Variant ataxia telangiectasia identified during evaluation for short stature.

Ataxia telangiectasia (A-T) (OMIM 208900) is an autosomal recessive multisystem disorder characterised by progressive cerebellar ataxia, telangiectasias, immunodeficiency and a predisposition to malignancy. 'Variant' A-T has later onset of neurological symptoms and slower progression compared with the 'classic' form. A woman presented with short stature in late childhood. Karyotype revealed rearrangements involving chromosomes 7 and 14. A chromosomal breakage disorder gene panel demonstrated compound heterozygote mutations in her ATM gene including one mutation c.7271T>G with residual ATM function, confirming the diagnosis of variant A-T. Since diagnosis, she has developed progressive cerebellar ataxia and telangiectasias. Long-standing restrictive and aversive feeding behaviours presented challenges for her management and necessitated gastrostomy.

Videoocular assessment of eye movement activity in an ataxia-telangiectasia: a case study.

PURPOSE: Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by progressive neurological deficits, including prominent oculomotor dysfunction. We report 5 cases of eye movement assessment in children 9-15 years old with A-T. METHODS: Three different oculomotor tasks (gaze holding, visually guided saccades and visual search) were used, and video-oculography was performed. Additionally, the scale for the assessment and rating of ataxia (SARA) score was used to assess severity of the cerebellar ataxia. RESULTS: Unstable gaze holding, nystagmus and saccadic intrusions were found. In addition to psychophysiological assessment results, we provide quantitative analysis of oculomotor activity, revealing a specific abnormal oculomotor pattern, consisting of (i) marked saccade hypermetria, (ii) unstable gaze holding, and (iii) gaze-evoked nystagmus. CONCLUSION: Our study opens the prospect to evaluate efficacy and safety of alternative methods for supporting the patient and improving his/her life quality.

Patient-Reported Outcomes and Medical Provider Satisfaction Among Adult and Pediatric Ataxia-Telangiectasia Patients.

PURPOSE: Ataxia-telangiectasia (A-T) is a rare genetic condition with malfunctioning DNA repair processes resulting in significant clinical findings, including progressive neurologic decline, elevated malignancy risk, immunodeficiency, oculocutaneous telangiectasias, and severe pulmonary disease. Research has been limited into the quality of life of such patients and yet to be completed are studies quantitatively analyzing psychosocial, physical, and cognitive patient-reported outcomes (PROs) within the A-T population. METHODS: PRO evaluations of 90 international adult and pediatric A-T patients and their caregivers were completed via secure online administration of Patient-Reported Outcomes Measurement Information System (PROMIS) short forms evaluating anger, cognition, mood, social health, fatigue, pain, anxiety, and upper extremity function. The impact of age, gender, race/ethnicity, prior malignancy diagnosis, and current supportive treatment interventions on such PROs was additionally assessed. Finally, given the importance of medical providers in the care of A-T patients and the impact of patient satisfaction on healthcare outcomes, we further analyzed, via a novel survey, how patients and caregivers perceived their primary A-T healthcare provider's A-T expertise, trustworthiness, accessibility, and level of compassion. RESULTS/CONCLUSION: It was found that a diagnosis of A-T complexly impacts patient PROs, but such data offers the potential for preventative and therapeutic interventions to improve the care of such patients. While most A-T patients and their caregivers feel their primary A-T medical provider has expertise and compassion in addition to being accessible and trustworthy, a significant percentage of study subjects did not agree that their provider was an expert in A-T or overall trustworthy.

Correlation Between the SARA and A-T NEST Clinical Severity Scores in Adults with Ataxia-Telangiectasia.

Ataxia-Telangiectasia (A-T) is an autosomal recessive neurodegenerative disease associated with cerebellar ataxia and extrapyramidal features. A-T has a complex and diverse phenotype with varying rates of disease progression. The development of robust natural history studies and therapeutic trials relies on the accurate recording of phenotype using relevant and validated severity of illness indexes. We compared the commonly used Scale for the Assessment and Rating of Ataxia (SARA) and the disease-specific A-T Neurological Examination Scale Toolkit (A-T NEST), in our adult A-T cohort. We found a strong correlation between A-T NEST and the established SARA score, validating the use of A-T NEST and SARA in capturing the natural history of A-T patients.

The Care and Management of Children and Young People with Ataxia Telangiectasia Provided by Nurses and Allied Health Professionals: a Scoping Review.

