WI shows malformation of the cerebral cortex in both sylvian fissures (thick arrow) extending into the pericentral cortex and right parietal cortex as well as at the mesial aspect of the hemispheres in the form of a polymicrogyric pattern. (b) Axial T1WI shows an excessive hypointensity of the deep and subcortical white matter and also noted in the bilateral frontoparietal white matter (thin arrow). (C) Brain MRI of a 3-year-old boy with GJC2-hypomyelating leukodystrophy. (a) Axial T1WI shows iso/low signal intensity of the white matter (white arrow). (b) Axial T2WI exhibits an increased signal intensity of cerebral hemispheric white matter (black arrow). (D) Brain MRI of a 4-year-old boy with Salla disease. (a) FLAIR-WI demonstrates abnormal periventricular white matter signals (black arrow). (b) Sagittal T1WI shows thin dysplastic corpus callosum (white arrow). (E) Brain MRI of 11-year-old girl with megaloencephalic leukodystrophy with subcortical cysts. Axial T2WI shows diffuse superficial and deep white matter disease (thin arrow) with subcortical cysts (thick arrow). (F) Brain MRI of a 13-month-old boy with Canavan disease. (a) Axial T2WI demonstrates diffuse high signal intensity in the subcortical, deep, and periventricular white matter. The abnormalities also involve both globi pallidi, the thalami, and the posterior portion of the corpus callosum. (b) MR spectroscopy demonstrates increased N-acetylaspartate (NAA) peak intensity at 200 ms. (G) A 7-month-old-boy with Aicardi-Goutieres syndrome. (a) Brain MRI with axial T2WI at 29 days of age shows diffuse white matter with cystic changes in the periventricular areas (black arrow). (b) CT brain at the age of 6 months shows diffuse calcification in the basal ganglia. (H) Brain MRI of a 7-year-old boy with X-linked adrenoleukodystrophy. (a) Axial FLAIR-WI demonstrates extensive symmetrical white matter changes in the parieto-occipital region (thin arrow). (b) Gadolinium T1WI shows peripheral enhancement (thick arrow).