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Table of Contents    
Year : 2021  |  Volume : 69  |  Issue : 5  |  Page : 1363-1367

Clinical and Molecular Features of First Mexican Friedreich's Ataxia Patients with Compound Heterozygous FXN Mutations

1 Clinical Research Laboratory, Ataxias, Chorea and Other Rare Neurodegenerative Diseases, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez” (INNNMVS), Mexico City, Mexico
2 Department of Genetics, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”; Department of Biological Systems, Metropolitan Autonomous University-Xochimilco, Mexico City, Mexico
3 Department of Genetics, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, Mexico City, Mexico

Date of Submission10-Oct-2020
Date of Decision17-Jan-2021
Date of Acceptance29-Mar-2021
Date of Web Publication30-Oct-2021

Correspondence Address:
Nancy Monroy-Jaramillo
Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco Suárez, Ave. Insurgentes Sur 3877, La Fama, Tlalpan, 14269, Mexico City
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.329555

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 » Abstract 

Background: Friedreich's ataxia (FRDA) is caused by homozygous GAA repeat expansions or compound heterozygous (CH) mutations in FXN gene. Its broad clinical spectrum makes it difficult to identify, thus an accurate diagnosis can only be made by genetic testing.
Objective: This study aims to present data on FXN variants observed in patients with sporadic or recessive ataxia, including detailed data of the first CH Mexican patients.
Materials and Methods: One hundred and eight patients with recessive or sporadic cerebellar ataxia were referred to our institution between 2009 and 2019 for FXN molecular testing. This was achieved using a combined methodology of triplet repeat-primed PCR (polymerase chain reaction), long PCR, FXN sequencing and multiplex-ligation probe-amplification.
Results: Eighteen patients had a homozygous FXN genotype; whereas five were CH patients with a slow progression and phenotypic variability, including a late-onset case with spastic paraparesis, and a Charcot-Marie-Tooth-like case.
Conclusions: These first Mexican CH patients pose important implications for genetic counseling and FRDA management.

Keywords: Cardiomyopathy, compound heterozygous, diabetes, Friedreich's ataxia, FXN gene mutation, hearing loss, phenotypiv variability.
Key Messages: Although CH FXN mutations are rare in Mexican patients with recessive or sporadic cerebellar ataxia, clinicians should consider them when making FRDA diagnosis. In suspected FRDA cases, even with phenotypic variability and slow progression, a complete molecular study of FXN should be requested to completely rule it out.

How to cite this article:
Boll MC, Gasca-Saldaña D, Mayén-Lobo YG, Dávila-Ortiz de Montellano DJ, Monroy-Jaramillo N. Clinical and Molecular Features of First Mexican Friedreich's Ataxia Patients with Compound Heterozygous FXN Mutations. Neurol India 2021;69:1363-7

How to cite this URL:
Boll MC, Gasca-Saldaña D, Mayén-Lobo YG, Dávila-Ortiz de Montellano DJ, Monroy-Jaramillo N. Clinical and Molecular Features of First Mexican Friedreich's Ataxia Patients with Compound Heterozygous FXN Mutations. Neurol India [serial online] 2021 [cited 2021 Dec 7];69:1363-7. Available from:

Friedreich's ataxia (FRDA) usually occurs in people <25 years; however, ≈15% have a late-onset presentation (LOFA, >26 years).[1] Its main cause is a biallelic GAA repeat expansion within the first intron of FXN gene, but 2% to 5% of patients show one expanded allele paired with a point mutation or a large deletion in the second allele, namely, compound heterozygous individuals (CH).[2],[3]

A previous study in Mexican patients with recessive ataxia reported 9.3% FXN biallelic expansions.[4],[5]

Herein, we aimed to determine the frequency of FXN mutations in patients with sporadic or recessive ataxia over a 10-year period. Characteristics of the first CH Mexican patients are provided.

 » Materials and Methods Top

Between 2009 and 2019, one-hundred and eight Mexican patients (including five pairs of affected siblings) with sporadic or autosomal recessive ataxia were referred to our institution for FXN molecular analysis. Inclusion criteria were ataxic gait as a core feature of the phenotype and sporadic cases that were negative for dominant spinocerebellar ataxias types 2, 3, and 7.

