Friedreich’s ataxia

Summary

Friedreich’s ataxia is an autosomal recessive inherited multisystem disorder that has been in neurological awareness for more than 160 years. Its genetic basis was discovered in 1996, and since then considerable efforts have been made to elucidate the function of the product of the mutated FXN gene –⁠ frataxin. The goal is to find an optimal biological or gene therapy for this otherwise relentlessly progressive disease, which disables the carrier of the biallelic mutation within a few years of the disease onset. Currently, the first drug is available, approved specifically for Friedreich’s ataxia, while others are in various stages of clinical trials. This fact leads to a completely different view of the necessity of early diagnosis of the disease at the level of DNA analysis; it is necessary to revise the findings in patients with progressive ataxia in whom the molecular genetic diagnosis has not yet been performed, and to consider specifically the possibility of Friedreich’s ataxia also in patients with cardiomyopathy or progressive scoliosis. The article summarizes current knowledge about Friedreich’s ataxia, draws attention to the newly discovered symptoms of the disease, and provides insights into the metabolism of frataxin. In conclusion, the current directions of targeted treatment research are summarized.

Keywords:

diagnosis – Neuroanatomy – therapy – Friedreich’s ataxia – mitochondrial disease – frataxin

This is an unauthorised machine translation into English made using the DeepL Translate Pro translator. The editors do not guarantee that the content of the article corresponds fully to the original language version.

 

 

Introduction

Friedreich's ataxia (FA) is an autosomal recessively inherited disorder that causes progressive ataxia, dysarthria, impaired hemiplegia and vibratory sensation, as well as a number of other neurological or other somatic symptoms that may manifest during the course of the disease. However, it is not uncommon for scoliosis or cardiomyopathy to precede neurological manifestations [1]. Progression of the disease causes mobility impairment over years to decades, and the cause of death may be heart failure more often than in the general population, as well as severe diabetes mellitus or significant progression of neurological manifestations [2-7].

The disease was described by Nikolaus Friedreich in 1861. Its genetic basis (amplification of guanine adenine adenine [GAA] in intron 1 of the FXN gene located on the long arm of chromosome 9) was discovered 135 years later, in 1996 [8]. In recent years, great strides have been made in the study of the product of the affected gene, frataxin. This is a mitochondrial protein playing a role in mitochondrial Fe-S cluster biogenesis and thus secondarily in redox catalysis, lipid beta-oxidation, regulation of gene expression and DNA repair/replication [9-12].

 

Notes from history

Friedreich's ataxia is a disease known since 18 September 1861, when the German pathologist and neurologist Professor Nikolaus Friedreich presented the first six patients (a brother and sister from one family and four siblings from the other family -⁠ three sisters, one brother) with difficulties beginning around puberty at the Congress of German Naturalists and Physicians [13]. Initially, ataxia and dysarthria were predominant, and they gradually developed impaired hearing, muscle weakness, scoliosis, leg deformities, and some had cardiomyopathy. The symptoms of locomotor ataxia differed considerably from the cases described two years earlier under the same name as a separate entity by Duchenne [14]. The discussion regarding the content of the term "locomotor ataxia" continued for many years and involved many of the leading scientists and physicians of the time -⁠ e.g., Eisenmann, Hasse, Kussmaul, Virchow, Mobius, Grasset, Strumpel, Gowers, Charcot, etc. [15].

Friedreich followed his patients for 14 years, performing pathological and anatomical autopsies on four of them. He recognized axonal thinning of the dorsal spinal roots, described atrophy of the nuclei gracilis and small lesions of the fasciculi anterolaterales, degenerating fibers in the corpores restiformes. Based on his observations and investigations, he then published a total of five papers between 1863 and 1877, but the pivotal work was his last paper of 1877 and its postscript of the same year [16]. Over the years, he gradually crystallized a picture of a future independent nosological entity, but the then still far from developed neuroanatomical knowledge and limited investigative possibilities did not allow him to cover all aspects of the disease. Friedreich initially thought that this was the result of chronic spinal leptomeningitis, but it was not until 1876 that he considered the possibility of a hereditary disease on the basis of family history; however, he associated heredity only with the finding of abnormally thin trunk axons, which he considered to be an inborn pathology and a disposition to inflammatory spinal cord disease. The absence of tendon-muscle reflexes, described in 1875 by his pupil Wilhelm Heinrich Erb [17], had not yet been reported in early papers. Although Friedreich was very keen to improve the diagnosis and treatment of spinal cord disease and his papers contained detailed macroscopic and microscopic descriptions of the affected spinal structures, he had to face many opinions that this was not a new independent disease but most likely a case of lues or MS. It was not until 1882 that Augus Brousse et al. summarized the existing knowledge of the disease presented by Friedreich and emphasized that it was a separate entity, for which they proposed the name Friedreich's ataxia [18]. However, it did not take full hold until 1884, two years after Friedreich's death, when Charcot presented a young patient with hereditary ataxia during his lecture at the Salpêtrière and recognized that this was a special case of locomotor ataxia, which, although very similar to MS, was also very different -⁠ and he too called it Friedreich's ataxia [19].

During the following years, new findings on FA appeared sporadically. However, one cannot ignore the work of Harding in 1981, a very careful clinical study of 115 patients from 90 families, which already clearly confirmed autosomal recessive inheritance [17]. However, it was necessary to wait another 15 years to clarify the mutation. In 1996, Campuzano et al. published a groundbreaking paper in which they described an intron GAA repeat expansion in the X25 gene on chromosome 9 [8]. Nevertheless, it is interesting to note that according to MedLine publication data, only 39 papers on this topic were still published between 1993 and 2011 (over a period of 18 years); only since 2012 has interest in Friedreich's disease started to revive, and in the last 12 years MedLine has already searched 673 results for the keyword "Friedreich's ataxia".

Unlike many other ataxias, especially autosomal dominantly inherited ataxias, whose names have disappeared in the genetic era with the discovery of causal mutations, Friedreich's ataxia has persisted for more than 160 years; although it still defies our knowledge in some aspects, a concerted worldwide effort is now leading to targeted biological treatments, and gene therapy is also being intensively developed.

 

Prevalence

Friedreich's ataxia is a disease classified as rare, i.e. it affects less than 5 persons/10,000 inhabitants in the sense of internationally recognised agreement. The most commonly reported estimates of FA prevalence are between 2-4/100,000 population, although the primary sources of these calculations are often not explicitly stated [20]. This figure is well below the threshold set by orphan drug regulations in both Europe and the United States, although published data are probably burdened by some errors. One of them is the wider current clinical spectrum of molecularly diagnosed patients than the originally reported clinical criteria, which may lead to an underestimation of the number of patients diagnosed. The prevalence is also influenced by the attention given to the disease in a given population.

