Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation – a novel phenotype of the mitochondrial disease

Abstract

In 1999, based on a single family, spondyloepimetaphyseal dysplasia (SEMD) with mental retardation (MR) was described as a novel syndrome with probably X-linked recessive inheritance and unknown molecular defect (MIM 300232). Our purpose was to search for the causative defect in the originally described family and in an independently ascertained second family. All patients had slowly progressive neurodegeneration with central and peripheral involvement and identical skeletal dysplasia. Whole exome sequencing performed in two subjects showed a single plausible candidate - the p.Asp237Gly variant in AIFM1 (chr. Xq26.1). The p.Asp237Gly segregated with disease as indicated by linkage analysis [maximum logarithm of odds score (LOD) score at theta 0 for the two families was 3.359]. This variant had not been previously reported and it was predicted to be pathogenic by Polyphen2, SIFT, MutationTaster and Mutation Assessor. AIFM1 encodes mitochondria associated apoptosis-inducing factor. The AIFM1 gene has been linked with COXPD6 encephalomyopathy (MIM 300816), Cowchock syndrome (MIM 310490) and X-linked deafness with neuropathy (DFNX5, MIM 300614), none of which are similar to SEMD-MR. Our results place SEMD as the third instance of a skeletal phenotype associated with a mitochondrial disease (the others being EVEN-PLUS syndrome caused by mutations of HSPA9 and CODAS syndrome due to LONP1 mutations).

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

“…3). Patient 4 (family 3) has a de novo c.710A > G (p.(Asp237Gly)) mutation identical to the mutation previously reported in two H-SMD families by Mierzewska et al [7]. Patients 2 and 3 (family 2) had a c.710A > T (p.(Asp237Val)) mutation at the same nucleotide position.…”

“…(Asp240Asp)PS2PS3PM2PathogenicFamily 2 (P2, 3)c.710A > Tp. (Asp237Val)PS3PM2PM5 [7]PP1PP3PathogenicFamily 3 (P4) [5]c.710A > Gp. (Asp237Gly) (identical mutation as previously published [7] though in different ethnicity)PS1 [7]PS2PS3PM2PP3PathogenicFamily 4 (P5, 6, 7)c.705G > Cp.…”

“…(Asp237Val)PS3PM2PM5 [7]PP1PP3PathogenicFamily 3 (P4) [5]c.710A > Gp. (Asp237Gly) (identical mutation as previously published [7] though in different ethnicity)PS1 [7]PS2PS3PM2PP3PathogenicFamily 4 (P5, 6, 7)c.705G > Cp. (Gln235His)PS3PM2PP1 (very strong family segregation)PP3Likely pathogenicFamily 5 (P8)c.720C > Tp.…”

“…Although an X-linked pattern of inheritance and linkage to Xq25-27 had already been identified in the first family, 4, 6 H-SMD could not be associated to a specific causative gene until recently, when it was linked with a single missense mutation in AIFM1 , encoding mitochondrial apoptosis-inducing factor 1 (AIFM1). This was reported in a Polish family and originally published without MRI findings [6] and in an unrelated Polish family carrying an identical p.(Asp237Gly) mutation [7]. …”

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

“…Mutations in apoptosis‐inducing factor, mitochondria‐associated‐1 ( AIFM1 ) cause multiple distinct clinical phenotypes, including X‐linked Charcot‐Marie‐Tooth (CMT) disease type 4 (Cowchock syndrome, CMT4X) . AIFM1 ‐associated cerebellar ataxia has rarely been described . Individuals within families with AIFM1‐ associated disease typically develop symptoms in childhood or adolescence.…”