The burden of inherited leukodystrophies in children.

OBJECTIVES: Leukodystrophies are diseases of the white matter for which data concerning clinical characteristics, incidence, disease burden, and description of outcomes are sparse. The purpose of our study was to determine the incidence and most common types of inherited leukodystrophies in a population, the mortality and time course of deaths, common neurologic features in patients, and health care costs associated with leukodystrophies. METHODS: We conducted a retrospective, hospital- and clinic-based surveillance of inherited leukodystrophies among children younger than 18 years presenting to a regional children's hospital. We enrolled children evaluated from January 1, 1999, through December 31, 2007; clinical information was obtained from medical records. We calculated incidence based on state birth rates. RESULTS: A total of 122 children with an inherited leukodystrophy were identified; 542 patients were excluded. A total of 49% had epilepsy, 43% required a gastrostomy tube, and 32% had a history of developmental regression. Mortality was 34%; average age at death was 8.2 years. No final diagnosis was reported in 51% of patients. The most common diagnoses were metachromatic leukodystrophy (8.2%), Pelizaeus-Merzbacher disease (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (4.1%). Endocrine abnormalities and hypoplastic cerebellum were noted in significant portions of patients (15% and 14%). Average yearly per-patient medical costs were $22,579. Population incidence was 1 in 7,663 live births. CONCLUSIONS: Inherited leukodystrophies are associated with substantial morbidity and mortality in children. Overall population incidence is higher than generally appreciated (1 in 7,663 live births). Most leukodystrophies remain undiagnosed, but a logical algorithm based on prevalence could aid testing.

Hypoxaemia in acute respiratory and non-respiratory illnesses in neonates and children in a developing country.

AIMS: To determine, in sick neonates and children requiring admission to a hospital in the highlands of Papua New Guinea: (1) the incidence and severity of hypoxaemia; (2) the proportion with hypoxaemia who do not fulfil criteria for acute lower respiratory infection (ALRI); and (3) the power of clinical signs to predict hypoxaemia, according to age and disease category. METHODS: Age dependent normal values for transcutaneous oxygen saturation (SpO(2)) were established in 218 well neonates and children in Goroka. A total of 491 sick neonates and children were then studied on presentation to the paediatric department at Goroka Hospital. RESULTS: A total of 257 sick neonates and children (52%) were hypoxaemic. Hypoxaemia was present in 179/245 (73%) with clinical criteria for ALRI; 79/246 (32%) with non-ALRI illnesses (including meningitis, septicaemia, severe malnutrition, low birth weight, birth asphyxia, and congenital syphilis) were also hypoxaemic. For children aged 1 month to 5 years with ALRI, the clinical signs best predicting hypoxaemia were cyanosis, respiratory rate >60, poor feeding, or reduced spontaneous activity; in those without ALRI the best predictors were cyanosis, respiratory rate >60 per minute, and inability to feed, but the positive predictive value was much lower than for children with ALRI. For neonates cyanosis was predictive of hypoxaemia, but tachypnoea or inability to feed were not. CONCLUSIONS: Hypoxaemia is an under recognised complication of non-ALRI illnesses in children and in sick neonates in developing countries. Use of algorithms with high sensitivity for the recognition of hypoxaemia, and protocols for administration of oxygen to neonates, and to children with non-ALRI illnesses, might substantially reduce case fatality.

The derailed guidance receptor does not require kinase activity in vivo.

The Drosophila Derailed (DRL) receptor tyrosine kinase (RTK) controls key guidance events in the developing nervous system and mesoderm. Like other members of the "related to tyrosine kinases" (RYK) subfamily of RTKs, DRL has several highly unusual amino acid substitutions within the catalytic domain, raising the possibility that members of this subfamily are catalytically inactive. To test the role of DRL kinase activity in vivo, we mutated the invariant lysine required for catalytic activity of known kinases and examined the ability of this mutant to function in two assays: a dominant gain-of-function axon switch assay in the nervous system and phenotypic rescue of muscle attachment in drl mutants. We show that this predicted kinase-deficient DRL mutant is capable of functioning in both assays. Our results indicate that DRL does not require kinase activity in vivo and suggest that members of the RYK subfamily of RTKs transduce signals unconventionally.

Axon routing across the midline controlled by the Drosophila Derailed receptor.

In nervous systems with symmetry about the midline, many neurons project axons from one side to the other. Although several of the components controlling midline crossing have been identified, little is known about how axons choose the appropriate pathway when crossing. For example, in the Drosophila embryo axons cross the midline in one of two distinct tracts, the anterior or posterior commissure (AC or PC, respec tively). Here we show that the Derailed (Drl) receptor tyrosine kinase is expressed by neurons that project in the AC, and that in the absence of Drl such neurons often project abnormally into the PC. Conversely, misexpression of Drl in PC neurons forces them to cross in the AC. The behaviour of Drl-misexpressing neurons and the in vivo binding pattern of a soluble Drl receptor probe indicate that Drl acts as a guidance receptor for a repellent ligand present in the PC. Our results show that Drl is a novel component in the control of midline crossing.

Cell-type specific modular regulation of derailed in the Drosophila nervous system.

The derailed (drl) gene encodes a receptor tyrosine kinase (RTK) that governs aspects of axon guidance and muscle-epidermal interactions in the Drosophila embryo. To determine the types of neurons that express drl, we have examined a series of drl promoter fusions to axon-targeted reporters. We have identified enhancers that drive reporter expression in four distinct subtypes of embryonic neurons, all of which project axons in the anterior commissure of the developing nervous system. We also identified enhancers driving expression in the drl-expressing muscles and epidermal attachment cells. These enhancers define the classes of neurons projecting in the anterior commissure and can be used to precisely define axon pathfinding errors in drl and other mutants.