Friedreich's ataxia is the most common inherited ataxia, accounting for approximately 50% of all ataxia cases and approximately 75% in patients younger than 25 years [21]. A review of the prevalence of FA in European countries by Vankan et al. in 2013 revealed that the prevalence of FA in Europe shows large regional differences with a gradient of prevalence from west to east. The highest levels are observed in northern Spain, southern France and Ireland, and the lowest levels in Scandinavia [22]. In the Czech Republic, the current incidence is 1/200,000 inhabitants.

Worldwide, FA is more prevalent in the Caucasian population than in any other race, and the mutation is thought to have originated from a common European ancestor [23,22]. Its manifestation is found in patients originating from Europe, North Africa, the Middle East or India. In the USA, it occurs in Caucasians with an average prevalence of 3-4 per 100,000 cases [24-27]. Cases are very rarely observed in sub-Saharan Africa, China, Japan and Southeast Asia [20]. The frequency of FA carriers is estimated to be 1 in 75 people [27].

 

Pathophysiology

At present, FA is still classified by some authors as a neurodegenerative disease, although, as outlined above, it has been labelled a neurogenetic disease for many years, and in recent years, with new findings on the function of frataxin, a neurometabolic disease.

The basic problem is the relative lack of the FXN gene product, frataxin. At the outset, it should be noted that while all the physiological functions of frataxin and the consequences of its impaired metabolism help to elucidate the pathophysiology of FA, research is far from complete.

Depletion of frataxin is caused by mutation of FXN gene, which in 96% is caused by multiplication of GAA repeats on both alleles, in 4% point mutations or deletions of FXN gene on one of the alleles are involved in the pathology. All mutations cause a reduction (not absence!) of total functional frataxin levels.

To simplify, in a historical sequence, studies of cellular tissues and models first established that frataxin is involved in mitochondrial iron homeostasis [28], and only the continuation of this line of research turned attention to the decline of Fe-S cluster enzymes-both mitochondrial and extramitochondrial [28-33]. Fe-S clusters are found in the mitochondria, cytosol, endoplasmic reticulum and nucleus. They contribute to respiration, iron homeostasis, heme biosynthesis, oxidative phosphorylation, citric acid cycle, and DNA replication or repair as well as regulation of other pathways. For example, they are utilized by nuclear DNA polymerases and helicases [34-36], cytosolic enzymes such as RNase L Inhibitor 1 (RNase L Inhibitor 1; Rli1) and adenosine triphosphatase (ATPase) involved in protein synthesis [37], and mitochondrial enzymes, where they are cofactors of a number of enzymes with essential functions in ATP production or Krebs cycle functions [38-40].

Thus, any defect in their biosynthesis leads to numerous metabolic defects, including global mitochondrial dysfunction [29,41,42]. Energy production is affected, susceptibility to oxidative stress is increased [43], and there is also a secondary decrease in heme biosynthesis due to a defect in ferrochelatase [31,44-46]. This complex imbalance of activity leads to the generation of oxygen free radicals in both the mitochondrial matrix and the cytosol, resulting in glutathione depletion and increased lipid peroxidation [9].

In FA patients, oxidative stress has been suggested to result from the production of reactive oxygen species catalyzed by free iron accumulating in the mitochondria (Fenton reaction) and impaired oxidative stress signaling by the master regulator NRF2 (NF-E2 related factor; NF-E2 = nuclear factor erythroid 2), which allows reactive oxygen species to accumulate [11].

However, based on cellular models and in vivo studies, including studies of FA patients, it now appears that ferroptosis, one of the relatively newly discovered mechanisms of cell death, may play a major role in the pathogenesis of FA [47]. Ferroptosis is triggered by the accumulation of intracellular iron (not other metals) and lipid peroxidation. It is morphologically, biochemically and genetically distinct from apoptosis, necrosis and autophagy. In contrast to previously discovered types of cell death, transmission electron microscopy has shown that cells undergoing ferroptosis are characterized by structural changes with smaller mitochondria and increased mitochondrial membrane potential. The classical chromatin condensation typical of apoptosis or cell wall rupture observed in necrosis is absent [48]. The details of ferroptosis are still under investigation, but it is already known that during the last phase of the process, direct or indirect inactivation of phospholipid hydroperoxide glutathione peroxidase 4 (GPX4) causes the accumulation of peroxidized polyunsaturated fatty acids, ultimately leading to cell death [49]. Turchi et al. published a review article in 2020 addressing the typical markers of ferroptosis in FA and concluded that signs of iron-mediated cell death (increased production of lipid peroxides and subsequent increase in their derivative products, e.g. malondialdehyde) were confirmed in the plasma of FA patients. In addition, low glutathione levels and poor GPX activity, especially GPX4, were found in patients, also confirming the link between ferroptosis and FA pathophysiology [50].

In 2013 [51], the completion of the existing knowledge led to the conclusion that frataxin is not a general iron-binding storage protein (like ferritin), as it was assumed in the early research, but is directly involved in the biosynthesis of Fe-S clusters and the other pathologies found and briefly described above are a direct consequence of a defect in the biogenesis of this evolutionarily very old coenzyme [10,45,52-54].

Thus, the primary function of frataxin is to help form the Fe-S cluster and incorporate it into enzymes that require this prosthetic group [55,56]. The unique function of frataxin appears to be to accelerate the key step of sulfur transfer between the two components [57].

The primary site of Fe-S cluster biosynthesis is the mitochondria. This is a complex process that requires 17 other proteins. First, de novo formation of the Fe-S cluster on the skeletal protein takes place. It is then released from it and transiently bound to specific transport proteins that carry it to target apoproteins. A simplified view of the function of frataxin in Fe-S cluster formation is shown in Figure 1 (loosely based on [57]).

For the first step of iron-sulfur Fe-S biosynthesis (iron-sulfur cluster; ISC), a basic complex consisting of a cysteine desulfurase dimer (NFS1) is essential, with a scaphoid protein 2 (ISCU2) and a complex of two regulatory proteins, cysteine desulfurase activator (ISD11), mitochondrial matrix essential protein (MESP), and acyl carrier protein (ACP), bound to each dimer molecule [58,59].

The process of Fe-S complex formation further requires the participation in this first step of iron, free cysteine, the ferredoxin 2 (FDX2)-ferredoxin reductase (FDXR) complex, a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) donating electrons to the reaction to reduce sulfur from cysteine to sulfide, and frataxin. Frataxin mediates the conversion of cysteine to persulfide, and reduced ferredoxin 2 reduces persulfide to sulfide, allowing the formation of the Fe-S precursor on the scaphoid protein, after dimerization [2Fe-2S].

The second step is the transfer of the scaphod protein (U-type ISC protein member 2 [U-type ISC protein member 2; ISCU2]) with bound 2Fe-2S via chaperone stress proteins family A member 9 (HSPA9) and HSCB (heat-shock cognate B) to mitochondrial client proteins or acceptor proteins such as. glutaredoxin 5 (GLRX5) or A-type Fe-S cluster protein (A-type ISC protein; ISCA) and others.

