Topic 1.5. Early diagnosis of Friedreich ataxia
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
1.5 Early diagnosis of Friedreich ataxia
1.5.1 Background
1.5.2 Clinical picture
1.5.3 Laboratory studies
1.5.4 Disorders that share features with Friedreich ataxia in childhood
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.
1.5 Early diagnosis of Friedreich ataxia
Sub H. Subramony and Katherine Mathews
1.5.1 Background
There is concern that there is excessive delay in confirmation of the diagnosis of FRDA after symptom onset. This will be important as definitive therapies for FRDA become available, since earlier initiation of treatment may produce better results. The path to diagnosis for these patients likely varies by geography and by presenting signs or symptoms. In the case of the typical patient with childhood onset, often the journey begins with complaints about motor difficulties addressed to the primary pediatrician and then referral to other specialists, either neurologists or orthopedic surgeons. Alternatively, many individuals with FRDA are found to have scoliosis before onset of neurological symptoms and are referred to orthopedics. Thus, pediatricians, orthopedic surgeons and pediatric neurologists need to be familiar with FRDA as a possible diagnosis in children who have motor difficulties or spinal deformities.
Experience in Europe has detailed the problems with early diagnosis of rare diseases in general (49, 50). The EFACTS consortium assessed the time to diagnosis in their cohort of 619 FRDA individuals, with 3.3% being compound heterozygotes (51). The median time to diagnosis was 3 years with an inter-quartile range of 1-7 years. Cases diagnosed before 1996 (when gene testing became available) had a median delay of 4 years and this was reduced to a median of 2 years in those seen after 1996. Those with non-neurological onset had greater delay in diagnosis than those with neurological onset (median of 5 years compared to 3 years). Similarly, a FARA (Friedreich Ataxia Research Alliance) survey primarily among US patients (poster presented at the IARC meeting 2018, n=2579) found the mean time between symptom onset and diagnosis ranged from 2.4 years in children diagnosed below age 10 years; 3.9 years for patients aged 10 to 19 years; and 8.1 years for those aged 20 or above. The patients had often seen several health care providers before the correct diagnosis was made, with the common misdiagnoses being Charcot-Marie-Tooth disease (CMT), cerebral palsy, multiple sclerosis, “cerebellar abnormality” and inner ear disease.
1.5.2 Clinical picture
Prior to the availability of genetic testing, clinical diagnostic criteria for FRDA were developed by investigators from Canada and the UK (9, 10). Initial criteria had high positive predictive value (>90%) but low sensitivity (63%) (12). A more liberal set of criteria improved the sensitivity to 77% (52) (see Table 1.2).
It should be noted that despite a genetic etiology, most FRDA patients will not have a family history of FRDA because of the autosomal recessive inheritance pattern. With large sibships or in inbred populations, it is more likely the family history will include another affected family member.
Table 1.2 Diagnostic criteria for Friedreich ataxia
| Geoffroy et al. (9) | Harding (10) | Filla et al. (52) |
| Onset < 20 years | Onset < 25 years | Onset < 20 years |
| Progressive ataxia | Progressive ataxia | Progressive ataxia |
| Lower limb areflexia | Lower limb areflexia | Lower limb areflexia |
| Decreased vibration sense | Dysarthria after 5 years | One of the following:
Dysarthria, Babinski, LVH |
| Weakness | Small/absent sensory nerve action potentials (SAPs) | |
| Dysarthria |
Neurological onset
Symptoms
The majority of people with FRDA present with a neurological complaint; this was found in 90.7% of the large European cohort (51).
The mean age at onset for typical FRDA has been reported to range from 10.5 ± 7.4 years to 15.5 ± 8.0 years (9-11, 53, 54). In Harding’s study, 40% had onset before 10 years of age and 10% before 5 years and onset can occur as early as 2 years of age (10, 54). Some authors note a bimodal peak for age at onset, one just below 10 and then 12 to 15 (54, 55) but Harding observed a single peak at 10-12 years (10). Late onset (onset after 25 years) has been observed in 6% to 14% of genetically diagnosed FRDA and in 17% of the large EFACTS cohort (11, 12, 15, 51). Exact age at onset may be difficult to determine because parents may report that the child was always “clumsy” and earliest signs and symptoms can be non-specific.
