Obesity is a multifactorial disorder with high heritability (50-75%), which is probably higher in early-onset and severe cases. Although rare monogenic forms and several genes and regions of ...susceptibility, including copy number variants (CNVs), have been described, the genetic causes underlying the disease still remain largely unknown. We searched for rare CNVs (>100kb in size, altering genes and present in <1/2000 population controls) in 157 Spanish children with non-syndromic early-onset obesity (EOO: body mass index >3 standard deviations above the mean at <3 years of age) using SNP array molecular karyotypes. We then performed case control studies (480 EOO cases/480 non-obese controls) with the validated CNVs and rare sequence variants (RSVs) detected by targeted resequencing of selected CNV genes (n = 14), and also studied the inheritance patterns in available first-degree relatives. A higher burden of gain-type CNVs was detected in EOO cases versus controls (OR = 1.71, p-value = 0.0358). In addition to a gain of the NPY gene in a familial case with EOO and attention deficit hyperactivity disorder, likely pathogenic CNVs included gains of glutamate receptors (GRIK1, GRM7) and the X-linked gastrin-peptide receptor (GRPR), all inherited from obese parents. Putatively functional RSVs absent in controls were also identified in EOO cases at NPY, GRIK1 and GRPR. A patient with a heterozygous deletion disrupting two contiguous and related genes, SLCO4C1 and SLCO6A1, also had a missense RSV at SLCO4C1 on the other allele, suggestive of a recessive model. The genes identified showed a clear enrichment of shared co-expression partners with known genes strongly related to obesity, reinforcing their role in the pathophysiology of the disease. Our data reveal a higher burden of rare CNVs and RSVs in several related genes in patients with EOO compared to controls, and implicate NPY, GRPR, two glutamate receptors and SLCO4C1 in highly penetrant forms of familial obesity.
Bardet-Biedl syndrome is a rare genetic disease associated with hyperphagia and early-onset, severe obesity. There is limited evidence on how hyperphagia and obesity affect health-related quality of ...life in patients with Bardet-Biedl syndrome, and on how management of these symptoms may influence disease burden. This analysis evaluated changes in health-related quality of life in adults and children with Bardet-Biedl syndrome in a Phase 3 trial following 1 year of setmelanotide treatment (ClinicalTrials.gov identifier: NCT03746522).
Patients with Bardet-Biedl syndrome and obesity received 52 weeks of treatment with setmelanotide and completed various self-reported health-related quality of life measures. Patients aged < 18 years or their caregiver completed the Pediatric Quality of Life Inventory (PedsQL; meaningful improvement, 4.4-point change); adults aged ≥ 18 years completed the Impact of Weight on Quality of Life Questionnaire-Lite (IWQOL-Lite; meaningful improvement range, 7.7-12-point change). Descriptive outcomes were reported in patients with data both at active treatment baseline and after 52 weeks of treatment.
Twenty patients (< 18 years, n = 9; ≥ 18 years, n = 11) reported health-related quality of life at baseline and 52 weeks. For children and adolescents, PedsQL score mean change from baseline after 52 weeks was + 11.2; all patients with PedsQL impairment at baseline (n = 4) experienced clinically meaningful improvement. In adults, IWQOL-Lite score mean change from baseline was + 12.0. Of adults with IWQOL-Lite impairment at baseline (n = 8), 62.5% experienced clinically meaningful improvement. In adults, IWQOL-Lite score was significantly correlated with changes in percent body weight (P = 0.0037) and body mass index (P = 0.0098).
After 1 year of setmelanotide, patients reported clinically meaningful improvements across multiple health-related quality of life measures. This study highlights the need to address the impaired health-related quality of life in Bardet-Biedl syndrome, and supports utility of setmelanotide for reducing this burden. Trial Registration NCT03746522. Registered November 19, 2018, https://clinicaltrials.gov/ct2/show/NCT03746522 .
Abstract
Context
Long-term data on enzyme replacement treatment of hypophosphatasia (HPP) are limited.
Objective
To evaluate efficacy and safety of asfotase alfa in patients aged ≤5 years with HPP ...followed for up to 6 years.
Design
Phase 2 open-label study (July 2010 to September 2016).
Setting
Twenty-two sites; 12 countries.
Participants
Sixty-nine patients median (range) age: 16.0 (0.02 to 72) months with severe HPP and sign/symptom onset before age 6 months.
Intervention
Asfotase alfa 2 mg/kg three times/week or 1 mg/kg six times/week subcutaneously.
Main Outcome Measures
Primary efficacy measure: Radiographic Global Impression of Change (RGI-C) score −3 (severe worsening) to +3 (complete/near-complete healing). Additional outcome measures: respiratory status, growth, and safety. Post hoc analysis: characteristics of radiographic responders vs nonresponders at Year 1 (RGI-C: ≥+2 vs <+2).