This is a retrospective study that was approved by the Institutional Review Board or Independent Ethics Committee (IRB/IEC) and performed in accordance with the Helsinki Declaration (protocol_145/18). After giving written informed consent, patients were evaluated by a movement-disorder specialist following FRDA international criteria,[1] and a geneticist interrogated them for family history (FH). Laboratory tests, neurophysiological studies, brain magnetic resonance imaging (MRI), and transthoracic echocardiograms were performed.

Blood DNA was isolated by standard procedures. Positive samples for triplet repeat-primed PCR (TP-PCR)[6] as first screening were amplified with a second set of primers by long PCR.[2] In CH patients, the nonexpanded allele was direct sequenced[6] and analyzed with Mutation Surveyor Version 4.0 software, using the GenBank file NG_002601.2 as reference sequence. Then, multiplex ligation-dependent probe amplification (MLPA) was performed (APTX, SETX, FXN) for those patients with one FXN expanded allele and no sequence variants. Capillary electrophoresis for TP-PCR, sequencing, and MLPA was done on an AB3130 genetic analyzer (Life Technologies, Carlsbad, CA, USA).

 » Results Top

Originally, 98 nonrelated patients were recruited. Because some patients referred to having affected siblings, they were also enrolled in this study. Thus, we studied 108 patients, belonging to 98 families, from 21 Mexican states. Family history (FH), consistent with autosomal recessive inheritance, was considered positive if ataxia was reported by a first- or second-degree relative. FH was positive in 52 cases (53.06%).

Participants' age at onset (AAO) ranged from 1 to 53 years (mean ± standard deviation = 17.47 ± 11.43 years) with 62% identified as males. The observed wild-type FXN alleles varied from 6 to 22 GAA repeats, with 6 to 8 repetitions being the most frequent.

TP-PCR revealed 23/98 positive cases (23.47%); 18 of them showed biallelic FXN expansions (18.37%), ranging from 75 to 1,033 GAA repeats by long-PCR (no premutation allele was observed). The remaining five positive cases had a monoallelic expansion and were suspected as CH patients [Table 1]. The AAO in both groups was similar (P = 0.5247) [Table 2].
Table 1: Clinical, demographic, and genetic characteristics of patients with a compound heterozygous FXN genotype

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Table 2: Comparison of clinical and genetic characteristics between compound heterozygous and homozygous Friedreich's ataxia patients

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Sequencing analysis of the nonexpanded allele in CH patients revealed two point mutations: p.Met1Ile (Patient 1) and p.Q153H (Patient 2) [Figure 1]a and [Figure 1]b, being classified as pathogenic and of uncertain significance variants, respectively, at Varsome using the American College of Medical Genetics (ACMG) rules.
Figure 1: FXN mutations in Mexican patients with Friedreich's ataxia and compound heterozygous genotype. Partial electropherograms of FXN sequence showing (a) the c.3G > T variant in Patient 1 (P-1) and (b) the c.459A > C variant in Patient 2 (P-2) versus wild-type sequence in a control (CT). The lines above the sequence depict the site of the affected triplet. (c) The heterozygous deletion Ex3del (mean ratio = 0.6 in two-independent assays), identified by MLPA in Patient 3 (P-3) versus gene dosage in a control

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MLPA analysis evidenced a heterozygous deletion of exon 3 (Ex3del_FXN) in CH Patient 3 [Figure 1]c, mean ratio = 0.6 in two-independent assays), whereas CH Patients 4 and 5 did not show structural variations.

Additionally, six benign variants were observed in CH patients (rs145006100, rs2481598, rs3829062; and three novel intronic changes: c.186+4G > A, c.284 + 24G > C, c.511 + 53G > A), and the variant of uncertain significance, rs772778611, in Patients 1, 3, 4, and 5.

CH Patient 1 referred positive FH, with a deceased brother in young adulthood, allegedly with walking disability, diabetes mellitus, and a presumptive Charcot-Marie-Tooth disease (CMT).

None of the CH patients had diabetes, hearing loss, or a severe heart disease, with a mean functional staging FARS = 2.1, and a loss of autonomous ambulation (LAA) = 32.2 ± 9.98 years. CH Patients 2 and 4 had mild cerebellar atrophy [Table 1].

