KCNN2 mutation in autosomal-dominant tremulous myoclonus-dystonia

BACKGROUND: Despite recent advances in neurogenetics which have facilitated the identification of a number of dystonia genes, many familial dystonia syndromes remain without known cause. OBJECTIVE: To identify the cause of autosomal dominant tremulous myoclonus-dystonia in a UK kindred with affected individuals in three generations. METHODS: Known genetic causes of myoclonus-dystonia were excluded. We combined clinical and electrophysiological phenotyping with whole-exome sequencing and Sanger sequencing to identify candidate causal variants in a family with tremulous myoclonus-dystonia. RESULTS: The core phenotype consisted of childhood-onset dystonia predominantly affecting hands and neck, with a fast tremor with superimposed myoclonus, and in some, subtle cerebellar signs. We identified a novel missense variant in KCNN2 (NM_021614:c.1112G>A:p.(Gly371Glu)) which was the only variant we were able to identify segregating with the phenotype over three generations. This variant, which is absent from the most recent version of gnomAD, was predicted to be deleterious by SIFT and PolyPhen-2, and obtained an overall CADD score of 29.7. CONCLUSION: KCNN2 (potassium calcium-activated channel subfamily N member 2), a member of the KCNN family of potassium channel genes, is highly conserved across species and in humans is highly expressed in the brain, particularly the cerebellum. KCNN2 mutations have never been described as pathological in human disease, but are recognised abnormalities in two rodent models of fast, jerky tremor. Segregation, absence of the variant in the normal population and in silico prediction of a deleterious effect together with animal models compatible with the clinical phenotype are all in line with KCNN2 mutations being a plausible cause underlying myoclonus-dystonia

Psychiatric Manifestations of ATP13A2

Background: Biallelic mutations in ATP13A2 were identified as the cause of Kufor‐Rakeb disease, a pallido‐pyramidal syndrome characterised by young‐onset dystonia‐parkinsonism with vertical supranuclear gaze palsy, spasticity and cognitive decline. The phenotypic spectrum has broadened since, but predominantly psychiatric or behavioural manifestations have not been highlighted. / Cases: Here we report the clinical, radiological and genetic findings in two unrelated patients with ATP13A2 mutations. One patient had a prominent behavioural (autistic‐spectrum), the other a psychiatric (paranoid psychosis) presentation. Both had additional features such as delayed milestones, ataxia, pyramidal signs, upgaze restriction or impaired cognition to varying extent, but these were partly subtle or developed later in the disease course. / Conclusion: Prominent behavioural or psychiatric features can be the first or most prominent manifestation of ATP13A2 ‐related disease. They may be a diagnostic clue in patients with ataxia, spasticity or parkinsonism, and may require an interdisciplinary neurological and psychiatric treatment approach

Rare TREM2 variants associated with Alzheimer’s disease display reduced cell surface expression

Rare variation in TREM2 has been associated with greater risk for Alzheimer’s disease (AD). TREM2 encodes a cell surface receptor expressed on microglia and related cells, and the R47H variant associated with AD appears to affect the ability of TREM2 to bind extracellular ligands. In addition, other rare TREM2 mutations causing early-onset neurodegeneration are thought to impair cell surface expression. Using a sequence kernel association (SKAT) analysis in two independent AD cohorts, we found significant enrichment of rare TREM2 variants not previously characterized at the protein level. Heterologous expression of the identified variants showed that novel variants S31F and R47C displayed significantly reduced cell surface expression. In addition, we identified rare variant R136Q in a patient with language-predominant AD that also showed impaired surface expression. The results suggest rare TREM2 variants enriched in AD may be associated with altered TREM2 function and that AD risk may be conferred, in part, from altered TREM2 surface expression. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-016-0367-7) contains supplementary material, which is available to authorized users