The Journal of rare disorders最新文献

Background: Prader-Willi syndrome (PWS) is a complex genetic neurodevelopmental disorder with endocrine disturbances, hyperphagia and often life-threatening obesity as key features. We investigated emotional-processing of food and eating behavior in PWS using startle response-modulation. Startle eyeblink response is an involuntary reflex activated by the autonomic nervous system in response to sudden or disturbing auditory/visual stimuli which may be modulated by the emotional valence of concurrently viewed visual stimuli.

Methodology: Differences in affective modulation of startle reflex were recorded in 13 individuals with PWS versus 8 healthy controls when viewing standard neutral, negative, positive and food-derived images. Electromyogram (EMG) of the orbicularis oculi muscle was measured in response to binaural white noise before and after consumption of a standard 500 Kcal meal. Participants reported their perceived emotional valence for each image, pre- and post-meal, using a 1-10 Likert rating scale.

Results: Subjective ratings of food images and urge to eat were significantly higher in PWS than controls and did not significantly decline post-meal. Acoustic startle responding was detected in PWS but was significantly lower than control participants under all conditions. Startle responses to food images in PWS were attenuated relative to other picture types with potentially abnormal emotional modulation of responses to non-food images which contrasted self-reported picture ratings. A stable positive emotional valence to food images was observed pre- and post-feeding with a sustained urge to consume food in PWS.

Conclusions: Emotional processing measured using startle modulation in response to non-food images was abnormal in PWS which may reflect unique physiological attributes such as hypotonia and abnormal skin conductivity due to increased fat mass. Alternatively, disruption of autonomic or sympathetic nervous system functioning reported in PWS may impact on hunger and/or food drive states. Our findings parallel attentional/processing attributes of affective stimuli reported in autism spectrum disorder and support the feasibility of eyeblink startle modulation to assess food motivation in PWS and provide preliminary data to optimize methodological parameters.

Background: Prader-Willi syndrome (PWS) is a rare obesity-related genetic disorder often caused by a deletion of the chromosome 15q11-q13 region inherited from the father or by maternal disomy 15. Growth hormone deficiency with short stature, hypogonadism, cognitive and behavioral problems, analgesia, decreased gastric motility and decreased ability to vomit with hyperphagia are common in PWS leading to severe obesity in early childhood, if not controlled. Substance P (SP) and beta-endorphin (BE) are neuropeptides involved with centrally and peripherally mediated pain perception, emotional regulation, and gastric motility impacting nausea, emesis and feeding patterns.

Objective: The goal of this study was to investigate potential mechanisms for PWS symptom development for pain, emotion and gastric motility and plasma levels of substance P and beta-endorphin between PWS and unrelated unaffected children.

Methodology: Plasma samples were collected from 23 Caucasian children with PWS and 18 unrelated, unaffected siblings with an average age of 8.2 ±2.0 years and age range of 5 to 11 years following an overnight fast and neuropeptide substance p and beta-endorphin levels were assessed using Multiplex sandwich immunoassays using the Luminex magnetic-bead based platform. Linear regression analysis was carried out on log-transformed values adjusted for age, sex, and body mass index (BMI).

Results: The mean plasma SP (57 ± 23 pg/ml) and BE (592 ± 200 pg/ml) levels in PWS were significantly higher than SP (35 ± 20 pg/ml, F=10.5, P<0.01) and BE (402 ± 162 pg/ml, F=10.8, P<0.01) levels found in unrelated, unaffected siblings suggesting a previously uncharacterized neuroendocrine pathophysiology in PWS.

Conclusions: The increased BE and SP plasma levels relative to unrelated, unaffected siblings may contribute to hyperphagia, abnormal pain sensation and adrenal insufficiency seen in PWS. Increases in SP levels may be modulated by central and/or peripheral actions of BE on opioid, GABA or POMC precursors and may reflect loss of feedback inhibitory control. Further studies are needed to confirm and elucidate the biochemical basis for observed disturbances in neuropeptide levels seen in our study and may impact on the development and persistence of symptoms commonly seen in PWS.

Background: Feeding problems are common in boys with Barth syndrome and may contribute to the population's propensity for growth delay and muscle weakness. The purpose of this study was to quantify and describe these feeding issues and examine altered taste perception and sensory sensitivity as contributing factors.

