| 1. |
|
|
| 2. |
- Almasoudi, Wejdan, et al.
(författare)
-
Co-occurrence of CLCN2-related leukoencephalopathy and SPG56
- 2023
-
Ingår i: Clinical Parkinsonism and Related Disorders. - : Elsevier BV. - 2590-1125. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Family Report: Two rare autosomal recessive neurological disorders, leukoencephalopathy with ataxia and spastic paraplegia 56 (SPG56), were found in members of the same family. Two siblings presented with spastic paraplegia, cognitive impairment, bladder and bowel dysfunction and gait ataxia; their consanguineous parents were unaffected. Ophthalmological examination revealed chorioretinopathy. Brain MRI showed T2 hyperintensities and T1 hypointensities in the internal capsules, cerebral peduncles, pyramidal tracts and middle cerebellar peduncles. Both affected siblings were homozygous for CYP2U1 c.947A > T p.(Asp316Val), a known cause for SPG56. However, they were also homozygous for the novel variant CLCN2 c.607G > T, p.(Gly203Cys), classified as a variant of unknown significance. Testing of additional family members revealed homozygosity for both variants in an additional brother, whom we initially considered unaffected. Both male CLCN2 carriers were infertile, and review of the literature revealed one reported case with azoospermia, however the brother had no overt signs of SPG56. His testicular biopsy revealed incomplete maturation arrest in spermatogenesis; clinically we found mild memory impairment and hand tremor and MRI showed similar changes as his siblings. We consider CLCN2 c.607G > T pathogenic because of the neuroradiological and clinical findings, including azoospermia. Conclusion: Considerable workup may be required to determine the pathogenicity of novel variants, and to unambiguously associate phenotype with genotype. In very rare disorders, highly specific clinical or biomarker combinations provide sufficient evidence for a variant's pathogenicity. Phenotypic variation of monogenic disorders described in the literature may be attributed to a second co-occurring monogenic disorder, especially in consanguineous families. SPG56 may have reduced penetrance.
|
|
| 3. |
- Brolin, Kajsa, et al.
(författare)
-
Insights on Genetic and Environmental Factors in Parkinson's Disease from a Regional Swedish Case-Control Cohort
- 2022
-
Ingår i: Journal of Parkinson's Disease. - 1877-718X. ; 12:1, s. 153-171
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Risk factors for Parkinson's disease (PD) can be more or less relevant to a population due to population-specific genetic architecture, local lifestyle habits, and environmental exposures. Therefore, it is essential to study PD at a local, regional, and continental scale in order to increase the knowledge on disease etiology.OBJECTIVE: We aimed to investigate the contribution of genetic and environmental factors to PD in a new Swedish case-control cohort.METHODS: PD patients (n = 929) and matched population-based controls (n = 935) from the southernmost county in Sweden were included in the cohort. Information on environmental exposures was obtained using questionnaires at inclusion. Genetic analyses included a genome-wide association study (GWAS), haplotype assessment, and a risk profile analysis using cumulative genetic risk scores.RESULTS: The cohort is a representative PD case-control cohort (64% men, mean age at diagnosis = 67 years, median Hoehn and Yahr score 2.0), in which previously reported associations between PD and environmental factors, such as tobacco, could be confirmed. We describe the first GWAS of PD solely composed of PD patients from Sweden, and confirm associations to well-established risk alleles in SNCA. In addition, we nominate an unconfirmed and potentially population-specific genome-wide significant association in the PLPP4 locus (rs12771445).CONCLUSION: This work provides an in-depth description of a new PD case-control cohort from southern Sweden, giving insights into environmental and genetic risk factors for PD in the Swedish population.
|
|
| 4. |
|
|
| 5. |
- Fiesel, Fabienne C., et al.
(författare)
-
Substitution of PINK1 Gly411 modulates substrate receptivity and turnover
- 2023
-
Ingår i: Autophagy. - : Informa UK Limited. - 1554-8627 .- 1554-8635. ; 19:6, s. 1711-1732
-
Tidskriftsartikel (refereegranskat)abstract
- The ubiquitin (Ub) kinase-ligase pair PINK1-PRKN mediates the degradation of damaged mitochondria by macroautophagy/autophagy (mitophagy). PINK1 surveils mitochondria and upon stress accumulates on the mitochondrial surface where it phosphorylates serine 65 of Ub to activate PRKN and to drive mitochondrial turnover. While loss of either PINK1 or PRKN is genetically linked to Parkinson disease (PD) and activating the pathway seems to have great therapeutic potential, there is no formal proof that stimulation of mitophagy is always beneficial. Here we used biochemical and cell biological methods to study single nucleotide variants in the activation loop of PINK1 to modulate the enzymatic function of this kinase. Structural modeling and in vitro kinase assays were used to investigate the molecular mechanism of the PINK1 variants. In contrast to the PD-linked PINK1G411S mutation that diminishes Ub kinase activity, we found that the PINK1G411A variant significantly boosted Ub phosphorylation beyond levels of PINK1 wild type. This resulted in augmented PRKN activation, mitophagy rates and increased viability after mitochondrial stress in midbrain-derived, gene-edited neurons. Mechanistically, the G411A variant stabilizes the kinase fold of PINK1 and transforms Ub to adopt the preferred, C-terminally retracted conformation for improved substrate turnover. In summary, we identify a critical role of residue 411 for substrate receptivity that may now be exploited for drug discovery to increase the enzymatic function of PINK1. The genetic substitution of Gly411 to Ala increases mitophagy and may be useful to confirm neuroprotection in vivo and might serve as a critical positive control during therapeutic development. Abbreviations: ATP: adenosine triphosphate; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; Ub-CR: ubiquitin with C-terminally retracted tail; CTD: C-terminal domain (of PINK1); ELISA: enzyme-linked immunosorbent assay; HCI: high-content imaging; IB: immunoblot; IF: immunofluorescence; NPC: neuronal precursor cells; MDS: molecular dynamics simulation; PD: Parkinson disease; p-S65-Ub: ubiquitin phosphorylated at Ser65; RMSF: root mean scare fluctuation; TOMM: translocase of outer mitochondrial membrane; TVLN: ubiquitin with T66V and L67N mutation, mimics Ub-CR; Ub: ubiquitin; WT: wild-type.
