Homozygosity for c 6325T>G transition in the ATM gene causes an atypical, late-onset variant form of ataxia-telangiectasia

Abstract: The number of primary immune deficiencies exceeds 350, approximately a quarter of them having neurological implications. Severe central nervous system infections may occur in an even higher proportion. Beyond listing in a table of all diseases with a neurological impact, the author gives detailed analysis of one typical disorder. Ataxia telangiectasia is caused by biallelic mutation of the ATM gene resulting in genomic instability, increased cancer risk, immune deficiency and a predominantly cerebellar neurodegeneration. The most common classic form is characterized by gait and limb ataxia, oculomotor apraxia, choreoathetosis, disturbance of speech and swallowing, less often by other movement disorders. There is no remarkable cognitive deficit. Telangiectasia of the conjunctivae and skin usually appears after 6 years of age. Frequent, especially severe sino-pulmonary infections may indicate the immune deficiency present in 60 to 80% of patients, who are also prone to malignancies. The clinical course is sometimes atypical or has a late onset which results in diagnostic difficulties. Serum alpha-fetoprotein level is elevated in nearly all patients. Brain MRI shows progressive cerebellar atrophy starting at the age of 7–8 years. DNA testing of the ATM gene is necessary for the diagnosis. The detected biallelic pathogenic variants provide help for family planning and for possible gene therapies in the future. Ataxia telangiectasia has to be differentiated from a number of other disorders, some of which also belong to primary immune deficiencies. The disorder has no causal treatment at present, the patients live until their young adult ages. Orv Hetil. 2018; 159(49): 2057–2064.

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An atypical presentation of ataxia telangiectasia in a school-aged boy secondary to an intronic mutation

LymphoSign Journal ◽

10.14785/lymphosign-2020-0004 ◽

2020 ◽

Vol 7 (2) ◽

pp. 57-60

Author(s):

Ori Scott ◽

Yael Dinur-Schejter ◽

Julia Upton ◽

Stephen Feanny

Keyword(s):

Splice Site ◽

Ataxia Telangiectasia ◽

Late Onset ◽

Gene Sequencing ◽

Splice Site Mutation ◽

Site Mutation ◽

Intronic Mutation ◽

Progressive Cerebellar Ataxia ◽

Atm Gene ◽

High Index Of Suspicion

Background: Ataxia telangiectasia typically presents in early pre-school years with progressive cerebellar ataxia and oculocutaneous telangiectasias. Referral to Immunology is often made after diagnosis has been established, as patients are prone to both humoral and cellular immune abnormalities. Case presentation: We herein report a 10-year old boy, previously undiagnosed, who presented with recurrent pneumonias. On history, frequent falls and speech difficulty were reported, with no telangiectasias on exam. Screening with alpha-fetoprotein was abnormal, followed by ATM gene sequencing, showing a homozygous intronic mutation. Over the next 3 years the patient deteriorated neurologically, and developed appreciable telangiectasias. Conclusion: A review of the literature demonstrates that intronic/splicing mutations may result in atypical ataxia telangiectasia phenotypes and delayed presentations. We advise immunologists to have a high index of suspicion for ataxia telangiectasia when assessing a patient with immunodeficiency and neurologic regression, regardless of age, and even in the absence of telangiectasias. Statement of novelty: We present a case of phenotypically atypical (“leaky”) ataxia telangiectasia resulting from a novel homozygous splice-site mutation in the ATM gene. Given high reported prevalence of intronic and splice-site mutations in ATM, we recommend full gene sequencing in patients suspected to have ataxia telangiectasia, especially in those with late onset or unusual manifestations.

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Association of Ataxia Telangiectasia Mutated (ATM) Gene Mutation/Deletion with Rhabdomyosarcoma

Cancer Biology & Therapy ◽

10.4161/cbt.231 ◽

2003 ◽

Vol 2 (1) ◽

pp. 88-92 ◽

Cited By ~ 9

Author(s):

Peilin Zhang ◽

Kunjan S. Bhakta ◽

Pier Lorenzo Puri ◽

Robert Newbury ◽

James Feramisco ◽

...

