|Year : 2020 | Volume
| Issue : 3 | Page : 283-285
A rare case of ataxia-telangiectasia-like disorder with MRE11 mutation
Rohan R Mahale, Nishanth Reddy, Pavagada Mathuranth, Pooja Mailankody, Hansashree Padmanabha, Chandra Sadnavalli Retnaswami
Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
|Date of Submission||20-Nov-2019|
|Date of Decision||27-Mar-2020|
|Date of Acceptance||27-Mar-2020|
|Date of Web Publication||06-Nov-2020|
Dr. Rohan R Mahale
Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka.
Source of Support: None, Conflict of Interest: None
| Abstract|| |
The prototypical disorder for the early-onset cerebellar ataxia with cerebellar atrophy is ataxia telangiectasia (AT). AT belongs to “DNA-repair defects” or “DNA-repair deficiency” disorders. The ATM (Ataxia-telangiectasia mutated kinase) gene mutated in AT is central to deoxyribonucleic acid (DNA) damage response (DDR) signaling. Other genes implicated in DDR signaling are MRE11A (Meiotic recombination 11). Mutation of this gene results in ataxia-telangiectasia-like disorder (ATLD). We report a boy who presented with mild cerebellar ataxia and dystonia with cerebellar atrophy on brain imaging. Clinical exome sequencing showed compound heterozygous variants in MRE11 gene. He was diagnosed as ATLD, which has not been reported in Indian subcontinent so far.
Keywords: Ataxia-telangiectasia-like disorders, cerebellar ataxia, cerebellar atrophy
|How to cite this article:|
Mahale RR, Reddy N, Mathuranth P, Mailankody P, Padmanabha H, Retnaswami CS. A rare case of ataxia-telangiectasia-like disorder with MRE11 mutation. J Pediatr Neurosci 2020;15:283-5
| Introduction|| |
The deoxyribonucleic acid (DNA) damage response (DDR) or DNA repair defects cause rare inherited diseases, termed as “DNA-repair defects” or “DNA-repair deficiency.” Among them is ataxia telangiectasia (AT). The ATM (Ataxia-telangiectasia mutated kinase) gene mutated in AT is central to DDR signaling. Other genes implicated in DDR signaling are MRE11A (Meiotic recombination 11) and NBN (NBS1) genes. Mutation of these genes results in ataxia-telangiectasia-like disorder 1 (ATLD) and Nijmegen breakage syndrome, respectively. The clinical presentation of ATLD is similar to AT but without telangiectasia, raised serum alpha fetoprotein, and immunodeficiency. Here, we report a boy who presented with mild cerebellar ataxia and dystonia with cerebellar atrophy on brain imaging. Clinical exome sequencing showed compound heterozygous variants in MRE11 gene. He was diagnosed as ATLD, which has not been reported in Indian subcontinent so far.
| Case Report|| |
A 14-year-old boy born out of non-consanguineous parentage with normal perinatal history and motor and language milestones was brought with the history of imbalance while walking since the age of 6 years. The imbalance while walking was insidious in onset and slowly progressive for 3–4 years and static till the presentation to us. There was no diurnal variation. He was able to play with peers. There was no history of incoordination of upper limbs, speech disturbance, tremulousness of head, abnormal posturing of limbs, myoclonus, or seizures. He had younger male sibling of 6 years of age who was asymptomatic. There was no history of similar complaints in other family members. Systemic examination was unremarkable. There was no oculocutaneous telangiectasia, cataract, tendon xanthomas, scoliosis, or high arched feet. Neurological examination showed normal cognition and speech. Fundus examination was normal. Visual acuity and visual fields were normal. There was no external ophthalmoplegia. Vertical and horizontal saccades had normal latency and velocity but were hypometric. He had horizontal and vertical saccadic pursuits. Other cranial nerves were normal. Motor examination showed hypotonic limbs with hyporeflexia. Muscle power was grade 5/5 in both upper and lower limbs. Sensory examination was normal. There was mild finger–nose and knee–heel incoordination on both sides. Tandem gait was impaired. Gait was slightly wide-based and ataxic. Romberg’s sign was negative. Plantar response was flexor. There was mild finger dystonia of both outstretched hands with mild fidgetiness while sitting. Complete blood counts and renal, hepatic, and thyroid functions were normal. Fasting lipid profile and serum total creatine phosphokinase were normal. Serum alpha fetoprotein; immunoglobulins G, A, and M; and vitamin E levels were normal. Chest X-ray and ultrasonography of abdomen and pelvis were normal. Nerve conduction study was normal. Brain magnetic resonance imaging (MRI) showed pan cerebellar atrophy [Figure 1]. Clinical exome sequencing showed compound heterozygous variants in the MRE11 gene. A heterozygous 5′ splice site proximal variation in intron 4 of the MRE11 gene that affects the positions 4 to 7 nucleotides downstream of donor splice site of exon 4 (c.314+4_314+7 del) was detected. The sequencing of variant was not carried out in parents in order to confirm the significance due to financial constraints.