The third step is the maturation of [2Fe-2S] to [4Fe-4S] clusters in mitochondria and subsequent delivery to mitochondrial client proteins.

The fourth, so far hypothesized, step is the export of an unknown precursor molecule (X) generated by Fe-S biosynthesis to the cytoplasm via the ABC transporter from ATP-binding cassette sub-family B member 7 (ABCB7) and other components. Finally, this precursor molecule is processed through the cytosolic iron-sulfur protein assembly (cytosolic iron-sulfur protein assembly; CIA) pathway to mature and deliver Fe-S to client proteins [60].

 

Clinical picture

Before the discovery of the molecular genetic basis of FA, a great emphasis was placed on the fulfilment of the so-called diagnostic criteria for the diagnosis. In 1976, Geoffroy et al. divided a group of 50 studied patients into four groups [61]:

Ia -⁠ typical FA with complete image:

                Obligatory criteria: onset of difficulties before the end of puberty and never after the age of 20, ataxia, progression of ataxia in the last 2 years without remission, dysarthria, impairment of semi-hotic and vibratory sensation in the lower limbs, weakening of muscle strength, tendon-muscle areflexia in the lower limbs;

    other common progressive symptoms, the presence of which is not necessary for the diagnosis: positive Babinski's sign, pes cavus, scoliosis, cardiomyopathy.

Ib -⁠ typical FA with incomplete picture: clinical picture and disease evolution identical to group Ia, but lacking pes cavus.

IIa -⁠ atypical FA: differs from group Ia by the slow progression of ataxia and a very mild degree of scoliosis.

IIb -⁠ other diseases.

 

As can be seen from today's perspective, the application of these criteria must necessarily have underestimated the number of patients, and this was no better a few years later, in 1981, when Harding published a large clinical study on 115 patients. All were progressive disease, and the age of onset of symptoms was less than 25 years (mean 10.5 years). The only constant symptoms in the first 5 years after presentation were trunk and limb ataxia and lower limb areflexia. Dysarthria, central motoneuron impairment, hemiplegia, and vibratory sensory impairment developed during life in all but not necessarily in the first 5 years. Scoliosis and cardiomyopathy were found in more than two-thirds of the patients. Pes cavus, distal amyotrophy, optic atrophy, nystagmus and deafness were less common. About 10% of the patients had diabetes mellitus -⁠ according to the results of the study, it was more frequently associated with the occurrence of optic atrophy and hearing impairment [17].

After finding the causative gene for FA [8], the clinical and molecular genetic findings could finally be compared. The first comprehensive and ground-breaking work in this field was published by Alexandra Durrova et al. in 1996. They analysed the DNA of 187 patients with disease onset between 2-51 years. Although only 103 patients in this cohort met Harding's clinical criteria, 140 patients had homozygous GAA repeat expansions. Thus, it appeared that about a quarter of the patients with typical mutations had atypical clinical findings -⁠ 19 patients had disease onset after the age of 25 years, 13 patients had prominent tendon-muscle reflexes, 4 of them even increased, 21 patients did not show positive Babinski's sign, and another 10 patients had DNA analysis performed even though they had not been followed up for the required 5 years and their clinical picture was incomplete [62].

In 1997, Ludger Schols' team [63] followed up with another cohort of 102 patients with progressive ataxia from 92 unrelated families. According to Harding's diagnostic criteria, there were 32 patients with a typical picture and 70 patients with an atypical phenotype -⁠ these were divided into three groups -⁠ 21 patients with early cerebellar ataxia, 34 patients with idiopathic cerebellar ataxia and 15 patients with multisystem atrophy. Interestingly, of the 32 patients with a clearly typical picture, a causative mutation in the FXN gene was found in only 27 of them. In contrast, despite the atypical clinical picture, the diagnosis was confirmed at the molecular genetic level in half of the atypical cases with early onset ataxia. Overall, FA was confirmed in 24% of atypical cases. Table 1 is also very useful from today's perspective on the indications for DNA analysis in patients with progressive ataxia and clearly shows that using only the typical symptoms according to Harding is not sufficient and results in a relatively large number of unrecorded positive FA patients. Some cumulative data of patients with verified FA in the Czech Republic are shown in the last column for comparison.

Durrova et al. [62] in 1996 clearly pointed out the necessity of monitoring and molecular genetic examination of patients with atypical course. Additional indication criteria for DNA analysis of the FXN gene in patients with progressive ataxia were artificially created with the aim of the highest yield of positive results. Of interest is the work of Filo et al. in 2000 [64], in which they compared the yield of the diagnostic criteria of Harding [17], the criteria used in the Quebec Cooperative study of Friedreich ataxia (QCSFA) [61] and the criteria used by Filo's group (Table 2).

The results showed that most patients can be captured using the Filla criteria (sensitivity 77%, predictive value 96%). The Harding QCSFA criteria have lower sensitivity (both 63%) and comparable predictive value (96/98%).

Currently, it is generally accepted that the onset of FA is most often between 10 and 15 years of age, but patients with onset between 1 and 2 years of age, but also in the 8th decade, have been described, so the age of onset is not a key diagnostic criterion.

The most frequent first neurological symptom is ataxic gait due to impaired proprioception, which the patient is usually not aware of at first, but sometimes he/she may report, for example, a feeling of vertigo at the top of stairs. The uncertainty is exacerbated when vision is disabled, so that some patients notice as the first symptom a disturbance in orientation when getting up at night. In neurological findings, this corresponds to a positive Romberg's sign, often with decreased tendon-muscle reflexes in the lower limbs and positive pyramidal irritation phenomena already in the early stages. Further progression of the disease is individual, and it is usually reported that dysarthria, weakness of the lower limbs, deterioration of hemiplegia, especially in the lower limbs, and impaired vibratory sensation are already evident within 5 years of the onset of the disease. This is the result of progressive degeneration of the dorsal root ganglia, posterior spinal cord fascicles, dorsal spinocerebellar pathway in combination with involvement of the pyramidal pathway and cerebellum. Affection of peripheral sensory and motor neurons leads to mixed axonal peripheral neuropathy. Pes cavus is common (55%) but usually does not cause significant problems for patients. More bothersome in the late stages of the disease is the progressive equinovarus or other deformities sometimes making standing and walking impossible [65,66]. Restless legs syndrome is common in individuals with FA; according to Frauscher, it affects 32-50% of individuals [67]. Scoliosis is present in approximately two-thirds of individuals with FA on clinical evaluation and in 100% on radiographic evaluation. Milbrandt's study found that 49 of 77 individuals with FA had scoliosis; ten were treated with a brace and 16 required spinal surgery [68]. Autonomic difficulties are more common in more advanced stages, with patients being particularly bothered by cold acral lower limbs with cyanosis; bradycardia is less common.

