X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1

Abstract

An X-linked condition characterized by the combination of hypomyelinating leukodystrophy and spondylometaphyseal dysplasia (H-SMD) has been observed in only four families, with linkage to Xq25-27, and recent genetic characterization in two families with a common AIFM1 mutation. In our study, 12 patients (6 families) with H-SMD were identified and underwent comprehensive assessment accompanied by whole-exome sequencing (WES). Pedigree analysis in all families was consistent with X-linked recessive inheritance. Presentation typically occurred between 12 and 36 months. In addition to the two disease-defining features of spondylometaphyseal dysplasia and hypomyelination on MRI, common clinical signs and symptoms included motor deterioration, spasticity, tremor, ataxia, dysarthria, cognitive defects, pulmonary hypertension, nystagmus, and vision loss due to retinopathy. The course of the disease was slowly progressive. All patients had maternally inherited or de novo mutations in or near exon 7 of AIFM1, within a region of 70 bp, including synonymous and intronic changes. AIFM1 mutations have previously been associated with neurologic presentations as varied as intellectual disability, hearing loss, neuropathy, and striatal necrosis, while AIFM1 mutations in this small region present with a distinct phenotype implicating bone. Analysis of cell lines derived from four patients identified significant reductions in AIFM1 mRNA and protein levels in osteoblasts. We hypothesize that AIFM1 functions in bone metabolism and myelination and is responsible for the unique phenotype in this condition.Electronic supplementary materialThe online version of this article (doi:10.1007/s10048-017-0520-x) contains supplementary material, which is available to authorized users.

Clinical spectrum of AIFM1‐associated disease in an Irish family, from mild neuropathy to severe cerebellar ataxia with colour blindness

“…Families with AIFM1 ‐associated SEMD with neurodegeneration exhibit notably homogeneous clinical features, including distinct dysmorphic appearance, skeletal abnormalities, and hypomyelination . In contrast, III‐1 and III‐4 had only very mild thoracic scoliosis.…”

“…Families with AIFM1-associated SEMD with neurodegeneration exhibit notably homogeneous clinical features, including distinct dysmorphic appearance, skeletal abnormalities, and hypomyelination. 2,8 In contrast, III-1 and III-4 had only very mild thoracic scoliosis. In our family, only one individual had white matter abnormalities on MRI which were relatively non-specific and not felt to be typical for the appearances of hypomyelination.…”

“…6 Since gene discovery in 1999, 7 AIFM1-associated cerebellar ataxia has been reported in 24 individuals from 13 families and 83% of cases expressed spondyloepimetaphyseal dysplasia (SEMD) with central hypomyelination phenotype. 2,8 Here, we report a large family with X-linked AIFM1-associated disease. Eight affected individuals from three generations displayed variable age at onset and severity of symptoms, including novel phenotypic features, and a distinct neurophysiological pattern of peripheral nerve involvement.…”

“…Since gene discovery in 1999, AIFM1 ‐associated cerebellar ataxia has been reported in 24 individuals from 13 families and 83% of cases expressed spondyloepimetaphyseal dysplasia (SEMD) with central hypomyelination phenotype …”

Heterozygous variants in the mechanosensitive ion channelTMEM63Aresult in transient hypomyelination during infancy

“…2 MRI pattern recognition often helps to obtain an MRI-based diagnosis in leukodystro- 3 phies and enables targeted genetic testing [7,8], but genetic heterogeneity may require a 4 more comprehensive approach. Next generation sequencing (NGS) has rapidly improved 5 the diagnosis of previously elusive or novel phenotypes with whole exome sequencing 6 (WES) and whole genome sequencing (WGS) now directly responsible for implicating a 7 large number of genes with leukodystrophies, greatly reducing the number of unsolved 8 cases [2,[9][10][11][12]. 9 Myelination is a protracted developmental process that progresses in infancy following 10 a fixed pattern and is almost complete by the age of 24 months.…”