AIFM1-associated X-linked spondylometaphyseal dysplasia with cerebral hypomyelination

Am J Med Genet A. 2021 Apr;185(4):1228-1235. doi: 10.1002/ajmg.a.62072. Epub 2021 Jan 13.


Spondylometaphyseal dysplasia with cerebral hypomyelination (SMD-H) is a very rare but distinctive phenotype, unusually combining spondylometaphyseal dysplasia with hypomyelinating leukodystrophy. Recently, SMD-H has been associated with variants confined to a specific intra-genic locus involving Exon 7, suggesting that AIFM1 plays an important role in bone development and metabolism as well as cerebral myelination. Here we describe two further affected boys, one with a novel intronic variant associated with skipping of Exon 7 of AIFM1 and the other a synonymous variant within Exon 7 of AIFM1. We describe their clinical course and radiological and genetic findings, providing further insight into the natural history of this condition.

Keywords: AIFM1; SMD-H; cerebral hypomyelination; hypomyelinating leukodystrophy; skeletal dysplasia; spondylometaphyseal dysplasia.

Publication types

  • Case Reports

MeSH terms

  • Apoptosis Inducing Factor / genetics*
  • Bone Development / genetics
  • Exons
  • Genetic Diseases, X-Linked / diagnosis
  • Genetic Diseases, X-Linked / diagnostic imaging
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Diseases, X-Linked / pathology
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Mutation / genetics
  • Nervous System Malformations / diagnosis
  • Nervous System Malformations / diagnostic imaging
  • Nervous System Malformations / genetics*
  • Nervous System Malformations / pathology
  • Osteochondrodysplasias / diagnosis
  • Osteochondrodysplasias / diagnostic imaging
  • Osteochondrodysplasias / genetics*
  • Osteochondrodysplasias / pathology
  • Pedigree


  • AIFM1 protein, human
  • Apoptosis Inducing Factor

Supplementary concepts

  • Spondylometaphyseal Dysplasia, X-Linked