Speech and swallowing disorders are present to varying degrees in all patients with FA [69]. Dysarthria worsens as the disease progresses, speech slows down and the time the patient is able to speak decreases [70]. Mild dysphonia is sometimes observed [71]. Most patients report swallowing problems in more advanced stages due to orofacial discoordination [72].

    Sleep-disordered breathing and sleep apnoea are more common in patients with FA than in the healthy population. Corben found a 21% incidence of obstructive sleep apnea in patients with FA compared to approximately 5% incidence in the general population [73].

Patients with FA usually do not complain of visual impairment. Nevertheless, in about a quarter of patients optic nerve atrophy is confirmed on ophthalmological examination [74,75]. According to a 2009 study by Fortuna et al. it was found that only 19% of these patients had subjective difficulties [76,77]. Subclinical optic nerve atrophy can now be well verified by optical coherence tomography (OCT), which demonstrates a reduced average thickness of the peripapillary nerve fiber layer (retinal nerve fiber layer; RNFL) in most patients. Unlike optic neuropathies in other mitochondrial diseases, the papillomacular bundle is preserved in FA, leading to improved visual acuity. It appears that contrast sensitivity testing is more useful than visual acuity or perimeter testing for simple detection of subclinical optic neuropathy [78]. A summary of neuro-ophthalmic signs is shown in Figure 2.

    Cardiomyopathy, a heart disease, results from mitochondrial proliferation, loss of contractile proteins and subsequent development of myocardial fibrosis. It is demonstrable in more than two-thirds of patients with FA based on ancillary investigative methods. Concentric/asymmetric hypertrophy or dilatation of the left ventricular wall occurs, and dilated cardiomyopathy with arrhythmias is more frequently associated with mortality compared with hypertrophic cardiomyopathy [79]. A longitudinal study identified two groups; a "low risk" group (approximately 80%) with a normal ejection fraction that slowly declined and remained in the normal range, and a "high risk" group (approximately 20%) whose ejection fraction declined into the abnormal range and was associated with high mortality [80]. The "high-risk" group was associated with longer GAA expansions on the shorter allele, but not with disease duration or progression of the neurological picture. Electrocardiography (ECG) is overwhelmingly abnormal, with T-wave inversion, left axis deviation, and repolarization abnormalities observed most frequently [79].

Cardiomyopathy can manifest, even in severe form, before the onset of neurological symptoms [81,82]. Arrhythmias (especially atrial fibrillation) and congestive heart failure often occur in the later stages of the disease. Coronary artery disease may occur and should be considered in the setting of angina and/or sudden deterioration of cardiac function [5,83]. Heart transplantation is one of the options to improve quality of life and prolong life in patients with severe cardiomyopathy. Experience with long-term survival (5, 8 and 19 years) of FA patients after heart transplantation was published by McCormick et al. in 2017 [84]. In the Czech Republic, heart transplantation was performed in a patient with FA 16 years ago [85], at a time when heart failure was imminently life-threatening. At 3 months after transplantation, she was able to walk moderately atactically without support. Although the disease slowly progressed, she gave birth to a healthy son in 2017, and the pregnancy did not worsen her neurological findings or cardiac function. She currently has to use a wheelchair but is fully able to care for her son. Pregnancy generally does not worsen the condition of patients with FA, and there has been no increased incidence of spontaneous abortion or preterm birth, pre-eclampsia or cesarean delivery [86].

Diabetes mellitus in patients with FA is most likely due to defects in insulin action and/or reduced insulin secretion fromb pancreatic cells. It is likely that both of these mechanisms are involved in the pathogenesis, with the prerequisite of glucose intolerance beingb cell dysfunction due to mitochondrial dysfunction and endoplasmic reticulum stress [87,88]. It is not yet fully understood why only a proportion of patients with FA develop diabetes. The incidence of diabetes in FA has been reported to range from 6-19% [7], and in a 1968 paper by Hewer it was as high as 23% [89], while in the Czech Republic it was 5/44 (11%).

Other problems that FA patients complain about and that affect their quality of life are progressive hearing loss, urinary problems and, last but not least, cognitive problems.

Hearing impairment is usually presented by FA patients as a problem with communication in noisy environments or when more than one person is talking at the same time [90]. Hearing tests usually find normal middle ear and cochlear function, but pathology is detected at the level of the auditory nerve [91]. This is matched by histological findings of severe degeneration of the auditory and vestibular neurons [92]. The progression of hearing difficulties correlates with the overall progression of the disease [93].

Bladder symptoms, including urinary frequency and urgency, were reported quite frequently, approximately between 40-80% of individuals, and were rated as very bothersome by less than one-third of patients [94,95].

Patients with FA show significantly lower performance in certain cognitive domains compared to control participants, but surprisingly, these do not usually limit their social functioning. In the cohort of 44 Czech patients studied in detail, there are 11 patients with completed secondary education and 9 with university education. Naeije's meta-analysis of cognitive profiles from 18 papers published between 1950 and 2021 looked at patients' performance in attention/performance, language, memory, visual-spatial functions, emotions and social-cognitive performance. A total of 13 studies reported a significant association with disease severity, and six studies reported an association between cognitive performance and cerebellar changes [96]. It has been shown that motor and mental reaction times can be significantly prolonged in patients with FA [97,98], as well as motor planning is significantly impaired [99], and the ability to form concepts and visuospatial reasoning is impaired with reduced information processing speed [100]. Impaired inhibition and cognitive flexibility have also been demonstrated [101]. The results are consistent with a cerebellar role in the pathophysiology of FA cognitive impairment.

Only the possibility to diagnose FA with a tangible result of DNA analysis made it possible to find other patients with this disease, some of them with atypical features not fully meeting Harding's criteria.

The first distinguishing feature was the later onset of the disease, therefore the term late-onset FA (LOFA) was used for these atypical forms in patients with the manifestation of the first symptoms between 26-39 years, and very late-onset FA (VLOFA) for patients with the onset of the disease after 40 years. The oldest patient started having dysarthric difficulties at the age of 80 years [102].

It appears that later disease onset is usually correlated with the length of the shorter mutant allele [103,104].

Another atypical picture is FA with retained reflexes (Friedreich's ataxia with retained reflexes; FARR), usually for more than 10 years after the onset of the disease. The reflexes are usually well-acquired to increased, and sometimes clonus is evident. These patients tend to have a later age of onset of first symptoms and do not suffer from more severe cardiomyopathy or scoliosis [105,106].

Spastic paraparesis without more obvious signs of ataxia can also be a phenotypic variant of FA. Patients with symptom onset between 25-35 years of age whose expanded alleles contained between 131-156 repeats [107] or a compound heterozygote with a missense variant of p.Gly130Val [108] have been described. Investigations of other currently undetectable mutations directly in the FXN gene, as well as the search for variants in non-coding regions of the genome that might provide an explanation for the atypical pattern, are being intensively pursued [109].

