Korean J Lab Med.  2010 Oct;30(5):516-520. 10.3343/kjlm.2010.30.5.516.

Identification of a Novel Splicing Mutation in the ARSA Gene in a Patient with Late-infantile Form of Metachromatic Leukodystrophy

• Kang DH
• Lee DH
• Hong YH
• Lee ST
• Jeon BR
• Lee YK
• Ki CS
• Lee YW

• KMID: 1022044
• DOI: http://doi.org/10.3343/kjlm.2010.30.5.516

Abstract

Metachromatic leukodystrophy (MLD; MIM 250100), a severe neurodegenerative disorder inherited as an autosomal recessive trait, is caused by mutations in the arylsulfatase A (ARSA) gene. Although several germ line ARSA mutations have been identified in patients with MLD of various ethnic backgrounds elsewhere in the world, no genetically confirmed cases of MLD have been reported in Korea. Recently, we identified a mutation in the ARSA gene of a Korean male with MLD. A male infant with late-infantile form of MLD had been admitted to our hospital for further examination. His neuromuscular symptoms, which included inability to walk at the age of 12 months, gradually worsened, even after allograft bone marrow transplantation; he died at the age of 9 yr. His elder brother had also been diagnosed with MLD. To confirm the presence of a genetic abnormality, all the coding exons of the ARSA gene and the flanking introns were amplified by PCR. A molecular analysis of the ARSA gene revealed both a novel heterozygous splicing mutation (c.1101+1G>T) in intron 6 and a heterozygous missense mutation in exon 2 (c.296G>A; Gly99Asp). The patient's elder brother who had MLD is believed to have had the same mutation, which may be correlated with a rapidly deteriorating clinical course. This study identified a novel mutation in the ARSA gene, related to a late-infantile form of MLD with a lethal clinical course and suggested that molecular diagnosis of patients may be useful in early diagnosis and for deciding intervention measures for their family members.

Keyword

Metachromatic leukodystrophy; ARSA; Novel mutation; Korean

MeSH Terms

Cerebroside-Sulfatase/*genetics
Exons
Heterozygote
Humans
Infant
Introns
Leukodystrophy, Metachromatic/diagnosis/*genetics
Magnetic Resonance Imaging
Male
*Mutation
Mutation, Missense
*RNA Splicing
RNA, Messenger/genetics

Figure

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  Fig. 1. Brain magnetic resonance image. Axial T2-weighted image shows bilateral, diffuse confluent hyperintensities in the periventricular white matter and cerebral atrophy.

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  Fig. 2. Mutation analysis of the arylsulfatase A (ARSA) gene in a Korean patient with metachromatic leukodystrophy. Direct sequencing of the ARSA gene shows overlapped peaks (solid arrow) at the nucleotide position 296 due to a heterozygous G-to-A transition (c.296G>A; Gly99Asp) (A) and overlapped peaks (open arrow) at the consensus splicing donor site in the intron 6 due to a heterozygous G-to-T transversion (c.1101+1G>T) (B).

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