Results
During median (minimum, maximum) 2.3 (0.02, 5.8) years of treatment, RGI-C scores improved significantly at Month 6 +2.0 (−1.7, +3.0), Year 1 +2.0 (−2.3, +3.0), and Last Assessment +2.3 (−2.7, +3.0); P < 0.0001 all. Of 24 patients requiring respiratory support at Baseline, 11 (46%) no longer needed support. Height/weight z scores generally increased. Nine patients died (13%). All patients experienced at least one adverse event; pyrexia was most common. Compared with responders n = 50 (72%), nonresponders n = 19 (28%) had more severe disease at Baseline and a higher rate of neutralizing antibodies (NAbs) at Last Assessment.
Conclusions
Most infants/young children given asfotase alfa showed early radiographic and clinical improvement sustained up to 6 years; radiographic nonresponders had more severe disease and more frequent NAbs at Last Assessment.
Most infants and young children with hypophosphatasia, treated with asfotase alfa, showed improved skeletal manifestations, respiratory function, and growth within 1 year, maintained up to 6 years.
To report clinical characteristics and medical history data obtained retrospectively for a large cohort of pediatric patients with perinatal and infantile hypophosphatasia.
Medical records from ...academic medical centers known to diagnose and/or treat hypophosphatasia were reviewed. Patients born between 1970 and 2011 with hypophosphatasia and any of the following signs/symptoms at age <6 months were eligible: vitamin B6–dependent seizures, respiratory compromise, or rachitic chest deformity (NCT01419028). Patient demographics and characteristics, respiratory support requirements, invasive ventilator–free survival, and further complications of hypophosphatasia were followed for up to the first 5 years of life.
Forty-eight patients represented 12 study sites in 7 countries; 13 patients were alive, and 35 were dead (including 1 stillborn). Chest deformity, respiratory distress, respiratory failure (as conditioned by the eligibility criteria), failure to thrive, and elevated calcium levels were present in >70% of patients between birth and age 5 years. Vitamin B6–dependent seizures and respiratory distress and failure were associated significantly (P < .05) with the risk of early death. Serum alkaline phosphatase activity in all 41 patients tested (mean SD: 18.1 15.4 U/L) was below the mean lower limit of normal of the reference ranges of the various laboratories (88.2 U/L). Among the 45 patients with relevant data, 29 had received respiratory support, of whom 26 had died at the time of data collection. The likelihood of invasive ventilator–free survival for this cohort decreased to 63% at 3 months, 54% at 6 months, 31% at 12 months, and 25% at 5 years.
Patients with perinatal or infantile hypophosphatasia and vitamin B6–dependent seizures, with or without significant respiratory distress or chest deformities, have high morbidity and mortality in the first 5 years of life.
ClinicalTrials.gov: NCT01419028.
Myxomycetes (plasmodial slime molds, Amoebozoa) are often perceived as widely distributed, confounding to the "everything is everywhere" hypothesis. To test if gene flow within these spore-dispersed ...protists is restricted by geographical barriers, we chose the widespread but morphologically unmistakable species Hemitrichia serpula for a phylogeographic study. Partial sequences from nuclear ribosomal RNA genes (SSU) revealed 40 ribotypes among 135 specimens, belonging to three major clades. Each clade is dominated by specimens from a certain region and by one of two morphological varieties which can be differentiated by SEM micrographs. Partial sequences of the protein elongation factor 1 alpha (EF1A) showed each clade to possess a unique combination of SSU and EF1A genotypes. This pattern is best explained assuming the existence of several putative biospecies dominating in a particular geographical region. However, occasional mismatches between molecular data and morphological characters, but as well heterogeneous SSU and heterozygous EF1A sequences, point to ongoing speciation. Environmental niche models suggest that the putative biospecies are rather restricted by geographical barriers than by macroecological conditions. Like other protists, myxomycetes seem to follow the moderate endemicity hypothesis and are in active speciation, which is most likely shaped by limited gene flow and reproductive isolation.
Mutations in multiple genes of the growth hormone/IGF‐I axis have been identified in syndromes marked by growth failure. However, no pathogenic human mutations have been reported in the six ...high‐affinity IGF‐binding proteins (IGFBPs) or their regulators, such as the metalloproteinase pregnancy‐associated plasma protein A2 (PAPP‐A2) that is hypothesized to increase IGF‐I bioactivity by specific proteolytic cleavage of IGFBP‐3 and ‐5. Multiple members of two unrelated families presented with progressive growth failure, moderate microcephaly, thin long bones, mildly decreased bone density and elevated circulating total IGF‐I, IGFBP‐3, and ‐5, acid labile subunit, and IGF‐II concentrations. Two different homozygous mutations in PAPPA2, p.D643fs25* and p.Ala1033Val, were associated with this novel syndrome of growth failure. In vitro analysis of IGFBP cleavage demonstrated that both mutations cause a complete absence of PAPP‐A2 proteolytic activity. Size‐exclusion chromatography showed a significant increase in IGF‐I bound in its ternary complex. Free IGF‐I concentrations were decreased. These patients provide important insights into the regulation of longitudinal growth in humans, documenting the critical role of PAPP‐A2 in releasing IGF‐I from its BPs.