 » Discussion Top

We confirmed the low frequency of FXN mutations in Mexican patients with sporadic or autosomal recessive ataxias (23.47%) versus other reported populations (e.g., FRDA represents 75% of the recessive ataxias in Caucasians).[1] Genetic counseling was offered to FRDA-confirmed cases; 18.37% of them showed biallelic FXN expanded alleles, and 5.1% were CH patients.

We observed that CH patients have phenotypic differences compared with individuals homozygous for (GAA) n expansions, in contrast with the classic FRDA phenotype, in which an earlier onset has faster progression, and nearly all patients developing cardiomyopathy at some point in their lives.[3] Our CH patients had a slightly slower progression (time of LAA-AAO ranged from 11 to 20 years), without diabetes, severe heart disease, or hearing loss [Table 1]. However, because of our small sample size, these differences were nonsignificant [Table 2].

LOFA patients with smaller GAA expansions generally show a mild phenotype even in the absence of cardiomyopathy; they may mimic hereditary spastic paraplegias with subsequent development of ataxic symptoms.[1] As is the case of Patient 5, who showed spastic paraparesis as the first symptom, and subsequently presented minimal ataxic gait and fine movements, without cardiac manifestation. The presence of nucleotide interruptions of the GAA tract modulating FXN methylation levels[1] may be associated with LOFA, but this was not tested in our patient.

Sixty-seven FXN mutations have been documented in the Human Gene Mutation Database (HGMD). The mutation identified in Patient 1 (p.M1I) has been published in FRDA cases;[7],[8] in fact, the initiator codon is a mutation hotspot with three documented additional substitutions p.M1T/S/L (rs142133355, rs149724959, and rs147643987, respectively) resulting in a shortened protein,[7],[8],[9] and supposedly from a common founder.[10] This variant is found in gnomAD database (frequency = 0.00000913) and reported in ClinVar: VCV000003983.1.

The mutation p.Q153H observed in Patient 2 is also a recurrently mutated amino acid (p.Q153H/R, rs780387020, and rs77781994, respectively), and is found in gnomAD database (frequency = 0.00000398). Q153 is clustered to the affected residues p.I154F and p.W155R located in one surface of the frataxin-causing FRDA.[2],[10] These mutations decrease the interaction of frataxin with the iron-sulfur biogenesis Nfs1/ISCU complex through ISD11.[11]

Five gross exonic deletions and and one spanning the entire gene are reported in HGMD; CH patients carrying exonic deletions are considered rare and severe variants of early-onset FRDA. Interestingly, Patient 3 (AAO = 9 years), with an FXN_Ex3del, has a slow disease progression.

Because no CH patients' relatives were included, we could not check whether the expanded allele and the other FXN mutations were in cis or trans.

The two remaining CH patients, in whom no second mutation was identified, may present rare rearrangements or intronic variants, undetected by our FXN analysis,[12] or be FRDA carriers with another Friedreich-like ataxia.[13] The observed phenotypic variability in CH patients depends on the expression of partially functional mutant FXN, epigenetics,[1] and the pathogenicity of mutations present in the expanded allele (i.e., number of GAA repeats, sequence interruptions) and the nonexpanded allele. Thereby, CH patients may mimic diverse phenotypes such as CMT (Patient 1), or spastic paraparesis (Patient 5), delaying their diagnosis and causing an inappropriate management of the disease (e.g., Patient 2 diagnosed after 14 years of disease progression). Our results emphasize the need to screen repeat expansions, dosage, and point mutations to rule out the FRDA molecular diagnosis avoiding additional time-consuming/expensive analyses. Recently, it has been described a CMT-like case carrying the first biallelic FXN point mutation;[14] however, our cases negative for FXN analysis did not report that presentation.

Patient 1 also presented autoimmune hypothyroidism; this concomitant condition has been described in one pediatric FRDA patient, highlighting that in case of presenting cardiomyopathy could be exacerbated when they coincide.[15] Although the echocardiogram was normal at the time of the patient's assessment, clinicians should be aware of this possibility.

Little is known about FXN variants in Latin Americans, whereas similar findings to ours have been reported in Brazilian patients.[12] The underlying cause for 76.53% of our cases remains unknown and should be explored by whole-genome sequencing.