The rate of progression of FA is variable. The average time from symptom onset to wheelchair dependence is ten years [110,111]. A number of studies have found that progression is faster in patients with earlier onset [95,112,113].

In a study conducted in the early 1980s, the mean age at death was 37 years [17]. In a more recent study, the mean and median ages at death were 36.5 and 30 years, respectively, and survival into the 6th and 7th decades was documented. The most common cause of death was cardiomyopathy (38/61), with the remainder (17/61) being non-cardiac (most commonly pneumonia) or unknown cause (6/61) [27,83].

 

Laboratory and neuroimaging diagnostic methods

The diagnosis of FA can only be made on the basis of molecular genetic testing. Although clinical picture and laboratory methods may help to speed up the application of genetic testing, they are currently of more research value in elucidating the detailed picture of FA for targeted treatment. On the other hand, the atactic patient should be comprehensively investigated in the initial phase to exclude, in particular, an acquired cause of the reported symptoms, as shown in Figure 3.

 

Laboratory methods

Genetic diagnostics

Friedreich's ataxia is an autosomal recessive disease caused exclusively by a mutation in the FXN gene, which leads to reduced levels of the functional protein frataxin. In 96% of patients with FA, the disease is caused by the expression of GAA repeats in the first intron of the FXN (X25) gene on both of its alleles, leading to a reduction in transcription of mRNA for frataxin to approximately 10% of normal levels [56]. The remaining 4% of patients are compound heterozygotes, where they have a GAA repeat expansion on one allele and either a point mutation or deletion of the FXN gene on the other allele, which also leads to reduced frataxin expression or altered function, usually resulting in a slightly different clinical picture.

Normal chromosomes carry 7-34 GAA repeats, whereas chromosomes from FA patients carry 66 to >1,700 triplets, which interfere with frataxin transcription to varying degrees. FA patients have been shown to have a 65-95% decrease in frataxin, whereas heterozygous carriers have about 50% of normal frataxin levels and are free of clinical symptoms [114].

In the remaining 4% of FA patients, a repeat mutation is typical on one allele, and the other mutation is a point mutation or deletion. Again, there is a lack of functional frataxin. A number of point mutations of the FXN gene have already been published with different effects on the clinical picture and disease course -⁠ Galea et al. divided a set of 111 compound heterozygotes into three subgroups based on the pathogenic non-expansion variant: (1) null variant (no frataxin is produced), (2) moderate/severe effect on frataxin function, and (3) minimal effect on frataxin function [115]. Compared with patients with biallelic GAA expansion, subgroup 1 had earlier onset and higher incidence of diabetes mellitus but minimal cardiac symptoms. A study by Greeley et al. found a nearly tenfold increase in diabetes mellitus in compound heterozygotes compared with the classic biallelic repeat form [116].

Residual frataxin levels are determined by the size of the GAA repeat of the smaller of the two alleles. The size of the minor GAA expansion is statistically correlated with age at disease onset, severity of neurological symptoms, and cardiomyopathy [117].

Research shows that dynamic mutation, i.e. the multiplication of GAA repeats, can change when passed from parents to offspring. Lengthening of the expanded alleles can occur during transmission from the mother, but usually not more than 200 GAAs, because longer alleles tend to contract. In paternal transmission, shortening of the extended stretch may also occur. Somatic instability in FA probably begins after early embryonic development and continues throughout life [118]. Interestingly, repeat numbers in fibroblasts tend to regress, whereas in lymphocytes, root ganglia and cerebellum, numbers increase with age, correlating with the progression of neurological symptoms with age [119].

Practical note: If FA is suspected, any physician can send 4 ml of blood in K3EDTA (tri-potassium salts of ethylenediaminetetraacetic acid) together with the application form to the genetic laboratory of the Institute of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University in Prague, Úval 84/1, 150 06 Prague 5.

 

Electrodiagnostic findings

In the time before the causative mutation was found, electrophysiological studies were widely used to refine the diagnosis, but it turned out that these findings were non-specific and could not be used as a basis for the diagnosis.

In FA, both large and small neurons of the posterior spinal ganglia are primarily damaged [120]. It is thought to be a developmental hypoplasia rather than degeneration, but research is not yet complete [121]. Failure of trophic support results in a lack of myelinated nerve fibers in the dorsal roots and peripheral sensory nerves as well as in the posterior spinal cord ganglia [15,122]. The classic finding of hypo -⁠ to areflexia of the tendon-muscle reflexes is attributed to a disruption of the centripetal portion of the reflex arc, but some electromyographic findings do not exclude a mild involvement of the anterior horns of the spinal cord as well, which may lead to chronic denervation [15,123]. Nerve conduction velocity studies in FA usually show motor nerve conduction velocities greater than 40 m/s with reduced or absent sensory nerve action potential with absent H reflex [124,125]. In patients in whom central responses could also be recorded during SEP, conduction velocity was usually slightly alternated to the brainstem level, but a clear reduction was evident from the brainstem to the cortex [125,126].

Also, the duration of central motor conduction during transcranial magnetic stimulation (motor evoked potential; MEP) is prolonged and worsens with disease progression, which corresponds with the findings on MRI -⁠ see below. Based on more recent studies involving children, some MEP abnormalities may precede clinical manifestations [127,128].

Similarly, examination of brainstem auditory evoked potentials (BAEP) shows clearly pathological but non-specific changes [129,130]. In FA, both basic mechanisms by which neural activity in the auditory brainstem is disrupted have been demonstrated -⁠ a reduction in the number of activated auditory nerve fibres (deafferentation) and a reduction in the degree of neural synchrony (dyssynchrony) [131].

Recently, there has been a renewed focus on optic pathway examination [75,77,131], because with more advanced methods, both thinning of the retinal nerve fiber layer and fibers in the optic nerve can be verified. This correlates with both electroretinogram findings and visual evoked potentials [76].

 

Imaging methods

In contrast to electrophysiological methods, the constantly improving neuroimaging techniques are now an important aid -⁠ although also not in the diagnosis of the disease, but in the discovery of a more comprehensive knowledge of the involvement of the nervous system in this disease [133,134].

 

Morphology imaging

Magnetic resonance imaging was used in the diagnosis of FA before genetic testing was available [133,135,136]. A consistent finding was thinning of the cervical spinal cord [137]. Atrophy of the cerebellum and brainstem was more variable, but in more recent studies, images clearly confirm degeneration of the superior cerebellar peduncles [138] containing most of the efferent fibers of the nuclei dentati. Hypointensity of the nuclei dentati on T2-weighted images (iron-related) may be a potential biomarker of FA at high magnetic field strength [139].