|Figure 1: Brain magnetic resonance imaging (MRI) T2-weighted imaging axial (A and B) shows cerebellar atrophy (red arrow); sagittal images (C) show cerebellar atrophy (red arrow)|
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| Discussion|| |
AT is an autosomal recessive DNA-repair defect characterized by progressive cerebellar ataxia, telangiectasia, immunodeficiency, radiation sensitivity, and malignancy predisposition. Mutation of MRE11 gene has been found to cause ATLD.MRE11 gene encodes a protein (Mre11) with nuclease and DNA-binding activity. This Mre11 protein with Rad50 and Nbs1 protein forms the MRN complex, which interacts with ATM kinase causing its activation and initiating signaling network of cellular response to DNA damage. Till date, around 23 cases of ATLD belonging to two families from the United Kingdom (one native from Pakistan), one family from Italy, three families from Saudi Arabia, three families from Japan, and one family from Pakistan has been reported. The clinical presentation of patients with ATLD is similar to those of patients with AT that includes progressive cerebellar ataxia, oculomotor apraxia, and cellular hypersensitivity to ionizing radiations, but have mild presentation and slow progression. They may have facial dyskinesia, choreoathetosis, and dystonia. Telangiectasia, immunodeficiency, and increased α-fetoprotein have not been reported. Oculomotor abnormalities such as inability to initiate voluntary saccades; saccade hypometria; delayed convergence and impaired smooth pursuit; vestibulo-ocular reflex and optokinetic nystagmus; saccadic intrusions; drifts; and spontaneous, gaze-evoked, and down-beat nystagmus have been reported. Severe cerebellar atrophy particularly in the vermis has been found in ATLD as per postmortem studies. The number of granule cells, parallel fibers, Bergmann glial cells, and Purkinje cells is reduced in ATLD. Stewart et al. reported four probands from two unrelated English families presenting with AT-like symptoms and had MRE11 mutations. One family had homozygous mutations and the other had compound heterozygous mutations. Delia et al. reported two Italian siblings who were compound heterozygotes for MRE11 mutations (1422C→A; 1714C→T). They presented with early childhood onset cerebellar ataxia, oculomotor apraxia, and choreoathetoid movements. Laboratory studies showed normal levels of immunoglobulins and alpha fetoprotein. Fernet et al. reported 10 patients with ATLD from three unrelated Saudi Arabian families. The age of the patients ranged from 5 to 37 years and had early-onset, slowly progressive cerebellar ataxia and oculomotor apraxia with no tumor development. Uchisaka et al. reported two siblings with ATLD with compound heterozygous mutations in MRE11 gene and developed lung adenocarcinoma.
| Conclusion|| |
Our patient had early-onset, slowly progressive for initial few years, later static cerebellar ataxia with saccade and pursuit dysfunction, dystonia, and choreiform movements. There was no oculocutaneous telangiectasia, raised serum alpha fetoprotein levels, or reduced immunoglobulins. This is the first genetically confirmed reported case of ATLD from the Indian sub-continent.
We are thankful to the MedGenome Labs Ltd, Bengaluru, India, for conducting the genetic analysis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kashimada A, Hasegawa S, Nomura T, Shiraku H, Moriyama K, Suzuki T, et al
. Genetic analysis of undiagnosed ataxia-telangiectasia-like disorders. Brain Dev 2019;41:150-7.
Verhagen MM, Abdo WF, Willemsen MA, Hogervorst FB, Smeets DF, Hiel JA, et al
. Clinical spectrum of ataxia-telangiectasia in adulthood. Neurology 2009;73:430-7.
Kulkarni A, Wilson DM III. The involvement of DNA-damage and repair defects in neurological dysfunction. Am J Hum Genet 2008;82:539-66.
Stracker TH, Roig I, Knobel PA, Marjanović M The ATM signalling network in development and disease. Front Genet 2013;4:37.
Khan AO, Oystreck DT, Koenig M, Salih MA Ophthalmic features of ataxia telangiectasia-like disorder. J AAPOS 2008;12:186-9.
Oba D, Hayashi M, Minamitani M, Hamano S, Uchisaka N, Kikuchi A, et al
. Autopsy study of cerebellar degeneration in siblings with ataxia-telangiectasia-like disorder. Acta Neuropathol 2010;119:513-20.
Stewart GS, Maser RS, Stankovic T, Bressan DA, Kaplan MI, Jaspers NGJ, et al
. The DNA double-strand break gene hMre11 is mutated in individuals with ataxia-telangiectasia-like disorder. Cell 1999;99:577-87.
Delia D, Piane M, Buscemi G, Savio C, Palmeri S, Lulli P, et al
. MRE11 mutations and impaired ATM-dependent responses in an Italian family with ataxia-telangiectasia-like disorder. Hum Mol Genet 2004;13:2155-63.
Fernet M, Gribaa M, Salih MA, Seidahmed MZ, Hall J, Koenig M Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder. Hum Mol Genet 2005;14:307-18.
Uchisaka N, Takahashi N, Sato M, Kikuchi A, Mochizuki S, Imai K, et al
. Two brothers with ataxia-telangiectasia-like disorder with lung adenocarcinoma. J Pediatr 2009;155:435-8.