Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3

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

Patient perspective in hereditary ataxia

Background: Hereditary ataxia is a group of rare disorders. Healthcareproviders and public authorities may have limited knowledge about thisdiagnosis. We asked the patients if they feel well-informed about thediagnosis and whom they usually turn to for support.Methods: Adult patients with a diagnosis of progressive cerebellar ataxiawere identified in the diagnosis register of Scania region or were recruitedthrough a patient organization. All patients were examined clinically. Asurvey with 32 multiple choice and open-ended questions was distributedthrough a secure online tool. Written and informed consent was obtainedfrom every participant. Our study is ethically approved.Results: Participants (N¼79) were aged between 22 and 80 years, onsetvaried from 1 to 73 years. The most common symptom at onset was“impaired balance”. The SARA score median was 10 (SD 9,06). Progress wasdescribed as slow by 87,3% (N¼69). Genetic testing was recalled by 56,9%(N¼45) of which 38% (N¼30) received a genetic diagnosis. Among patientswho had a genetic diagnosis, 76.7% felt “well-informed” (36.7%) or “partlywell informed” (40.0%) about their diagnosis. Among patients who did nothave a genetic diagnosis, 59.2% felt (fully: 22.4%; partly: 36.7%) wellinformed.This difference did not reach statistical significance (Pearson Chi-Square 0,17, Cramer’s V 0,2). On the question “what helps you feel better?”, “exercise” was the predominant answer 40,5% (N¼ 32) followed by “socialsupport from close family” and “medication”. Patients answered that closefamily and friends is the first instance they turn to for moral support (N¼62).Conclusions: This patient-perspective study on hereditary ataxia highlightsthe need to improve the disease-related information that healthservice providers give to their patients, even when the exact geneticsubtype has been established. Physiotherapy and support from closefamily are important for the wellbeing of patients with hereditary ataxia

A Swedish SCA34 family with late onset ataxia, cerebellar atrophy and ocular movement abnormalities with a novel mutation in ELOVL4

Background: To investigate the clinical and radiological presentation of anew ELOVL4mutation in a Swedish family.Methods:We compiled information on a Swedish family with 6 affectedmembers. Four of these had undergone neurological and radiological examinations. Two patients were independently analysed genetically bywhole exome or whole genome sequencing.Results: All examined affected family members showed slowly progressivecerebellar ataxia with balance impairment starting at between 42 and 70years, ocular movement disturbances with nystagmus, hypermetric saccades or vertical gaze palsy, and cerebellar atrophy on imaging. None of theaffected family members had erytrokeratodermia variabilis, but three haddry skin or psoriasis. Two members had seizures, one had intermittentmuscular cramps. One deceased obligate carrier had dementia and one ofthe members examined had mild cognitive dysfunction (MMSE 23/30). Oneindividual had poor night vision. One individual had a diagnosis ofschizophrenia since age 25 years. We identified a novel heterozygousvariant ELOVL4 c.511A>C, p.(Ile171Leu) (NM_022726.4) in affected individuals. When this was discovered in the first family member it was reported as a variant of uncertain significance (VUS). However, aftersegregation analysis and detailed clinical information for the entire family,the variant could be reclassified as likely pathogenic according to the ACMG classification system (PMID: 25741868) and Jarvik et al (PMID: 27236918).Conclusions: So far, including the present report, eight different ELOVL4-variants have been described in SCA34 patients. Our examinations provideadditional knowledge to the presentation of this rare neurodegenerativedisorder

Ataxia-pancytopenia syndrome with SAMD9L mutations

Abstract Objective: We describe the neurologic, neuroradiologic, and ophthalmologic phenotype of 1 Swedish and 1 Finnish family with autosomal dominant ataxia-pancytopenia (ATXPC) syndrome and SAMD9L mutations. Methods: Members of these families with germline SAMD9L c.2956C>T, p.Arg986Cys, or c.2672T>C, p.Ile891Thr mutations underwent structured interviews and neurologic and ophthalmologic examinations. Neuroimaging was performed, and medical records were reviewed. Previous publications on SAMD9L-ATXPC were reviewed. Results: Twelve individuals in both families were affected clinically. All mutation carriers examined had balance impairment, although severity was very variable. All but 1 had nystagmus, and all but 1 had pyramidal tract signs. Neurologic features were generally present from childhood on and progressed slowly. Two adult patients, who experienced increasing clumsiness, glare, and difficulties with gaze fixation, had paracentral retinal dysfunction verified by multifocal electroretinography. Brain MRI showed early, marked cerebellar atrophy in most carriers and variable cerebral periventricular white matter T2 hyperintensities. Two children were treated with hematopoietic stem cell transplantation for hematologic malignancies, and the neurologic symptoms of one of these worsened after treatment. Three affected individuals had attention deficit hyperactivity disorder or cognitive problems. Retinal dysfunction was not previously reported in individuals with ATXPC. Conclusions: The neurologic phenotype of this syndrome is defined by balance or gait impairment, nystagmus, hyperreflexia in the lower limbs and, frequently, marked cerebellar atrophy. Paracentral retinal dysfunction may contribute to glare, reading problems, and clumsiness. Timely diagnosis of ATXPC is important to address the risk for severe hemorrhage, infection, and hematologic malignancies inherent in this syndrome; regular hematologic follow-up might be beneficial

SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies

Germline mutations in the SAMD9 and SAMD9L genes, located in tandem on chromosome 7, are associated with a clinical spectrum of disorders including the MIRAGE syndrome, ataxia–pancytopenia syndrome and myelodysplasia and leukemia syndrome with monosomy 7 syndrome. Germline gain-of-function mutations increase SAMD9 or SAMD9L’s normal antiproliferative effect. This causes pancytopenia and generally restricted growth and/or specific organ hypoplasia in non-hematopoietic tissues. In blood cells, additional somatic aberrations that reverse the germline mutation’s effect, and give rise to the clonal expansion of cells with reduced or no antiproliferative effect of SAMD9 or SAMD9L include complete or partial chromosome 7 loss or loss-of-function mutations in SAMD9 or SAMD9L. Furthermore, the complete or partial loss of chromosome 7q may cause myelodysplastic syndrome in these patients. SAMD9 mutations appear to associate with a more severe disease phenotype, including intrauterine growth restriction, developmental delay and hypoplasia of adrenal glands, testes, ovaries or thymus, and most reported patients died in infancy or early childhood due to infections, anemia and/or hemorrhages. SAMD9L mutations have been reported in a few families with balance problems and nystagmus due to cerebellar atrophy, and may lead to similar hematological disease as seen in SAMD9 mutation carriers, from early childhood to adult years. We review the clinical features of these syndromes, discuss the underlying biology, and interpret the genetic findings in some of the affected family members. We provide expert-based recommendations regarding diagnosis, follow-up, and treatment of mutation carriers

Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3

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