RESUMEN
Advances in understanding the etiology of Parkinson disease have been driven by the identification of causative mutations in families. Genetic analysis of an Australian family with three males displaying clinical features of early-onset parkinsonism and intellectual disability identified a â¼45 kb deletion resulting in the complete loss of RAB39B. We subsequently identified a missense mutation (c.503C>A [p.Thr168Lys]) in RAB39B in an unrelated Wisconsin kindred affected by a similar clinical phenotype. In silico and in vitro studies demonstrated that the mutation destabilized the protein, consistent with loss of function. In vitro small-hairpin-RNA-mediated knockdown of Rab39b resulted in a reduction in the density of α-synuclein immunoreactive puncta in dendritic processes of cultured neurons. In addition, in multiple cell models, we demonstrated that knockdown of Rab39b was associated with reduced steady-state levels of α-synuclein. Post mortem studies demonstrated that loss of RAB39B resulted in pathologically confirmed Parkinson disease. There was extensive dopaminergic neuron loss in the substantia nigra and widespread classic Lewy body pathology. Additional pathological features included cortical Lewy bodies, brain iron accumulation, tau immunoreactivity, and axonal spheroids. Overall, we have shown that loss-of-function mutations in RAB39B cause intellectual disability and pathologically confirmed early-onset Parkinson disease. The loss of RAB39B results in dysregulation of α-synuclein homeostasis and a spectrum of neuropathological features that implicate RAB39B in the pathogenesis of Parkinson disease and potentially other neurodegenerative disorders.
Asunto(s)
Genes Ligados a X , Discapacidad Intelectual/genética , Degeneración Nerviosa/genética , Enfermedad de Parkinson/genética , alfa-Sinucleína/metabolismo , Proteínas de Unión al GTP rab/genética , Sustitución de Aminoácidos , Australia , Secuencia de Bases , Dopamina/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Discapacidad Intelectual/fisiopatología , Cuerpos de Lewy/metabolismo , Masculino , Persona de Mediana Edad , Modelos Moleculares , Datos de Secuencia Molecular , Mutación Missense , Degeneración Nerviosa/fisiopatología , Enfermedad de Parkinson/fisiopatología , Linaje , Análisis de Secuencia de ADN , Eliminación de Secuencia , Sustancia Negra/fisiopatología , Proteínas de Unión al GTP rab/metabolismoRESUMEN
BACKGROUND: Prenatal alcohol exposure (PAE) is a leading cause of significant neurobehavioral and neurocognitive deficits. Its potential consequences for eating behaviors, nutritional status, and other nutritional issues in childhood have received little attention. METHODS: Nineteen children (11 boys, 8 girls) of mean age 9.6 years, referred for fetal alcohol spectrum disorder (FASD) screening and assessment, were analyzed with physical exams and caregiver questionnaires to identify possible abnormalities in food and eating behaviors. Fourteen children contributed 24-hour diet recalls and were assessed for nutritional status. RESULTS: Seventy-nine percent of participants were diagnosed with FASD and 63.2% had confirmed PAE. Fifty percent of girls were overweight or obese, whereas 37% of boys had reduced stature, weight, or body mass index for their age. Recurring feeding problems included constant snacking (36.8%), lack of satiety (26.3%), and picky eating/poor appetite (31.6%). None had oral feeding problems. Constipation was common (26.3%). Macronutrient intakes were largely normal, but sugar consumption was excessive (140 to 190% of recommendations) in 57% of subjects. Vitamin A intake exceeded the upper limit for 64% of participants, whereas ≥50% had intakes <80% of recommended daily allowances (RDAs) for choline, vitamin E, potassium, ß-carotene, and essential fatty acids; 100% had vitamin D intakes <80% of the RDA. CONCLUSIONS: PAE may be associated with altered acquisition and distribution of body mass with increasing age. Disordered eating was common. The increased feeding behaviors surrounding lack of satiety suggest that self-regulation may be altered. Constipation could reflect low dietary fiber or altered gastrointestinal function. These exploratory data suggest that children with PAE may be at risk for nutritional deficiencies, which are influenced by inappropriate food preferences, disordered eating patterns, medication use, and the stressful dynamics surrounding food preparation and mealtime.