Transcriptional profiling of peripheral blood mononuclear cells identifies inflammatory phenotypes in Ataxia Telangiectasia.

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.

Multidisciplinary Management of Ataxia Telangiectasia: Current Perspectives.

Ataxia telangiectasia (A-T) is a rare autosomal recessive disease caused by mutations in the ataxia telangiectasia mutated (ATM) gene. In the absence of a family history, the diagnosis of A-T is usually not made until the child is older and symptomatic. Classic A-T is characterized by a constellation of clinical symptoms including progressive ataxia, oculocutaneous telangiectasias and sinopulmonary disease and is usually associated with absence of ATM protein. Other laboratory features associated with A-T include elevated serum levels of alpha-fetoprotein (AFP) and increased chromosomal breakage with in vitro exposure to ionizing radiation. Sinopulmonary symptoms can occur to varying degrees across the lifespan. Some children will also have hypogammaglobulinemia and impaired antibody responses requiring supplemental gamma globulin. People with hypomorphic ATM mutations are often considered to have mild A-T with onset of ataxia and neurological progression occurring later in life with less impairment of the immune system. The risk of malignancy, however, is significantly increased in people with either classic or mild A-T. While hematological malignancies are most common in the first two decades of life, solid organ malignancies become increasingly common during young adulthood. Deterioration of neurologic function with age is associated with dysphagia with aspiration, growth faltering, loss of ambulation and decline in pulmonary function, morbidities that contribute to shortened life expectancy and decreased quality of life. Premature death is often due to malignancies or chronic respiratory insufficiency. A-T is currently managed with supportive care and symptomatic treatment. Current clinical trials, however, represent progress and hope towards disease-modifying therapies for A-T.

Growth in ataxia telangiectasia.

BACKGROUND: Ataxia telangiectasia (A-T) is a DNA repair disorder that affects multiple body systems. Neurological problems and immunodeficiency are two important features of this disease. At this time, two main severity groups are defined in A-T: classic (the more severe form) and mild. Poor growth is a common problem in classic A-T. An objective of this study was to develop growth references for classic A-T. Another objective was to compare growth patterns in classic A-T and mild A-T with each other and with the general population, using the CDC growth references. A final objective was to examine the effects of chronic infection on height. RESULTS: We found that classic A-T patients were smaller overall, and suffered from height and weight faltering that continued throughout childhood and adolescence. When compared to the CDC growth references, the median heights and weights for both male and female patients eventually fell to or below the 3rd centile on the CDC charts. Height faltering was more pronounced in females. Birthweight was lower in the classic A-T group compared to mild A-T and the general population, whereas birth length was not. Finally, we investigated height and BMI faltering in relation to number of infections and found no association. CONCLUSIONS: Classic A-T appears to affect growth in utero. Although children appear to grow well in very early life, faltering begins early, and is unrelenting.

Xeroderma pigmentosum-Cockayne syndrome complex.

Xeroderma pigmentosum-Cockayne syndrome complex is a very rare multisystem degenerative disorder (Orpha: 220295; OMIM: 278730, 278760, 278780, 610651). Published information on XP-CS is mostly scattered throughout the literature. We compiled statistics related to symptom prevalence in XP-CS and have written a clinical description of the syndrome. We also drew on clinical practices used in XP and in Cockayne syndrome without XP to aid management of XP-CS.Extensive searches of the literature identified 43 XP-CS patients. The diagnosis had been confirmed with molecular or biochemical methods in 42 of them. Clinical features of each patient were summarized in spreadsheets and summary statistics were generated from this data. XP patients are classified into complementation groups according to the gene that is mutated. There are four groups in XP-CS, and classification was available for 42 patients. Twenty-one were in the XP-G complementation group, 13 in XP-D, 5 in XP-B, and 3 in XP-F. Overall, the clinical features of XP-CS are very similar to those of CS without XP, with the exception of skin cancers in XP-CS. However, one intriguing finding was that cancer incidence was lower in XP-CS compared to XP alone or XP-neurological disorder. The cancer rate in XP-CS was higher than in CS without XP, an unsurprising finding. There is preliminary evidence for the existence of severity groups in XP-CS, as is the case in CS.Although health problems in XP-CS vary both in severity and in when they the first occur, there was overall homogeneity between all complementation groups and putative severity groups. Severely affected patients met fewer milestones and died at younger ages compared to more mildly affected patients.

