Novel GCH1 variant in Dopa-responsive dystonia and Parkinson's disease

Background: GTP cyclohydrolase I (GCH1) mutations are the commonest cause of Dopa-responsive dystonia (DRD). Clinical phenotypes can be broad, even within a single family. Methods: We present clinical, genetic and functional imaging data on a British kindred in which affected subjects display phenotypes ranging from DRD to Parkinson's disease (PD). Twelve family members were studied. Clinical examination, dopamine transporter (DAT) imaging, and molecular genetic analysis of GCH1 and the commonest known familial PD-related genes were performed. Results: We have identified a novel missense variant, c.5A>G, p.(Glu2Gly), within the GCH1 gene in affected family members displaying a range of phenotypes. Two affected subjects carrying this variant had abnormal DAT imaging. These two with abnormal DAT imaging had a PD phenotype, while the remaining three subjects with the novel GCH1 variant had normal DAT imaging and a DRD phenotype. Conclusions: We propose that this GCH1 variant is pathogenic in this family and these findings suggest that similar mechanisms involving abnormal GTP cyclohydolase I may underlie both PD and DRD. GCH1 genetic testing should be considered in patients with PD and a family history of DRD

Characterization of Brain Lysosomal Activities in GBA-Related and Sporadic Parkinson’s Disease and Dementia with Lewy Bodies

Mutations in the GBA gene, encoding the lysosomal hydrolase glucocerebrosidase (GCase), are the most common known genetic risk factor for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). The present study aims to gain more insight into changes in lysosomal activity in different brain regions of sporadic PD and DLB patients, screened for GBA variants. Enzymatic activities of GCase, β-hexosaminidase, and cathepsin D were measured in the frontal cortex, putamen, and substantia nigra (SN) of a cohort of patients with advanced PD and DLB as well as age-matched non-demented controls (n = 15/group) using fluorometric assays. Decreased activity of GCase (− 21%) and of cathepsin D (− 15%) was found in the SN and frontal cortex of patients with PD and DLB compared to controls, respectively. Population stratification was applied based on GBA genotype, showing substantially lower GCase activity (~ − 40%) in GBA variant carriers in all regions. GCase activity was further significantly decreased in the SN of PD and DLB patients without GBA variants in comparison to controls without GBA variants. Our results show decreased GCase activity in brains of PD and DLB patients with and without GBA variants, most pronounced in the SN. The results of our study confirm findings from previous studies, suggesting a role for GCase in GBA-associated as well as sporadic PD and DLB

ACO2 homozygous missense mutation associated with complicated Hereditary spastic paraplegia

Objective: To identify the clinical characteristics and genetic etiology of a family affected with hereditary spastic paraplegia (HSP). Methods: Clinical, genetic, and functional analyses involving genome-wide linkage coupled to whole-exome sequencing in a consanguineous family with complicated HSP. Results: A homozygous missense mutation was identified in the ACO2 gene (c.1240T>G p.Phe414Val) that segregated with HSP complicated by intellectual disability and microcephaly. Lymphoblastoid cell lines of homozygous carrier patients revealed significantly decreased activity of the mitochondrial aconitase enzyme and defective mitochondrial respiration. ACO2 encodes mitochondrial aconitase, an essential enzyme in the Krebs cycle. Recessive mutations in this gene have been previously associated with cerebellar ataxia. Conclusions: Our findings nominate ACO2 as a disease-causing gene for autosomal recessive complicated HSP and provide further support for the central role of mitochondrial defects in the pathogenesis of HSP