Methodology: A cross-sectional, two-group comparison design was used to examine feeding preferences and behaviors, chemical taste perception, and sensory sensitivities in fifty boys with (n=24) and without (n=26) Barth ages 4-17 years. Taste perception was measured using chemical test strips saturated with phenylthiocarbamide (PTC) and sodium benzoate (NaB). Feeding problems were documented by parents using a Food Inventory, while sensory sensitivities were recorded using a Short Sensory Profile.

Results: Boys with Barth differed significantly from typical peers with regards to problem feeding behaviors. For boys with Barth, food refusal and food selectivity were identified as being present in 50% the sample, while 70% of had identified problems related to gagging or swallowing foods. About half of all Barth families noted that their child's eating habits did not match the family's and that separate meals were often prepared. As demonstrated in previous research, about 50% of boys with Barth demonstrated probable or definite differences in taste/smell sensitivity, which was significantly higher than controls. On tests of chemical taste perception, boys with Barth were significantly more likely to be supertasters to PTC and non-tasters to NaB. Taster-status did not directly relate to the presence of feeding problems, however, taste/smell sensitivity did significantly relate to food selectivity by type and texture.

Conclusions: Results indicate feeding problems in at least 50-70% of boys with Barth syndrome, and suggest that behaviors are often present before 6 months of age. Differences in taste perception may influence dietary choices in boys with Barth, particularly their craving of salty foods. Taste/smell sensitivity also appears to influence food selectivity, and therefore may be important to consider in this population, particularly in light of dietary influences on cardiac function, energy consumption, and overall growth.

Background: Osteogenesis imperfecta (OI) type V is a dominantly inherited skeletal dysplasia characterized by fractures and progressive deformity of long bones. In addition, patients often present with radial head dislocation, hyperplastic callus, and calcification of the forearm interosseous membrane. Recently, a specific mutation in the IFITM5 gene was found to be responsible for OI type V. This mutation, a C to T transition 14 nucleotides upstream from the endogenous start codon, creates a new start methionine that appears to be preferentially used by the translational machinery. However, the mechanism by which the lengthened protein results in a dominant type of OI is unknown.

Methods and results: We report 7 ethnically diverse (African-American, Caucasian, Hispanic, and African) individuals with OI type V from 2 families and 2 sporadic cases. Exome sequencing failed to identify a causative mutation. Using Sanger sequencing, we found that all affected individuals in our cohort possess the c.-14 IFITM5 variant, further supporting the notion that OI type V is caused by a single, discrete mutation. Our patient cohort demonstrated inter-and intrafamilial phenotypic variability, including a father with classic OI type V whose daughter had a phenotype similar to OI type I. This clinical variability suggests that modifier genes influence the OI type V phenotype. We also confirm that the mutation creates an aberrant IFITM5 protein containing an additional 5 amino acids at the N-terminus.

Conclusions: The variable clinical signs in these cases illustrate the significant variability of the OI type V phenotype caused by the c.-14 IFITM5 mutation. The affected individuals are more ethnically diverse than previously reported.

Brain vascular malformations are resource-intensive to manage effectively, are associated with serious neurological morbidity, lack specific medical therapies, and have no validated biomarkers for disease severity and progression. Investigators have tended to work in "research silos" with suboptimal cross-communication. We present here a paradigm for interdisciplinary collaboration to facilitate rare disease research. The Brain Vascular Malformation Consortium (BVMC) is a multidisciplinary, inter-institutional group of investigators, one of 17 consortia in the Office of Rare Disease Research Rare Disease Clinical Research Network (RDCRN). The diseases under study are: familial Cerebral Cavernous Malformations type 1, common Hispanic mutation (CCM1-CHM); Sturge-Weber Syndrome (SWS); and brain arteriovenous malformation in hereditary hemorrhagic telangiectasia (HHT). Each project is developing biomarkers for disease progression and severity, and has established scalable, relational databases for observational and longitudinal studies that are stored centrally by the RDCRN Data Management and Coordinating Center. Patient Support Organizations (PSOs) are a key RDCRN component in the recruitment and support of participants. The BVMC PSOs include Angioma Alliance, Sturge Weber Foundation, and HHT Foundation International. Our networks of clinical centers of excellence in SWS and HHT, as well as our PSOs, have enhanced BVMC patient recruitment. The BVMC provides unique and valuable resources to the clinical neurovascular community, and recently reported findings are reviewed. Future planned studies will apply successful approaches and insights across the three projects to leverage the combined resources of the BVMC and RDCRN in advancing new biomarkers and treatment strategies for patients with vascular malformations.