Ataxia telangiectasia (AT) and ataxia oculomotor apraxia type 2 (AOA2) are autosomal recessive ataxias caused by mutations in genes involved in maintaining DNA integrity. Lifespan in AT is greatly shortened (20s-30s) due to increased susceptibility to malignancies (leukemia/lymphoma). Lifespan in AOA2 is uncertain. We describe a woman with variant AT with two novel mutations in ATM (IVS14+2T>G and 5825C>T, p.A1942V) who died at age 48 with pancreatic adenocarcinoma. Her mutations are associated with an unusually long life for AT and with a cancer rarely associated with that disease. We also describe two siblings with AOA2, heterozygous for two novel mutations in senataxin (3 bp deletion c.343-345 and 1398T>G, p.I466M) who have survived into their 70s, allowing us to characterize the longitudinal course of AOA2. In contrast to AT, we show that persons with AOA2 can experience a prolonged lifespan with considerable motor disability.

Ataxia-telangiectasia is a multisystem disorder characterized by progressive neurologic impairment, variable immunodeficiency, impaired organ maturation, x-ray hypersensitivity, oculocutaneous telangiectasia, and a predisposition to malignancy. To evaluate clinical and immunologic features of Iranian patients with ataxia-telangiectasia, the records of 104 patients with ataxia-telangiectasia (54 male, 50 female) with the age range of 1.6-23.5 years were reviewed. The Iranian Primary Immunodeficiency Registry was used as the data source. Progressive ataxia was seen in all the patients. Other symptoms were eye movement disorders (n = 84), slurred speech (n = 70), mental retardation (n = 10), and ocular (n = 87) and cutaneous (n = 73) telangiectasia. Three patients developed leukemia and lymphoma, and 17 patients had family history of malignancy. Positive correlation was seen between clinical immunologic symptoms and immunoglobulin deficiencies (P = 0.004). The predominant infections were sinopulmonary and acute and recurrent infections (78 cases). Infections included pneumonia (56 patients), otitis media (34 patients), and sinusitis (50 patients). Average serum alpha-fetoprotein level was 149 +/- 137 ng/dL. The incidence of ataxia-telangiectasia in Iran is high, possibly due to familial marriages. Treatment should be focused on supportive management to prolong survival.

BACKGROUND:

Ataxia-telangiectasia is a multisystem, life-limiting, recessively inherited genetic disorder caused by mutations in the Ataxia-telangiectasia mutated gene. It is characterized by the onset of changes in neurological and immunological development, organ maturation in childhood, as well as a high incidence of malignancies.

CASE:

We describe a case of an 11-year-old girl with a history of progressive ataxia and new finding of bilateral pelvic masses. Given an elevated alpha-fetoprotein, the pre-operative working diagnosis was a malignant germ cell tumor. Final ovarian pathology revealed a non-Hodgkin B-cell lymphoma with Burkitt-like morphology.

SUMMARY:

We present the first case of a primary ovarian non-Hodgkin B-cell lymphoma in a child with Ataxia-telangiectasia.

Copyright © 2013 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

Ataxia telangiectasia (A-T) is a rare autosomal recessive multisystem disease. The diagnosis of A-T is based on the typical clinical picture: ataxia and telangiectasia. However, an increase in (alpha-fetoprotein (AFP) level and the identification of the A-T mutated gene (ATM) assist in an early diagnosis. Here we report two cases of A-T diagnosed in our hospital (case 1: a 7-year-old boy; case 2: an 8-year-old girl). Both of these patients had typical clinical pictures of ataxia and telangiectasia, AFP was also increased (case 1:471.2 ng/dL; case 2: 196 ng/dL). T-cell dysfunction was noted in both patients. Case 1 had IgG2 deficiency and case 2 had IgA, IgG2 and IgG3 deficiency. Case 2 developed malignant lymphoma at 9 years of age and died of pneumonia with respiratory failure at 10 years of age. Because of rhe rarity of A-T in Taiwan, we report two cases to help pediatricians make an early diagnosis of A-T if they have a patient with progressive ataxia and oculocutaneous telangiectasia.

