Hypomyelinating leukodystrophies (HMLs) are disorders involving aberrant myelin formation. The prototype of primary HMLs is the X-linked Pelizaeus-Merzbacher disease (PMD) caused by mutations in PLP1. Recently, homozygous mutations in GJA12 encoding connexin 47 were found in patients with autosomal-recessive Pelizaeus-Merzbacher-like disease (PMLD). However, many patients of both genders with PMLD carry neither PLP1 nor GJA12 mutations. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD, in which linkage to PLP1 and GJA12 was excluded. Using homozygosity mapping and mutation analysis, we have identified a homozygous missense mutation (D29G) not previously described in HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60) in all affected individuals. The D29G mutation completely segregates with the disease-associated phenotype. The pathogenic effect of D29G on Hsp60-chaperonin activity was verified by an in vivo E. coli complementation assay, which demonstrated compromised ability of the D29G-Hsp60 mutant protein to support E. coli survival, especially at high temperatures. The disorder, which we have termed MitCHAP-60 disease, can be distinguished from spastic paraplegia 13 (SPG13), another Hsp60-associated autosomal-dominant neurodegenerative disorder, by its autosomal-recessive inheritance pattern, as well as by its early-onset, profound cerebral involvement and lethality. Our findings suggest that Hsp60 defects can cause neurodegenerative pathologies of varying severity, not previously suspected on the basis of the SPG13 phenotype. These findings should help to clarify the important role of Hsp60 in myelinogenesis and neurodegeneration.

We conclude that children with ADHD demonstrate objective daytime somnolence, which may explain the beneficial effects of treatment with stimulant medications. Primary sleep disorders, especially sleep-disordered breathing and periodic limb movement disorder, should be looked for in children with ADHD.

ABSTRACT. Objectives. After resection of hypothalamic/pituitary tumors, children are at risk for development of hormonal deficiencies, obesity, and hypersomnolence. However, the prevalence and pathophysiology of these complications are unclear. The purpose of this study was to assess the prevalence and severity of hypersomnolence in children after resection of pituitary tumors and to study the potential factors that contribute to this sleepiness if present. We further hypothesized that decrements in orexin levels may contribute to the sleepiness.Methods. Six children who underwent hypothalamic/ pituitary surgery were identified. Five of these patients and 5 matched control subjects underwent overnight polysomnography followed by a multiple sleep latency test. Children who had a primary sleep disorder (eg, obstructive sleep apnea) underwent treatment and were restudied subsequently (n ‫؍‬ 2). Blood levels of pituitary hormones were measured. Blood and cerebrospinal fluid (CSF) were drawn from 4 patients and 3 control subjects to measure orexin levels.Results. Endocrine control was appropriate in all children. Although patients had longer sleep duration but similar sleep efficiency than control subjects, relatively severe daytime somnolence was present (mean sleep latency: 10.3 ؎ 5.3 minutes vs 26.2 ؎ 1.1 minute in control subjects). Sleepiness did not correlate with body mass index or age. Furthermore, serum and CSF orexin levels did not differ between patients and control subjects.Conclusions. Severe daytime sleepiness is frequent among children who undergo pituitary/hypothalamic surgery and does not seem to result from inappropriate cortisol or thyroxine replacement, disturbed nocturnal sleep, or low levels of orexin in the serum or CSF. We therefore speculate that other, unidentified neurohormonal mechanisms may mediate the excessive sleepiness of these patients. Pediatrics 2002;110(6). URL: http:// www.pediatrics.org/cgi/content/full/110/6/e74; sleep, excessive daytime sleepiness, adolescents, orexin (hypocretin), brain tumors, craniopharyngioma.