Kaufman oculocerebrofacial syndrome (KOS) is a recessive neurodevelopmental disorder characterized by intellectual disability and lack of speech. KOS is caused by inactivating mutations in UBE3B, but ...the underlying biological mechanisms are completely unknown. We found that loss of Ube3b in mice resulted in growth retardation, decreased grip strength, and loss of vocalization. The brains of Ube3b
−/− mice had hypoplasia of the corpus callosum, enlarged ventricles, and decreased thickness of the somatosensory cortex. Ube3b
−/− cortical neurons had abnormal dendritic morphology and synapses. We identified 22 UBE3B interactors and found that branched-chain α-ketoacid dehydrogenase kinase (BCKDK) is an in vivo UBE3B substrate. Since BCKDK targets several metabolic pathways, we profiled plasma and cortical metabolomes from Ube3b
−/− mice. Nucleotide metabolism and the tricarboxylic acid cycle were among the pathways perturbed. Substrate-induced mitochondrial respiration was reduced in skeletal muscle but not in liver of Ube3b
−/− mice. To assess the relevance of these findings to humans, we identified three KOS patients who had compound heterozygous UBE3B mutations. We discovered changes in metabolites from similar pathways in plasma from these patients. Collectively, our results implicate a disease mechanism in KOS, suggest that it is a metabolic encephalomyopathy, and provide an entry to targeted therapies.
The aorta is the largest artery in the body, yet processes underlying aortic pathology are poorly understood. The arterial media consists of circumferential layers of elastic lamellae and smooth ...muscle cells (SMCs), and many arterial diseases are characterized by defective lamellae and excess SMCs; however, a mechanism linking these pathological features is lacking. In this study, we use lineage and genetic analysis, pharmacological inhibition, explant cultures, and induced pluripotent stem cells (iPSCs) to investigate supravalvular aortic stenosis (SVAS) patients and/or elastin mutant mice that model SVAS. These experiments demonstrate that multiple preexisting SMCs give rise to excess aortic SMCs in elastin mutants, and these SMCs are hyperproliferative and dedifferentiated. In addition, SVAS iPSC-derived SMCs and the aortic media of elastin mutant mice and SVAS patients have enhanced integrin β3 levels, activation, and downstream signaling, resulting in SMC misalignment and hyperproliferation. Reduced β3 gene dosage in elastin-null mice mitigates pathological aortic muscularization, SMC misorientation, and lumen loss and extends survival, which is unprecedented. Finally, pharmacological β3 inhibition in elastin mutant mice and explants attenuates aortic hypermuscularization and stenosis. Thus, integrin β3-mediated signaling in SMCs links elastin deficiency and pathological stenosis, and inhibiting this pathway is an attractive therapeutic strategy for SVAS.
Gerodermia osteodysplastica is an autosomal recessive disorder characterized by wrinkly skin and osteoporosis. Here we demonstrate that gerodermia osteodysplastica is caused by loss-of-function ...mutations in SCYL1BP1, which is highly expressed in skin and osteoblasts. The protein localizes to the Golgi apparatus and interacts with Rab6, identifying SCYL1BP1 as a golgin. These results associate abnormalities of the secretory pathway with age-related changes in connective tissues.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Limited real-world data from routine clinical care are available on the safety and effectiveness of treatment with taliglucerase alfa in patients with Gaucher disease (GD).
Taliglucerase Alfa ...Surveillance (TALIAS), a multinational prospective Drug Registry of patients with GD, was established to evaluate the long-term safety (primary objective) and effectiveness (secondary objective) of taliglucerase alfa. We present an interim analysis of the data from the Drug Registry collected over the 5-year period from September 2013 to January 2019.
A total of 106 patients with GD (15.1% children aged < 18 years; 53.8% females) treated with taliglucerase alfa have been enrolled in the Drug Registry, as of January 7, 2019. The median duration of follow-up was 795 days with quartiles (Q1, Q3) of 567 and 994 days. Fifty-three patients (50.0%) were from Israel, 28 (26.4%) were from the United States, and 25 (23.6%) were from Albania. At the time of enrollment, most patients (87.7%) had received prior enzyme replacement therapy (ERT). Thirty-nine of the 106 patients had treatment-emergent adverse events (AEs). Twelve of the 106 patients experienced serious AEs; two patients experienced four treatment-related serious AEs. Four patients died, although none of the deaths was considered to be related to taliglucerase alfa treatment by the treating physicians. Nine patients discontinued from the study, including the four who died. At baseline, patients with prior ERT had a higher mean hemoglobin concentration and platelet counts than treatment-naïve patients, likely reflecting the therapeutic effects of prior treatments. During follow-up, the hemoglobin concentration and platelet counts increased in the treatment-naïve patients and remained relatively constant or increased slightly in patients with prior ERT. Spleen and liver volumes decreased in treatment-naïve patients.
