Zhihong Wang1, Yanhong Lin1, Dezhu Zheng1, Aizhen Yan1, Xiangdong Tu1, Juan Lin1, Fenghua Lan2. 1. Research Center for Molecular Diagnosis of Genetic Diseases, Dongfang Hospital, Xiamen University Medical College, Fuzhou, China. 2. Research Center for Molecular Diagnosis of Genetic Diseases, Dongfang Hospital, Xiamen University Medical College, Fuzhou, China. Electronic address: fhlan@xmu.edu.cn.
Abstract
BACKGROUND: Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal storage disorder caused mainly by variants in arylsulfatase A (ARSA) gene. MLD can be divided into three major clinical forms according to the age of onset: late infantile, juvenile, and adult. We report two siblings of late infantile MLD presenting with cerebellar ataxia as the only first clinical symptom. METHODS: Because of the unspecific neurological manifestation, whole-exome sequencing (WES) was performed to find disease-causing mutations for molecular diagnosis. Then successive MRI and ARSA activity determination were performed to further confirm the diagnosis. Moreover, the prenatal diagnosis was carried out on the basis of molecular diagnosis. RESULTS: The siblings exhibited compound heterozygous variants {[c.302G>T]+[c.1344dupC]} in the ARSA gene, and both of the variants have been reported as disease-causing mutations previously. The results of MRI and low ARSA activity confirmed the diagnosis of MLD. Prenatal diagnosis showed that the fetus was a heterozygous carrier. CONCLUSIONS: It is recommended that WES be considered as a first line diagnostic procedure to discover potential disease-causing genetic variants in affected individuals with hereditary traits but without definite clinical diagnosis. However, the final diagnosis should be confirmed by comprehensive evaluations including biochemical, enzymatic or imaging investigations.
BACKGROUND:Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal storage disorder caused mainly by variants in arylsulfatase A (ARSA) gene. MLD can be divided into three major clinical forms according to the age of onset: late infantile, juvenile, and adult. We report two siblings of late infantile MLD presenting with cerebellar ataxia as the only first clinical symptom. METHODS: Because of the unspecific neurological manifestation, whole-exome sequencing (WES) was performed to find disease-causing mutations for molecular diagnosis. Then successive MRI and ARSA activity determination were performed to further confirm the diagnosis. Moreover, the prenatal diagnosis was carried out on the basis of molecular diagnosis. RESULTS: The siblings exhibited compound heterozygous variants {[c.302G>T]+[c.1344dupC]} in the ARSA gene, and both of the variants have been reported as disease-causing mutations previously. The results of MRI and low ARSA activity confirmed the diagnosis of MLD. Prenatal diagnosis showed that the fetus was a heterozygous carrier. CONCLUSIONS: It is recommended that WES be considered as a first line diagnostic procedure to discover potential disease-causing genetic variants in affected individuals with hereditary traits but without definite clinical diagnosis. However, the final diagnosis should be confirmed by comprehensive evaluations including biochemical, enzymatic or imaging investigations.
Authors: Alisa A Shaimardanova; Daria S Chulpanova; Valeriya V Solovyeva; Aysilu I Mullagulova; Kristina V Kitaeva; Cinzia Allegrucci; Albert A Rizvanov Journal: Front Med (Lausanne) Date: 2020-10-20