Dataset Information

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.

SUBMITTER: Alfadhel M

PROVIDER: S-EPMC8155587 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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

Alfadhel Majid M Almuqbil Mohammed M Al Mutairi Fuad F Umair Muhammad M Almannai Mohammed M Alghamdi Malak M Althiyab Hamad H Albarakati Rayyan R Bashiri Fahad A FA Alshuaibi Walaa W Ba-Armah Duaa D Saleh Mohammed A MA Al-Asmari Ali A Faqeih Eissa E Altuwaijri Waleed W Al-Rumayyan Ahmed A Balwi Mohammed Ali MA Ababneh Faroug F Alswaid Abdulrahman Faiz AF Eyaid Wafaa M WM Almontashiri Naif A M NAM Alhashem Amal A Hundallah Khalid K Bertoli-Avella Aida A Bauer Peter P Beetz Christian C Alrifai Muhammad Talal MT Alfares Ahmed A Tabarki Brahim B

Frontiers in pediatrics 20210513

<b>Background:</b> 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. <b>Methods:</b> We conducted a retrospective chart review of a consecutive series of patients diagnosed with different types of LD from four large tertiary referral centers i ...[more]

PMID: 34055681

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Project description:Metachromatic leukodystrophy (MLD) is a glycosphingolipid storage disease caused by deficiency of the lysosomal enzyme arylsulfatase A (ASA) or its activator protein saposin B. MLD can affect all age groups in severity varying from a severe fatal form to milder adult onset forms. Diagnosis is usually made by measuring leukocyte ASA activity. However, this test can give false negative or false positive laboratory results due to pseudodeficiency of ASA and saposin B deficiency, respectively. Therefore, we aimed to evaluate patients with suspected MLD in a Turkish population by comprehensive clinical, biochemical, radiological, and genetic analyses for molecular and phenotypic characterization. We analyzed 28 suspected MLD patients and 41 relatives from 24 families. ASA activity was found to be decreased in 21 of 28 patients. Sixteen patients were diagnosed as MLD (11 late infantile, 2 juvenile and 3 adult types), 2 MSD, 2 pseudodeficiency (PD) and the remaining 8 patients were diagnosed as having other leukodystrophies. Enzyme analysis showed that the age of onset of MLD did not correlate with residual ASA activity. Sequence analysis showed 11 mutations in ARSA, of which 4 were novel (p.Trp195GlyfsTer5, p.Gly298Asp, p.Arg301Leu, and p.Gly311Asp), and 2 mutations in SUMF1 causing multiple sulfatase deficiency, and confirmed the diagnosis of MLD in 2 presymptomatic relatives. All individuals with confirmed mutations had low ASA activity and urinary sulfatide excretion. Intra- and inter-familial variability was high for the same ARSA missense genotypes, indicating the contribution of other factors to disease expression. Imaging findings were evaluated through a modified brain MRI scoring system which indicated patients with protein-truncating mutations had more severe MRI findings and late-infantile disease onset. MRI findings were not specific for the diagnosis. Anti-sulfatide IgM was similar to control subjects, and IgG, elevated in multiple sulfatase deficiency. In conclusion, the knowledge on the biochemical, clinical and genetic basis of MLD was expanded, a modified diagnostic laboratory algorithm for MLD based on integrated evaluation of ASA activity, urinary sulfatide excretion and genetic tests was devised.

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Dataset Information

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

Publications

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

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