Ataxia telangiectasia (A-T) is a rare, multisystem progressive condition that typically presents in early childhood. In the absence of cure, people with A-T require coordinated multidisciplinary care to manage their complex array of needs and to minimize the disease burden. Although symptom management has proven benefits for this population, including improved quality of life and reduced complications, there is a need for guidance specific to the nursing and allied healthcare teams who provide care within the community. A scoping review, adopting the Joanna Briggs Institute methodology, was undertaken. It aimed to identify and map the available expertise from nursing and allied healthcare and management of children and young people with A-T ≤ 18 years of age. A rigorous search strategy was employed which generated a total of 21,118 sources of evidence, of which 50 were selected for review following screening by experts. A range of interventions were identified that reported a positive impact on A-T-related impairments, together with quality of life, indicating that outcomes can be improved for this population. Most notable interventions specific to A-T include therapeutic exercise, inspiratory muscle training, and early nutritional assessment and intervention. Further research will be required to determine the full potential of the identified interventions, including translatability to the A-T setting for evidence related to other forms of ataxia. Large gaps exist in the nursing and allied health evidence-base, highlighting a need for robust research that includes children and young people with A-T and their families to better inform and optimize management strategies.

Ataxia-telangiectasia and combined hepatocellular-cholangiocarcinoma: A case report.

Ataxia-telangiectasia (A-T) is a rare autosomal recessive disease characterized by ataxia, cutaneous and ocular telangiectasia, impaired immunity with susceptibility to sino-pulmonary infections, radiation sensitivity, and cancers particularly of hemato-lymphoid origin. Liver function tests abnormalities and elevated alfa feto-protein have been reported in A-T; however, there is no reported case of combined hepatocellular-cholangiocarcinoma (cHCC-CC) in literature. These tumors should be treated in similar fashion as in general population; however, reduction of chemotherapy dose might be helpful in decreasing chemo-toxicity.

A child with polyarthritis and chronic lung disease: a case report of ataxia-telangiectasia.

BACKGROUND: Ataxia-telangiectasia (A-T) is a rare autosomal recessive DNA repair disorder, characterized by progressive cerebellar degeneration, telangiectasia, immunodeficiency, recurrent sinopulmonary infections, radiation sensitivity, premature aging and predisposition to cancer. Although the association with autoimmune and chronic inflammatory conditions such as vitiligo, thrombocytopenia and arthritis has occasionally been reported, an onset with articular involvement at presentation is rare. CASE PRESENTATION: We herein report the case of a 7-year-old Caucasian girl who was admitted to the Rheumatology Department with a history of febrile chough and polyarthritis which led initially to the suspicion of an autoinflammatory disease. She had overt polyarthritis with knees deformities and presented with severe pneumonia. A chest Computed Tomography (CT) scan showed bilateral bronchiectasis, parenchymal consolidation and interstitial lung disease; rheumatoid factor and type I interferon signature resulted negative, therefore excluding COatomer Protein subunit Alpha (COPA) syndrome. A diagnosis of sarcoidosis had been suspected based on histological evidence of granulomatous liver inflammation, but ruled out after detecting normal angiotensin converting enzyme and chitotriosidase blood levels. Based on her past medical history characterized by at least six episodes of pneumonia in the previous 4 years, immunological phenotyping was performed. This showed complete IgA and IgE deficiency with defective antigen-specific antibodies to Pneumococcal, Tetanus toxin and Hemophilus Influenzae B vaccines. Additionally, low numbers of B cells and recent thymic emigrants (RTE) were found (CD4Ra 1.4%), along with a low CD4+/CD8 + T cells ratio (< 1). Finally, based on gait disturbances (wobbly wide-based walking), serum alfa-fetoprotein was dosed, which resulted increased at 276 ng/ml (normal value < 7 ng/ml). A diagnosis of Ataxia-Telangiectasia was made, strengthened by the presence of bulbar telangiectasia, and then confirmed by Whole Exome Sequencing (WES). CONCLUSIONS: Although rare, A-T should always be ruled out in case of pulmonary bronchiectasis and gait disturbances even in the absence of bulbar or skin telangiectasia. Autoimmune and granulomatous disorders must to be considered as differential diagnosis.

Development of cancer surveillance guidelines in ataxia telangiectasia: A Delphi-based consensus survey of international experts.

