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| 2. |
- Gorcenco, Sorina, et al.
(författare)
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Clinical and genetic analyses of a Swedish patient series diagnosed with ataxia
- 2024
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Ingår i: Journal of Neurology. - 0340-5354. ; 271:1, s. 526-542
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary ataxia is a heterogeneous group of complex neurological disorders. Next-generation sequencing methods have become a great help in clinical diagnostics, but it may remain challenging to determine if a genetic variant is the cause of the patient’s disease. We compiled a consecutive single-center series of 87 patients from 76 families with progressive ataxia of known or unknown etiology. We investigated them clinically and genetically using whole exome or whole genome sequencing. Test methods were selected depending on family history, clinical phenotype, and availability. Genetic results were interpreted based on the American College of Medical Genetics criteria. For high-suspicion variants of uncertain significance, renewed bioinformatical and clinical evaluation was performed to assess the level of pathogenicity. Thirty (39.5%) of the 76 families had received a genetic diagnosis at the end of our study. We present the predominant etiologies of hereditary ataxia in a Swedish patient series. In two families, we established a clinical diagnosis, although the genetic variant was classified as “of uncertain significance” only, and in an additional three families, results are pending. We found a pathogenic variant in one family, but we suspect that it does not explain the complete clinical picture. We conclude that correctly interpreting genetic variants in complex neurogenetic diseases requires genetics and clinical expertise. The neurologist’s careful phenotyping remains essential to confirm or reject a diagnosis, also by reassessing clinical findings after a candidate genetic variant is suggested. Collaboration between neurology and clinical genetics and combining clinical and research approaches optimizes diagnostic yield.
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| 3. |
- Gorcenco, Sorina, et al.
(författare)
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Patients’ Perspective in Hereditary Ataxia
- 2022
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Ingår i: Cerebellum. - : Springer Science and Business Media LLC. - 1473-4222.
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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.
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- Prudencio, Mercedes, et al.
(författare)
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Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3
- 2020
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 12:566
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Tidskriftsartikel (refereegranskat)abstract
- Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.
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| 5. |
- Wallenius, Joel, et al.
(författare)
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Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4 : A poly-glycine disease.
- 2024
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Ingår i: American Journal of Human Genetics. - 0002-9297 .- 1537-6605. ; 111:1, s. 82-95
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Tidskriftsartikel (refereegranskat)abstract
- Autosomal-dominant ataxia with sensory and autonomic neuropathy is a highly specific combined phenotype that we described in two Swedish kindreds in 2014; its genetic cause had remained unknown. Here, we report the discovery of exonic GGC trinucleotide repeat expansions, encoding poly-glycine, in zinc finger homeobox 3 (ZFHX3) in these families. The expansions were identified in whole-genome datasets within genomic segments that all affected family members shared. Non-expanded alleles carried one or more interruptions within the repeat. We also found ZFHX3 repeat expansions in three additional families, all from the region of Skåne in southern Sweden. Individuals with expanded repeats developed balance and gait disturbances at 15 to 60 years of age and had sensory neuropathy and slow saccades. Anticipation was observed in all families and correlated with different repeat lengths determined through long-read sequencing in two family members. The most severely affected individuals had marked autonomic dysfunction, with severe orthostatism as the most disabling clinical feature. Neuropathology revealed p62-positive intracytoplasmic and intranuclear inclusions in neurons of the central and enteric nervous system, as well as alpha-synuclein positivity. ZFHX3 is located within the 16q22 locus, to which spinocerebellar ataxia type 4 (SCA4) repeatedly had been mapped; the clinical phenotype in our families corresponded well with the unique phenotype described in SCA4, and the original SCA4 kindred originated from Sweden. ZFHX3 has known functions in neuronal development and differentiation n both the central and peripheral nervous system. Our findings demonstrate that SCA4 is caused by repeat expansions in ZFHX3.
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