We report four patients with ataxia-telangiectasia syndrome that presented varied neurologic evolution. Three patients initially presented neurologic alterations of slow progression, evolving to late immunocompromised conditions. The fourth patient presented, from symptom onset, immune and neurologic debilitation, that were both severe and of fast progression. The chronological sequence of the most commonly observed immunocompromised conditions were in our patients, in ascending order, IgA deficiency, IgG2 deficiency and the neutrophil phagocytosis stage and common variable immunodeficiency. The first two reports are of sisters in whom the diagnosis was done between the ages of three and six years, having ocular apraxia, cerebellar ataxia and telangiectasia. Slow progression of neurologic debilitation was observed, without presentation of intermittent infections. The patients began presenting accentuated immunocompromised conditions at the ages of 14 and 17 years, dying at the ages of 16 and 20 years, respectively, due to severe infections that were resistant to treatment. The diagnosis of the third case was established when the patient was two years old, presenting ataxia and telangiectasia. Syndrome progression was slow, presenting at the age of eight years more accentuated neurologic disorders and IgA deficiency. The fourth case presented significant neurologic compromise at the age of five, simultaneous to IgA and IgG2 deficiency, and repeating pneumonias and sinusitis. At this time, intravenous gammaglobulin reposition was done. The neurologic and immune disorders progressed rapidly, and at the age of eight presented the inability to walk. At this time inversion of the CD4/CD8 ration was verified through laboratory tests.

Ataxia telangiectasia is a multisystem disease with an autosomal recessive inheritance. It is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, humoral and cellular immunodeficiencies and high incidence of neoplasia and radiosensitivity. A 5 year retrospective survey included 24 patients belonging to 17 families. Cerebellar ataxia was the first clinical symptom and was usually noticed when the child began to walk. Mean age of onset was 2.9+/-1.8 years. Oculocutaneous telangiectasia was present in 17 cases and appeared between 2 and 8 years and then spread in a characteristic symmetrical pattern. When ocular telangiectasia was absent (6 cases), the diagnostic of ataxia telangiectasia was retained on oculomotor apraxia (2 cases), recurrent sinopulmonary infections (3 cases) and/or a sib with typical ataxia telangiectasia (1 case). Recurrent sinopulmonary infections, absence or low serum level of IgA (78 p.100) and lymphopenia revealed immunodeficiency. Among 12 patients, chromosomal instability was observed in 5. Balanced rearrangements involving chromosomes 2, 7, 14, 22, 1, 3 and 11. The responsible gene, ATM, encodes a large protein kinase with a phosphatidylinositol 3-kinase-like domain. Ataxia telangiectasia patients have a 100 fold higher risk of cancer than the general population. We reported, in the same family two patients who developed neoplasia, (lymphoma and leukemia). During follow-up, a progressive worsening was observed in all cases. Three patients have died.

Ataxia-telangiectasia (A-T) is a rare multisystem, neurodegenerative genetic disorder. We present a case of a 6-year-old girl who had a history of frequent respiratory infections and also had ocular and immunological features of this syndrome. The absence of neurological symptoms, which is very unusual for a patient of this age, raised many difficulties in the diagnosis of the disease. It is concluded that a normal neurological assessment must not exclude the diagnosis of A-T and delay the proper interventional measures.

Ataxia-telangiectasia (AT) is an autosomal recessive inherited disease caused by mutational inactivation of the ATM gene. It is a multisystemic disease, characterized by progressive neurological dysfunction, especially in the cerebellum, oculo-cutaneous telangiectasia, immunodeficiency, recurrent sino-pulmonary infections and high incidence of neoplasms. The responsible gene, ATM, encodes a large protein that belongs to a family of protein kinases with a phosphatidylinositol 3-kinase (Pi3K) domain. ATM is a key regulator of cell cycle checkpoints that causes DNA repair or apoptosis. Several studies report ATM function in target cells (such as neurons, fibroblast, endothelium, germ cells, lymphocytes). The pleiotropic phenotypes of AT reflect the multifaceted activities of ATM protein. In nucleus (lymphocytes, fibroblasts, germ cells) ATM is involved in regulation of cell-cycle checkpoints; in cytoplasm ATM regulates redox state (neurons).

BACKGROUND:

Ataxia telangiectasia (AT) is one of the combined immunodeficiency syndromes with immunologic, neurologic, endocrinologic, hepatic and cutaneous abnormalities. Regarding the fact that autoimmune disorders; such as autoimmune hemolytic anemia (AIHA), are not generally expected in the course of AT, we present a patient with an unusual presentation of these two conditions.

CASE PRESENTATION:

An otherwise seemingly normal girl, who had developed limping at the age of 11 months old, referred to Namazi Hospital, Shiraz, Iran, due to pallor and latitude at the age of 3 yrs and was diagnosed of AIHA. After 2 years of therapeutic course she developed ocular telangiectasia and ataxic gate.

CONCLUSION:

This case emphasizes on the possibility of ataxia telangiectasia coexistence with autoimmune disorders that must be taken into consideration by physicians.

