Introduction

Friedreich ataxia (FRDA), the most common of the hereditary ataxias, is an autosomal recessive, multisystem disorder affecting approximately 1 in 29,000 individuals and has a carrier frequency of 1 in 85 in individuals of Caucasian background [1],[2]. The hallmark neurological features of FRDA include progressive afferent and cerebellar ataxia, dysarthria, fixation instability, impaired vibration sense and proprioception, and pyramidal weakness. Most affected individuals have absent lower limb reflexes, but some have retained reflexes and may have spasticity. Scoliosis, diabetes, foot deformity and cardiomyopathy are common non-neurological features [3]-[5]. Pathology related to FRDA includes degeneration of the dorsal root ganglia and posterior columns of the spinal cord, spinocerebellar tracts, corticospinal tracts, dentate nuclei of the cerebellum and the heart [6],[7]. FRDA is due to mutations in FXN [8]. In about 96% of mutant alleles there is homozygosity for a pathological expansion of a GAA trinucleotide repeat in intron one of FXN whilst in the other 4% there is compound heterozygosity for an intron 1 GAA repeat expansion in one allele and a point mutation or deletion in the other [8]-[10]. The GAA expansion results in a reduction of frataxin, a mitochondrial membrane protein involved in iron sulfur protein production, storage and transport [11],[12]. Since the discovery of the molecular basis underlying this disorder in 1996, there has been an abundance of studies exploring the nature of the mutation, the role of frataxin, disease progression and disease modifying agents [11],[13]-[15]. Although no specific therapies have been identified that can alter the course of this devastating disease, a number of promising compounds have been identified [11],[16]. However the challenge for clinicians to provide effective, evidence-based clinical management for the multifaceted issues facing people with FRDA endures.

In 2003, “Revalidatie Geneeskundige Richtlijn Ataxie van Friedreich” was written by a special task force under the auspices of ‘Vereniging Spierziekten Nederland’. These were the first guidelines that provided an evidence base to the clinical management of people with FRDA. These guidelines were subsequently updated and adapted for international use in September 2007 (http://www.vsn.nl/hulpverleners/protocol_detail.php?protocol_id=17). In 2009, Ataxia UK launched “Management of ataxia: towards best clinical practice”, developed to provide recommendations for the management of people with inherited ataxia, including FRDA (http://www.ataxia.org.uk/pages/resources-and-publications.html). Whilst this further initiative was welcomed, it was apparent that issues specific to FRDA required disease specific guidelines. Furthermore, it was apparent that the multiple gaps in evidence surrounding service delivery may provide a platform for ongoing research.

Method

Assembling the Executive Committee and Specialist Working Groups

An executive committee (MBD, DL, MP, JBS and LAC) was convened to oversee the process of guideline development. Clinicians with expertise in FRDA were recruited to contribute to the guidelines through invitations from the executive. Thirty-nine individuals participated in the writing of these guidelines. This group advanced the topics and corresponding clinical questions which would be the foundation of the guidelines. Specialist working groups (SWGs) related to specific topics were established. There were two face-to-face meetings during the guideline development phase that were attended by some of the 39 authors, otherwise communication was facilitated by teleconference and email. Each member of the SWGs was asked to formally declare any potential conflict of interest however none were present that required removal of any individual from the writing groups.

Developing topics and clinical questions

An initial topic list was developed by MBD and LAC. This list was refined by discussion with the executive and the SWGs (see Table 1 for the final topic list). The specific topics within the guidelines comprised a description of the topic, associated natural history, investigations, an evaluation of the evidence and graded recommendations. Where possible, clinical review questions were developed around the PICO framework (patients/population, intervention, comparison and outcome) [17] which formed the basis of the examination of available evidence.

Table 1 List of topics included in the clinical management guidelines
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Literature search and evaluation of the literature

A literature review was conducted for each topic. Clinical databases included in the search were PubMed, MEDLINE, CINAHL, Best Practice, Cochrane Database of Systematic Reviews, EMBASE and Scopus. Guideline SWGs evaluated the available evidence according to the templates developed by the Guidelines International Network (http://www.g-i-n.net/) for diagnostic and intervention studies.