In particular, diffusion weighted imaging (DWI) is useful for quantifying the extent of neurodegeneration, assessing the molecular function and microarchitecture of neural tissue, which according to recent studies is probably more affected than previously described [140].

A detailed summary of neuroimaging findings in FA can be found in a 2018 paper by Luisa Selvadurai et al [134]. The histologically detected spinal cord changes in terms of thinning and anterior flattening due to atrophy of the ascending dorsal pathways (fasciculus gracilis and cuneatus) and spinocerebellar tract along with the descending corticospinal tract were also confirmed in vivo by MRI studies. The pathology of the ascending system appears to arise from transsynaptic anterograde atrophy due to primary pathology in the dorsal root ganglia. This disrupts the transmission of information about deep sensing, vibration and proprioception to the cerebellum and cerebral cortex [141,142]. Corticospinal tract involvement results from reduced numbers of Betz cells in the motor cortex, atrophy of the corticospinal decussation in the medullary pyramids [15], and loss of axons and myelin in the spinal tract with a maximum in the thoracic spinal cord [143]. Involvement of the tractus corticospinalis causes decreased muscle strength and hyperreflexia, later superimposed by peripheral motoneuron involvement in FA [143,144].

Quantitative studies revealing abnormalities in iron redistribution in addition to atrophy are another typical finding on MRI that confirms the histological findings of shrunken nuclei dentati with loss of large neurons [145,146]. In addition, white matter reduction has been confirmed not only in the cerebellum, but also in the cerebrum and structures connecting the brain to the lower brain [135,148]. The most pronounced changes were found in the spinocerebellar, cerebelo-thalamo-cerebral pathways and the radiatio optica. Interesting, although logical given the ubiquitous need for frataxin in all mitochondria, are the findings of damaged frontooccipital fasciculi [149] as well as the corpus callosum [150,151]. However, these are still pilot findings that need to be refined due to the inhomogeneity of the cohorts studied -⁠ especially in the number of GAA repeats and the progression of the disease.

Other work [152] has found functional and structural changes in the gray matter of the brain and spinal cord [153] of FA patients, both in the cortex and subcortical gray matter. While the structural changes relate to brain cell loss, functional imaging shows both an increase and decrease in brain activation. These changes are diffuse, not yet allowing a specific pattern to be found for use in disease detection or progression [134]. One of the most recent studies addressing this issue [154] followed patients aged 11-26 years for 3 years, approximately 1.5-9 years after the onset of the disease. Using a multimodal imaging protocol, macrostructural changes in the brain were found in terms of lower white but not grey matter volume. Microstructural changes were confirmed mainly in the pyramidal pathway and cerebellum. The changes gradually progressed to atrophy of the entire cerebellum, the superior cerebellar peduncle, the posterior arm of the capsula interna and the superior portion of the corona radiata. It seems that these data could already be useful as biomarkers in clinical trials or the introduction of new drugs.

Various hypotheses have been proposed to explain these new findings -⁠ one of them is the idea that the changes found are the result of neurodevelopmental changes embedded prenatally. It is based on the idea that the complete absence of frataxin leads to embryonic death [155], and thus the lack of frataxin during intrauterine development affects neurodevelopment. In this context, then, we might view the above changes as hypoplasias rather than atrophies [120] or directly as a complicated system of hypoplastic and reactive regenerative changes.

 

Metabolic function imaging

Advances in the study of metabolism and in imaging techniques are leading to more detailed imaging not only of morphology but also of the biochemical processes occurring in tissues. In the case of FA, we are particularly interested in mitochondrial metabolism. Current technologies are not yet able to detect ATP production directly, but other markers are already available -⁠ e.g. pyruvate, lactate, glutamate, gammaaminobutyric acid (GABA) [156]. Magnetic resonance spectroscopy (MRS) can quantify myoinositol and N-acetylaspartate (NAA) as a quantifier of pathological changes in vivo even before cell bodies die [56]. The rate and changes in iron concentration can also be quantified -⁠ particularly yielding changes in the nucleus dentatus cerebelli, where atrophy with low iron levels was confirmed in the early stages of the disease, followed by iron accumulation in the later stages, but with an already stable nuclear volume [157]. However, the atrophy of the cerebellar structure in advance of iron accumulation suggests that iron deposition is a late consequence of the genetic defect and therefore the use of this as a biomarker is questionable.

However, these methods are not crucial for the diagnosis; their optimization and the search for further details of metabolism are being worked on, mainly to find reliable markers of the efficacy of the targeted treatment being introduced and/or to find new treatments to restore frataxin levels [111,158,159].

 

Treatment

The basic treatment has been symptomatic treatment, i.e. an attempt to influence the progressive clinical symptoms of FA as described in the previous text. Although the first targeted pharmacological treatment is now available, it is obviously necessary to continue symptomatic therapy in parallel.

Multidisciplinary care is essential, i.e. regular monitoring and treatment of difficulties by a neurologist, cardiologist, orthopaedic surgeon, physiotherapist, speech therapist, occupational therapist, psychologist, possibly a psychiatrist and, in the case of the development of diabetes, a diabetologist. According to other difficulties, an ophthalmologist, urologist, otolaryngologist are involved in the treatment.

Opinions on rehabilitation [160-163] are unanimous in the sense that it is the most effective method to date with virtually no side effects, slowing the progression of the disease, preserving mobility and self-sufficiency for as long as possible, and improving the mood and general well-being of patients. However, it depends on the intensity and regularity of the exercise and professional supervision is essential. The minimum length of intensive residential rehabilitation is 4 weeks, while at least 6-week rehabilitation cycles are better evaluated. In this context, both objective and subjective barriers to longer rehabilitation stays should be noted. Milne's 2018 study commendably highlights the pitfalls that may prevent a patient from undergoing rehabilitation -⁠ e.g., distance to a specialist facility, travel costs, work and family situation [162]. To this must be added the patient's current psychological state and their fears of self-care in unfamiliar surroundings.

The exercise program should primarily include procedures to affect cerebellar and spinal symptoms to improve daily independent functioning, reduce fatigue and pain, protect against muscle weakness, osteoporosis, joint contractures and reduce the risk of falls. Increased patient fatigability must be taken into account when designing a rehabilitation programme. More frequent but shorter exercise units are more effective. The main focus is on influencing both supporting and targeting motor skills, improving motor coordination, training at the taxa and influencing intrinsic tremor. The Vojt method is suitable for stabilizing trunk stability as a prerequisite for goal-directed movement, followed by training of phasic limb movements. Exercises according to Frenkel (exercises to re-educate normal movements of patients with ataxia) and Feldenkrais (training of slow repetitive targeted movements) are mainly chosen. In patients with spinal deformities, in addition to the Vojta method, exercises according to Klapp and Schrott are included and respiratory physiotherapy is performed. Cardiac conditioning exercises should be prescribed and monitored with respect to the patient's underlying cardiac disease. From a certain degree of disability onwards, it is necessary to apply aids to improve the patient's stability -⁠ canes, crutches, walkers. This should be done on a strictly individual basis; due to ataxia, single-point support may paradoxically cause a deterioration in stability in some patients. Speech therapy is an integral part of this, with efforts to influence cerebellar saccadic explosive speech as well as dysphagia, and occupational therapy, aiming to make the patient's self-sufficiency and management of activities of daily living as good as possible [163].