A progressive gait unsteadiness is the usual complaint at the onset in over 84% of cases (10, 11, 15, 54). Motor milestones are not delayed. Complaints can range from gait unsteadiness to “clumsiness” and tripping, falls, and poor hand function (9, 10). Other features that can bring the child to attention include a decline in athletic performance and an inability to keep up with peers in motor skills such as bike riding. Dysarthria, tremor and vertigo and “asthenia” are the initial complaints in some individuals (51, 54). An unsteady stance and fidgety body movements to stand in place can result in a misdiagnosis of chorea (55-58).
Progression of symptoms is slow and may be missed over short periods of time. Harding criteria suggest progression over 2 years that is unremitting (10).
Signs
The discussion below is based on some of the larger FRDA clinical series and personal observations of the authors. It should be noted that the prevalence of various signs may not reflect early disease because the publications referred to patients assessed in various stages of the disease, with a mean duration ranging from 3.7 to 22 years.
Cerebellar signs and ataxia
Children with FRDA appear to lose the ability to stand on one foot, or tandem stance or stand with feet together with eyes closed very early in the process (59). Thus, in studies of the natural history of FRDA, these abilities were lost in almost all patients by the time they were seen at their initial visits. Gait becomes somewhat broad based and clumsy and there is an associated decline in the ability to run and jump. Many children appear to be fidgety (the term “static ataxia” was used by Friedreich for this sign and it may have a resemblance to chorea). In large clinical series gait ataxia was universal, characterized by a broadening inter-foot distance observed during stance and gait; lower limb ataxia is also nearly universal and is detected by the heel to shin slide revealing a side to slide oscillation of the heel on the shin bone.
Truncal and upper limb ataxia, as detected using the finger to nose test, rapid alternating movements and finger chase test, develop later in the disease.
Other clinical signs that indicate cerebellar disease include abnormal eye movements and dysarthria. Dysarthria may not become universal until after 10 years from onset (10) and was evident in only 60% by 5 years after onset. Nystagmus, the best-known feature of cerebellar dysfunction, may occur only in a minority of FRDA patients (10, 11, 52, 54, 55), but jerky pursuit, dysmetric saccades and fixation instability are more common. In studies done prior to molecular testing, a pattern of increased fixation instability, inaccurate saccades and impaired smooth pursuit with normal saccade velocity were reported (60-62). Fixation instability is characterized by easily visible, to and fro oscillations of the eyes during attempted fixation on a stationary object (square wave jerks).
Peripheral nerve signs and “neuropathy”
At an early stage in the disease, there is evidence for peripheral sensory nerve dysfunction (primarily proprioception) that contributes to the gait ataxia. Lower limb areflexia (often with areflexia in the arms as well) occurs within 5 years of onset in over 85% of cases (10, 11, 15, 52, 54). Sense of vibration is impaired in 69% to 93% of cases (10, 11, 15, 52, 54). Position sense can be lost even when vibration sense is preserved, but is not universal even 10 years after onset.
Muscle weakness
Muscle weakness occurs relatively late in FRDA (10, 11, 15, 54, 63). Harding (10) noted “pyramidal” weakness almost universally 10 to 15 years after onset, but in a substantial number even before that. The weakness is diffuse and different in pattern from that seen in muscular dystrophies. It is accompanied by ataxic difficulties in the leg and does not give rise to classical signs of weakness seen in muscular dystrophies, such as the Gowers maneuver.
Preserved neurological function
Cognition is preserved and there is no learning disability.
Non-neurological onset
Fewer than 10% of patients with FRDA have a non-neurological symptom at onset (10, 51, 63). Scoliosis is the most common non-neurological presentation followed by cardiomyopathy. Even when patients seek attention primarily for neurological symptoms, many may have a history of scoliosis detected by past screening examinations. Given that up to 5% of children have idiopathic scoliosis (64), the question of when a pediatrician or orthopedic surgeon should look more closely for a neuromuscular disorder is difficult to answer (65, 66). Some elements of a neurological examination (Table 1.3) should be included in the evaluation of children with scoliosis and any progression of motor disability should prompt neurological consultations. Also, FRDA gene tests should be strongly considered with early onset cardiomyopathy, despite two recent reviews of hypertrophic cardiomyopathy making no mention of FRDA (67, 68). Given that the FRDA repeat expansion cannot be detected by genetic sequencing, it should be kept in mind in children with suspected genetic cardiomyopathy.