Grading of evidence and recommendations

A range of international methods of grading of evidence and recommendations were reviewed. These included those recommended by the American Academy of Neurology (AAN) (USA), Scottish Intercollegiate Guidelines Network (SIGN), National Institute of Health and Clinical Excellence (NICE) (UK) and the National Health and Medical Research Council (NHMRC) Australia. Given no one method was identified as clearly superior, the evidence and subsequent recommendations were graded according to the criteria developed by the NHMRC [18] (see Table 2 for levels of evidence and Table 3 for grading of recommendations). In order to indicate the strength of the body of evidence underscoring the recommendation and to ascertain if application of the evidence may result in improved health outcomes, recommendations were allocated a grading (A-D) according to the level of evidence (I to IV) available. Recommendations allocated Grade A were underpinned by a body of evidence that can be trusted to guide practice. Grade B recommendations included those for which a body of evidence can be trusted to guide practice in most situations. Grade C recommendations comprised those for which the body of evidence provides some support but care should be taken in its application, whereas an allocation of Grade D indicated the body of evidence underlying the recommendation is weak and must be applied with caution [18]. Where no clear Level I, II III or IV evidence was available but where there was sufficient consensus within the specialist working group, good practice points (GPP) were provided. A GPP is the recommended best practice based on clinical experience and the expert opinion of the SWG. SWGs were encouraged to consult widely with colleagues and peers to ensure consistency of evidence. Every effort was made to achieve consensus within the group. However for the sections on Dysarthria and Dysphagia, the recommendations were sent to the executive group for a final independent decision. On one occasion (Genetic testing of asymptomatic minors) no consensus was reached and both viewpoints are presented. Draft iterations of the guidelines were circulated to all authors involved in producing the guidelines for comment and feedback. The final draft was sent to advocacy groups representing individuals with FRDA.

Table 2 Levels of evidence and grading of recommendations (National Health and Medical Research Council 1999 [19])
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Table 3 National Health and Medical Research Council grading of evidence for recommendations [18]
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Results

The guidelines comprise 9 sections and 25 subsections (see Table 1). There are 146 recommendations related to 1) the neurological components of FRDA; 2) the heart, cardiovascular and respiratory system; 3) scoliosis; 4) diabetes mellitus; 5) genetic issues; 6) FRDA due to FXN compound heterozygosity; 7) pregnancy issues; 8) quality of life issues. There were three recommendations graded as A, six graded as B, 28 graded as C, 17 graded as D and 92 GPP. The full guidelines are available on the internet (http://www.curefa.org/physicians.html). The following provides a summation of the recommendations from each topic (Table 4).

Table 4 The neurological components of Friedreich ataxia
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Conclusion

The molecular basis of Friedreich ataxia was established in 1996 [8]. The time since this pivotal discovery has seen an explosion in the understanding of the underlying mutation and the pathogenesis of the condition, the phenotype and potential pharmacological interventions. Despite this surge of information, significant gaps remain in understanding the best clinical interventions for people with FRDA. In the absence of treatments that lessen the impact of the condition, it is crucial that appropriate clinical intervention is explored and documented. This paper has reported the methodology and outcome of developing clinical management guidelines for people with FRDA. In so doing it has highlighted the disparate nature of FRDA requiring considerable depth and breadth in terms of clinical management expertise.

The principle purpose of clinical management guidelines is to provide “systematically developed statements to assist the practitioner and the patient to make decisions about appropriate health care for specific clinical circumstances” [75]. In addition clinical management guidelines play a significant role in identifying the gaps in the evidence and providing direction for ongoing high-quality studies that will underpin future iterations of the guidelines. Sixty-two percent of recommendations are based on expert opinion or good practice. For example areas such as the management of diabetes mellitus in FRDA, the complexity of genetic issues associated with symptomatic and presymptomatic testing, sexual function and quality of life have little evidence to reliably inform recommendations. In addition, areas such as the management of heart issues, dysarthria, dysphagia and scoliosis have low quality evidence guiding intervention. Whilst the development of these guidelines provides a critical first step in the provision of appropriate clinical care for people with FRDA, it also highlights the urgency of undertaking high-quality clinical studies that will ensure the delivery of optimum intervention for people with FRDA. These guidelines will be reviewed every three years and it is hoped subsequent iterations will rely less on expert opinion and more on high quality clinical studies.