AIMP1 – Hypomyelinating Leukodystrophy 3

Biallelic pathogenic variants in AIMP1 cause Hypomyelinating Leukodystrophy 3, an autosomal recessive early-onset neurodegenerative disorder characterized by microcephaly, axial hypotonia, spasticity, seizures, developmental delay, and cerebral hypomyelination. Clinical exome sequencing in a 2-year-old girl revealed a novel homozygous splice site variant c.603+1G>A, with cDNA analysis confirming loss of the intron 5 donor splice site, use of a cryptic acceptor within exon 5, and skipping of 24 nucleotides leading to an in-frame deletion p.Val194_Gln201del (PMID:36652953).

This single-family report provides limited genetic evidence (gene-disease association: Limited) with autosomal recessive inheritance and no additional segregation data. Functional splicing assays demonstrate a deleterious effect on transcript processing, while neuronal cell models expressing HLD3-associated mutants (including p.Gln39Ter) show impaired neuronal differentiation that is rescued by ibuprofen, supporting a loss-of-function mechanism (PMID:32384815).

Key Take-home: The identification of AIMP1 splice variants expands the mutational spectrum of hypomyelinating leukodystrophy 3 and informs molecular diagnosis in early-onset hypomyelination syndromes.

References

• Neuropediatrics • 2023 • A Novel Homozygous Splice Site Variant in AIMP1 Gene Causing Hypomyelinating Leukodystrophy: Case Report and Review of the Literature. PMID:36652953
• Medicines • 2020 • Rare Neurologic Disease-Associated Mutations of AIMP1 are Related with Inhibitory Neuronal Differentiation Which is Reversed by Ibuprofen. PMID:32384815

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