Comorbid Medical Conditions in Friedreich Ataxia

Shinnick, Julianna; Schadt, Kimberly; Strawser, Cassandra; Wilcox, Nicholas S.; Perlman, Susan; Wilmot, George; Gómez, Christopher M.; Mathews, Katherine D.; Yoon, Grace; Zesiewicz, Theresa A.; Hoyle, Chad; Subramony, S. H.; Yiu, Eppie M; Delatycki, Martin B.; Brocht, Alicia; Farmer, Jennifer M.; Lynch, David R.

doi:10.1177/0883073816643408

Cited by 7 publications

(5 citation statements)

References 28 publications

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“…By seven months of age, 70% of male mice exhibited rectal prolapse. While intestinal impairments are not among the most debilitating symptoms in FRDA, clinical reports have shown that the prevalence of diseases such as Crohn's disease, ulcerative colitis, and irritable bowel syndrome is 2 to 3.6 times higher in FRDA patients compared to the non-FRDA population (Shinnick et al, 2016). In addition, it was reported that 64% of patients complain of bowel symptoms (Lad et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Anatomical and functional analysis of the corticospinal tract in an FRDA mouse model

Nishiyama,

Kalambogias,

Imai

et al. 2024

Preprint

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Friedreich’s ataxia (FRDA) is one of the most common hereditary ataxias. It is caused by a GAA repeat in the first intron of the FXN gene, which encodes an essential mitochondrial protein. Patients suffer from progressive motor dysfunction due to the degeneration of mechanoreceptive and proprioceptive neurons in dorsal root ganglia (DRG) and cerebellar dentate nucleus neurons, especially at early disease stages. Postmortem analyses of FRDA patients also indicate pathological changes in motor cortex including in the projection neurons that give rise to the cortical spinal tract (CST). Yet, it remains poorly understood how early in the disease cortical spinal neurons (CSNs) show these alterations, or whether CSN/CST pathology resembles the abnormalities observed in other tissues affected by FXN loss. To address these questions, we examined CSN driven motor behaviors and pathology in the YG8JR FRDA mouse model. We find that FRDA mice show impaired motor skills, exhibit significant reductions in CSN functional output, and, among other pathological changes, show abnormal mitochondrial distributions in CSN neurons and CST axonal tracts. Moreover, some of these alterations were observed as early as two months of age, suggesting that CSN/CST pathology may be an earlier event in FRDA disease than previously appreciated. These studies warrant a detailed mechanistic understanding of how FXN loss impacts CSN health and functionality.

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Section: Discussionmentioning

confidence: 99%

Anatomical and functional analysis of the corticospinal tract in an FRDA mouse model

Nishiyama,

Kalambogias,

Imai

et al. 2024

Preprint

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“…The FACOMS natural history study presents an opportunity for identification of suitable external control groups. The significant overlap in trial sites and investigators (some of whom helped develop FRDA standard of care guidelines) ensures a similar approach to overall patient management for FRDA and comorbid conditions 30,31 . In addition, at the time of the study, there were no approved or effective disease modifying therapies for FRDA, minimizing confounding in the comparison of groups from two different studies.…”

Section: Discussionmentioning

confidence: 99%

“…The significant overlap in trial sites and investigators (some of whom helped develop FRDA standard of care guidelines) ensures a similar approach to overall patient management for FRDA and comorbid conditions. 30 , 31 In addition, at the time of the study, there were no approved or effective disease modifying therapies for FRDA, minimizing confounding in the comparison of groups from two different studies. The overlap in trial sites and the reliance on the same investigator to provide training on mFARS assessments further contributed to consistency in methodology and scoring of mFARS in patients originating from both studies.…”

Section: Discussionmentioning

confidence: 99%

Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data

Lynch,

Goldsberry,

Rummey

et al. 2023

Ann Clin Transl Neurol

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ObjectiveThe natural history of Friedreich ataxia is being investigated in a multi‐center longitudinal study designated the Friedreich ataxia Clinical Outcome Measures Study (FACOMS). To understand the utility of this study in analysis of clinical trials, we performed a propensity‐matched comparison of data from the open‐label MOXIe extension (omaveloxolone) to that from FACOMS.MethodsMOXIe extension patients were matched to FACOMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline modified Friedreich Ataxia Rating scale (mFARS) score, and baseline gait score. The change from baseline in mFARS at Year 3 for the MOXIe extension patients compared to the matched FACOMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis.ResultsData from the MOXIe extension show that omaveloxolone provided persistent benefit over 3 years when compared to an untreated, matched cohort from FACOMS. At each year, in all analysis populations, patients in the MOXIe extension experienced a smaller change from baseline in mFARS score than matched FACOMS patients. In the primary pooled population (136 patients in each group) by Year 3, patients in the FACOMS matched set progressed 6.6 points whereas patients treated with omaveloxolone in MOXIe extension progressed 3 points (difference = −3.6; nominal p value = 0.0001).InterpretationThese results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity‐matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations.

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“…Within the FACOMS cohort in the United States, growth hormone deficiency and inflammatory bowel disease appear more common than expected among FRDA patients. 113 In addition, case reports suggest that nephrotic syndrome and Graves’ disease may be associated at other times. 113–116 Cancer does not seem to be an association of FRDA.…”

Section: Specific Care Aspectsmentioning

confidence: 99%

“… 113 In addition, case reports suggest that nephrotic syndrome and Graves’ disease may be associated at other times. 113–116 Cancer does not seem to be an association of FRDA. 117 , 118 Whether these represent true biological associations will be revealed over time.…”

Section: Specific Care Aspectsmentioning

confidence: 99%

Friedreich Ataxia: Multidisciplinary Clinical Care

Lynch¹,

Schadt²,

Kichula³

et al. 2021

JMDH

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Friedreich ataxia (FRDA) is a multisystem disorder affecting 1 in 50,000–100,000 person in the United States. Traditionally viewed as a neurodegenerative disease, FRDA patients also develop cardiomyopathy, scoliosis, diabetes and other manifestation. Although it usually presents in childhood, it continues throughout life, thus requiring expertise from both pediatric and adult subspecialist in order to provide optimal management. The phenotype of FRDA is unique, giving rise to specific loss of neuronal pathways, a unique form of cardiomyopathy with early hypertrophy and later fibrosis, and diabetes incorporating components of both type I and type II disease. Vision loss, hearing loss, urinary dysfunction and depression also occur in FRDA. Many agents are reaching Phase III trials; if successful, these will provide a variety of new treatments for FRDA that will require many specialists who are not familiar with FRDA to provide clinical therapy. This review provides a summary of the diverse manifestation of FRDA, existing symptomatic therapies, and approaches for integrative care for future therapy in FRDA.

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Comorbid Medical Conditions in Friedreich Ataxia

Cited by 7 publications

References 28 publications

Anatomical and functional analysis of the corticospinal tract in an FRDA mouse model

Anatomical and functional analysis of the corticospinal tract in an FRDA mouse model

Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data

Friedreich Ataxia: Multidisciplinary Clinical Care

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