Keyword(s):

Gene Mutation ◽

Ataxia Telangiectasia ◽

Ataxia Telangiectasia Mutated ◽

Atm Gene

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Ataxias with Autosomal, X-Chromosomal or Maternal Inheritance

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100007733 ◽

2009 ◽

Vol 36 (4) ◽

pp. 409-428 ◽

Cited By ~ 25

Author(s):

Josef Finsterer

Keyword(s):

Ataxia Telangiectasia ◽

Large Scale ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

Late Onset ◽

Fragile X ◽

Axonal Neuropathy ◽

Friedreich Ataxia ◽

Point Mutations ◽

Spinocerebellar Ataxias

Heredoataxias are a group of genetic disorders with a cerebellar syndrome as the leading clinical manifestation. The current classification distinguishes heredoataxias according to the trait of inheritance into autosomal dominant, autosomal recessive, X-linked, and maternally inherited heredoataxias. The autosomal dominant heredoataxias are separated into spinocerebellar ataxias (SCA1-8, 10-15, 17-23, 25-30, and dentato-rubro-pallido-luysian atrophy), episodic ataxias (EA1-7), and autosomal dominant mitochondrial heredoataxias (Leigh syndrome, MIRAS, ADOAD, and AD-CPEO). The autosomal recessive ataxias are separated into Friedreich ataxia, ataxia due to vitamin E deficiency, ataxia due to Abeta-lipoproteinemia, Refsum disease, late-onset Tay-Sachs disease, cerebrotendineous xanthomatosis, spinocerebellar ataxia with axonal neuropathy, ataxia telangiectasia, ataxia telangiectasia-like disorder, ataxia with oculomotor apraxia 1 and 2, spastic ataxia of Charlevoix-Saguenay, Cayman ataxia, Marinesco-Sjögren syndrome, and autosomal recessive mitochondrial ataxias (AR-CPEO, SANDO, SCAE, AHS, IOSCA, MEMSA, LBSL CoQ-deficiency, PDC-deficiency). Only two of the heredoataxias, fragile X/tremor/ataxia syndrome, and XLSA/A are transmitted via an X-linked trait. Maternally inherited heredoataxias are due to point mutations in genes encoding for tRNAs, rRNAs, respiratory chain subunits or single large scale deletions/duplications of the mitochondrial DNA and include MELAS, MERRF, KSS, PS, MILS, NARP, and non-syndromic mitochondrial disorders. Treatment of heredoataxias is symptomatic and supportive and may have a beneficial effect in single patients.**Please see page 424 for abbreviation list.

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Patient with ataxia telangiectasia undergoing elective staging laparoscopy: a case report and literature review

Journal of the Pakistan Medical Association ◽

10.47391/jpma.01740 ◽

2021 ◽

Vol 71 (11) ◽

pp. 2656-2658

Author(s):

Muhammad Adeel Bashir ◽

Huma Saleem

Keyword(s):

Ataxia Telangiectasia ◽

Autosomal Recessive ◽

Perioperative Management ◽

Rare Condition ◽

Staging Laparoscopy ◽

Recurrent Infections ◽

Ataxia Telangiectasia Mutated ◽

Atm Gene ◽

Autosomal Recessive Condition ◽

Insight Into

Ataxia telangiectasia is a rare autosomal recessive condition which develops due to a mutation in the ataxia telangiectasia mutated gene (ATM gene). As a result of this mutation, the ability of the DNA to undergo repair is undermined. The resulting cellular demise is responsible for the diverse presentation of the clinical condition. Neurological symptoms such as cerebellar ataxia, abnormal eye movements and malignancies occur commonly. Immunodeficiency predisposes these patients to recurrent infections. Perioperative management of patients with this rare condition can be associated with increased morbidity. Therefore, it is recommended that patients with ataxia telangiectasia should be managed in a multidisciplinary center, under the supervision of senior clinicians who have the insight into the clinical needs of such patients. We report herein, the perioperative management of a patient with Ataxia telangiectasia undergoing laparoscopic procedure. Continuous....

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