Background and purpose: Ataxia-telangiectasia (A-T) is a rare, autosomal recessive, multisystem disorder that leads to progressive neurodegeneration with cerebellar ataxia and peripheral polyneuropathy. Cerebellar neurodegeneration is well described in A-T. However, peripheral nervous system involvement is an underdiagnosed but important additional target for supportive and systemic therapies. The aim of this study was to conduct neurophysiological measurements to assess peripheral neurodegeneration and the development of age-dependent neuropathy in A-T.

Methods: In this prospective study, 42 classical A-T patients were assessed. The motor and sensory nerve conduction of the median and tibial nerves was evaluated. Data were compared to published standard values and a healthy age- and gender-matched control group of 23 participants. Ataxia scores (Klockgether, Scale for the Assessment and Rating of Ataxia) were also assessed.

Results: In A-T, neurophysiological assessment revealed neuropathic changes as early as the first year of life. Subjective symptomatology of neuropathy is rarely described. In the upper extremities, motor neuropathy was predominantly that of a demyelinating type and sensory neuropathy was predominantly that of a mixed type. In the lower extremities, motor and sensory neuropathy was predominantly that of a mixed type. We found significant correlations between age and the development of motor and sensory polyneuropathy in A-T compared with healthy controls (p < 0.001).

Conclusions: In A-T, polyneuropathy occurs mostly subclinically as early as the first year of life. The current study of a large national A-T cohort demonstrates that development of neuropathy in A-T differs in the upper and lower extremities.

Introduction: Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disease with widespread systemic manifestations and marked variability in clinical phenotypes. In this study, we sought to determine whether transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) defines subsets of individuals with A-T beyond mild and classic phenotypes, enabling identification of novel features for disease classification and treatment response to therapy.

Methods: Participants with classic A-T (n = 77), mild A-T (n = 13), and unaffected controls (n = 15) were recruited from two outpatient clinics. PBMCs were isolated and bulk RNAseq was performed. Plasma was also isolated in a subset of individuals. Affected individuals were designated mild or classic based on ATM mutations and clinical and laboratory features.

Results: People with classic A-T were more likely to be younger and IgA deficient and to have higher alpha-fetoprotein levels and lower % forced vital capacity compared to individuals with mild A-T. In classic A-T, the expression of genes required for V(D)J recombination was lower, and the expression of genes required for inflammatory activity was higher. We assigned inflammatory scores to study participants and found that inflammatory scores were highly variable among people with classic A-T and that higher scores were associated with lower ATM mRNA levels. Using a cell type deconvolution approach, we inferred that CD4 + T cells and CD8 + T cells were lower in number in people with classic A-T. Finally, we showed that individuals with classic A-T exhibit higher SERPINE1 (PAI-1) mRNA and plasma protein levels, irrespective of age, and higher FLT4 (VEGFR3) and IL6ST (GP130) plasma protein levels compared with mild A-T and controls.

Conclusion: Using a transcriptomic approach, we identified novel features and developed an inflammatory score to identify subsets of individuals with different inflammatory phenotypes in A-T. Findings from this study could be used to help direct treatment and to track treatment response to therapy.

Keywords: Bioinformatics; Genetic diseases; T cells.

Introduction: Ataxia telangiectasia (AT) is a rare disorder characterized by neurodegeneration, combined immunodeficiency, a predisposition to malignancies, and high clinical variability. Profiling of microRNAs (miRNAs) may offer insights into the underlying mechanisms of complex rare human diseases, as miRNAs play a role in various biological functions including proliferation, differentiation, and DNA repair. In this study, we investigate the differential expression of miRNAs in samples from AT patients to identify miRNA patterns and analyze how these patterns are related to the disease.

Methods: We enrolled 20 AT patients (mean age 17.7 ± 9.6 years old) and collected clinical and genetic data. We performed short non-coding RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) and fibroblasts to compare the miRNA expression profile between AT patients and controls.

Results: We observed 42 differentially expressed (DE)-miRNAs in blood samples and 26 in fibroblast samples. Among these, three DE-miRNAs, miR-342-3p, miR-30a-5p, and miR-195-5p, were further validated in additional AT samples, confirming their dysregulation.