Worldwide variation in human growth and the World Health Organization growth standards: a systematic review.

OBJECTIVE: The World Health Organization (WHO) has established a set of growth curves for use as international standards in children up to age 5. The WHO's position is that all economically advantaged children who were breastfed as infants grow similarly. As a result, a single set of growth charts can be used to judge growth in any child, regardless of race or ethnicity. The goal of this study was to compare mean heights, weights and head circumferences from a variety of studies with the WHO's data. DESIGN: We compared data from the WHO's Multicentre Growth Reference Study (MGRS) with data from studies performed in 55 countries or ethnic groups. DATA SOURCES: PubMed, WHO Global Database on Child Growth and Malnutrition, SciELO, Google Scholar, Textbooks and Ministries of Statistics and Public Health. ELIGIBILITY CRITERIA: Large recent studies (1988-2013) of economically advantaged groups, including comparisons with cohorts of breastfed children wherever possible. RESULTS: Height varied somewhat among different national and ethnic groups. Means were generally within 0.5 of an SD of the MGRS means. Weight varied more than height, but the low MGRS means were seen as endorsing slenderness in the midst of an obesity epidemic. The mean head circumference varied widely. In many groups, means were consistently 0.5-1 SD above the MGRS mean. Head size in breastfed children at any age examined was far closer to local norms than to the MGRS means. CONCLUSIONS: Height and weight curves may not be optimal fits in all cases. The differences between national or ethnic group head circumference means were large enough that using the WHO charts would put many children at risk for misdiagnosis of macrocephaly or microcephaly. Our findings indicate that the use of a single international standard for head circumference is not justified. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (# CRD42013003675).

A comprehensive description of the severity groups in Cockayne syndrome.

Cockayne syndrome (CS) is a rare degenerative disorder with a common set of symptoms but a very wide variation in phenotype. The variation is sufficiently wide that CS patients have traditionally been described in three different severity groups. Unfortunately, there is no single source for information about the different severity groups. This problem can complicate not only diagnosis, but accurate prognosis as well. The goal of this study was to describe the phenotypic variation in CS as completely as possible. This article provides extensive descriptions of traits common to each group and their degree of severity in each group. Forty-five people with CS were surveyed and information from the published literature was used to increase the sample sizes for calculations. This study provides new information, including statistical data for each of the three severity groups (mean age at death, average head circumference, and average length or stature). The study includes cerebro-oculo-facial syndrome (COFS) as a severe form of CS, based on results of recently published genetic studies performed by other authors. This study proposes revised names for CS severity groups: severe, moderate, and mild. The groups were formerly called Type II/early onset CS, Type I/classical CS, and Type III/atypical/mild/late-onset CS, respectively. A fourth newly documented group, UV sensitivity only/adult onset, is also described. Average ages of death were calculated as 5.0 years (severe), 16.1 years (moderate), and 30.3 years (mild).

H2AX phosphorylation within the G1 phase after UV irradiation depends on nucleotide excision repair and not DNA double-strand breaks.

The variant histone H2AX is phosphorylated in response to UV irradiation of primary human fibroblasts in a complex fashion that is radically different from that commonly reported after DNA double-strand breaks. H2AX phosphorylation after exposure to ionizing radiation produces foci, which are detectable by immunofluorescence microscopy and have been adopted as clear and consistent quantitative markers for DNA double-strand breaks. Here we show that in contrast to ionizing radiation, UV irradiation mainly induces H2AX phosphorylation as a diffuse, even, pan-nuclear staining. UV induced pan-nuclear phosphorylation of H2AX is present in all phases of the cell cycle and is highest in S phase. H2AX phosphorylation in G(1) cells depends on nucleotide excision repair factors that may expose the S-139 site to kinase activity, is not due to DNA double-strand breaks, and plays a larger role in UV-induced signal transduction than previously realized.