1,721,032 research outputs found
Genetic obesity: an update with emerging therapeutic approaches
Full text linkBased on the genetic contribution, childhood obesity can be classified into 3 groups: common polygenic obesity, syndromic obesity, and monogenic obesity. More genetic causes of obesity are being identified along with the advances in the genetic testing. Genetic obesities including syndromic and monogenic obesity should be suspected and evaluated in children with early-onset morbid obesity and hyperphagia under 5 years of age. Patients with syndromic obesity have early-onset severe obesity associated specific genetic syndromes including Prader-Willi syndrome, Bardet-Biedle syndrome, and Alstrom syndrome. Syndromic obesity is often accompanied with neurodevelopmental delay or dysmorphic features. Nonsyndromic monogenic obesity is caused by variants in single gene which are usually involved in the regulation of hunger and satiety associated with the hypothalamic leptin-melanocortin pathway in central nervous system. Unlike syndromic obesity, patients with monogenic obesity usually show normal neurodevelopment. They would be presented with hyperphagia and early-onset severe obesity with additional clinical symptoms including short stature, red hair, adrenal insufficiency, hypothyroidism, hypogonadism, pituitary insufficiencies, diabetes insipidus, increased predisposition to infection or intractable recurrent diarrhea. Identifying patients with genetic obesity is critical as new innovative therapies including melanocortin 4 receptor agonist have become available. Early genetic evaluation enables to identify treatable obesity and provide timely intervention which may eventually achieve favorable outcome by establishing personalized management
Updates on Paget’s Disease of Bone
Full text linkPaget's disease of the bone is a prevalent bone disease characterized by disorganized bone remodeling; however, it is comparatively uncommon in East Asian countries, including China, Japan, and Korea. The exact cause still remains unknown. In genetically susceptible individuals, environmental triggers such as paramyxoviral infections are likely to cause the disease. Increased osteoclast activity results in increased bone resorption, which attracts osteoblasts and generates new bone matrix. Fast bone resorption and formation lead to the development of disorganized bone tissue. Increasing serum alkaline phosphatase or unique radiographic lesions may serve as the diagnostic indicators. Common symptoms include bone pain, bowing of the long bones, an enlarged skull, and hearing loss. The diagnosis is frequently confirmed by radiographic and nuclear scintigraphy of the bone. Further, bisphosphonates such as zoledronic acid and pamidronate are effective for its treatment. Moreover, biochemical monitoring is superior to the symptoms as a recurrence indicator. This article discusses the updates of Paget's disease of bone with a clinical case
Efficacy and safety of idursulfase beta in the treatment of mucopolysaccharidosis II: A phase-3, 2-part study compared with a historical placebo cohort
No full textPURPOSE: To investigate the efficacy and safety of idursulfase beta (0.5 mg/kg weekly) in the treatment of mucopolysaccharidosis II, compared with a historical placebo from a previous idursulfase trial (TKT024). METHODS: The study comprised 2 sequential parts. In part 1, a randomized, double-blind study, idursulfase or idursulfase beta were given for 52 weeks. In the open, single-cohort part 2 study, additional participants received idursulfase beta for 52 weeks. Data from the idursulfase beta groups from parts 1 and 2 were pooled for comparisons with the historical placebo group (n = 32). The primary end point was a change in the 6-minute walk test at week 53. RESULTS: Participants in the idursulfase beta groups (n = 24) were male Asians (mean age, 12.0 years). Idursulfase beta was superior to placebo in 6-minute walk test improvement (62.2 vs 7.3 m, P < .0001). Decrease in urine glycosaminoglycan excretion (-71.13% vs 21.39%, P < .0001) and reduction in the liver (-26.67% vs -0.80%, P < .0001) and spleen volumes (-26.46% vs 7.2%, P < .0001) were significant. The safety profile of idursulfase beta was satisfactory. CONCLUSION: Idursulfase beta is a safe and effective treatment option in mucopolysaccharidosis II, addressing crucial somatic ailments presented by patients
Effects of recombinant human growth hormone treatment on growth, body composition, and safety in infants or toddlers with Prader-Willi syndrome: a randomized, active-controlled trial
Full text linkBACKGROUND: Prader-Willi syndrome (PWS) is a rare complex genetic disorder and is characterized by short stature, muscular hypotonia, abnormal body composition, psychomotor retardation, and hyperphagia. Recombinant human growth hormone (rhGH) treatment improves the symptoms in children with PWS, and early treatment results in more favorable outcomes. However, systematic studies in infants and toddlers under 2 years of age are lacking. This multicenter, randomized, active-controlled, parallel-group, open-label, Phase III study aimed to evaluate the safety of rhGH (Eutropin, LG Chem, Ltd.) and its efficacy on growth, body composition, and motor and cognitive development in infants and toddlers with PWS compared with a comparator treatment (Genotropin, Pfizer, Inc.). Eligible Korean infants or toddlers with PWS were randomly assigned to receive Eutropin or comparator (both 0.24 mg/kg/week, 6 times/week) for 1 year. Height standard deviation score (SDS), body composition, and motor and cognitive development were measured.