Discussion: We identified an AT-related miRNA signature in blood cells and fibroblast samples collected from a group of AT patients. We also predicted several dysregulated pathways, primarily related to cancer, immune system control, or inflammatory processes. The findings suggest that miRNAs may provide insights into the pathophysiology and tumorigenesis of AT and have the potential to serve as useful biomarkers in cancer research.

Ataxia Telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disease caused by mutations in the ataxia telengiectasia mutated (ATM) gene. The gene is on chromosome 11q22-23 and codes for the protein kinase ATM, which plays an essential role in DNA damage repair. In this study, we review the clinical characteristics of 13 A-T patients, 2 of whom displayed novel mutations. Thirteen patients with ataxia-telangiectasia from 10 unrelated families were referred to Immunology, Asthma and Allergy Research Institute, Tehran, Iran. After clinical confirmation, blood samples were collected from the patients and their parents. Genetic analysis for 8 patients was conducted using whole-exome sequencing; in the other 3 patients, polymerase chain reaction was used, followed by sequencing. We identified 11 different mutations in the ATM gene. Two patients had mutations as compound heterozygous, while 9 other patients were homozygous for the mutations. Among these, 2 likely pathogenic mutations (ie, c.2639-1G>A and c.7940_7970del​TTCCAGCAGA​CCAGCCAATT​ACTAAACTTAA) have not been reported. Our study highlights the significance of next-generation sequencing techniques in identifying novel ATM mutations in A-T patients. Although all reported A-T mutations reside in 1 gene, the absence of a mutation hotspot for this gene necessitates the use of next-generation sequencing techniques. Specifically, we identified 2 mutations that have not been reported previously, emphasizing the importance of continued research in this area. This study provides new insights into the genetic underpinnings of A-T and underscores the potential clinical implications of identifying novel mutations.

Background and aim: Ataxia-telangiectasia (AT) and ataxia-oculomotor apraxia type 2 (AOA2) are both autosomal recessive cerebellar ataxias characterized by elevated serum alpha-fetoprotein (AFP) levels. However, the source and clinical implications of this increase, as well as its relationship with liver diseases are unknown. In this study, we investigated the frequency of liver diseases and their relationship with high AFP in patients with AT and AOA2.

Materials and methods: The study involved 19 adult patients (13 patients with AT and 6 patients with AOA2) who were followed between January 1992 and March 2023. The demographic and clinical characteristics, serum levels of liver enzymes and AFP, liver imaging, and survival data were retrospectively reviewed.

Results: The mean age of patients was 26.8±5.1 years (11 men and 8 women).While 69% (9/13) of AT patients had elevated liver enzymes and 56% (5/9) had abnormal liver imaging, both were normal in all AOA2 patients.Liver enzyme elevation was associated with the presence of comorbid disease (p=0.007), but not with AFP level (p=0.33) in AT patients. Hepatosteatosis was not associated neither with comorbidity (p=0.524) nor AFP level (p=0.905) in this group. During a median follow-up of 17 (1-29) years, 5 AT patients passed away due to cancer (4 patients) and sepsis (1 patient). AFP level was not associated with the occurrence of cancer (p=0.382).

Conclusion: This study found a high prevalence of liver disease (69%) in AT, unlike in AOA, independent of AFP levels. Since comorbid diseases, especially cancer, were associated with elevated liver enzymes, adult AT patients with abnormal liver functions should be screened for the development of cancers.

Ataxia telangiectasia (A-T), caused by biallelic variants in the ATM gene, is a multisystemic and severe syndrome characterized by progressive ataxia, telangiectasia, hyperkinesia, immunodeficiency, increased risk of malignancy, and typically death before the age of 30. In this retrospective study we describe the phenotype of 14 pediatric and adult A-T patients evaluated at the Karolinska University Hospital in Sweden during the last 12 years. Most of the patients in this cohort were severely affected by ataxia and wheelchair use started at a median age of 9 years. One patient died before the age of 30 years, but five patients had survived beyond this age. Four patients received prophylactic immunoglobulin replacement therapy due to hypogammaglobulinemia and respiratory complications ranged from mild to moderate severity. Three patients developed type 2 diabetes in young adulthood and nine patients (64%) had a history of elevated liver function tests. Four patients were diagnosed with cancer at ages 7, 41, 47, and 49 years. All the ATM variants in these patients were previously reported as pathogenic except one, c.6040G > A, which results in a p.Glu2014Lys missense variant. With increased life expectancy, A-T complications such as diabetes type 2 and liver disease may become more common. Despite having severe neurological presentations, the A-T patients in this case series had relatively mild infectious and respiratory complications.

