Abstract Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2, n = 421), SCA3 ( n = 268), SCA6 ( n = 117), other SCAs ( n = 97), Friedreich ataxia (FRDA, n = 178), Niemann-Pick disease type C (NPC, n = 57), and ataxia-telangiectasia ( n = 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression ( n = 2; SCA2) or treatment response ( n = 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores ( n = 18 studies (SARA: n = 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset; n = 17), genetic stratification ( n = 9), and imaging measures of atrophy ( n = 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes.
Objective We evaluated the prevalence of pathogenic repeat expansions in replication factor C subunit 1 (RFC1) and disabled adaptor protein 1 (DAB1) in an undiagnosed ataxia cohort from North America. Methods A cohort of 596 predominantly adult-onset patients with undiagnosed familial or sporadic cerebellar ataxia was evaluated at a tertiary referral ataxia center and excluded for common genetic causes of cerebellar ataxia. Patients were then screened for the presence of pathogenic repeat expansions in RFC1 (AAGGG) and DAB1 (ATTTC) using fluorescent repeat-primed PCR (RP-PCR). Two additional undiagnosed ataxia cohorts from different centers, totaling 302 and 13 patients, respectively, were subsequently screened for RFC1, resulting in a combined 911 subjects tested. Results In the initial cohort, 41 samples were identified with 1 expanded allele in the RFC1 gene (6.9%), and 9 had 2 expanded alleles (1.5%). For the additional cohorts, we found 20 heterozygous samples (6.6%) and 17 biallelic samples (5.6%) in the larger cohort and 1 heterozygous sample (7.7%) and 3 biallelic samples (23%) in the second. In total, 29 patients were identified with biallelic repeat expansions in RFC1 (3.2%). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%), and 3 had spinocerebellar ataxia (10%). No patients were identified with expansions in the DAB1 gene (spinocerebellar ataxia type 37). Conclusions In a large undiagnosed ataxia cohort from North America, biallelic pathogenic repeat expansion in RFC1 was observed in 3.2%. Testing should be strongly considered in patients with ataxia, especially those with CANVAS or neuropathy.
Abstract Background and Aims Omaveloxolone, an Nrf2 activator, is an investigational drug that targets targets inflammation and mitochondrial dysfunction, metabolic, and bioenergetic pathways. Omaveloxolone is an analog of bardoxolone, methyl which has been shown to improve kidney function in multiple studies of chronic kidney diseases. The MOXIe Part 2 trial investigated omaveloxolone in patients with Friedreich’s ataxia (FA), a rare and serious hereditary disease caused by mitochondrial dysfunction that affects multiple organ systems resulting in ataxia, cardiomyopathy, and reduced lifespan. The study met its primary efficacy endpoint, and omaveloxolone improved neurological function, as assessed by the modified Friedreich’s ataxia rating scale (mFARS). We report the effect of omaveloxolone on kidney function in this patient population. Method The MOXIe trial (NCT02255435) was an international, multi-center, double-blind, placebo-controlled, randomized trial that enrolled 103 patients between 16 and 40 years of age with genetically confirmed FA. Patients were randomized 1:1 to receive either omaveloxolone 150 mg or placebo administered once daily for 48 weeks. The trial included 24 patients that were younger than 18 years of age. Baseline eGFR for the overall patient population receiving placebo or omaveloxolone was 109.2 ± 21.7 and 113.4 ± 14.7 mL/min/1.73 m2, respectively. Baseline eGFR for the pediatric population receiving placebo or omaveloxolone was 99.1 ± 33.7 and 106.3 ± 15.6 mL/min/1.73 m2, respectively. Serum creatinine was collected at baseline, Weeks 4, 12, 18, 24, 36 and 48 on-treatment and 4-weeks off-treatment at Week 52. Glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for patients ≥ 18 years of age. For patients <18 years of age, the Bedside Schwartz equation was used to calculate eGFR. Results In placebo patients, mean (SD) eGFR decreased by 4.4 ± 11.0 mL/min/1.73 m2 from baseline whereas patients receiving omaveloxolone had an average increase of +7.0 ± 10.7 mL/min/1.73 m2 from baseline after 48 weeks, resulting in a difference of 11.4 mL/min/1.73 m2 between treatment groups. At Week 52, mean eGFR was -4.2 ± 10.9 mL/min/1.73 m2 relative to baseline in placebo patients and remained +0.9 ± 10.8 mL/min/1.73 m2 above baseline in omaveloxolone patients after 4-weeks off-treatment. In pediatric patients randomized to placebo, at week 48 eGFR decreased by -11.3 ± 14.3 mL/min/1.73 m2 whereas patients receiving omaveloxolone had an average increase of +5.5 ± 14.5 mL/min/1.73 m2 from baseline, resulting in a difference of 16.8 mL/min/1.73 m2 between treatment groups. Conclusion Patients with FA randomized to placebo in the MOXIe trial had eGFR declines over 48 weeks that were similar to rates of decline observed in the most rapidly progressing forms of chronic kidney disease. The rapid kidney function decline in FA reflects the multi-system nature of the disease whereby mitochondrial dysfunction, and associated chronic inflammation, affects not only the central nervous system but also the heart and possibly the kidney. In contrast to placebo, treatment with omaveloxolone improved eGFR in patients with FA and the effects were sustained through one year of treatment. The durability of eGFR improvements are consistent with those observed with its analog, bardoxolone methyl, in clinical trials for various forms of CKD.
Spinocerebellar ataxia type 6 (SCA6) is the most recently identified mutation causing autosomal-dominant cerebellar ataxia without retinal degeneration (ADCA). The SCA6 mutation is allelic with episodic ataxia type 2(EA-2), but the two differ clinically because of the presence of progressive, rather than episodic, ataxia in SCA6. SCA6 accounts for 12% of families with ADCA in an ethnically heterogeneous population of patients. Clinical examination, quantitative eye movement testing, and imaging data show that the brainstem is normal in most patients with SCA6, especially within the first 10 years of symptoms. Most patients show progressive ataxia from the onset, but several patients show an episodic course resembling EA-2. Thus, SCA6 mutations not only account for patients with ADCA I and ADCA III phenotypes but also for some patients presenting with episodic features that are typical for EA-2. Interestingly, a compound heterozygote for the SCA6 expansion manifested an earlier onset and more rapid course than family members with the same larger expanded allele.
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