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Response from Tushar Vidhale, MD (Dated: July 8th, 2022)
Respected Editor and Dr. Pulst,
Thank you for your interest in our case. We agree with your comment that Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by bi-allelic expansion of an intronic GAA repeat in the frataxin (FXN) gene, but our patient had eight GAA repeats on allele-1 and 37 repeats (pre-mutated allele) on allele-2. The pre-mutated allele can be responsible for the disease, in
rare cases, by causing somatic expansion or pre-mutation in cell populations. But this occurs only when in the setting of the second allele in the clear pathogenic range of expansion. This intronic GAA expansion further silences the FXN gene, resulting in pathologically suppressed levels of the frataxin protein. As per the respected reader, even though the patient had the probability of compound
heterozygous mutation with a pathogenic point mutation in one allele, the second allele would not be pathogenic at 37 GAA repeats.
Usually, individuals with ataxia who are heterozygous for an expanded GAA repeat (> 66) may contain a separate loss-of-function mutation in the FXN gene copy over the allele with normal GAA repeat length. In the relevant clinical context, these patients should be considered to have Friedreich ataxia.  However, in populations where the prevalence of Friedreich ataxia carriers is high, such an individual may have a different disorder respon...
Usually, individuals with ataxia who are heterozygous for an expanded GAA repeat (> 66) may contain a separate loss-of-function mutation in the FXN gene copy over the allele with normal GAA repeat length. In the relevant clinical context, these patients should be considered to have Friedreich ataxia.  However, in populations where the prevalence of Friedreich ataxia carriers is high, such an individual may have a different disorder responsible for ataxia apart from being a carrier for Friedreich ataxia.  Nevertheless, investigators should look for an FXN loss-of-function mutation in heterozygosity with the GAA repeat expansion whenever possible, both by sequencing the FXN coding exons and the adjoining intronic sequences and by gene-dosage determination to rule out significant deletions.  These types of facilities are only available in the research faculties which are not available in our case, the same has been accepted as a limitation of our case. Sharma P et al. studied the carrier frequency estimation in a sample of 790 healthy study subjects across India. They reported the prevalence of “carrier state” to be 0.63% i.e. 5 in 790. They reported an approximately 19% prevalence of long-normal alleles (>12 alleles) with the longest repeats being 28.  The estimated prevalence of FRDA is 1/1,00,000 based on carrier frequency in the Indian population.  We believe that due to the low prevalence of Friedreich ataxia carriers in India, we should investigate for mutations on other alleles even in heterozygous pre-mutated states, where FRDA has a high clinical likelihood. Even so, Sharma P et al. and the paper by Mukerji M et al. lack the data on the frequency of permutated alleles in the Indian population. [2,3] This underlines the lack of data on pre-mutated alleles in India. A study by Sharma R et al. shows that somatic instability of borderline alleles, which are not generally thought to cause disease, imparts a risk for clinical disease development.  Individual somatic cells in different organs may have dramatically varying allele sizes, implying that traditional DNA testing may be insufficient for phenotypic prediction in persons with borderline alleles.  In FRDA, the allele size at the lower end of the pathogenic allele range is not clearly entrenched. Although the actual frequency of borderline alleles has not been determined, they account for less than 1% of FXN alleles. As per Cook A et al. “In terms of genetics of FRDA, till date important clarifications still need to be made, particularly with regards to the specific
chromatin modifiers responsible for silencing the FXN gene and the extent of this heterochromatization, and the epigenetic basis of FRDA”.  As more and more literature is published, FRDA is being studied and reported as an gene silencing disorder with epigenetic basis. 
In our case, clinical presentation along with radiological investigations pointed us towards the possibility of the FRDA despite the borderline pre-mutated heterozygous state. We already accepted the limitation in our case was the inability to perform the full genome sequencing or exome sequencing which could have predicted the point mutation or deletion.
In our case, we barely aggravated any of our findings (radiological and clinical), and a most likely diagnosis of FRDA was considered. Nowhere, we tried to manipulate or exaggerate our findings. During the care of this patient, we took opinions from our neurology department, but we did not mention them in the acknowledgment as they were not involved in the writing of the case report. Furthermore, a patient hospitalized in an internal medicine department is routinely checked and advised by the neurology department at our tertiary care hospital.
As per the respected reader, interpretation of genetic tests needs subspecialty expertise provided by medical geneticists, genetic counselors, or neurogeneticists. However, these kinds of facilities are not available at our institute, and the case was managed in resource-limited settings.
According to the esteemed reader, errors of overinterpreting genetic test results and, even more so, erroneous interpretation can be harmful to patients and their relatives. In the present clinical setting, we tried to explain the intricacies of genetic tests to the patient and their relatives. We explained the disease's degenerative nature and the clinical likelihood of the FRDA. However, in the absence of a thorough genetic workup, we left this to the patient's next of kin, whether or not to further go for a workup. Clinically his next of kin (his son) was normal. We believe that, from an ethical point of view, as a physician, we managed the patient with the best of our abilities, clinical acumen, and available resources.
