UFM1 – Hypomyelinating Leukodystrophy 6 (H-ABC variant)

UFM1 encodes ubiquitin-fold modifier 1, a ubiquitin-like protein involved in posttranslational modification. Loss of UFM1 function causes a severe hypomyelinating leukodystrophy with atrophy of the basal ganglia and cerebellum, classified as hypomyelinating leukodystrophy 6 (MONDO:0012905). Patients present in early infancy with global neurodevelopmental arrest, extrapyramidal features, and profound sensory deficits.

Seventeen unrelated Roma patients from 14 families were homozygous for a promoter deletion c.-273_-271delTCA disrupting UFM1 expression, identified by homozygosity mapping and confirmed by WES and Sanger sequencing (16 probands [PMID:28931644]). A subsequent Bulgarian cohort of 9 additional infants carrying the same deletion demonstrated congruent features, including inspiratory stridor, dysphagia, seizures, microcephaly, and rapid regression ([PMID:35189806]). All patients shared a common haplotype, establishing a founder effect and autosomal recessive inheritance.

Genetic spectrum is limited to this single upstream deletion; no other missense or loss-of-function variants have been reported. Segregation analysis revealed full homozygosity in all affected individuals; no additional segregating relatives were documented. Carrier screening in 1,000 Roma controls yielded a carrier frequency of 3%–25%, supporting a population-specific founder allele ([PMID:28931644]).

Functional studies using luciferase reporter assays demonstrated that c.-273_-271delTCA reduces promoter activity and UFM1 expression in CNS-derived cell lines, indicating a haploinsufficiency mechanism ([PMID:28931644]). This concordant experimental evidence links the promoter mutation to deficient ufmylation in neural tissues.

Integration of these data supports a strong gene–disease association: a recurrent founder mutation with clear segregation, a consistent phenotype in 25 probands, and mechanistic validation. No conflicting reports have been described. Key take-home: testing for the UFM1 founder deletion is recommended in Roma infants with early-onset hypomyelinating leukodystrophy and H-ABC radiological features to enable accurate diagnosis and genetic counseling.

References

• Neurology • 2017 • UFM1 founder mutation in the Roma population causes recessive variant of H-ABC. PMID:28931644
• CNS & neurological disorders drug targets • 2023 • Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience. PMID:35189806

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