Progression of Friedreich ataxia: quantitative characterization over 5 years

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ObjectiveFriedreich ataxia (FA) is a progressive neuromuscular disorder caused by GAA triplet repeat expansions or point mutations in the FXN gene. FA is associated with increased risk of diabetes mellitus (DM). This study assessed the age‐specific prevalence of FA‐associated DM and its impact on neurologic outcomes.Research Design and MethodsParticipants were 811 individuals with FA from 12 international sites in a prospective natural history study (FA Clinical Outcome Measures Study, FACOMS). Physical function was assessed, using validated instruments. Multivariable regression analyses examined the independent association of DM with outcomes.ResultsMean age of participants was 30.1 years (SD 15.3, range: 7–82), 50% were female, and 94% were non‐Hispanic white. 9% (42/459) of adults and 3% (10/352) of children had DM. Individuals with FA‐associated DM were older (P < 0.001), had longer GAA repeat length on the least affected FXN allele (P = 0.037), and more severe FA (P = 0.0001). Of individuals with DM, 65% (34/52) were taking insulin. Even after accounting statistically for both age and GAA repeat length, DM was independently associated with greater FA symptom burden (P = 0.010), reduced capacity to perform activities of daily living (P = 0.021), and a decrease of 0.33 SDs on a composite performance measure (95% CI: −0.56–0.11, P = 0.004); the relative impact of DM was most apparent in younger individuals.Conclusions DM‐associated FA has an independent adverse impact on well‐being in affected individuals, particularly at younger ages. In future, evidence‐based approaches for identification and management of FA‐related DM may improve both health and function.

Section: Methodsmentioning

confidence: 97%

“…811 individuals with FA were enrolled between 2004 and 2015, and re‐evaluated annually at 12 international sites 6. Information from the most recent visit was used in the present study.…”

Section: Methodsmentioning

confidence: 99%

“…Performance measures were also assessed, including: 25‐Foot Walk (T25FW),6, 9, 18 9‐Hole Peg Test (9HPT),6, 13 and Contrast Letter Acuity (vision score) 6, 9, 19…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impact of diabetes in the Friedreich ataxia clinical outcome measures study

McCormick

Farmer

Perlman

et al. 2017

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Selected missense mutations impair frataxin processing in Friedreich ataxia

Clark

Butler

Isaacs

et al. 2017

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ObjectiveFrataxin (FXN) is a highly conserved mitochondrial protein. Reduced FXN levels cause Friedreich ataxia, a recessive neurodegenerative disease. Typical patients carry GAA repeat expansions on both alleles, while a subgroup of patients carry a missense mutation on one allele and a GAA repeat expansion on the other. Here, we report that selected disease‐related FXN missense mutations impair FXN localization, interaction with mitochondria processing peptidase, and processing.MethodsImmunocytochemical studies and subcellular fractionation were performed to study FXN import into the mitochondria and examine the mechanism by which mutations impair FXN processing. Coimmunoprecipitation was performed to study the interaction between FXN and mitochondrial processing peptidase. A proteasome inhibitor was used to model traditional therapeutic strategies. In addition, clinical profiles of subjects with and without point mutations were compared in a large natural history study.Results FXNI 154F and FXNG 130V missense mutations decrease FXN 81–210 levels compared with FXNWT, FXNR 165C, and FXNW 155R, but do not block its association with mitochondria. FXNI 154F and FXNG 130V also impair FXN maturation and enhance the binding between FXN 42–210 and mitochondria processing peptidase. Furthermore, blocking proteosomal degradation does not increase FXN 81–210 levels. Additionally, impaired FXN processing also occurs in fibroblasts from patients with FXNG 130V. Finally, clinical data from patients with FXNG 130V and FXNI 154F mutations demonstrates a lower severity compared with other individuals with Friedreich ataxia.InterpretationThese data suggest that the effects on processing associated with FXNG 130V and FXNI 154F mutations lead to higher levels of partially processed FXN, which may contribute to the milder clinical phenotypes in these patients.

Measuring peripheral nerve involvement in Friedreich’s ataxia

Creigh

Mountain

Sowden

et al. 2019

Objective Experimental therapies under development for Friedreich’s Ataxia (FRDA) require validated biomarkers. In‐vivo reflectance confocal microscopy (RCM) of skin is a noninvasive way to quantify Meissner’s corpuscle (MC) density and has emerged as a sensitive measure of sensory polyneuropathies. We conducted a prospective, cross‐sectional study evaluating RCM of MCs and conventional peripheral nerve measures as candidate peripheral nerve markers in FRDA. Methods Sixteen individuals with FRDA and 16 age‐ and gender‐matched controls underwent RCM of MC density and morphology, skin biopsies for epidermal nerve fiber density (ENFD), nerve conduction studies (NCS), and quantitative sensory testing (QST) including touch, vibration, and cooling thresholds. Results MC densities were measurable in all participants with FRDA, and were lower at digit V (hand), thenar eminence, and arch (foot) compared to controls. By contrast, sensory NCS showed floor effects and were obtainable in only 13% of FRDA participants. QST thresholds for touch, vibration, and cooling were higher at the hand and foot in FRDA than controls. Reductions in ENFDs were present in more severely affected individuals with FRDA (Friedreich’s Ataxia Rating Scale (FARS) >60) compared to matched controls, although skin biopsies were not well tolerated in children. MC densities, ENFDs, and touch and vibration thresholds were associated with clinical disease severity (FARS and modified FARS) and duration since symptom onset. Interpretation MC density, ENFD, and QST thresholds provide structural and physiologic markers of sensory involvement in FRDA. Longitudinal evaluation is needed to determine whether these measures can identify changes associated with disease progression or treatment.