Abstract
The PLP1 gene, located on chromosome Xq22, encodes the proteolipid protein 1 and its isoform DM20. Mutations in PLP1 cause a spectrum of white matter disorders of variable severity. Here we report on four additional HEMS patients from three families harboring three novel PLP1 mutations in exon 3B detected by targeted next-generation sequencing. Patients experienced psychomotor delay or nystagmus in the first year of age and then developed ataxic–spastic or ataxic syndrome, compatible with a phenotype of intermediate severity in the spectrum of PLP1-related disorders. Regression occurred at the beginning of the third decade of the eldest patient. Extrapyramidal involvement was rarely observed. Brain MRI confirmed the involvement of structures that physiologically myelinate early, although the pattern of abnormalities may differ depending on the age at which the study is performed. These new cases contribute to expanding the phenotypic and genotypic spectrum of HEMS. Additional studies, especially enriched by systematic functional evaluations and long-term follow-up, are welcome to better delineate the natural history of this rare hypomyelinating leukodystrophy.
Highlights
Introduction nal affiliationsThe PLP1 gene, located on chromosome Xq22, encodes the proteolipid protein 1—the most abundant protein of myelin sheath in the central nervous system (CNS)—and its isoform DM20 that derives from alternative splicing due to an acceptor site within the exon3, with subsequent production of a smaller protein that lacks the PLP1-specific domain encoded by amino acids 117–151 [1]
We present four unreported hypomyelination of early myelinated structures (HEMS) patients from three families harboring three novel PLP1 mutations in exon 3B and describe their main clinical, genetic and neuroradiological data, to expand the phenotypic and genotypic spectrum of this rare hypomyelinating leukodystrophy
Selected patients had a diagnosis of HEMS and were found to have a hemizygous mutation in the exon 3B or intron 3 of the PLP1 gene
Summary
Introduction nal affiliationsThe PLP1 gene, located on chromosome Xq22, encodes the proteolipid protein 1—the most abundant protein of myelin sheath in the central nervous system (CNS)—and its isoform DM20 that derives from alternative splicing due to an acceptor site within the exon3, with subsequent production of a smaller protein that lacks the PLP1-specific domain encoded by amino acids 117–151 [1]. The PLP1 gene, located on chromosome Xq22, encodes the proteolipid protein 1—the most abundant protein of myelin sheath in the central nervous system (CNS)—and its isoform DM20 that derives from alternative splicing due to an acceptor site within the exon. Mutations in PLP1 alter myelin formation, and cause a spectrum of disorders with distinct genotype–phenotype correlations and variable severity (Table S1), most of them belonging to the group of hypomyelinating leukodystrophies. Leukodystrophies are genetic disorders primarily and predominantly. Affecting the white matter of the CNS with or without peripheral nervous system myelin involvement. Among the PLP1-related disorders, Pelizaeus-Merzbacher disease (PMD). Is the more severe and best-known condition. Features of hypomyelination of early myelinated structures (HEMS) have been described in less than twenty cases [2]
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