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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.

An amendment to this paper has been published and can be accessed via the original article.

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).

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.

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, pannuclear 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 G₁ 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.

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. Keywords: ataxia telangiectasia, ataxia telangiectasia mutated, DNA damage repair

Loss-of-function variants in the low-density lipoprotein receptor-related protein 10 (LRP10) gene have been associated with autosomal-dominant Parkinson’s disease (PD), PD dementia, and dementia with Lewy bodies (DLB). Moreover, LRP10 variants have been found in individuals diagnosed with progressive supranuclear palsy and amyotrophic lateral sclerosis. Despite this genetic evidence, little is known about the expression and function of LRP10 protein in the human brain under physiological or pathological conditions. To better understand how LRP10 variants lead to neurodegeneration, we first performed an in-depth characterisation of LRP10 expression in post-mortem brains and human-induced pluripotent stem cell (iPSC)-derived astrocytes and neurons from control subjects. In adult human brain, LRP10 is mainly expressed in astrocytes and neurovasculature but undetectable in neurons. Similarly, LRP10 is highly expressed in iPSC-derived astrocytes but cannot be observed in iPSC-derived neurons. In astrocytes, LRP10 is present at trans-Golgi network, plasma membrane, retromer, and early endosomes. Interestingly, LRP10 also partially co-localises and interacts with sortilin-related receptor 1 (SORL1). Furthermore, although LRP10 expression and localisation in the substantia nigra of most idiopathic PD and DLB patients and LRP10 variant carriers diagnosed with PD or DLB appeared unchanged compared to control subjects, significantly enlarged LRP10-positive vesicles were detected in a patient carrying the LRP10 p.Arg235Cys variant. Last, LRP10 was detected in Lewy bodies (LB) at late maturation stages in brains from idiopathic PD and DLB patients and in LRP10 variant carriers. In conclusion, high LRP10 expression in non-neuronal cells and undetectable levels in neurons of control subjects indicate that LRP10-mediated pathogenicity is initiated via cell non-autonomous mechanisms, potentially involving the interaction of LRP10 with SORL1 in vesicle trafficking pathways. Together with the specific pattern of LRP10 incorporation into mature LBs, these data support an important mechanistic role for disturbed vesicle trafficking and loss of LRP10 function in neurodegenerative diseases.

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.

Astrocytes are the most populous cell type of the human central nervous system and are essential for physiological brain function. Increasing evidence suggests multiple roles for astrocytes in Parkinson's disease, nudging a shift in the research focus, which historically pivoted around ventral midbrain dopaminergic neurons (vmDANs). Studying human astrocytes and other cell types in vivo remains challenging. However, in vitro-reprogrammed human stem cell-based models provide a promising alternative. Here, we describe a novel protocol for astrocyte differentiation from human stem cell-derived vmDAN-generating progenitors. This protocol simulates the regionalization, gliogenic switch, radial migration and final differentiation that occur in the developing human brain. We characterized the morphological, molecular and functional features of these ventral midbrain patterned astrocytes with a broad palette of techniques and identified novel candidate midbrain-astrocyte specific markers. In addition, we developed a new pipeline for calcium imaging data analysis called deCLUTTER2+ (deconvolution of Ca2+ fluorescent patterns) that can be used to discover spontaneous or cue-dependent patterns of Ca2+ transients. Altogether, our protocol enables the characterization of the functional properties of human ventral midbrain patterned astrocytes under physiological conditions and in disease.

Tissue analysis is commonly used in ecology and agronomy to portray plant nutrient signatures. Nutrient concentration data, or ionomes, belongs to the compositional data class, i.e., multivariate data that are proportions of some whole, hence carrying important numerical properties. Statistics computed across raw or ordinary log-transformed nutrient data are intrinsically biased, hence possibly leading to wrong inferences. Our objective was to present a sound and robust approach based on a novel nutrient balance concept to classify plant ionomes. We analyzed leaf N, P, K, Ca, and Mg of two wild and six domesticated fruit species from Canada, Brazil, and New Zealand sampled during reproductive stages. Nutrient concentrations were (1) analyzed without transformation, (2) ordinary log-transformed as commonly but incorrectly applied in practice, (3) additive log-ratio (alr) transformed as surrogate to stoichiometric rules, and (4) converted to isometric log-ratios (ilr) arranged as sound nutrient balance variables. Raw concentration and ordinary log transformation both led to biased multivariate analysis due to redundancy between interacting nutrients. The alr- and ilr-transformed data provided unbiased discriminant analyses of plant ionomes, where wild and domesticated species formed distinct groups and the ionomes of species and cultivars were differentiated without numerical bias. The ilr nutrient balance concept is preferable to alr, because the ilr technique projects the most important interactions between nutrients into a convenient Euclidean space. This novel numerical approach allows rectifying historical biases and supervising phenotypic plasticity in plant nutrition studies.