Ataxia‐telangiectasia (A‐T) is one of the most frequent recessive ataxias worldwide. The disease results from biallelic pathogenic variants in the ATM gene, coding for a high‐molecular‐weight protein kinase involved in double‐strand breaks repair. It is usually characterized by childhood‐onset cerebellar ataxia, oculocutaneous telangiectasia, and early mortality. 1 Its molecular diagnosis is challenging because of the unusually large sequence of ATM, the extensive allelic heterogeneity with >600 reported pathogenic variants 2 and the increasing recognition of atypical phenotypic presentations such as mild and slow progressing variants that defy the classical picture of an invariably deadly disorder of childhood. 3 Here we describe the case of a 21‐year‐old patient with early‐onset mildly progressive cerebellar ataxia, where a confirmatory diagnosis of A‐T caused by 2 novel ATM pathogenic variants could be done by the combination of next‐generation sequencing and ATM functional studies.
This 21‐year‐old woman was referred to our neurogenetic unit at the age of 17 for the study of a slowly progressive childhood‐onset ataxia. She was born from nonconsanguineous healthy parents (Fig. 1A). At the age of 5, frequent falls and a progressive incoordination in her gait led her parents to consult a pediatric neurology unit. The results of magnetic resonance imaging showing cerebellar atrophy (Fig. 1B) and the finding of mild lower limb ataxia and dysarthria led to a diagnosis of likely genetic ataxia at that time. Our first evaluation showed in a fully unassisted ambulatory patient a mild axial and appendicular ataxia (scale for the assessment and rating of ataxia [SARA] score, 7). She presented a fractionated smooth pursuit and slow and hypometric horizontal and vertical saccades. There was no evidence of oculo‐motor apraxia, and other movement disorders were absent. Noteworthy, ocular or skin telangiectasias were absent. The disorder evolved during the next 4 years with a mild progression of ataxia (SARA score, 10) and the appearance of billateral distal chorea and a subtle left‐hand dystonia in the upper limbs (Video S1). The biochemical work‐up highlighted the presence of elevated serum α‐fetoprotein (15 times normal values) and reduced levels of immunoglobulins A and E. A next‐generation sequencing panel for ataxias revealed the presence of 2 novel variants in compound heterozygous form in the ATM gene: (NM_000051) c.1373G>A(p. Cys458Tyr) and c.8785_8788delAGGT(p. Arg2929Metfs * 2) (Fig. 1C). To increase the diagnostic certainty of this finding, we functionally assessed the ATM repairing capacity of double‐strand breaks by means of an etoposide‐induced DNA damage in lymphocytes assay (Supplemental Material). We found an increased frequency of chromosomal aberrations after ex vivo treatment with etoposide (Fig. 1D) confirming a deficiency in the DNA damage repair mechanisms.
Figure 1.
(A) Pedigree chart. Arrow indicates index case. Numbers over figures corresponded to current age/age at onset. (B) Magnetic resonance imaging sagittal T1‐weighted image showing cerebellar atrophy. (C) Alignment showing identified variants in the patient. (D) Chromosomal aberrations (both break and exchange type) following acute treatment with etoposide representative image metaphase containing chromosomal aberrations is shown. AT, ataxia telangiectasia; SEM, standard error of the mean.
The case reported here highlights the importance of combining information from clinical, genetic, and functional assays in the diagnostic exercise of progressive and complex ataxias. Although there have been initial descriptions of variant A‐T phenotypes, 3 , 4 only after the recent widespread availability of molecular studies of ATM has there been an increasing recognition of the atypical phenotype 5 such as that reported. In addition, the description of the pathogenic effect of 2 novel variants in ATM expands the spectrum of known causative mutations of A‐T.
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique.
J.P.M.: 1A, 1C, 3A
M.G.C.: 1C, 3A, 3B
L.Z.: 1C, 3A
S.R.Q.: 1A, 1B, 1C, 3A
M.K.: 1A, 1B, 1C, 3B
Disclosures
Ethical Compliance Statement: This study was approved by the Institutional Ethics Committee of the Hospital JM Ramos Mejia of Buenos Aires, Argentina. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the patient provided verbal and written consent. For this work but because this article is a case report no institutional review board approval was necessary.
Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months: Josefina Perez Maturo has received scholarship support from Argentinean National Science Council (CONICET). Marcelo Kauffman and Marcela Gonzalez Cid have received grant support from Ministry of Health of Buenos Aires City, Argentinean National Science Council (CONICET). Marcelo Kauffman has received grant support from Argentinean Ministry of Science and Technology and serves as Associate Editor of the journal Neurología Argentina. The rest of the authors declare that they have no conflict of interest.
Supporting information
Appendix S1. Additional details about methodology.
Video S1. This video shows main findings during neurological examination in the case reported. Segment 1 shows the presence of fractionated smooth pursuit and slow and hypometric horizontal and vertical saccades. Segments 2 to 4 shows the presence of mild lower and upper limb ataxia at the SARA scale. Segments 5 and 6 shows mild impairment in gait and stance predominant visible when walking or stand in tandem. Segment 7 shows the presence of bilateral distal choreic movements and subtle left‐hand dystonia in upper limbs.
References
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Associated Data
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Supplementary Materials
Appendix S1. Additional details about methodology.
Video S1. This video shows main findings during neurological examination in the case reported. Segment 1 shows the presence of fractionated smooth pursuit and slow and hypometric horizontal and vertical saccades. Segments 2 to 4 shows the presence of mild lower and upper limb ataxia at the SARA scale. Segments 5 and 6 shows mild impairment in gait and stance predominant visible when walking or stand in tandem. Segment 7 shows the presence of bilateral distal choreic movements and subtle left‐hand dystonia in upper limbs.