An atypical form of AOA2 with myoclonus associated with mutations in SETX and AFG3L2

Abstract

BackgroundHereditary ataxias are a heterogeneous group of neurodegenerative disorders, where exome sequencing may become an important diagnostic tool to solve clinically or genetically complex cases.MethodsWe describe an Italian family in which three sisters were affected by ataxia with postural/intentional myoclonus and involuntary movements at onset, which persisted during the disease. Oculomotor apraxia was absent. Clinical and genetic data did not allow us to exclude autosomal dominant or recessive inheritance and suggest a disease gene.ResultsExome sequencing identified a homozygous c.6292C > T (p.Arg2098*) mutation in SETX and a heterozygous c.346G > A (p.Gly116Arg) mutation in AFG3L2 shared by all three affected individuals. A fourth sister (II.7) had subclinical myoclonic jerks at proximal upper limbs and perioral district, confirmed by electrophysiology, and carried the p.Gly116Arg change. Three siblings were healthy.Pathogenicity prediction and a yeast-functional assay suggested p.Gly116Arg impaired m-AAA (ATPases associated with various cellular activities) complex function.ConclusionsExome sequencing is a powerful tool in identifying disease genes. We identified an atypical form of Ataxia with Oculoapraxia type 2 (AOA2) with myoclonus at onset associated with the c.6292C > T (p.Arg2098*) homozygous mutation. Because the same genotype was described in six cases from a Tunisian family with a typical AOA2 without myoclonus, we speculate this latter feature is associated with a second mutated gene, namely AFG3L2 (p.Gly116Arg variant).We suggest that variant phenotypes may be due to the combined effect of different mutated genes associated to ataxia or related disorders, that will become more apparent as the costs of exome sequencing progressively will reduce, amplifying its diagnostics use, and meanwhile proposing significant challenges in the interpretation of the data.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0159-0) contains supplementary material, which is available to authorized users.

A novel mutation of AFG3L2 might cause dominant optic atrophy in patients with mild intellectual disability

“…Very recently, a novel c.346A>G, p.G116R mutation in the N-terminal domain of AFG3L2 protein was reported in a patient presenting spontaneous myoclonus at proximal limb associated to pyramidal signs. As for the cases we report here, this young patient did not present cerebellar ataxia, oculomotor abnormalities or sensory deficits ( Mancini et al, 2015 ), although we cannot exclude that they will develop these symptoms later in life.…”

Prevalence and phenotype of the c.1529C>T SPG7 variant in adult‐onset cerebellar ataxia in Italy

“…Thus, we may speculate that, in cases with p.Ala510Val, the phenotype is modulated by variants acting on SPG7/AFG3L2 expression or on AFG3L2 itself. A role for AFG3L2 as modifier has already been proven by our group in a family with ataxia with oculomotor apraxia type 2 [7].…”

Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy

“…Dominant mutations in AFG3L2 were initially found in individuals affected with SCA28 and do localize in exons 15 and 16, in addition to one in exon 10. 22 Recessive consanguineous AFG3L2 mutations in exon 15 were also identified in a spastic ataxia-neuropathy syndrome 23 (SPAX5), whereas 2 additional dominant AFG3L2 variants were identified in an individual affected with myoclonus and pyramidal signs 24 and a recessive mutation in another family affected with microcephaly, early onset seizures, spasticity, and basal ganglia atrophy. 25 Of interest, the 8 missense AFG3L2 variants that we identified in individuals with DOA are involving other domains than those identified earlier, thus explaining the absence of clinical overlap between all the symptoms previously described for AFG3L2 mutations and the optic atrophy found in this study.…”