In our settings, it is not always possible to contact a neurogeneticist or other such professional due to the relative non - availability of such practitioners or the patient's inability to pay for such services (here in this case the annual income of the patient was below USD 1250 [no insurance]). Though we have a neurology department, it is not possible to do NCS testing (most of the time machines are in a non-working state), or many facilities are yet unavailable. With great efforts, we were able to convince the relatives for the costly triplet primed PCR assay. For even making an MRI or any radiological scan, the patient’s affordability is an issue that we felt at every stage of treatment. In India (or any other Low-middle income country), such types of cases are handled by Internal medicine physicians (internists) primarily with neurological opinions from neurology consultants, which has happened in our case. These other factors must also be considered in the context of this case report.
We don't want to rule out completely the possibility that this might be a pre-mutated carrier state of FRDA; neither we want to mislead the scientific community. Irrespective of the genetics and diagnosis, the diagnostic dilemma we faced, and the clinical course of the patient are indeed was interesting and worth reporting. We already have accepted our limitations in the published version that we did not have access to advanced investigations required to certainly diagnose these kinds of borderline cases.
The reader is a renowned neurogeneticist and neurologist, as well as considering his vast experience in the said field, we will be more than happy to connect, discuss and collaborate with the esteemed professor on this topic.
1 Schulz JB, Boesch S, Bürk K, et al. Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol 2009;5:222–34. doi:10.1038/nrneurol.2009.26
2 Sharma P, Sonakar AK, Tyagi N, et al. Genetics of Ataxias in Indian Population: A Collative Insight from a Common Genetic Screening Tool. Genet Genomics Next 2022;3:n/a.doi:10.1002/ggn2.202100078
3 Mukerji M, Choudhry S, Saleem Q, et al. Molecular analysis of Friedreich’s ataxia locus in the Indian population: Friedreich’s ataxia in India. Acta Neurol Scand 2000;102:227–9.doi:10.1034/j.1600-0404.2000.102004227.x
4 Sharma R, De Biase I, Gómez M, et al. Friedreich ataxia in carriers of unstable borderline GAA triplet-repeat alleles. Ann Neurol 2004;56:898–901. doi:10.1002/ana.20333
5 Cook A, Giunti P. Friedreich’s ataxia: clinical features, pathogenesis and management. Br Med Bull 2017;124:19–30. doi:10.1093/bmb/ldx034
We read with great interest the article by Vidhale and colleagues.1 They provide a detailed description of a man presenting with a relatively rapidly progressing neurodegenerative disease including his neuroimaging findings.
After testing for a few DNA repeat expansion diseases, the authors arrived at the conclusion that their patient’s diagnosis was Friedreich ataxia (FRDA). FRDA is a recessive neurodegenerative disease caused by bi-allelic expansion of an intronic GAA repeat in the frataxin (FXN) gene. Their patient had 5 and 37 GAA repeats. The lower limit for full penetrance alleles is > 66 GAA repeats.2 Thus, it is not apparent how their patient meets diagnostic criteria for FRDA.
The 37 GAA repeat allele falls at the lower end of premutation alleles (range 34-65), so named as these alleles do not cause disease, but can rarely expand to the disease range during meiosis. In rare cases, somatic expansion of pre-mutations in cell populations has been postulated to cause disease, but this occurs only in the setting of the 2nd allele in the clear pathogenic range of expansion.
The authors alternatively postulate that the patient could represent a compound heterozygous state based on his clinical presentation. Comparison with cases of very late-onset FRDA (vLOFA), however, clearly shows that the patient’s course is too rapid and severe for vLOFA. Even if the patient were to carry a pathogenic point mutation in one of the allel...
The authors alternatively postulate that the patient could represent a compound heterozygous state based on his clinical presentation. Comparison with cases of very late-onset FRDA (vLOFA), however, clearly shows that the patient’s course is too rapid and severe for vLOFA. Even if the patient were to carry a pathogenic point mutation in one of the alleles, the second allele would still not be pathogenic at 37 GAA repeats.
In summary, the case report points to the fact that interpretation of genetic tests needs subspecialty expertise provided by medical geneticists, genetic counsellors or neurogeneticists. The neurologist can play an important role in classifying the neurologic phenotype and guide further evaluations. I sincerely doubt that the official report of the genetic testing laboratory suggested a diagnosis of FRDA. Errors of overinterpreting genetic test results and, even more so, erroneous interpretation can be harmful to patients and their relatives.
1. Vidhale TA, Gupta HR, Pj R, Gandhi C. Very late-onset Friedreich's ataxia with rapid course mimicking as possible multiple system atrophy cerebellar type. BMJ Case Rep. 2021 Jul 23;14(7):e242073. doi: 10.1136/bcr-2021-242073.
2. Bidichandani SI, MBBS, PhD and Martin B Delatycki, MBBS, FRACP, PhD.Friedreich ataxia. https://www.ncbi.nlm.nih.gov/books/NBK1281/2017 (accessed August 11 2021)
Stefan-M. Pulst, MD Dr med
University of Utah