RESULTS: Thirty-four subjects (less than 24 months old) were randomized into either the Eutropin (N = 17) group or the comparator (N = 17) group. After 52 weeks of rhGH treatment, height SDS and lean body mass increased significantly from baseline in both groups: the mean height SDS change (SD) was 0.75 (0.59) in the Eutropin group and 0.95 (0.66) in the comparator group, and the mean lean body mass change (SD) was 2377.79 (536.25) g in the Eutropin group and 2607.10 (641.36) g in the comparator group. In addition, percent body fat decreased significantly: the mean (SD) change from baseline was - 8.12% (9.86%) in the Eutropin group and - 7.48% (10.26%) in the comparator group. Motor and cognitive developments were also improved in both groups after the 1-year treatment. The incidence of adverse events was similar between the groups.
CONCLUSIONS: rhGH treatment for 52 weeks in infants and toddlers with PWS improved growth, body composition, and motor and cognitive development, and efficacy and safety outcomes of Eutropin were comparable to those of Genotropin. Hence, Eutropin is expected to provide safe and clinically meaningful improvements in pediatric patients with PWS.
TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (identifier: NCT02204163) on July 30, 2014.
URL: https://clinicaltrials.gov/ct2/show/NCT02204163?term=NCT02204163&rank=1
Using low-dose octreotide with diazoxide-resistant congenital hyperinsulinism resulting from com-pound heterozygous mutations in the ABCC8 gene
Full text linkTiming is everything: Clinical courses of Hunter syndrome associated with age at initiation of therapy in a sibling pair
Full text linkHunter syndrome, or mucopolysaccharidosis (MPS) II, is a rare lysosomal disorder characterized by progressive, multi-system disease. As most symptoms cannot be reversed once established, early detection and treatment prior to the onset of clinical symptoms are critical. However, it is difficult to identify affected individuals early in disease, and therefore the long-term outcomes of initiating treatment during this optimal time period are incompletely described. We report long-term clinical outcomes of treatment when initiated prior to obvious clinical signs by comparing the courses of two siblings with neuronopathic Hunter syndrome (c.1504 T > G[p.W502G]), one who was diagnosed due to clinical disease (Sibling-O, age 3.7 years) and the other who was diagnosed before disease was evident (Sibling-Y, age 12 months), due to his older sibling's findings. The brothers began enzyme replacement therapy within a month of diagnosis. Around the age of 5 years, Sibling-O had a cognitive measurement score in the impaired range of <55 (average range 85-115), whereas Sibling-Y at this age received a score of 91. Sibling-O has never achieved toilet training and needs direct assistance with toileting, dressing, and washing, while Sibling-Y is fully toilet-trained and requires less assistance with daily activities. Both siblings have demonstrated sensory-seeking behaviors, hyperactivity, impulsivity, and sleep difficulties; however, Sibling-O demonstrates physical behaviors that his brother does not, namely biting, pushing, and frequent elopement. Since the time of diagnosis, Sibling-O has had significant joint contractures and a steady deterioration in mobility leading to the need for an adaptive stroller at age 11, while Sibling-Y at age 10.5 could hike more than 6 miles without assistance. After nearly a decade of therapy, there were more severe and life-limiting disease manifestations for Sibling-O; data from caregiver interview indicated substantial differences in Quality of Life for the child and the family, dependent on timing of ERT. The findings from this sibling pair provide evidence of superior somatic and neurocognitive outcomes associated with presymptomatic treatment of Hunter syndrome, aligned with current considerations for newborn screening
The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects
Full text linkBACKGROUND: Gaucher disease (GD) is caused by a deficiency of beta-glucocerebrosidase, encoded by GBA. Haplotype analyses previously demonstrated founder effects for particular GBA mutations in Ashkenazi Jewish and French-Canadian populations. This study aimed to investigate the clinical characteristics and mutation spectrum of GBA in Korean GD patients and to identify founder effect of GBA p.G85E in non-neuronopathic GD patients. RESULTS: The study cohort included 62 GD patients from 58 unrelated families. Among them, 18 patients from 17 families harbored the p.G85E mutation. Haplotype analysis was performed for 9 probands and their parents for whom DNA samples were available. In 58 unrelated probands, the GBA mutation p.L483P was the most common (30/116 alleles, 26%), followed by p.G85E (16%), p.F252I (13%), and p.R296Q (9%). The median age at diagnosis of the 18 patients harboring the p.G85E mutation was 3.8 (range 1.2-57) years. No patients developed neurological symptoms during follow-up periods of 2.2-20.3 (median 13.9) years. The size of the shared haplotype containing GBA p.G85E was 732 kbp, leading to an estimated age of 3075 years. CONCLUSION: The GBA p.G85E mutation, which appears to be neuroprotective despite producing distinctive visceromegaly and skeletal symptoms, exhibited a potential founder effect in Korean GD patients
Ataxia Associated with CADASIL: a Pathology-Confirmed Case Report and Literature Review
No full textCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is primarily characterized by migraine, stroke, mood disturbances, and cognitive decline. Ataxia has seldom been reported as a presenting symptom. Here, we review reports of CADASIL presenting as ataxia and compare these to the first pathologically confirmed case of CADASIL presenting with progressive ataxia. A 50-year-old woman presented with progressive truncal ataxia. Brain magnetic resonance imaging (MRI) revealed white matter hyperintensities in the bilateral anterior temporal lobes, external capsules, and periventricular areas, but not the cerebellum. Electron microscopy of skin biopsy material revealed multiple granular osmiophilic materials. Genetic testing confirmed a c.4552C > A mutation in exon 25 of the NOTCH3 gene. CADASIL is a rare cause of progressive ataxia, and only four cases of CADASIL presenting with ataxia have been reported in the literature. We also discuss the possible pathophysiology of cerebellar ataxia associated with CADASIL
Genetic Analysis Using a Next Generation Sequencing-Based Gene Panel in Patients With Skeletal Dysplasia: A Single-Center Experience
Full text linkSkeletal dysplasia (SD), a heterogeneous disease group with rare incidence and various clinical manifestations, is associated with multiple causative genes. For clinicians, accurate diagnosis of SD is clinically and genetically difficult. The development of next-generation sequencing (NGS) has substantially aided in the genetic diagnosis of SD. In this study, we conducted a targeted NGS of 437 genes – included in the nosology of SD published in 2019 – in 31 patients with a suspected SD. The clinical and genetic diagnoses were confirmed in 16 out of the 31 patients, and the diagnostic yield was 51.9%. In these patients, 18 pathogenic variants were found in 13 genes (COL2A1, MYH3, COMP, MATN3, CTSK, EBP, CLCN7, COL1A2, EXT1, TGFBR1, SMAD3, FIG4, and ARID1B), of which, four were novel variants. The diagnosis rate was very high in patients with a suspected familial SD and with radiological evidence indicating clinical SD (11 out of 15, 73.3%). In patients with skeletal involvement and other clinical manifestations including dysmorphism or multiple congenital anomalies, and various degrees of developmental delay/intellectual disability, the diagnosis rate was low (5 out of 16, 31.2%) but rare syndromic SD could be diagnosed. In conclusion, NGS-based gene panel sequencing can be helpful in diagnosing SD which has clinical and genetic heterogeneity. To increase the diagnostic yield of suspected SD patients, it is important to categorize patients based on the clinical features, family history, and radiographic evidence
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