Table 1.3 Early diagnosis of Friedreich ataxia: helpful clinical and laboratory features
|
Late onset Friedreich ataxia
Individuals with onset at ages above 25 or even after age 40 (very late onset) usually have neurological signs similar to those seen with classical onset FRDA, but atypical features such as prominent spasticity and lack of significant sensory neuronopathy are more common (69-73). Systemic features such as cardiomyopathy, skeletal deformities and diabetes tend not to occur. Thus, FRDA should be considered in an individual with adult onset progressive ataxia if a clear autosomal dominant history is not evident.
1.5.3 Laboratory studies
Brain MRI and spinal cord MRIs are typically normal in FRDA. While some earlier series reported cerebellar atrophy, most recent data suggest that significant cerebellar atrophy in the clinical context is not a feature of FRDA, though quantitative measures may detect subtle changes (74, 75). Volumetric data can also suggest spinal cord atrophy but this can be difficult to detect in clinical scans.
Electromyographic studies typically reveal a “pure sensory” neuropathy with loss or diminished amplitudes of sensory nerve action potentials in a generalized fashion, striking in children because they typically have very robust responses compared to adults (76). Motor nerve studies are normal, but most importantly, do not reveal conduction velocities in the “demyelinating” range (typically lower than 38 to 40 meters/sec in the upper limbs).
Over 70% of people with FRDA have subtle and non-specific ECG abnormalities such as ST segment changes and T wave inversion. Echocardiogram may show a hypertrophic cardiomyopathy.
Genetic testing for FRDA is the preferred diagnostic test. It is important to note that the GAA expansion leading to FRDA cannot be detected by next generation sequencing technology. Testing for the FRDA repeat expansion is included in some commercial genetic testing panels for ataxia. While over 96% of people with FRDA have a homozygous GAA expansion, about 3% to 4% have only one allele with the expansion, and the other has a conventional mutation. Thus, anyone with ataxia who has one expanded allele should have the other allele sequenced.
For more details, see section 1.2: Genetics and pathophysiology of FRDA, and Chapter 11: Genetic issues in Friedreich ataxia.
1.5.4 Disorders that share features with Friedreich ataxia in childhood
The number of disorders that lead to gait and motor difficulties in childhood is large. Thus, rarer disorders such as FRDA may not figure prominently in the differential diagnosis when a primary care physician or orthopedic surgeon evaluates these children. Such disorders range from cerebral palsy (CP), including so called “ataxic CP”, spinal dysraphic states and many neurological disorders, including spinal cord disorders, CMT, and other inherited ataxias (77). Another common motor impairment in children has been labeled developmental coordination disorder (DCD) (78).
Inherited neuropathies such as CMT constitute a significant misdiagnosis in FRDA. Findings of imbalance resembling gait ataxia can occur in CMT. When CMT is combined with tremor (Roussy Levy syndrome) it can superficially resemble FRDA (10). Most CMT is dominantly inherited but variable penetrance may lead to misleading family history and sporadic cases can occur with recessive forms or spontaneous mutations. CMT type 1 leads to severe slowing motor nerve velocities and such a finding will exclude FRDA, as noted above.
CP typically causes symptoms before 2 years of age and delay in motor and cognitive skill development occurs very early in life. In addition, the deficits are stable and static with no regression. Spasticity is common. However, deficits related to an early static dysfunction in the brain may show some changes related to body growth and maturation of neurological function as a child grows.
DCD is characterized by impairment of motor coordination unrelated to intellectual disability and other recognized neurological disorders (78). These children usually come to medical attention before 10 years of age but the range is from 5-18 years of age, thus overlapping the age of onset of FRDA. The symptoms may involve fine movements or gross movements and either improve or persist unchanged into adult life. Common symptoms include problems with writing, drawing, dressing, pouring a drink and participation in outdoor activities.
Numerous other disorders can cause ataxic and non-ataxic motor difficulties in childhood but the distinct phenotype of FRDA should allow for easy distinction.
Professor, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Email: katherine-mathews@uiowa.edu
Sub H. Subramony, MD
Professor of Neurology and Pediatrics, University of Florida College of Medicine, Gainesville, Florida, USA
Email: s.subramony@neurology.ufl.edu
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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.
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.
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.