The phenotypic variability observed in CH patients could be related to the length of the expanded allele and the type of mutation in the second allele (with its corresponding amount of residual frataxin). These findings should be considered when developing future specific mutation-directed therapeutics.

This study presents the first Mexican patients with a CH FXN genotype, expanding the clinical and mutational spectrum of FRDA. Our findings have important implications for genetic counseling and management of FRDA Mexican patients.


We would like to thank all the patients who participated in this study.

Financial support and sponsorship

DGS was supported by a master's grant from CONACyT #960931.

Conflicts of interest

There are no conflicts of interest.

 » References Top

Bidichandani SI, Delatycki MB. Friedreich Ataxia. 1998 Dec 18 [Updated 2017 Jun 1]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, et al. editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.  Back to cited text no. 1
Campuzano V, Montermini L, Molto MD, Pianese L, Cossee M, Cavalcanti F, et al. Friedreich's ataxia: Autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996;271:1423-7.  Back to cited text no. 2
Galea CA, Huq A, Lockhart PJ, Tai G, Corben LA, Yiu EM, et al. Compound heterozygous FXN mutations and clinical outcome in Friedreich ataxia. Ann Neurol 2016;79:485-95.  Back to cited text no. 3
Gomez M, Clark RM, Nath SK, Bhatti S, Sharma R, Alonso E, et al. Genetic admixture of European FRDA genes is the cause of Friedreich ataxia in the Mexican population. Genomics 2004;84:779-84.  Back to cited text no. 4
Rasmussen A, Gomez M, Alonso E, Bidichandani SI. Clinical heterogeneity of recessive ataxia in the Mexican population. J Neurol Neurosurg Psychiatry 2006;77:1370-2.  Back to cited text no. 5
Ryan F. Best Practice Guidelines for Molecular Analysis of Friedreich Ataxia. (EMQN). 2001:1-5.  Back to cited text no. 6
Cossee M, Durr A, Schmitt M, Dahl N, Trouillas P, Allinson P, et al. Friedreich's ataxia: Point mutations and clinical presentation of compound heterozygotes. Ann Neurol 1999;45:200-6.  Back to cited text no. 7
Potter NT, Miller CA, Anderson IJ. Mutation detection in an equivocal case of Friedreich's ataxia. Pediatr Neurol 2000;22:413-5.  Back to cited text no. 8
Zuhlke C, Laccone F, Cossee M, Kohlschutter A, Koenig M, Schwinger E. Mutation of the start codon in the FRDA1 gene: Linkage analysis of three pedigrees with the ATG to ATT transversion points to a unique common ancestor. Hum Genet 1998;103:102-5.  Back to cited text no. 9
Labuda M, Labuda D, Miranda C, Poirier J, Soong BW, Barucha NE, et al. Unique origin and specific ethnic distribution of the Friedreich ataxia GAA expansion. Neurology 2000;54:2322-4.  Back to cited text no. 10
Shan Y, Napoli E, Cortopassi G. Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones. Hum Mol Genet 2007;16:929-41.  Back to cited text no. 11
Barcia G, Rachid M, Magen M, Assouline Z, Koenig M, Funalot B, et al. Pitfalls in molecular diagnosis of Friedreich ataxia. Eur J Med Genet 2018;61:455-8.  Back to cited text no. 12
Peluzzo TM, Bonadia LC, Donatti A, Molck MC, Jardim LB, Marques W, Jr., et al. Frequency and genetic profile of compound heterozygous Friedreich's ataxia patients-the Brazilian experience. Cerebellum 2019;18:1143-6.  Back to cited text no. 13
Candayan A, Yunisova G, Cakar A, Durmus H, Basak AN, Parman Y, et al. The first biallelic missense mutation in the FXN gene in a consanguineous Turkish family with Charcot-Marie-Tooth-like phenotype. Neurogenetics 2020;21:73-8.  Back to cited text no. 14
Thrasher B, Whitham J, Law J. Worsening cardiac function in a patient with Friedreich's ataxia secondary to profound hypothyroidism. ECEDReports 2018;5:e6-8.  Back to cited text no. 15


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  [Table 1], [Table 2]


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