Synopsis
Pregnancy‐associated plasma protein‐A2 (PAPP‐A2) is a highly specific protease for the cleavage of insulin‐like growth factor (IGF)‐binding proteins. PAPP‐A2 homozygous loss‐of‐function mutations alter IGF‐I transport and cause growth defects in patients.
This new syndrome of short stature is characterized by:
Mild but progressive postnatal growth failure, moderate microcephaly, and decreased bone density with mild skeletal abnormalities.
Elevated concentrations of circulating total IGF‐I, IGFBP‐3, and IGFBP‐5, acid labile subunit, IGF‐II, and basal insulin, with increased ternary complex formation.
Very low levels of free IGF‐I and bioactive IGF.
Pregnancy‐associated plasma protein‐A2 (PAPP‐A2) is a highly specific protease for the cleavage of insulin‐like growth factor (IGF)‐binding proteins. PAPP‐A2 homozygous loss‐of‐function mutations alter IGF‐I transport and cause growth defects in patients.
Abstract
Context
Pappalysins (PAPP-A, PAPP-A2) modulate body growth by increasing insulin-like growth factor I (IGF-I) bioavailability through cleavage of insulin-like growth factor binding proteins ...(IGFBPs) and are inhibited by stanniocalcins (STC1, STC2). Normative data on these novel factors, as well as on free IGF-I and uncleaved fractions of IGFBPs, are not well established.
Objective
This work aimed to determine serum concentrations of PAPP-A, PAPP-A2, STC1, and STC2 in relationship with other growth hormone (GH)-IGF axis parameters during development.
Methods
Full-term newborns (150; gestational age: 39.30 ± 1.10 weeks), 40 preterm newborns (30.87 ± 3.35 weeks), and 1071 healthy individuals (aged 1-30 years) were included in the study and divided according to their Tanner stages (males and females): I:163 males, 154 females; II:100 males, 75 females; III:83 males, 96 females; IV: 77 males, 86 females; and V:109 males,128 females.
Results
Serum concentrations of PAPP-A, PAPP-A2, STC1, STC2, IGFBP-2, total IGFBP-4, and total IGFBP-5 were elevated at birth and declined throughout childhood. In postnatal life, PAPP-A2 concentrations decreased progressively in concomitance with the free/total IGF-I ratio; however, stanniocalcin concentrations remained stable. PAPP-A2 concentrations positively correlated with the free/total IGF-I ratio (r = +0.28; P < .001) and negatively with the intact/total IGFBP-3 ratio (r = –0.23; P < .001). PAPP-A concentrations inversely correlated with intact/total IGFBP-4 ratio (r = –0.21; P < .001), with PAPP-A concentrations being lower in females at all ages. Association studies indicate the importance of stanniocalcins and pappalysins in the control of this axis in an age-specific manner.
Conclusion
This study provides reference values of pappalysins and stanniocalcins, which modulate IGF-I activity by changing the concentrations of cleaved and uncleaved IGFBPs.
Impaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway might contribute to obesity in patients with Bardet-Biedl syndrome and Alström syndrome, rare genetic diseases associated with ...hyperphagia and early-onset severe obesity. We aimed to evaluate the effect of setmelanotide on bodyweight in these patients.
This multicentre, randomised, 14-week double-blind, placebo-controlled, phase 3 trial followed by a 52-week open-label period, was performed at 12 sites (hospitals, clinics, and universities) in the USA, Canada, the UK, France, and Spain. Patients aged 6 years or older were included if they had a clinical diagnosis of Bardet-Biedl syndrome or Alström syndrome and obesity (defined as BMI >97th percentile for age and sex for those aged 6-15 years and ≥30 kg/m
for those aged ≥16 years). Patients were randomly assigned (1:1) using a numerical randomisation code to receive up to 3·0 mg of subcutaneous setmelanotide or placebo once per day during the 14-week double-blind period, followed by open-label setmelanotide for 52 weeks. The primary endpoint, measured in the full analysis set, was the proportion of patients aged 12 years or older who reached at least a 10% reduction in bodyweight from baseline after 52 weeks of setmelanotide treatment. This study is registered with ClinicalTrials.gov, NCT03746522.
Between Dec 10, 2018, and Nov 25, 2019, 38 patients were enrolled and randomly assigned to receive setmelanotide (n=19) or placebo (n=19; 16 with Bardet-Biedl syndrome and three with Alström syndrome in each group). In terms of the primary endpoint, 32·3% (95% CI 16·7 to 51·4; p=0·0006) of patients aged 12 years or older with Bardet-Biedl syndrome reached at least a 10% reduction in bodyweight after 52 weeks of setmelanotide. The most commonly reported treatment-emergent adverse events were skin hyperpigmentation (23 61% of 38) and injection site erythema (18 48%). Two patients had four serious adverse events (blindness, anaphylactic reaction, and suicidal ideation); none were considered related to setmelanotide treatment.
Setmelanotide resulted in significant bodyweight reductions in patients with Bardet-Biedl syndrome; however, these results were inconclusive in patients with Alström syndrome. These results support the use of setmelanotide and provided the necessary evidence for approval of this drug as the first treatment for obesity in patients with Bardet-Biedl syndrome.
Rhythm Pharmaceuticals.
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