Abstract
Leukodystrophies (LDs) are heterogeneous genetic disorders characterized by abnormal white matter in the central nervous system. Some of the LDs are progressive and often fatal. In general, LD is primarily diagnosed based on the neuroimaging; however, definitive diagnosis of the LD type is done using genetic testing such as next-generation sequencing. The aim of this study is to identify the genetic causes of LD in two independent Jordanian cases that exhibit MRI findings confirming LD with no definitive diagnosis using whole exome sequencing (WES). The most likely causative variants were identified. In one case, the homozygous pathogenic variant NM_000049.2:c.914C>A;p.Ala305Glu, which is previously reported in ClinVar, in the gene ASPA was identified causing Canavan disease. In the second case, the homozygous novel variant NM_000487.5:c.256C>G;p.Arg86Gly in the gene ARSA was identified causing metachromatic leukodystrophy. The two variants segregate in their families. The phenotypes of the two studied cases overlap with assigned diseases. The present study raises the importance of using WES to identify the precise neurodevelopmental diseases in Jordan.
Highlights
Leukodystrophies (LDs) are a group of heterogeneous inherited metabolic disorders affecting the white matter and caused by defect in the myelin sheet [1]
The clinical characteristics of the two girls were collected from the clinician reports, MRI findings, and the developmental delay as reported by the parents
Besides the LD, as reported in the MRI findings of the two patients, patient TF106 1 exhibits atonia in her muscles, blindness, and seizure
Summary
Leukodystrophies (LDs) are a group of heterogeneous inherited metabolic disorders affecting the white matter and caused by defect in the myelin sheet [1]. These disorders occur usually in the first months of life, accompanied by hypotonia, and gradually become spastic diplegia or quadriplegia, developmental delay, seizures, ataxia, and dyskinesia. The inheritance patterns of the described LD types are autosomal recessive (20 types), de novo dominant (8 types), X-linked recessive (1 type), and X-linked dominant (1 type; Table 1). These inheritance patterns strongly suggest LDs as monogenic/Mendelian disorders. The most common types of LDs are metachromatic leukodystrophy, Canavan disease, Krabbe disease, Alexander disease, and X-linked adrenoleukodystrophy [1]
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