A randomized pilot efficacy and safety trial of diazoxide choline controlled-release in patients with Prader-Willi syndrome.

INTRODUCTION: Prader-Willi syndrome (PWS) is a complex genetic condition characterized by hyperphagia, hypotonia, low muscle mass, excess body fat, developmental delays, intellectual disability, behavioral problems, and growth hormone deficiency. This study evaluated the safety and efficacy of orally administered Diazoxide Choline Controlled-Release Tablets (DCCR) in subjects with PWS. METHOD: This was a single-center, Phase II study and included a 10-week Open-Label Treatment Period during which subjects were dose escalated, followed by a 4-week Double-Blind, Placebo-Controlled Treatment Period. RESULTS: Five female and eight male overweight or obese, adolescent and adult subjects with genetically-confirmed PWS with an average age of 15.5±2.9 years were enrolled in the study. There was a statistically significant reduction in hyperphagia at the end of the Open-Label Treatment Period (-4.32, n = 11, p = 0.006). The onset of effect on hyperphagia was rapid and greater reductions in hyperphagia were seen in subjects with moderate to severe Baseline hyperphagia (-5.50, n = 6, p = 0.03), in subjects treated with the highest dose (-6.25, n = 4, p = 0.08), and in subjects with moderate to severe Baseline hyperphagia treated with the highest dose (-7.83, n = 3, p = 0.09). DCCR treatment resulted in a reduction in the number of subjects displaying aggressive behaviors (-57.1%, n = 10, p = 0.01), clinically-relevant reductions in fat mass (-1.58 kg, n = 11, p = 0.02) and increases in lean body mass (2.26 kg, n = 11, p = 0.003). There was a corresponding decrease in waist circumference, and trends for improvements in lipids and insulin resistance. The most common adverse events were peripheral edema and transient increases in glucose. Many of the adverse events were common medical complications of PWS and diazoxide. CONCLUSION: DCCR treatment appears to address various unmet needs associated with PWS, including hyperphagia and aggressive behaviors in this proof-of-concept study. If the results were replicated in a larger scale study, DCCR may be a preferred therapeutic option for patients with PWS.

The importance of preconception and prenatal genetic evaluation in heart transplant individuals and fetal and postnatal cardiac monitoring in their offspring.

A 24-year-old woman with a history of idiopathic dilated cardiomyopathy status post heart transplant gave birth to a healthy term female infant. At 5 months of age, the infant was diagnosed with severe left ventricular dysfunction with an ejection fraction of 18% and moderate non-compaction of the left ventricle. She received a heart transplant at 7 months of age. Familial dilated cardiomyopathy was diagnosed. Genetic testing revealed a likely pathogenic variant in the TPM1 gene. Fetal cardiac screening is critical for offspring of heart transplant recipients, especially when the reason for transplant was cardiomyopathy. Early genetic consultation and counselling is necessary for all heart transplant recipients, preferably prenatally. Postnatal screening of offspring is essential at birth, at 3-month intervals until 1 year of age, and then annually until the risk for familial cardiomyopathy is assessed.

Prader-Willi Syndrome due to an Unbalanced de novo Translocation t(15;19)(q12;p13.3).

Prader-Willi syndrome (PWS) is a complex, multisystem genetic disorder characterized by endocrine, neurologic, and behavioral abnormalities. We report the first case of an unbalanced de novo reciprocal translocation of chromosomes 15 and 19, 45,XY,-15,der(19)t(15;19)(q12;p13.3), resulting in monosomy for the PWS critical chromosome region. Our patient had several typical features of PWS including infantile hypotonia, a poor suck and feeding difficulties, tantrums, skin picking, compulsions, small hands and feet, and food seeking, but not hypopigmentation, a micropenis, cryptorchidism or obesity as common findings seen in PWS at the time of examination at 6 years of age. He had seizures noted from 1 to 3 years of age and marked cognitive delay. High-resolution SNP microarray analysis identified an atypical PWS type I deletion in chromosome 15 involving the proximal breakpoint BP1. The deletion extended beyond the GABRB3 gene but was proximal to the usual distal breakpoint (BP3) within the 15q11q13 region, and GABRA5, GABRG3, and OCA2 genes were intact. No deletion of band 19p13.3 was detected; therefore, the patient was not at an increased risk of tumors from the Peutz-Jeghers syndrome associated with a deletion of the STK11 gene.

Sebaceous adenomas in an MYH associated polyposis patient of Indian (Gujarati) origin.

MYH associated polyposis is an autosomal recessive polyposis syndrome with a high risk of large bowel cancer, caused by mutations in the DNA repair gene MYH. Founder mutations have been described in different ethnic groups. Muir Torre Syndrome is the association of internal malignancies with sebaceous gland tumours; Lynch Syndrome/Hereditary Non Polyposis Cancer is the best known cause. There has been a previous report of sebaceous gland tumours in an Italian patient with MYH associated polyposis. We describe a man of Indian (Gujarati) descent who has MYH associated polyposis and multiple sebaceous adenomas of the skin.