Topic 1.1. Clinical Features of Friedreich ataxia - Clinical Management Guidelines for Friedreich Ataxia

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This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.

Topic Contents

1.1 Clinical features of Friedreich ataxia
1.1.1 Symptom onset and presenting symptoms
1.1.2 Diagnostic criteria
1.1.3 Incidence and progression of clinical features

Disclaimer / Intended Use / Funding

Disclaimer
The Clinical Management Guidelines for Friedreich ataxia (‘Guidelines’) are protected by copyright owned by the authors who contributed to their development or said authors’ assignees.

These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.

Guidelines users must seek out the most recent information that might supersede the diagnostic and treatment recommendations contained within these Guidelines and consider local variations in clinical settings, funding and resources that may impact on the implementation of the recommendations set out in these Guidelines.

The authors of these Guidelines disclaim all liability for the accuracy or completeness of the Guidelines, and disclaim all warranties, express or implied to their incorrect use.

Intended Use
These Guidelines are made available as general information only and do not constitute medical advice. These Guidelines are intended to assist qualified healthcare professionals make informed treatment decisions about the care of individuals with Friedreich ataxia. They are not intended as a sole source of guidance in managing issues related to Friedreich ataxia. Rather, they are designed to assist clinicians by providing an evidence-based framework for decision-making.

These Guidelines are not intended to replace clinical judgment and other approaches to diagnosing and managing problems associated with Friedreich ataxia which may be appropriate in specific circumstances. Ultimately, healthcare professionals must make their own treatment decisions on a case-by-case basis, after consultation with their patients, using their clinical judgment, knowledge and expertise.
Guidelines users must not edit or modify the Guidelines in any way – including removing any branding, acknowledgement, authorship or copyright notice.

Funding
The authors of this document gratefully acknowledge the support of the Friedreich Ataxia Research Alliance (FARA). The views and opinions expressed in the Guidelines are solely those of the authors and do not necessarily reflect the official policy or position of FARA.

1.1 Clinical features of Friedreich ataxia

Antoine Duquette and Ludger Schöls

1.1.1 Symptom onset and presenting symptoms

The disease which came to be known as Friedreich ataxia (FRDA) (1) was first described by the German pathologist Nikolaus Friedreich in a series of five papers published between 1863 and 1877 (2-6). At the time, Friedreich described a new hereditary spinal disease associated with kyphoscoliosis and fatty degeneration of the heart. The disease is most often caused by a pathogenic expansion in the first intron of the frataxin gene (7) and the size of the expansion influences the clinical presentation. Typically, the disease begins in early adolescence with gait instability (8). Scoliosis may also be the initial symptom, especially in patients with a younger age of onset (8).

1.1.2 Diagnostic criteria

The first set of diagnostic criteria for FRDA were proposed by Geoffroy and colleagues in 1976 (9). Seven primary signs and symptoms were considered obligatory for diagnosis: onset before the end of puberty and never after the age of 20; ataxia of gait; progression of ataxia within the last two years; dysarthria; decrease of joint position and/or vibration sense in lower limbs; muscle weakness; and deep tendon areflexia in the lower limbs. Four clinical features were considered secondary, but not obligatory for diagnosis: extensor plantar response; pes cavus; scoliosis; and cardiomyopathy. These criteria, however, proved to be difficult to use in younger individuals in whom some of the features deemed to be obligatory, such as muscle weakness and sensory loss, would develop later. To overcome this challenge, Anita Harding proposed a new set of criteria (10). Obligatory criteria included an onset of symptoms before the age of 25, progressive unremitting ataxia of the limbs and gait, as well as absence of the knee and ankle jerks. Dysarthria and extensor plantar responses were considered important secondary criteria.

While diagnostic criteria have been critical to guide research and clinical care, they restricted the expected presentation of individuals with FRDA. The identification of the genetic basis of the disease (7) has led to a significant expansion of clinical phenotypes associated with FRDA. The limitations of the criteria rapidly became apparent as genetically confirmed individuals had onset after the age of 25 or with retained tendon reflexes (11, 12). In fact, the phenotype of late-onset FRDA is often predominantly spasticity with very little ataxia (13).

1.1.3 Incidence and progression of clinical features

Neurological signs and symptoms

In longitudinal studies, the neurological symptoms progress over time. Loss of ambulation obviously has a significant impact on independence and quality of life. For individuals with disease onset before the age of 15, loss of ambulation occurs on average 11.5 years after disease onset with the sequential loss of stance with feet apart and eyes closed, followed by stance with feet together and, finally, normal stance (14). Dysarthria is a nearly universal feature in FRDA (11, 12, 15) and spectral measures can detect changes in speech over time (16). The prevalence and frequency of ocular square-wave jerks increases over time, but this rarely translates into functional impairment (17). Overall, using the Friedreich Ataxia Rating Scale (FARS), the disease seems to progress faster in younger individuals (18). While disease progression may indeed slow down with time, this could also reflect the limitations of clinical scales currently in use.

Neurogenic bladder

Lower urinary tract symptoms, including hesitancy, retention, urgency, and incontinence, have been reported in 59% to 82% of individuals with FRDA (19, 20).

Orthopedic involvement

In cohorts with genetically confirmed FRDA, between 60% and 84% have scoliosis (11, 12, 15, 21). Pes cavus, which is slightly less frequent, is also observed in a majority of individuals with FRDA (11, 12, 15, 21).

Cardiac involvement and diabetes mellitus

Heart involvement in FRDA has been described by Nikolaus Friedreich in his original series of publications and cardiac disease is recognized as the most common cause of mortality in FRDA (22). In fact, in addition to GAA repeat length, left ventricular mass index and left ventricular ejection fraction are independent predictors of mortality (23). ECG abnormalities such as T-wave inversions are found in 83% of individuals with FRDA (12). While 78.6% of people with FRDA exhibit normal left ventricular function, ejection fraction declines slowly over time even if it remains within the normal range (23).

Diabetes mellitus is another significant issue associated with FRDA and often requires insulin therapy; prevalence has been estimated to be between 8% and 32% (11, 12, 15).

Visual impairment and hearing loss

While clinically significant visual loss is reported in a minority of people with FRDA, anterior and posterior visual pathway involvement is nearly universal (24). Hearing loss is also increased in FRDA relative to the general population, and abnormal speech perception has been described in up to 90% of people with FRDA (25).

Antoine Duquette, MD, MSc, FRCP(C)
Associate Clinical Professor, Centre hospitalier de l’Université de Montréal, Montréal, Québec, Canada
Email: antoine.duquette@umontreal.ca

Ludger Schöls, MD
Professor of Neurology, Eberhard-Karls University, Tübingen, Germany
Email: Ludger.Schoels@uni-tuebingen.de

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It is our expectation that going forward individual topics can be updated in real-time in response to new evidence versus a re-evaluation and update of all topics simultaneously.