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.

Background: Ataxia-telangiectasia (A-T) is a DNA repair disorder characterized by changes in several organs and systems. Advances in clinical protocols have resulted in increased survival of A-T patients, however disease progression is evident, mainly through metabolic and liver changes.

Objective: To identify the frequency of significant hepatic fibrosis in A-T patients and to verify the association with metabolic alterations and degree of ataxia.

Methods: This is a cross-sectional study that included 25 A-T patients aged 5 to 31 years. Anthropometric data, liver, inflammatory, lipid metabolism and glucose biomarkers (oral glucose tolerance test with insulin curve-OGTT) were collected. The Cooperative Ataxia Rating Scale was applied to assess the degree of ataxia. The following were calculated: Homeostasis Model Assessment-Insulin Resistance, Homeostasis Model Assessment-Adiponectin (HOMA-AD), Matsuda index, aspartate aminotransferase (AST): platelet ratio index, nonalcoholic fatty liver disease fibrosis score and BARD score. Liver ultrasonography and transient liver elastography by FibroScan^® were performed.

Results: Significant hepatic fibrosis was observed in 5/25 (20%). Patients in the group with significant hepatic fibrosis were older (p < 0.001), had lower platelet count values (p = 0.027), serum albumin (p = 0.019), HDL-c (p = 0.013) and Matsuda index (p = 0.044); and high values of LDL-c (p = 0.049), AST (p = 0.001), alanine aminotransferase (p = 0.002), gamma-glutamyl transferase (p = 0.001), ferritin (p = 0.001), 120-min glycemia by OGTT (p = 0.049), HOMA-AD (p = 0.016) and degree of ataxia (p = 0.009).

Conclusions: A non-invasive diagnosis of significant hepatic fibrosis was observed in 20% of A-T patients associated with changes in liver enzymes, ferritin, increased HOMA-AD, and the severity of ataxia in comparison with patients without hepatic fibrosis.

Background: Ataxia-telangiectasia (A-T) is a rare autosomal-recessive multisystem disorder characterized by pronounced cerebellar ataxia, telangiectasia, cancer predisposition, and altered body composition. Liver diseases with steatosis, fibrosis, and hepatocellular carcinoma are frequent findings in older patients but sensitive noninvasive diagnostic tools are lacking.

Objectives: To determine the sensitivity of transient elastography (TE) as a screening tool for early hepatic tissue changes and serum biomarkers for liver disease.

Methods: Thirty-one A-T patients aged 2 to 25 years were examined prospectively from 2016-2018 by TE. In addition, we evaluated the diagnostic performance of liver biomarkers for steatosis and necroinflammatory activity (SteatoTest and ActiTest, Biopredictive, Paris) compared to TE. For calculation and comparison, patients were divided into two groups (<12, >12 years of age).

Results: TE revealed steatosis in 2/21 (10%) younger patients compared to 9/10 (90%) older patients. Fibrosis was present in 3/10 (30%) older patients as assessed by TE. We found a significant correlation of steatosis with SteatoTest, alpha-fetoprotein (AFP), HbA1c, and triglycerides. Liver stiffness correlated significantly with SteatoTest, ActiTest, HbA1c, and triglycerides.

Conclusion: Liver disease is a common finding in older A-T patients. TE is an objective measure to detect early stages of steatosis and fibrosis. SteatoTest and ActiTest are a good diagnostic assessment for steatosis and necroinflammatory activity in patients with A-T and confirmed the TE results.