BACKGROUND/OBJECTIVES: Ataxia telangiectasia (A-T) is a multiorgan disorder with increased vulnerability to cancer. Despite this increased cancer risk, there are no widely accepted guidelines for cancer surveillance in people affected by A-T. We aimed to understand the current international practice regarding cancer surveillance in A-T and agreed-upon approaches to develop cancer surveillance in A-T. DESIGN/METHODS: We used a consensus development method, the e-Delphi technique, comprising three rounds. Round 1 consisted of a Delphi questionnaire and a survey that collected the details of respondents' professional background, experience, and current practice of cancer surveillance in A-T. Rounds 2 and 3 were designed based on previous rounds and modified according to the comments made by the panellists. The pre-specified consensus threshold was ≥75% agreement. RESULTS: Thirty-five expert panellists from 13 countries completed the study. The survey indicated that the current practice of cancer surveillance varies widely between experts and centres'. Consensus was reached that evidence-based guidelines are needed for cancer surveillance in people with A-T, with separate recommendations for adults and children. Statements relating to the tests that should be included, the age for starting and stopping cancer surveillance and the optimal surveillance interval were also agreed upon, although in some areas, the consensus was that further research is needed. CONCLUSION: The international expert consensus statement confirms the need for evidence-based cancer surveillance guidelines in A-T, highlights key features that the guidelines should include, and identifies areas of uncertainty in the expert community. This elucidates current knowledge gaps and will inform the design of future clinical trials.

Exploration of clinical and genetic findings in Ataxia-Telangiectasia (AT) patients from the Indian subcontinent.

BACKGROUND: Ataxia-Telangiectasia (AT) is a rare autosomal recessive neurodegenerative disorder. It is caused by mutations in the Ataxia-Telangiectasia mutated (ATM) gene, which codes for protein ATM serine/threonine kinase. OBJECTIVE: We aim to describe the clinical and radiological findings in children and adolescents of 20 molecularly confirmed cases of AT. We aim to correlate these findings with the genotype identified among them. METHODS: This retrospective study included 20 patients diagnosed clinically and genetically with AT over 10 years. The clinical, radiological and laboratory data were extracted from the hospital's electronic medical records. Molecular testing was done using next generation sequencing and Sanger sequencing. In silico predictions were performed for the variants identified by applying Cryp-Skip, Splice site prediction by Neural Network, Mutation Taster and Hope prediction tool. RESULTS: Consanguinity was documented in nearly half of the patients. Telangiectasia was absent in 10%. Microcephaly was seen in 40% cases. The incidence of malignancy in our study population was low. Molecular testing done in the 18 families (20 patients) identified 23 variants of which ten were novel. Biallelic homozygous variants were noted in 13 families and compound heterozygous in 5 families. Out of the 13 families who were homozygous, 8 families (61.5%) (9 patients) have history of consanguinity. In silico prediction of novel missense variants, NM_000051.4 (ATM_v201): c.2702T > C showed disruption of the α-helix of ATM protein and NM_000051.4 (ATM_v201): c.6679C > G is expected to disturb the rigidity of protein structure in the FAT domain. The four novel splice site variants and two intronic variants result in exon skipping as predicted by Cryp-Skip. CONCLUSIONS: AT should be confirmed by molecular testing in young-onset cerebellar ataxia, even without telangiectasia. Awareness of this rare disease will facilitate study of larger cohorts from Indian population to characterize variants and determine its prevalence in this population.

Homozygous ATM mutation due to germline uniparental isodisomy in patient with T acute lymphoblastic leukemia and hepatosplenic T-cell lymphoma.

Uniparental disomy has long been recognized as a significant cause of genetic disease in imprinting-associated conditions. More recently, it has increasingly been implicated as a potentially significant cause of autosomal recessive disease. Here we report a case of a patient with a history of leukemia and αß hepatosplenic T-cell lymphoma who was diagnosed with ataxia telangiectasia via paired tumor-germline testing at age 20. Germline testing detected a homozygous pathogenic variant in the ATM gene. Parental testing identified this variant only in the mother, leading to suspicion for non-paternity or an atypical cause of autosomal recessive disease. Additional analysis of the proband's sample identified a 54 megabase region at chr11q13.4-q25 with alleles all derived from a single parent, consistent with uniparental isodisomy as causative of autosomal recessive ataxia telangiectasia in this case. This report provides further evidence that uniparental isodisomy should be considered in the potential etiology of autosomal recessive conditions, including in the setting of paired tumor-germline testing. Confirming the method of inheritance is particularly important in cases such as this one where being a heterozygous carrier has medical management implications for cancer screening for relatives as well as for cascade testing and family planning for relatives.

The investigated case of etiology of chylous pleural effusion: Ataxia-telangiectasia.

Ataxia-telangiectasia is an autosomal recessive, rare, neurodegenerative multisystem disorder characterized by ataxia-telangiectasia, cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure associated with increased malignancy risk. Clinical diagnosis is made with ataxia-telangiectasia mutated (ATM) gene. Our case, who was diagnosed as ataxia-telangiectasia while investigating the etiology of chylous pleural effusion, is presented because of its rare occurrence.