Clinical and Pathological Phenotypes of LRP10 Variant Carriers with Dementia

BACKGROUND: Rare variants in the low-density lipoprotein receptor related protein 10 gene (LRP10) have recently been implicated in the etiology of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). OBJECTIVE: We searched for LRP10 variants in a new series of brain donors with dementia and Lewy pathology (LP) at autopsy, or dementia and parkinsonism without LP but with various other neurodegenerative pathologies. METHODS: Sanger sequencing of LRP10 was performed in 233 donors collected by the Netherlands Brain Bank. RESULTS: Rare, possibly pathogenic heterozygous LRP10 variants were present in three patients: p.Gly453Ser in a patient with mixed Alzheimer's disease (AD)/Lewy body disease (LBD), p.Arg151Cys in a DLB patient, and p.Gly326Asp in an AD patient without LP. All three patients had a positive family history for dementia or PD. CONCLUSION: Rare LRP10 variants are present in some patients with dementia and different brain pathologies including DLB, mixed AD/LBD, and AD. These findings suggest a role for LRP10 across a broad neurodegenerative spectrum

Early-onset parkinsonism caused by alpha-synuclein gene triplication: Clinical and genetic findings in a novel family

Introduction: Triplications of SNCA, the gene encoding for α-synuclein, cause a very rare Mendelian form of early-onset parkinsonism combined with cognitive and autonomic dysfunctions. Only six families with SNCA triplications have been described so far, limiting our knowledge of the associated phenotype. In this study, we report clinical and genetic findings in a new Italian family with SNCA triplication. Methods: The patients' phenotype was assessed by neurological examination, neuropsychological tests, and brain imaging (MRI and SPECT-DaTSCAN). For the genetic investigation, we used three independent techniques: genome-wide SNP microarrays, fluorescence in situ hybridization (FISH), and multiplex ligation-dependent probe amplification (MLPA). Results: Genetic studies documented the presence of four copies of the SNCA gene in the affected family members. FISH experiments and the segregation in the family were consistent with a heterozygous triplication of the SNCA locus. The patients carrying the SNCA triplication developed early-onset parkinsonism combined with depression, behavior disturbances, sleep disorders, and cognitive decline; marked autonomic dysfunctions were not observed. Brain imaging revealed fronto-parietal atrophy and a severe striatal dopaminergic deficit. Conclusion: The identification of this novel family contributes to the genetic and clinical characterization of this rare form. Our data reinforce the view that SNCA triplications cause early-onset parkinsonism, with prominent non-motor features

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

Objective: The study was undertaken to identify a monogenic cause of early onset, generalized dystonia. Methods: Methods 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. Results: We identified a heterozygous variant, c.388G&gt;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&gt;A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G&gt;C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A&gt;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. Interpretation: We 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.</p

Broadening the phenotype of TARDBP mutations: the TARDBP Ala382Thr mutation and Parkinson’s disease in Sardinia

Mutations in the TARDBP gene are a cause of autosomal dominant amyotrophic lateral sclerosis (ALS) and of frontotemporal lobar degeneration (FTLD), but they have not been found so far in patients with Parkinson’s disease (PD). A founder TARDBP mutation (p.Ala382Thr) was recently identified as the cause of ~30% of ALS cases in Sardinia, a Mediterranean genetic isolate. We studied 327 consecutive Sardinian patients with clinically diagnosed PD (88 familial, 239 sporadic) and 578 Sardinian controls. One family with FTLD and parkinsonism was also included. The p.Ala382Thr heterozygous mutation was detected in eight unrelated PD patients (2.5%). The three patients from the FTLD/parkinsonism family also carried this mutation. Within the control group, there were three heterozygous mutation carriers. During follow-up, one of these individuals developed motoneuron disease and another, a rapidly progressive dementia; the third remains healthy at the age of 79 but two close relatives developed motoneuron disease and dementia. The eight PD patients carrying the p.Ala382Thr mutation had all sporadic disease presentation. Their average onset age was 70.0 years (SD 9.4, range 51–79), which is later but not significantly different from that of the patients who did not carry this mutation. In conclusion, we expand the clinical spectrum associated with TARDBP mutations to FTLD with parkinsonism without motoneuron disease and to clinically definite PD. The TDP-43 protein might be directly involved in a broader neurodegenerative spectrum, including not only motoneuron disease and FTLD but also PD