 

Advances in pharmacological therapy

At the same time as progress in the study of pathophysiological processes caused by frataxin deficiency, a number of substances affecting both the function of the mitochondrial respiratory chain and inhibiting the production of free radicals have been tested [164].

One promising drug was idebenone, a synthetic analogue of coenzyme Q10. Many studies have been performed [165-168], but they have not clearly confirmed either clinical improvement or myocardial pathology. Similarly unsuccessful were studies with carnitine [169,170], which improves the penetration of fatty acids into the mitochondria, or deferiprone [171,172], an iron-lowering drug. Studies of a number of other drugs (amantadine, interferon gamma, histone deacetylase inhibitors, insulin/insulin-like growth factor 1, etc.) have been generally inconclusive, either because of small numbers of patients or little/no improvement in clinical status. They are summarized in a 2016 review by Tanya Aranca et al [21].

Figure 4 highlights the continuously updated Friedreich's Ataxia Research Alliance (FARA) website, focusing on current activities aimed at finding a cure for FA.

A number of studies are currently underway to optimize metabolism impaired by frataxin deficiency as an essential agent for the formation of Fe-S clusters required in many other mitochondrial and cytoplasmic reactions:

Improving mitochondrial function and reducing oxidative stress

Omaveloxolone -⁠ a small molecule that activates the transcription of the NRF2 gene, which regulates the production of antioxidant and anti-inflammatory proteins. So far, it is the only drug approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) [174, 175].

Vatiquinone, alpha-tocotrienol quinone (international nonproprietary name for EPI-743 Edison Pharmaceuticals/BioElectron [Mountain View, CA, USA]), an orally bioavailable molecule being developed for inherited metabolic mitochondrial diseases. Through NADPH quinone oxidoreductase 1 (NQO1), it enhances the synthesis of glutathione, a compound essential for the control of oxidative stress [176]. It follows a study with EPI-A0001, aa -tocopheryl quinone [6]. Its purpose is to improve mitochondrial and cellular function through the enzyme 15-lipoxygenase affecting ferroptosis.

 

    Modulation of frataxin-controlled metabolic pathways

Leriglitazone (PPAR-g or PPARG; peroxisome proliferator-activated receptor gamma) is a selective peroxisome proliferator-activated receptor gamma agonist that crosses the blood-brain barrier and improves mitochondrial function and energy production in preclinical models [177].

Dimethyl fumarate and its active metabolite monomethyl fumarate lead to amelioration and reduction of the extent of myelin and neuronal damage, through the nuclear factor NRF2 pathway [178].

 

Increasing the availability of frataxin -⁠ frataxin stabilizers or increasing its levels

CTI-1601 -⁠ a recombinant fusion protein designed to deliver human frataxin into the mitochondria of FA patients. A drug designed to increase frataxin levels in patients with FA. The goal is to replace the missing frataxin by delivering a synthetic version of frataxin with carriers that allow first entry into cells and then entry into mitochondria [179].

Etravirine -⁠ a non-nucleoside reverse transcriptase inhibitor, approved in many countries as a treatment for human immunodeficiency virus (HIV) infection. Tested for its potential ability to potentiate the translation process that converts mRNA to frataxin, thereby increasing its levels in cells [180].

 

Increase in FXN gene expression

DT-216P2, a small molecule designed to specifically target GAA repeat multiplication in the FXN gene, unblock the transcriptional apparatus and restore production of functional frataxin mRNA [181].

 

Gene therapy

Gene therapy is the expected treatment. Attempts to remove GAA repeats have already been made using CRISPR technology in mice. In some heart and liver cells, the excess number was successfully removed, but the efficiency was low and did not sufficiently increase frataxin in the heart [182]. However, another study in 2023 in a mouse model and in non-human primates showed that expression of frataxin from intravenously administered adeno-associated virus (AAV) can sufficiently increase the amount of frataxin to treat cardiac symptoms associated with the disease [183]. However, it should also be considered that overexpression of frataxin is toxic and should be carefully controlled [184]. An overview of the efforts to date and the limitations in the introduction of gene therapy are reviewed in a 2022 article by Sivakumar and Cherqui [185].

 

In conclusion of this chapter, it is worth mentioning the internationally discussed scales analysing the severity and progression of cerebellar symptoms and other manifestations of both FA and other ataxic diseases. In general, these examinations are above standard, disproportionately burdensome for the examiner in normal practice, but in the field of research and in the era of expectation of various targeted drugs, they are the only way to quantify the natural course of the disease and the effectiveness of treatment. In 2006, the simpler clinical Scale for the Assessment and Rating of Ataxia (SARA) was proposed as an alternative to the most widely used but extensive scale, The International Cooperative Ataxia Rating Scale (ICARS) [186]. It is based on a functional assessment of eight items assessing gait, standing, sitting, speech (dysarthria), fine motor skills of the hands (target pursuit test and finger-nose taxis), diadochokinesis and lower limb taxis (heel-knee, shin slide). The final score ranges from 0 (no ataxia) to 40 (very severe ataxia). The validity of the scale has been and is being studied in a number of papers, one of the most recent being an article published in 2023 by the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) [187]. Another scale that is currently being discussed in conjunction with monitoring the outcomes of innovative FA therapies is the Friedreich's Ataxia Rating Scale/modified FARS (FARS/mFARS). This is an examination that assesses in detail autonomic dysfunction in addition to postural and static stability, upper and lower limb coordination, speech function, sensation (peripheral neuropathy), and upper and lower limb muscle strength [188]. Due to its laboriousness and significantly higher time requirements, it is mainly used in clinical trials, not to test already established drugs or other treatments. Because the validity and comparability of scaling results between different patient populations for all tests is strongly influenced by the experience of the investigator, training at a facility that has long been involved in this field is advisable before the actual investigation.

 

Conclusion

Motto: "Details have been added or changed, and some of the physiological interpretations proposed by Friedreich are no longer tenable, but the main clinical and pathological observations and ideas are sound and enduring." [189]

 

Friedreich's ataxia is an autosomal recessively inherited disease that all neurologists have known for more than a century and a half, yet they have been unable to help patients. Interestingly, the basis of knowledge about this disease was known from the beginning thanks to Friedreich's studies and gradually crystallized into a picture of a disease that, although primarily affecting the nervous system, also negatively affects other organ systems.

