Case Report A homozygous nonsense mutation of ATM gene in a Chinese family with five ataxia telangiectasia children: lesson for prenatal diagnosis

Case Report

A homozygous nonsense mutation of

ATM

gene in a

Chinese family with five ataxia telangiectasia

children: lesson for prenatal diagnosis

Shuhua An1_{, Jinying Li}1_{, Wenjie Gao}1_{, Yali Zhang}2_{, Guiling Mo}3_{, Liyuan Tian}1_{, Yakun Wang}1_{, Quanheng Li}1

1_{The First Department of Respiratory, Children’s Hospital of Hebei Province, Shijiazhuang, Hebei Province, China;} 2_{Department of Pediatrics, The Second Hospital of Handan City, Handan, Hebei Province, China;} 3_{Department of}

Molecular Genetics, Guangzhou Kingmed Center for Clinical Laboratory Co., Ltd., Guangzhou, Guangdong, China Received December 26, 2015; Accepted March 8, 2016; Epub July 1, 2016; Published July 15, 2016

Abstract: Ataxia-telangiectasia (AT) is a hereditary neurodegenerative disease. We presented a Chinese family with healthy non-consanguineous parents and all-five children presenting with unsteady gait. Genetic analysis of two living siblings showed an ATM homozygous nonsense mutation (c.6100C>T) that has not been reported in Chinese patients, while both parents were compound heterozygous. Limited expertise and lack of diagnosis may lead to the neglect of disease and bring a great tragedy to the family. Prenatal diagnosis may be desirable to identify fetuses at risk of AT when the nature and location of ATM mutation in a family have been identified.

Keywords: Ataxia-telangiectasia (AT), ataxia-telangiectasia mutated (ATM), c.6100C>T, Chinese family, prenatal diagnosis

Introduction

Ataxia telangiectasia (AT) is a rare human auto-somal recessive disease in children character-ized mainly by progressive cerebellar ataxia, immunodeficiency, and oculocutaneous telan-giectasia [1]. The estimated prevalence of AT has been reported to vary from 1 in 40,000 to 1 in 300,000 live births [2]. The disease is caused by biallelic mutations of ataxia-telangi-ectasia mutated (ATM) gene that located on chromosome 11 q22-23 [3]. More than 700

ATM gene mutations have been reported in AT patients (http://www.hgmd.cf.ac.uk/ac/gene. php? gene=ATM), most are frameshift or non-sense mutations. No evidence for the existence of hotspot mutations is available up to now. AT is the most common cause of progressive atax-ia in childhood. It was suggested to be a more common variety of hereditary ataxias in Chinese children [4]. Several cases have been reported in China [5-7]. However, establish-ment of AT diagnosis is most difficult in very young children. Identification of ATM mutations present in a family may provide insights into the

prenatal diagnosis of the disease [8]. In this report, we presented a Chinese family with healthy non-consanguineous parents and all five children presenting with unsteady gait in their early childhood, of which three have died at their early ages. Genetic analysis of two living patients showed an ATM homozygous non-sense mutation (c.6100C>T) that has not been reported in Chinese patients.

Case report

respirato-ry infection, and congestion of the conjunctiva at the age 1 year, and two of them had died of respiratory infection. No family history other than the two living patients and their parents was known.

The proband had normal births and develop-ment until the age of 14 months, when he developed gait instability and bilateral conjunc-tiva telangiectasia (Figure 1). No cutaneous tel-angiectasia and slurred speech was observed. Laboratory testing revealed positive alpha feto-protein (AFP) test, low levels of immunoglobulin A (IgA, 0.05g/L) and immunoglobulin G (IgG, 0.03 g/L), as well as lymphopenia (3.98*109_/L, CD3+_{: 69.3%; CD4}+_{: 24.7%; CD8}+_{: 28.0%; CD-} 19+_{: 1.9%; NK: 23.4%). No abnormality in the}

chromosome examination was found. The chest CT scanning showed bilateral broncho-pneumonia with both lower lobe bronchiecta-sis, while concurrent of infection could not be excluded. No thymic abnormalities were found (Figure 2). Brain magnetic resonance imaging (MRI) showed bilateral cerebellar atrophy and sinusitis (Figure 3). Genetic analysis of the ATM gene in proband and his only living sister identi-fied a homozygous nonsense mutation located in exon 42 (c.6100C>T, p.(Arg2034*)), while both the parents were found to be compound heterozygous for the (c.6100C>T, p.(Arg2034*)).

Discussion

AT is a progressive disorder characterized by early-onset cerebellar ataxia, oculocutaneous Figure 1. Bilateral ocular telangiectasias of the proband. A. Right eye; B. Left eye.

telangiectasia, and immune defects. The onset of the disease generally occurs between the age of 1 and 2 years with abnormal head move-ments, loss of balance, slurred speech, and abnormal eye movements [9]. The clinical cou- rse is variable. Telangiectasias appearing in the ocular, face and ears at 3-5 years of age, are often neglected, or even remain absent in vari-ant AT [10]. The serum AFP level has been eval-uated to help the diagnosis of the infants with ataxia symptoms [11], and elevated AFP level was reported in AT patient. Other associated features include T- and B-cell abnormalities with IgA and IgG deficiencies [10, 12], and a predisposition to malignancy [13]. The high inci-dence of sinopulmonary infections has also been described [14].

Our study here described a Chinese family with all five children presenting with gait disturbance from health non-consanguineous parents, of which three had died at their early ages. The diagnosis was elucidated by the typical clinical presentation of gait instability and bilateral conjunctiva telangiectasia. Blood tests showed positive AFP test, reduced levels of serum IgA and IgG, and lymphopenia in the fifth child (pro-band), the findings consistent with AT. No cuta-neous telangiectasia and chromosome breaks were noted in our patient, partially consistent with the results reported by Jeong et al. [2], which indicated the bilaterally ocular telangiec-tasia with no cutaneous telangiectelangiec-tasia. However, there was no slurred speech in the proband of our study. Whereas, the bilateral bronchopneumonia was evident on CT scan with both lower lobe bronchiectasis, and brain

MRI showed cerebellar atrophy and sinusitis, further confirmed the diagnosis of AT.

AT is well known to be associated with muta-tions in the ATM gene, expressed ubiquitously and encoding a serine/threonine protein kinase involved in monitoring and maintaining DNA integrity, cell cycle regulation, and coordinate cell-signaling pathways [15]. Mutations in ATM

the best of our acknowledgement all the ATM mutations identified in Chinese were no homo-zygous mutation like this [7].

To summary, our study showed a family case of AT with all five children affected, limited exper-tise and lack of diagnosis may lead to the neglect of the disease, thus bring a great trag-edy to the family. Genetic analysis showed an ATM homozygous nonsense mutation (c.6100C>T, p.(Arg2034*)) in the two living chil-dren, and both the parents were found to be compound heterozygous for the c.6100C>T, p.(Arg2034*). Limited expertise and lack of diagnosis may lead to the neglect of disease and bring a great tragedy to the family. Prenatal diagnosis may therefore be desirable to identify fetuses at risk of AT when the nature and the location of ATM mutation presented in a family have been identified.

Acknowledgements

This work was financially supported by the Hebei Province Science and Technology Plan Project (13277725D).

Disclosure of conflict of interest

None.

Address correspondence to: Shuhua An, The First Department of Respiratory, Children’s Hospital of Hebei Province, Shijiazhuang 050031, Hebei Provi- nce, China. Tel: +86-13582115776; Fax: +86-3118- 5911192; E-mail: [email protected]

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