Heterozygous EIF2AK2 Variant Causes Adolescence-Onset Generalized Dystonia Partially Responsive to DBS.
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ABSTRACT:
SUBMITTER: Magrinelli F
PROVIDER: S-EPMC8810423 | biostudies-literature | 2022 Feb
REPOSITORIES: biostudies-literature
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Heterozygous <i>EIF2AK2</i> Variant Causes Adolescence-Onset Generalized Dystonia Partially Responsive to DBS.
Magrinelli Francesca F Moualek Dalila D Tazir Meriem M Pacha Lamia Ali LA Verghese Alice A Bhatia Kailash P KP Maroofian Reza R Houlden Henry H
Movement disorders clinical practice 20211121 2
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Project description:ObjectiveThe study was undertaken to identify a monogenic cause of early onset, generalized dystonia.MethodsMethods consisted of genome-wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients.ResultsWe identified a heterozygous variant, c.388G>A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR-mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon-inducible double-stranded RNA-dependent protein kinase activator A), the product of another gene causing monogenic dystonia.InterpretationWe identified EIF2AK2 variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia. ANN NEUROL 2021;89:485-497.
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Project description:Treatment outcomes from pallidal deep brain stimulation are highly heterogeneous reflecting the phenotypic and etiologic spectrum of dystonia. Treatment stratification to neurostimulation therapy primarily relies on the phenotypic motor presentation; however, etiology including genetic factors are increasingly recognized as modifiers of treatment outcomes. Here, we describe a 53 year-old female patient with a progressive generalized dystonia since age 25. The patient underwent deep brain stimulation of the globus pallidus internus (GPi-DBS) at age 44. Since the clinical phenotype included mobile choreo-dystonic features, we expected favorable therapeutic outcome from GPi-DBS. Although mobile dystonia components were slightly improved in the long-term outcome from GPi-DBS the overall therapeutic response 9 years from implantation was limited when comparing "stimulation off" and "stimulation on" despite of proper electrode localization and sufficient stimulation programming. In order to further understand the reason for this limited motor symptom response, we aimed to clarify the etiology of generalized dystonia in this patient. Genetic testing identified a novel heterozygous pathogenic SLC2A1 mutation as cause of glucose transporter type 1 deficiency syndrome (GLUT1-DS). This case report presents the first outcome of GPi-DBS in a patient with GLUT1-DS, and suggests that genotype relations may increasingly complement phenotype-based therapy stratification of GPi-DBS in dystonia.
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Project description:Hereditary defects of coenzyme Q10 biosynthesis cause steroid-resistant nephrotic syndrome (SRNS) as part of multiorgan involvement but may also contribute to isolated SRNS. Here, we report 26 patients from 12 families with recessive mutations in ADCK4. Mutation detection rate was 1.9% among 534 consecutively screened cases. Patients with ADCK4 mutations showed a largely renal-limited phenotype, with three subjects exhibiting occasional seizures, one subject exhibiting mild mental retardation, and one subject exhibiting retinitis pigmentosa. ADCK4 nephropathy presented during adolescence (median age, 14.1 years) with nephrotic-range proteinuria in 44% of patients and advanced CKD in 46% of patients at time of diagnosis. Renal biopsy specimens uniformly showed FSGS. Whereas 47% and 36% of patients with mutations in WT1 and NPHS2, respectively, progressed to ESRD before 10 years of age, ESRD occurred almost exclusively in the second decade of life in ADCK4 nephropathy. However, CKD progressed much faster during adolescence in ADCK4 than in WT1 and NPHS2 nephropathy, resulting in similar cumulative ESRD rates (>85% for each disorder) in the third decade of life. In conclusion, ADCK4-related glomerulopathy is an important novel differential diagnosis in adolescents with SRNS/FSGS and/or CKD of unknown origin.
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Project description:ObjectiveTo compare the efficacy in patients with different genotypes, identify the potential predictive factors, and summarize the complications of globus pallidus deep brain stimulation (GPi-DBS) treating early-onset dystonia.MethodsThree electronic databases (PubMed, Embase, and Cochrane databases) were searched with no publication data restriction. The primary outcomes were the improvements in Burke-Fahn-Marsden Dystonia Rating Scale motor (BFMDRS-M) and disability (BFMDRS-D) score. Pearson's correlation coefficients and a metaregression analysis were used to identify the potential predictive factors. This article was registered in Prospero (CRD42020188527).ResultsFifty-four studies (231 patients) were included. Patients showed significant improvement rate in BFMDRS-M (60.6%, p < 0.001) and BFMDRS-D (57.5%, p < 0.001) scores after treatment with GPi-DBS. BFMDRS-M score improved greater in the DYT-1-positive (p = 0.001) and DYT-11-positive (p = 0.008) patients compared to DYT-6-positive patients. BFMDRS-D score improved greater in the DYT-11 (+) compared to DYT-6 (+) patients (p = 0.010). The relative change of BFMDRS-M (p = 0.002) and BFMDRS-D (p = 0.010) scores was negatively correlated with preoperative BFMDRS-M score. In the metaregression analysis, the best predictive model showed that preoperative BFMDRS-M, disease duration (p = 0.047), and the age at symptom onset (p = 0.027) were important.ConclusionPatients with early-onset dystonia have a significant effect after GPi-DBS treatment, and DYT-1 (+) and DYT-11 (+) patients are better candidates for GPi-DBS. Lower preoperative score, later age of onset, and an earlier age at surgery probably predict better clinical outcomes.
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Project description:ObjectiveTo elucidate the genetic cause of an Egyptian family with dopa-responsive dystonia (DRD), a childhood-onset dystonia, responding therapeutically to levodopa, which is caused by mutations in various genes.MethodsRare variants in all coding exons of GCH1 were excluded by Sanger sequencing. Exome sequencing was applied for 1 unaffected and 2 affected family members. To investigate the functional consequences of detected genetic variants, urinary sepiapterin concentrations were determined by high-performance liquid chromatography.ResultsA heterozygous rare nonsynonymous variant in exon 1 of sepiapterin reductase (SPR, c.207C>G, p.Asp69Glu) was found in all affected family members. Urinary concentrations of sepiapterin were above the standard of normal controls in most SPR mutation carriers, suggesting functional biochemical consequences of the mutation. Variant filtering of all genes involved in the tetrahydrobiopterin pathway, required for levodopa synthesis, revealed an additional common variant in dihydrofolate reductase (DHFR, rs70991108). The presence of both variants was significantly stronger associated with the biochemical abnormality and the clinical disease state as opposed to 1 variant only.ConclusionsThe rare SPR mutation can cause autosomal dominant DRD with incomplete penetrance. The common DHFR variant might have synergistic effects on production of tetrahydrobiopterin and levodopa, thereby increasing penetrance.
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