|
|
| 6. |
|
|
| 7. |
- Garcia-Moreno, Hector, et al.
(författare)
-
Tau and neurofilament light-chain as fluid biomarkers in spinocerebellar ataxia type 3
- 2022
-
Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 29:8, s. 2439-2452
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Clinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures.METHODS: To evaluate total tau (t-tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and neurofilament light-chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD-1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t-tau and phosphorylated tau (p-tau181 ). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t-tau levels.RESULTS: Plasma t-tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non-Ataxia Signs was associated with t-tau in ataxic patients (p = 0.004). Pre-ataxic carriers showed higher cerebrospinal fluid t-tau and p-tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t-tau was elevated in MJDTg mice compared to wild-type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p < 0.001).CONCLUSION: Our results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials.
|
|
| 8. |
|
|
| 9. |
- Gorcenco, Sorina, et al.
(författare)
-
New generation genetic testing entering the clinic
- 2020
-
Ingår i: Parkinsonism and Related Disorders. - : Elsevier BV. - 1353-8020. ; 73, s. 72-84
-
Tidskriftsartikel (refereegranskat)abstract
- New generation sequencing (NGS) genetic testing is a powerful diagnostic tool and is increasingly used in the clinical workup of patients, especially in unusual presentations or where a positive family history suggests heritable disease. This review addresses the NGS technologies Targeted sequencing (TS), Whole exome sequencing (WES), Whole genome sequencing (WGS), and the use of gene panels or gene lists for clinical diagnostic purposes. These methods primarily assess nucleotide sequence but can also detect copy number variants and many tandem repeat expansions, greatly simplifying diagnostic algorithms for movement disorders. Studies evaluating the efficacy of NGS in diagnosing movement disorders have reported a diagnostic yield of up to 10.1% for familial and 15.7% for early-onset PD, 11.7–37.5% for dystonia, 12.1–61.8% for ataxia/spastic paraplegia and 11.3–28% for combined movement disorders. Patient selection and stringency in the interpretation of the detected variants and genotypes affect diagnostic yield. Careful comparison of the patient's or family's disease features with the previously reported phenotype associated with the same variant or gene can avoid false-positive diagnoses, although some genes are implicated in various phenotypes. Moving from TS to WES and WGS increases the number of patients correctly diagnosed, but for many patients, a genetic cause cannot be identified today. However, new genetically defined entities are discovered at rapid pace, and genetic databases and our knowledge of genotype-phenotype correlations expand steadily. We discuss the need for clear communication of genetic results and suggest a list of aspects to consider when reporting neurogenetic disorders using NGS testing.
|
|
| 10. |
- Gorcenco, Sorina, et al.
(författare)
-
Patients’ Perspective in Hereditary Ataxia
- 2022
-
Ingår i: Cerebellum. - : Springer Science and Business Media LLC. - 1473-4222.
-
Tidskriftsartikel (refereegranskat)abstract
- Hereditary ataxia represents a heterogeneous group of rare disorders with the chronic progression of motor symptoms that often become debilitating. Many forms include additional neurological, cognitive, or other symptoms. Most of these disorders lack specific treatment. We aimed to investigate aspects of patients’ quality of life, experiences, and expectations. Patients with a diagnosis of hereditary ataxia were identified from our center’s diagnostic register, direct referrals, and from a patient organization. We designed a questionnaire with 32 multiple-choice or open-ended questions on disability and impairment of daily life activities, the perceived effect of symptomatic and supportive therapies, coping strategies, and how they used and experienced various sources of information about their neurological disease. We also included the EQ-5D-3L quality-of-life instrument. Results were analyzed statistically for gender, age, and groups with and without a genetic diagnosis, and were compared to published data from the general population. Seventy-five patients returned the questionnaire. Patients reported considerable disease-related disability and impairment and had significantly lower quality-of-life scores than the general population. Physiotherapy and support from family or friends were important for patients’ overall well-being. Patients with a genetic diagnosis had a lower average age at onset and felt more well-informed about their disease than patients without a genetic diagnosis. Patients used internet sources but relied primarily on their doctors to obtain information about their disease. Our study provides insights into hereditary ataxia patients’ experiences that can lead to improvements in medical and nursing care for these patients.
|
|
