Attenuated variants of Lesch-Nyhan disease

Lesch–Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine–guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the classic disease, variant forms of the disease occur wherein some clinical features are absent or unusually mild. The current studies provide the results of a prospective and multi-centre international study focusing on neurological manifestations of the largest cohort of Lesch–Nyhan disease variants evaluated to date, with 46 patients from 3 to 65 years of age coming from 34 families. All had evidence for overproduction of uric acid. Motor abnormalities were evident in 42 (91%), ranging from subtle clumsiness to severely disabling generalized dystonia. Cognitive function was affected in 31 (67%) but it was never severe. Though none exhibited self-injurious behaviours, many exhibited behaviours that were maladaptive. Only three patients had no evidence of neurological dysfunction. Our results were compared with a comprehensive review of 78 prior reports describing a total of 127 Lesch–Nyhan disease variants. Together these results define the spectrum of clinical features associated with hypoxanthine–guanine phosphoribosyltransferase deficiency. At one end of the spectrum are patients with classic Lesch–Nyhan disease and the full clinical phenotype. At the other end of the spectrum are patients with overproduction of uric acid but no apparent neurological or behavioural deficits. Inbetween are patients with varying degrees of motor, cognitive, or behavioural abnormalities. Recognition of this spectrum is valuable for understanding the pathogenesis and diagnosis of all forms of hypoxanthine–guanine phosphoribosyltransferase deficiency

Raising Children in Exile: Experiences of Highly Educated Eritrean Migrants in the UK

Child-rearing practices can be challenging for migrants who often require socio-cultural and emotional adjustments. This article discusses parenting in exile with a focus on the experiences of highly educated Eritrean migrants in the UK. Qualitative data are collected from eighteen highly educated Eritrean migrants selected through purposive and snowball sampling from the UK. The findings indicate that highly educated Eritrea migrants aspire to avoid harmful traditional ways of treating children and all the repercussions associated with them. Moreover, with the help of their educational qualifications, my participants support their children in social and academic activities and guide them to cultivate bi-cultural coping skills. However, the migrant parents face challenges related to lack of parenting experiences and familiar support systems. The article contributes to the advancement of migration knowledge by adding new perspectives to the nexus of migration and child-raising

Imaging LDL receptor oligomerization during endocytosis using a co-internalization assay

Methods to probe receptor oligomerization are useful to understand the molecular mechanisms of receptor signaling. Here we report a fluorescence imaging method to determine receptor oligomerization state in living cells during endocytic internalization. The wild-type receptor is co-expressed with an internalization-defective mutant, and the internalization kinetics of each are independently monitored. If the receptor internalizes as an oligomer, then the wild-type and mutant isoforms will mutually influence each others’ trafficking properties, causing co-internalization of the mutant or co-retention of the wild-type at the cell surface. Using this approach, we found that the low density lipoprotein (LDL) receptor internalizes as an oligomer into cells, both in the presence and absence of LDL ligand. The internalization kinetics of the wild-type receptor are not changed by LDL binding. We also found that the oligomerization domain of the LDL receptor is located in its cytoplasmic tail.National Institutes of Health (U.S.) (NIH (R01 GM072670))Henry & Camille Dreyfus FoundationMassachusetts Institute of Technolog