Advances at all levels of knowledge are now leading to a number of attempts to mitigate the progression, and eventually to a real cure at the level of gene therapy. However, as the partial findings summarised in the previous article suggest, there are still many unresolved biochemical and molecular genetic processes awaiting further discovery.

 

List of abbreviations

AAV -⁠ adeno-associated virus

ABCB7 -⁠ ABC transporter from ATP-binding cassette sub-family B member 7

ACP -⁠ acyl carrier protein

ATP -⁠ adenosine triphosphate

CIA -⁠ cytosolic iron-sulfur assembly protein

EMA -⁠ European Medicines Agency

EFACTS -⁠ European Friedreich's Ataxia Consortium for Translational Studies

FA -⁠ Friedreich's ataxia

FARA -⁠ Friedreich's Ataxia Research Alliance

FARR -⁠ FA with retained reflexes (Friedreich's ataxia with retained reflexes)

FARS/mFARS -⁠ Friedreich's Ataxia Rating Scale / modified FARS

FDA -⁠ Food and Drug Administration

FDX2 -⁠ ferredoxin 2

FDXR -⁠ ferredoxin reductase

Fe-S -⁠ a grouping of iron and sulphur required for the function of many enzymes

FXN -⁠ name of the gene encoding the frataxin protein

GAA -⁠ guanine adenine adenine triplet

GABA -⁠ gammaaminobutyric acid

GLRX5 -⁠ glutaredoxin 5

GPX -⁠ glutathione peroxidase

GPX4 -⁠ glutathione peroxidase 4

HIV -⁠ human immunodeficiency virus

HSCB -⁠ heat-shock cognate B

HSPA9 -⁠ heat-shock protein family A member 9

ICARS -⁠ The International Cooperative Ataxia Rating Scale

ISC -⁠ iron-sulfur cluster

ISCA -⁠ A-type ISC protein

ISCU2 -⁠ U-type ISC protein member 2

ISD11 -⁠ cysteine desulfurase activator; essential mitochondrial matrix protein

K3EDTA -⁠ tri-potassium salt of ethylenediaminetetraacetic acid

LOFA -⁠ late-onset FA

MRS -⁠ magnetic resonance spectroscopy

NAA -⁠ N-acetylaspartate

NADPH -⁠ reduced form of nicotinamide adenine dinucleotide phosphate

NF-E2 -⁠ nuclear factor erythroid 2 (nuclear factor erythroid 2)

NFS1 -⁠ cysteine desulfurase

NQO1 -⁠ quinone oxidoreductase 1

NRF2 -⁠ gene regulating the production of antioxidant and anti-inflammatory proteins

NRF2 -⁠ NF-E2 related factor (NF-E2 related factor)

OCT -⁠ optical coherence tomography

PPAR-g = PPARG -⁠ peroxisome proliferator-activated receptor gamma

Rli1 -⁠ RNase L inhibitor 1 (RNase L inhibitor 1)

RNFL -⁠ retinal nerve fiber layer

SARA -⁠ Scale for the Assessment and Rating of Ataxia

VLOFA -⁠ very late-onset FA

X25 -⁠ previously used name of the gene encoding the frataxin protein

 

Financial support

UK Grant Agency; Project No. 226423: Prospective follow-up of patients with Friedreich's ataxia in the Czech Republic including longitudinal evaluation of serum neurofilament levels to assess disease progression. 2023-2026.

 

Conflict of interest

The authors have no conflict of interest in relation to this mini-monograph.

 

Table 1. Correlation of Friedreich's ataxia genotype/phenotype (loosely based on [63]).

Clinical signs	Clinical diagnosis/genetic diagnosis
	typical FA/ confirmed FA number 29	atypical FA/ confirmed FA number 9	typical FA/ unconfirmed FA number 3	atypical FA/ unconfirmed FA number 61	CZECH REPUBLIC Confirmed by FA number 44
beginning 25 years ago	29/29	7/9	3/3	14/61	41/44
atactic gait	29/29	9/9	3/3	61/61	44/44
ataxia of the limbs	29/29	9/9	3/3	61/61	44/44
Dysarthria	29/29	9/9	3/3	53/61	41/44
lower limb areflexion	29/29	3/9	3/3	10/61	35/44
axonal sensory neuropathy	19/19	8/8	2/2	15/20	N
Babinski's positive symptom	29/29	7/9	3/3	25/61	40/44
reduction of vibration sensing (less than 6/8)	25/27	5/9	3/3	33/50	40/44
atrophy of optics	0/12	1/9	0/3	2/9	34/44 (according to OCT)
reduced visual acuity	2/23	0/9	0/3	1/15	9/44
nystagmus	10/27	4/9	3/3	26/42	17/44
square wave jerks	21/26	3/9	0/3	0/33	36/44
vestibulo-ocular reflex	11/26	4/9	1/2	19/28
hearing impairment	9/19	2/9	0/3	7/41	8/44
Dysphagia	20/26	5/7	0/3	24/43	31/44
weakening of dorsal leg flexion	21/26	3/9	3/3	9/42	33/44
amyotrophy (leg muscles)	13/21	2/9	3/3	10/41	19/44
Incontinence	4/26	0/8	0/3	19/41	22/44
Scoliosis	23/24	4/8	1/3	3/38	38/44
foot deformities	25/29	6/9	2/3	12/40	33/44
diabetes	0/26	2/9	0/3	1/21	4/44
T-wave inversion on ECG	23/26	6/9	0/3	0/23	N
hypertrophic non-obstructive cardiomyopathy according to ECG	19/24	5/8	0/3	0/10	28/44
ECG or ECHO abnormalities	26/27	6/9	0/3	0/25	30/44
extended central motor lead to MEP	7/7	5/5	0/2	1/14	N
cervical spinal cord atrophy according to MRI	10/10	6/9	1/2	1/15	N
cerebellar atrophy according to MRI	5/10	3/9	2/2	11/15	N

in red: essential diagnostic criteria according to Harding (1981) [17],

grey column: cumulative data of patients with verified Friedreich's ataxia in the Czech Republic for indicative comparison

FA, Friedreich's ataxia; ECG, electrocardiography; ECHO, echocardiography; MEP, motor evoked potentials; N, not specified; OCT, optical coherence tomography

 

 

Table 2. Comparison of the yield of diagnostic criteria for Friedreich's ataxia (loosely based on [64]).

Quebec study Friedreich's ataxia (1976) [61]	Harding (1981) [17]	Filla et al. (1996) [117]
beginning before the 20th year	beginning 25 years ago	beginning before the 20th year
progressive ataxia	progressive ataxia	progressive ataxia
lower limb areflexion	lower limb areflexion	lower limb areflexion
		one of the following:   Dysarthria Babinski's positive symptom left ventricular hypertrophy
Dysarthria	dysarthria after 5 years
Weakness	Babinski's positive symptom
reduced vibration sensitivity	reduced or absent sensory action potential