Ataxia telangiectasia (A-T) is a devastating multi-system disorder characterized by progressive cerebellar ataxia, immunodeficiency, genetic instability, premature aging and growth retardation. Due to better care the patients get older than in the past and new disease entities like disturbed glucose tolerance and liver disease emerge. The objective of the present investigation is to determine the evolution of liver disease and its relation to age and neurological deterioration. The study included 67 patients aged 1 to 38 years with classical A-T. At least two measurements of liver enzymes were performed within a minimum interval of 6 months in 56 patients. The median follow-up period was 4 years (1-16 years). A total of 316 liver enzyme measurements were performed. For analysis, patients were divided into two age groups (Group 1: <12 years; group 2: ≥12 years). In addition, ultrasound of the liver and Klockgether Ataxia Score (KAS) were analyzed. We found significantly higher levels of alpha-fetoprotein (AFP) (226,8 ± 20.87 ng/ml vs. 565,1 ± 24.3 ng/ml, p < 0.0001), and liver enzymes like ALT (23.52 ± 0.77 IU/L vs. 87.83 ± 5.31 IU/L, p < 0.0001) in patients in group 2. In addition, we could show a significant correlation between age and AFP, GGT, and KAS. Ultrasound revealed hepatic steatosis in 11/19 (57.9%) patients in group 2. One female patient aged 37 years died due to a hepato-cellular carcinoma (HCC). Liver disease is present in the majority of older A-T patients. Structural changes, non-alcoholic fatty liver disease and fibrosis are frequent findings. Progress of liver disease is concomitant to neurological deterioration.

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.

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by neurodegeneration, combined immunodeficiency, and oculocutaneous telangiectasia. The hyper-IgM phenotype of A-T, correlating with a class-switch recombination defect, IgG and IgA deficiency, T helper and B cell lymphopenia, immune dysregulation, proinflammatory immune response, autoimmune disease, and a high risk of lymphomagenesis. Progressive liver disease is a hallmark of classical A-T with the hyper-IgM phenotype and manifests as non-alcoholic hepatic steatosis and fibrosis. We report a case of a 17-year-old male A-T patient, in whom a progressive granulomatous liver disease with portal hypertension, has led to massive splenomegaly and hypersplenism, metabolic liver insufficiency, bleeding from esophageal varices and pancytopenia. In this patient, an unusual severe disease course with a highly variable constellation of A-T symptomatology includes granulomatous skin, visceral, and internal organs disease with liver involvement. The liver disease is associated with the hyper-IgM immunophenotype and escalating neurodegeneration, creating a vicious circle of immune deficiency, permanent systemic inflammatory response, and organ-specific immunopathology.

Ataxia-telangiectasia (A-T) is an ultrarare autosomal recessive disorder and occurs in all racial and ethnic backgrounds. Clinically, children and young people with A-T are affected by sinopulmonary infections, neurological deterioration with concomitant bulbar dysfunction, increased sensitivity to ionizing radiation, immunodeficiency, a decline in lung function, chronic liver disease, endocrine abnormalities, cutaneous and deep-organ granulomatosis, and early death. Pulmonary complications become more frequent in the second decade of life and are a leading cause of death in individuals with A-T. Oropharyngeal dysphagia is common, progressive, and a risk factor for frequent respiratory infections. Immunodeficiency is non-progressive in most patients with A-T. If severe infections occur, one should be aware of other possible causes, such as aspiration. We provide an overview of current best practice recommendations, which are based on combinations of extrapolation from other diseases and expert opinion. These include proactive surveillance, monitoring, and early management to improve lung health in this devastating multisystem disease.

Ataxia telangiectasia is one of a group of recessive hereditary genomic instability disorders and is characterized by progressive neurodegeneration, immunodeficiency and cancer susceptibility. Heterozygotes for the mutated gene are more susceptible to cancer and to ischaemic heart disease. The affected gene, ATM (ataxia telangiectasia mutated), has been cloned and codes for a protein kinase (ATM), which orchestrates the cellular response to DNA double-strand breaks after ionising radiation. An underlying feature of ataxia telangiectasia is oxidative stress and there is chronic activation of stress response pathways in tissues showing pathology such as the cerebellum, but not in the cerebrum or liver. ATM has also been shown to be activated by insulin and to have a wider role in signal transduction and cell growth. Many, but not all, aspects of the phenotype can be attributed to a defective DNA damage response. The oxidative stress may result directly from accumulated DNA damage in affected tissues or ATM may have an additional role in sensing/modulating redox homeostasis. The basis for the observed tissue specificity of the oxidative damage in ataxia telangiectasia is not clear.