leptin and Abnormalities--Multiple

Topics: Abnormalities, Multiple; Diabetes Mellitus; Diagnosis, Differential; Humans; Hypertrophy; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Mutation; Pineal Gland; Prognosis; Receptor, Insulin; Recombinant Proteins; Syndrome

Topics: Abnormalities, Multiple; Child; Drug Resistance; Endocrine System Diseases; Energy Metabolism; Ghrelin; Homeostasis; Hormones; Humans; Hypothalamus, Middle; Insulin; Insulin Resistance; Leptin; Obesity; Peptide Fragments; Peptide Hormones; Peptide YY; Sympathetic Nervous System; Vagus Nerve

Leptin changes brain structure, neuron excitability and synaptic plasticity. It also regulates the development and function of feeding circuits. However, the effects of leptin on neurocognitive development are unknown.. To evaluate the effect of leptin on neurocognitive development.. A 5-year-old boy with a nonconservative missense leptin gene mutation (Cys-to-Thr in codon 105) was treated with recombinant methionyl human leptin (r-metHuLeptin) at physiologic replacement doses of 0.03 mg/kg/day. Cognitive development was assessed using the Differential Ability Scales (DAS), a measure of general verbal and nonverbal functioning; and selected subtests from the NEPSY, a measure of neuropsychological functioning in children.. Prior to treatment, the patient was morbidly obese, hypertensive, dyslipidemic, and hyperinsulinemic. Baseline neurocognitive tests revealed slower than expected rates of development (developmental age lower than chronological age) in a majority of the areas assessed. After two years, substantial increases in the rates of development in most neurocognitive domains were apparent, with some skills at or exceeding expectations based on chronological age. We also observed marked weight loss and resolution of hypertension, dyslipidemia and hyperinsulinemia.. We concluded that replacement with r-metHuLeptin is associated with weight loss and changes in rates of development in many neurocognitive domains, which lends support to the hypothesis that, in addition to its role in metabolism, leptin may have a cognitive enhancing role in the developing central nervous system.. ClinicalTrials.gov NCT00659828.

Topics: Abnormalities, Multiple; Child; Cognition; Cognition Disorders; Hormone Replacement Therapy; Humans; Leptin; Male; Mutation, Missense; Obesity, Morbid

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome due to mutations in genes encoding nuclear lamina proteins, lamins A/C (LMNA) or prelamin A processing enzyme, and zinc metalloproteinase (ZMPSTE24).. The aim of the study was to investigate the underlying genetic and molecular basis of the phenotype of a 7-yr-old girl with MAD belonging to a consanguineous pedigree and with severe progeroid features and lipodystrophy.. The patient developed mandibular hypoplasia during infancy and joint stiffness, skin thinning, and mottled hyperpigmentation at 15 months. Progressive clavicular hypoplasia, acroosteolysis, and severe loss of hair from the temporal and occipital areas were noticed at 3 yr. At 5 yr, cranial sutures were still open and lipodystrophy of the limbs was prominent. GH therapy from the ages of 3-7 yr did not improve the short stature. Severe joint contractures resulted in abnormal posture and decreased mobility. We studied her skin fibroblasts for nuclear morphology and immunoblotting and determined the in vitro effects of various pharmacological interventions on fibroblasts.. LMNA gene sequencing revealed a homozygous missense mutation, c.1579C>T, p.Arg527Cys. Immunoblotting of skin fibroblast lysate with lamin A/C antibody revealed no prelamin A accumulation. Immunofluorescence staining of the nuclei for lamin A/C in fibroblasts revealed marked nuclear morphological abnormalities. This abnormal phenotype could not be rescued with inhibitors of farnesyl transferase, geranylgeranyl transferase, or histone deacetylase.. Severe progeroid features in MAD could result from LMNA mutation, which does not lead to accumulation of prenylated lamin A or prelamin A.

Topics: Abnormalities, Multiple; Amino Acid Substitution; Anthropometry; Blotting, Western; Cell Nucleus; Child; DNA Mutational Analysis; Female; Fibroblasts; Hand Deformities, Congenital; Humans; Insulin; Lamin Type A; Leptin; Lipodystrophy; Mandible; Microscopy, Fluorescence; Mutation; Progeria; Skinfold Thickness

McKusick-Kaufman syndrome (MKS) is an autosomal recessive disorder characterized by post-axial polydactyly, congenital heart defects and hydrometrocolpos, a congenital structural abnormality of female genitalia. Mutations in the MKKS gene have also been shown to cause some cases of Bardet-Biedl syndrome (BBS) which is characterized by obesity, pigmentary retinopathy, polydactyly, renal abnormalities and hypogenitalism with secondary features of hypertension and diabetes. Although there is overlap in clinical features between MKS and BBS, MKS patients are not obese and do not develop retinopathy or have learning disabilities. To further explore the pathophysiology of BBS and the related disorder MKS, we have developed an Mkks(-/-) mouse model. This model shows that the absence of Mkks leads to retinal degeneration through apoptosis, failure of spermatozoa flagella formation, elevated blood pressure and obesity. The obesity is associated with hyperphagia and decreased activity. In addition, neurological screening reveals deficits in olfaction and social dominance. The mice do not have polydactyly or vaginal abnormalities. The phenotype of the Mkks(-/-) mice closely resembles the phenotype of other mouse models of BBS (Bbs2(-/-) and Bbs4(-/-)). These observations suggest that the complete absence of MKKS leads to BBS while the MKS phenotype is likely to be due to specific mutations.

Topics: Abnormalities, Multiple; Alleles; Animals; Bardet-Biedl Syndrome; Blood Pressure; Disease Models, Animal; Genes, Recessive; Humans; Leptin; Male; Mice; Mice, Knockout; Models, Genetic; Obesity; Phenotype; Proteins; Retinal Degeneration; Social Dominance; Sperm Tail; Syndrome