Allogeneic hematopoietic stem cell transplantation (HSCT) has not been a therapeutic option in ataxia telangiectasia (AT) due to overwhelming toxicity of conditioning in the context of the global DNA repair deficiency. Furthermore HSCT is unable to cure neurological involvement of AT. We report on a Turkish child with a Hyper IgM phenotype disorder, in which clinical aspects of AT were absent and thus, AT not diagnosed. He was transplanted with a reduced toxicity, but full intensity conditioning regimen comprising treosulfan, fludarabine and ATG. The peritransplant period was uneventful and the patient was discharged at day +57. 8 months after HSCT, the patient developed hepatopathy with monoclonal gammopathy of unclear significance and died due to hepatic failure and encephalopathy at the age of 32 months. Post mortem high throughput sequencing revealed a mutation in the ATM gene.

Ataxia-telangiectasia, a genetic disease caused by the homozygous mutation of the ATM gene, is frequently associated to a deficit of humoral and cellular immune functions. A decreased thymic output and skewed T cell and B cell receptor repertoires have been recently described in children over 7 years of age and in adults with this disease and have been proposed as a possible explanation for the immunodeficiency. To understand whether T cell defects arise early in life as a consequence of ATM gene mutations, we analysed the extent of thymic function by measuring the number of naïve T cells and by studying the heterogeneity of T cells by means of heteroduplex analysis, in two children less than 2 years old with a remarkable reduction of T cell count. We found that the thymic output is decreased in babies with ataxia-telangiectasia if compared with that observed in age-matched normal babies. The low production of new T cells is associated to a reduction of the diversity of alpha/beta, but not gamma/delta, T lymphocytes. Our data indicate that ATM mutation limits the generation of a wide alpha/beta T cell repertoire and this feature can be responsible for the immunodeficiency observed in ataxia-telangiectasia babies.

Mutations of the ataxia-telangiectasia-mutated (ATM) gene are responsible for the autosomal recessive disorder ataxia-telangiectasia(A-T). This study reports the first A-T prenatal diagnosis performed in Spain by direct molecular analysis. The pregnant woman had a previous child suffering from A-T due to a deletion in the ATM gene. The ATM coding region was sequenced in the A-T patient and her parents. Then, a specific polymerase chain reaction (PCR) to detect the deletion was performed for prenatal diagnosis. Additionally, polymorphic HLA loci were examined in order to exclude the possible contamination by maternal DNA. In this family of Gypsy origin, we carried out a rapid molecular diagnosis of A-T. Then, a prenatal diagnosis was carried out, identifying the deletion in the fetal DNA. Additionally, we performed a population study in unrelated Spanish Gypsies and in unrelated controls, showing that the deletion described could be a hotspot in the Spanish Gypsy population. The size of the coding region and the genomic structure, together with the absence of hotspots, make the mutation screening of the ATM gene difficult. The ability to identify ATM mutations provides a tool that can be applied in confirmatory diagnosis, genetic counselling, carrier prediction and prenatal diagnosis.

BACKGROUND:

Ataxia telangiectasia mutated (ATM) gene plays a key role in response to DNA lesions and is related to the invasion and metastasis of malignancy. Epidemiological studies have indicated associations between ATM rs1801516 polymorphism and different types of cancer, but their results are inconsistent. To further evaluate the effect of ATM rs1801516 polymorphism on cancer risk, we conducted this meta-analysis.

METHODS:

Studies were identified according to specific inclusion criteria by searching PubMed, Web of Science, and Embase databases. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) under recessive, dominant, codominant, and overdominant models of inheritance were calculated to estimate the association between rs1801516 polymorphism and cancer risk.

RESULTS:

A total of 37 studies with 12,879 cases and 18,054 controls were included in our study. No significant association was found between rs1801516 polymorphism and cancer risk in overall comparisons (AA vs GG + GA: OR = 0.91, 95% CI, 0.78-1.07; AA+GA vs GG: OR = 1.00, 95% CI, 0.90-1.11; AA vs GG: OR = 0.89, 95% CI, 0.75-1.06; GA vs GG: OR = 1.01, 95% CI, 0.91-1.13; GG + AA vs GA: OR = 1.00, 95% CI, 0.88-1.10). However, after subgroup analyses by region-specified population, significant associations were found in European (AA vs GG + GA: OR = 0.79, 95% CI, 0.65-0.96, P = 0.017; AA vs GG: OR = 0.79, 95% CI, 0.65-0.96, P = 0.017), South American (AA+GA vs GG: OR = 2.15, 95% CI, 1.37-3.38, P = 0.001; GA vs GG: OR = 2.19, 95% CI, 1.38-3.47, P = 0.001; GG + AA vs GA: OR = 0.46, 95% CI, 0.29-0.72, P = 0.001), and Asian (AA vs GG + GA: OR = 7.45, 95% CI, 1.31-42.46, P = 0.024; AA vs GG: OR = 7.40, 95% CI, 1.30-42.19, P = 0.024). Subgroup analyses also revealed that compared with subjects carrying a GG genotype, those carrying a homozygote AA had a decreased risk for breast cancer (AA vs GG: OR = 0.76, 95% CI, 0.59-0.98, P = 0.035), and the homozygote AA was associated with decreased cancer risk in subjects with family history (AA vs GG: OR = 0.68, 95% CI, 0.47-0.98, P = 0.039).

