A mosaic activating mutation in AKT1 associated with the Proteus syndrome.

BACKGROUND: The Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state. METHODS: We performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of unaffected tissues obtained from the same patients. We confirmed and extended an observed association, using a custom restriction-enzyme assay to analyze the DNA in 158 samples from 29 patients with the Proteus syndrome. We then assayed activation of the AKT protein in affected tissues, using phosphorylation-specific antibodies on Western blots. RESULTS: Of 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49G→A, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase, an enzyme known to mediate processes such as cell proliferation and apoptosis. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines. A pair of single-cell clones that were established from the same starting culture and differed with respect to their mutation status had different levels of AKT phosphorylation. CONCLUSIONS: The Proteus syndrome is caused by a somatic activating mutation in AKT1, proving the hypothesis of somatic mosaicism and implicating activation of the PI3K-AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. (Funded by the Intramural Research Program of the National Human Genome Research Institute.).

Motion analysis of a child with Niemann-Pick disease type C treated with miglustat.

Niemann-Pick disease type C (NPC) is a progressive neurodegenerative disorder for which there is no effective treatment other than supportive therapy. Recently, the oral medication miglustat has been offered as a possible therapy aimed at reducing pathological substrate accumulation. This article describes the use of computerized three-dimensional motion analysis to evaluate a 3-year-old child with NPC treated with miglustat for 12 months. Motion analysis provided quantitative data on the patient's gait. However, dementia and motor dysfunction progressed despite the treatment, and the patient lost the ability to walk between 9 and 12 months of the study. Motion analysis should be considered among the tools for measuring functional outcomes in future therapeutical trials of patients with neurodegenerative diseases. It is not possible to draw conclusions about miglustat therapy in NPC from a single patient experience.

When is enlargement of the subarachnoid spaces not benign? A genetic perspective.

Enlargement of the subarachnoid spaces is occasionally encountered during neuroimaging of children. This enlargement is generally regarded as a nonpathologic process that resolves uneventfully. However, there are several genetic disorders in which enlargement of the subarachnoid spaces can be an early sign, or the feature of an associated syndrome, that may aid in the underlying diagnosis. Recognizing subarachnoid space enlargement in these circumstances requires an understanding of the normal physiology of the subarachnoid space at different time points in a child's neurodevelopment. This article reviews the events shaping the subarachnoid space, both during normal physiologic maturation and in specific genetic disorders.

Novel compound heterozygous nonsense mutations in the hairless gene causing atrichia with papular lesions.

BACKGROUND: Atrichia with papular lesions (APL) is a rare autosomal recessive condition resulting from mutations in the hairless (HR) gene. OBJECTIVE: In the present study, we investigated the molecular basis of APL in a non-consanguineous Korean family. METHODS: Direct automated DNA sequencing of the HR gene and restriction digestion analysis were used to identify and confirm the mutation in our proband. RESULTS: Sequencing of the HR gene revealed two novel nonsense mutations in exons 2 and 4 which were subsequently confirmed via enzymatic restriction. No mutations have previously been detected in this population. CONCLUSION: The growing number of heterozygous mutations in non-consanguineous pedigrees supports the hypothesis that APL is more common than previously expected.

Improved pulmonary and growth outcomes in cystic fibrosis by newborn screening.

BACKGROUND: Newborn screening for cystic fibrosis (CF) is effective in improving long-term growth outcomes. However, there is conflicting evidence that early diagnosis maintains normal pulmonary function. Our goal was to determine if newborn screening results in improved longitudinal growth and maintenance of normal pulmonary function. METHODS: A retrospective study of individuals with CF born in Connecticut between 1983 and 1997 was conducted by medical record and CF Foundation Registry review. Growth, pulmonary function and bacterial acquisition/colonization data, from diagnosis through July 1, 2005, were compared in those diagnosed by newborn screen (n = 34) to those diagnosed by sweat test after symptom appearance (n = 21). RESULTS: Screened individuals demonstrated greater weight and height for age at diagnosis (P = 0.01 and 0.01) and through 15 years of age (P = 0.0002 and 0.01). Body mass index was higher in screened individuals (21 vs. 18 kg/m(2)) at 15 years of age (P = 0.01). At 15 years of age, screened individuals had a clinically higher forced expiratory volume in 1 second (FEV(1)) and forced vital capacity (FVC; 90% and 104% predicted) than non-screened individuals (74% and 91% predicted; P = 0.08 and 0.10). Over a 9-year period, from ages 6 to 15, percent predicted FEV(1) and FVC increased by 4% and 13% in screened individuals; and declined by 14% and 5% respectively in non-screened individuals (P = 0.01 and 0.02). Acquisition/colonization of Pseudomonas aeruginosa was similar between groups (P = 0.23). CONCLUSIONS: In this CF cohort, individuals diagnosed by newborn screening have improved growth and preservation of normal pulmonary function without increased risk of Pseudomonas aeruginosa colonization.

The von Hippel-Lindau (VHL) germline mutation V84L manifests as early-onset bilateral pheochromocytoma.

Von Hippel-Lindau (VHL) disease is a heritable tumor susceptibility syndrome caused by germline mutations in the VHL gene. The types of tumor that can occur in affected individuals include retinal and central nervous system hemangioblastoma, renal cell carcinoma, pheochromocytoma, and others. The pattern of tumor types that develops in a VHL-affected family defines the clinical subtype (1, 2A, 2B, 2C). Generally, it is difficult to accurately predict an individual's clinical phenotype based on their VHL mutation. However, in a few specific VHL mutations, a strong genotype-phenotype correlation has been established. We report here on the clinical findings in individuals from three unrelated families with a V84L VHL germline mutation, and present follow-up information regarding the only other reported family with this missense mutation. In each of these four families, the major clinical manifestation of VHL disease is multiple early-onset pheochromocytomas (VHL type 2C). This series of eight patients strengthens the correlation between the V84L mutation and the VHL type 2C phenotype, and improves our ability to provide prognostic and management recommendations for similarly affected individuals.