Myoclonus‐Dystonia Presentation of ATM Gene Mutation in a Canadian Mennonite

A 14-year-old female of Canadian Old Colony Mennonite ancestry, product of non-consanguineous union, with normal perinatal history and mild motor developmental delay, presented with gradual onset and progressive involuntary neck jerks and jerky tremulous movements in hands (especially during writing) over a period of 12 months. She had history of occasional gait imbalance in her early childhood, which was non-progressive. There was no history of coordination difficulty or tendency to fall. There was no relevant family history. However, one of her maternal aunts suffered from leukemia (Fig. 1). On examination, there were no telangiectasias. Dystonic neck movements with predominant retrocollis, associated with mild left torticollis and right laterocollis were observed. Myoclonic movements were noted in the hands, on outstretched posture and during writing, which were not stimulus sensitive. Extraocular movements, speech, and cognition were normal. Tone, power, and reflexes were normal in all four limbs. No pyramidal, parkinsonian, or cerebellar signs were noted. Scale for the assessment and rating of ataxia (SARA) score was 0/40. Gait was normal including tandem gait (Video 1). Magnetic resonance imaging (MRI) brain was normal. With a provisional diagnosis of myoclonus-dystonia syndrome (DYT-SGCE), a DYT11 genetics for epsilon-sarcoglycan gene was done and was reported normal. Whole exome sequencing revealed pathogenic compound heterozygous mutations in the ATM gene-missense c.6200C > A (p.Ala2067Asp) in one allele and nonsense c.5932G > T (p.Glu1978Ter) in the other. IgG (7.8 g/L, ref: 6.5-16 g/L), IgA (0.7 g/L, ref: 0.4–3.5 g/L) and IgM (1.3 g/L, ref: 0.5-3 g/L) levels were normal, but serum α-fetoprotein (AFP) was elevated - 90.7 μg/L (ref. <5 μg/L). After 3 months of initial trial with levodopa and carbidopa (100/25) 1 tablet three times a day, her violent retrocolic jerks reduced in severity. Botulinum toxin injections were planned for the residual cervical dystonia. Levetiracetam (up to 1 gram twice daily) was unhelpful for her myoclonus and clonazepam (0.5 mg twice daily) was prescribed. Some improvement in her myoclonic jerks noted on follow-up in 3 months and combined therapy with levodopa-carbidopa and clonazepam has been continued. Ataxia-telangiectasia (A-T) is a childhood-onset, autosomal recessive progressive cerebellar ataxia syndrome because of mutations in the ATM gene. ATM protein kinase regulates multiple signaling cascades responsible for activating cellular checkpoints and repairing DNA strand breaks. ATM also plays a major role in mitochondrial DNA repair and reactive oxygen species (ROS) metabolism. Cerebellar Purkinje cells are rich in mitochondria and are sensitive to oxidative stress induced DNA damage. Null ATM alleles truncate or severely destabilize the ATM protein, leading to lack of functional ATM. The dysfunctional ATM protein in addition induces expression of hypoxia inducible factor (HIF-1) and subsequently vascular endothelial growth factor (VEGF), leading to the development of telangiectasia.1 Tumor suppressor TP53, acts downstream of ATM, also gets impaired and subsequently causes upregulation of AFP gene, leading to increased serum level of AFP.1 On the other hand, myoclonus-dystonia syndrome is classically caused by the mutation in epsilon-sarcoglycan gene (DYT-SGCE). Dysfunction in the neural network comprising mainly the cerebellum along with the thalamus, globus pallidus internus and brainstem, is likely responsible for pathogenesis of M-D.2 Myoclonus-dystonia (M-D) phenotype has also been reported because of mutations in adenylyl cyclase type 5 (ADCY5) (axial hypotonia and nocturnal dyskinesia), potassium channel tetramerization domain containing 17 (KCTD17) (predominant cranio-cervical and speech involvement), calcium voltage-gated channel subunit alpha1 b (CACNA1B) (cardiac arrhythmia and painful cramps), reelin (RELN) (psychiatric features and enhanced startle), protein kinase c gamma (PRKCG) (cerebellar ataxia), G protein subunit alpha L (GNAL) (cervical and laryngeal dystonia), anoctamin 3 (ANO3) (cervical and laryngeal dystonia, and upper limb tremor), tubulin beta 2B class IIb (TUBB2B) (cognitive impairment, and epilepsy), alpha tocopherol transfer protein (TTPA) (ataxia and sensory loss), NK2 homeobox 1 (NKX2-1) (chorea, lung and thyroid dysfunction), tyrosine hydroxylase (TH) (levodopa responsive dystonia) and GTP cyclohydrolase 1 (GCH1) (levodopa responsive dystonia) genes.3 Although dystonic-myoclonic axial jerks4 and myoclonus with appendicular ataxia5 have been reported in variant A-T [(Table 1), M-D phenotype being the only presenting feature without any appendicular or truncal ataxia and other cerebellar signs is rare.6-9 Saunders-Pullman et al10 reported a c.6200 C > A (p.A2067D) mutation in the ATM gene presenting as cervical/brachial onset dystonia with cranial involvement mimicking DYT6 (THAP1) and myoclonus-dystonia presentation mimicking DYT 11 (SGCE) in Canadian Mennonites, without ocular telangiectasia, lack of prominent ataxia and without significant cerebellar atrophy on MRI. Recently Cherian et al11 have reported another case of similar presentation of variant A-T along with slow or hypometric saccades, because of homozygous missense mutation (c. 9156G > C; p. Trp3052Cys) in the ATM gene. Whether the same cerebello-thalamo-cortical circuitry is involved in M-D presentation of variant A-T cases, is unknown. Homozygous c.9022C > T (p.R3008C) or compound heterozygous IVS21 + 1 G > A; IVS55 + 5delG, IVS28-1G > C; IVS34 + 32insAlu, IVS19 + 2 T > G; c.8147 T > C(p.V2716A), c.3383A > G(p.Q1128R); c.8122 G > A(p.D2708N); c.513C > T(p.Y171Y), DupEx64 + 65; c.6108 T > G(p.Y2036X), The c.6200C > A missense mutation in the ATM gene results in a p.Ala2067Asp substitution, leading to protein instability and kinase deficiency. Higher residual level of the ATM protein in this case is likely responsible for less ataxia. Similarly, residual ATM protein can suppress HIF-1 and VEGF expression, resulting in absence of telangiectasia.1 Apart from early onset dystonia, Mennonites carrying this specific mutation (A-TWinnipeg) are found to have high propensity to developing lymphoblastoid malignancies and life-threatening adverse reaction to radiotherapy and chemotherapy.12 In the case series published by Nakamura et al,12 two patients with compound heterozygous mutation also had c.5932G > T (p.Glu1978Ter) mutation apart from the c.6200 C > A (p.Ala2067Asp) mutation, similar to our patient. c.5932G > T mutation in the ATM gene have also been reported in Polish and Russian population.13, 14 Clinicians need to be made aware of variant A-T phenotypes where ataxia can be minimal and other classic findings of A-T like telangiectasia, endocrinopathy, and cerebellar atrophy may be absent. ATM gene mutations can present with phenotypes similar to DYT6, DYT11, progressive myoclonus ataxia (PMA), benign hereditary chorea, juvenile Parkinson's disease, and distal spinal muscular atrophy (SMA). However, because of the risks associated with radiation exposure and higher rates of malignancy in these patients, early diagnosis is of utmost importance. Serum AFP can be a potential cost-effective screening tool and should be considered in patients presenting with early onset dystonia or myoclonus-dystonia, even in the absence of prominent ataxia or telangiectasia. Ataxia telangiectasia remains an important diagnostic consideration not only in patients with early onset cervical/brachial onset dystonia, but also in those with a myoclonus-dystonia phenotype, especially in Mennonite population. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. J.G.: 1B, 1C, 2A M.T.B.: 1B, 1C S.G.: 1B, 2B A.P.: 1A, 1B, 2B M.J.: 1A, 2B The authors confirm that the approval of an institutional review board/patient consent was not required for this work. We also confirm that the patient has given written informed consent for the publication of her video. 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. No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. M.J. receives speaker's fees and research funding from Allergan, AbbVie, Merz Pharmaceuticals, Boston Scientific, Valeo Pharma, Sunovion, and Paladin Labs. M.J. also receives grants from Parkinson society Canada, Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada (NSERC), Mathematics of Information Technology and Complex Systems (MITACS), Research Council of Norway, Parkinson Society of Southwestern Ontario, Dystonia Medical Research Foundation and Academic Medical Organization of Southwestern Ontario. J.G. receives fellowship funding from the Academic Medical Organization of Southwestern Ontario (AMOSO). M.T.B. receives fellowship funding from the Parkinson Society of Southwestern Ontario (PSSO). A.P. and S.G. do not declare any conflict of interest.