AIFM1 – Spondyloepimetaphyseal Dysplasia, Bieganski Type

AIFM1 encodes apoptosis-inducing factor mitochondrion-associated 1, a mitochondrial FAD-dependent NADH oxidoreductase. X-linked recessive variants in AIFM1 cause a unique combination of hypomyelinating leukodystrophy and spondyloepimetaphyseal dysplasia (H-SMD), also termed Bieganski type spondyloepimetaphyseal dysplasia (MONDO:0010275) in males and manifesting variably in carrier females (AIFM1).

In a cohort of 12 affected males from six unrelated families, whole-exome sequencing identified maternally inherited or de novo AIFM1 variants clustered within a 70 bp region surrounding exon 7, with clinical presentation between 12 and 36 months including motor deterioration, spasticity, tremor, ataxia, dysarthria, cognitive impairment, pulmonary hypertension, nystagmus, and vision loss due to retinopathy (PMID:28842795).

The variant spectrum includes missense, synonymous, and intronic changes; one recurrent missense change is c.710A>G (p.Asp237Gly), alongside changes such as c.1646C>T (p.Ala549Val) and c.705G>C (p.Gln235His) (PMID:28842795).

Segregation analysis demonstrated that c.710A>G (p.Asp237Gly) cosegregated with disease in 4 additional affected relatives across two families (LOD 3.359) (PMID:27102849), supporting X-linked recessive inheritance.

Functional studies in patient-derived osteoblast lines from four individuals revealed significant reductions in AIFM1 mRNA and protein levels, implicating haploinsufficiency in bone metabolism and myelination consistent with the combined skeletal and leukodystrophy phenotype (PMID:28842795).

The concordant genetic and experimental data establish a Strong gene-disease association. AIFM1 exon 7 testing should be included in diagnostic panels for early childhood-onset skeletal dysplasia with hypomyelination.

Key Take-home: AIFM1 X-linked recessive exon 7 variants cause H-SMD through haploinsufficiency, combining skeletal dysplasia and hypomyelinating leukodystrophy, and are amenable to molecular diagnosis.

References

• Neurogenetics • 2017 • X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1. PMID:28842795
• Clinical genetics • 2017 • Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease. PMID:27102849

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