CONCLUSIONS:

ATM rs1801516 polymorphism is not associated with overall cancer risk in total population. However, for subgroup analyses, this polymorphism is especially associated with breast cancer risk; in addition, it is associated with overall cancer risk in Europeans, South Americans, Asians, and those with family history.

BACKGROUND:

The onset of progressive cerebellar ataxia in early childhood is considered a key feature of ataxia-telangiectasia (A-T), accompanied by ocular apraxia, telangiectasias, immunodeficiency, cancer susceptibility and hypersensitivity to ionizing radiation.

METHODS:

We describe the clinical features and course of three Mennonite children who were diagnosed with A-T following the completion of therapy for lymphoid malignancies.

RESULTS:

Prior to cancer therapy, all had non-progressive atypical neurological abnormalities, with onset by age 30 months, including dysarthria, dyskinesia, hypotonia and/or dystonia, without telangiectasias. Cerebellar ataxia was noted in only one of the children and was mild until his death at age eight years. None had severe infections. All three children were "cured" of their lymphoid malignancies, but experienced severe adverse effects from the treatments administered. The two children who received cranial irradiation developed supratentorial primitive neuroectodermal tumors of the brain, an association not previously described, with fatal outcomes.

CONCLUSIONS:

The range of neurological presentations of A-T is broad. Ataxia and telangiectasias may be minimal or absent and the course seemingly non-progressive. The diagnosis of A-T should be considered in all children with neuromotor dysfunction or peripheral neuropathy, particularly those who develop lymphoid malignancies. The consequences of missing the diagnosis may be dire. Radiation therapy and radiomimetic drugs should be avoided in individuals with A-T.

Ataxia-telangiectasia (A-T) is a rare disease characterized by neurodegenerative alterations, telangiectasia, primary immunodeficiency, extreme sensitivity to radiation, and susceptibility to neoplasms. A-T patients have inactivation of ataxia-telangiectasia-mutated (ATM) protein, which controls DNA double-strand break repair and is involved in oxidative stress response, among other functions; dysfunctional control of reactive oxygen species may be responsible for many of the clinical manifestations of this disease. To the best of our knowledge, hepatic lesions of steatohepatitis have not previously been reported in A-T patients. The present study reports the case of a 22-year-old man diagnosed with A-T at the age of 6 years who was referred to our Digestive Disease Unit with a three-year history of hyperlipidemia and liver test alterations. Core liver biopsy showed similar lesions to those observed in nonalcoholic steatohepatitis. Immunohistochemical staining disclosed the absence of ATM protein in hepatocyte nuclei. We suggest that the liver injury may be mainly attributable to the oxidative stress associated with ATM protein deficiency, although other factors may have made a contribution. We propose the inclusion of A-T among the causes of nonalcoholic steatohepatitis, which may respond to antioxidant therapy.

The elevated serum alpha fetoprotein (AFP) concentration in ataxia-telangiectasia (A-T) patients has been known for decades, but the individual variation of AFP levels over time has not been studied. We have followed 12 patients (five girls and seven boys) for 1-12 years (mean 5.5 years) measuring in each patient AFP 2-8 (mean 4) times. Serum AFP levels were increased in all patients, mean 168.7 (range 40-373) kU/L, and without significant differences between the patients. There was a significant age related difference in the serum AFP level. A positive linear relationship (r=0.61, p=0.04) could be found between AFP level and age. Albumin levels were within normal range and did not change with age. Four patients had slightly increased aspartate aminotransferase (AST) levels. None of the patients had serological evidence of infectious hepatitis, and none had increased levels of carcinoembryonic antigen. Repeated standardized observations of gait function revealed no major difference in neurological deterioration between our patients. All had classical A-T disease and mainly truncating mutations; 21 out of 24 possible mutations were either frameshift or nonsense. Four were homozygous for the Norwegian ATM founder mutation. No correlation between serum AFP levels and the different ATM genotypes could be found. We conclude that serum AFP is not only elevated, but also is continuously increasing with age in patients with classical A-T disease.