The interim data showed no new or emergent safety signals. The overall interim data are consistent with the clinical program experience and known safety and effectiveness profile of taliglucerase alfa.
Williams syndrome (WS) is a congenital disorder affecting the vascular, connective tissue, and central nervous systems of 1 in 8,000 live births. Previous reports have reported high frequencies of ...cardiovascular abnormalities (CVAs) in small numbers of patients with WS. A retrospective review was undertaken of patients with WS evaluated at our institution from January 1, 1980 through December 31, 2007. WS was diagnosed by an experienced medical geneticist and/or by fluorescence in situ hybridization. CVAs were diagnosed using echocardiography, cardiac catheterization, or computed tomographic angiography. Freedom from intervention was determined using Kaplan-Meier analysis. The study group was 270 patients with WS. The age at presentation was 3.3 ± 5.9 years with follow-up of 8.9 ± 9.0 years (range 0 to 56.9). CVAs were present in 82% of the patients. The most common lesions were supravalvar aortic stenosis in 45% and peripheral pulmonary stenosis in 37%; 20% had both. Other common lesions included mitral valve prolapse and regurgitation in 15%, ventricular septal defect in 13%, and supravalvar pulmonary stenosis in 12%. Surgical or catheter-based interventions were performed in 21%. The rate of freedom from intervention was 91%, 81%, 78%, 72%, and 62% at 1, 5, 10, 20, and 40 years. Eight patients died. In conclusion, CVAs are common in patients with WS, but supravalvar aortic stenosis and peripheral pulmonary stenosis occurred less frequently in this large cohort than previously reported. In patients with WS and CVAs, interventions are common and usually occur by 5 years of age. Most patients with WS do not require intervention during long-term follow-up, and the overall mortality has been low.
Gaucher disease is an inherited pan-ethnic disorder that commonly begins in childhood and is caused by deficient activity of the lysosomal enzyme glucocerebrosidase. Two major phenotypes are ...recognized: non-neuropathic (type 1) and neuropathic (types 2 and 3). Symptomatic children are severely affected and manifest growth retardation, delayed puberty, early-onset osteopenia, significant splenomegaly, hepatomegaly, thrombocytopenia, anemia, severe bone pain, acute bone crises, and fractures. Symptomatic children with types 1 or 3 should receive enzyme replacement therapy, which will prevent debilitating and often irreversible disease progression and allow those with non-neuropathic disease to lead normal healthy lives. Children should be monitored every 6 months (physical exam including growth, spleen and liver volume, neurologic exam, hematologic indices) and have one to two yearly skeletal assessments (bone density and imaging, preferably with magnetic resonance, of lumbar vertebrae and lower limbs), with specialized cardiovascular monitoring for some type 3 patients. Response to treatment will determine the frequency of monitoring and optimal dose of enzyme replacement. Treatment of children with type 2 (most severe) neuropathic Gaucher disease is supportive. Pre-symptomatic children, usually with type 1 Gaucher, increasingly are being detected because of affected siblings and screening in high-prevalence communities. In this group, annual examinations (including bone density) are recommended. However, monitoring of asymptomatic children with affected siblings should be guided by the age and severity of manifestations in the first affected sibling. Treatment is necessary only if signs and symptoms develop.
Conclusion
: Early detection and treatment of symptomatic types 1 and 3 Gaucher disease with regular monitoring will optimize outcome. Pre-symptomatic children require regular monitoring. Genetic counseling is important.
To describe in detail the retinal structure and function of a group of patients with cobalamin C (cblC) disease.
Patients (n = 11, age 4 months to 15 years) with cblC disease (9/11, early onset) ...diagnosed by newborn screening underwent complete ophthalmic examinations, fundus photography, near-infrared reflectance imaging, and spectral-domain optical coherence tomography (SD-OCT). Electroretinograms (ERGs) were performed in a subset of patients.
Patients carried homozygous or compound heterozygote mutations in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. Late-onset patients had a normal exam. All early-onset patients showed a maculopathy; older subjects had a retina-wide degeneration (n = 4; >7 years of age). In general, retinal changes were first observed before 1 year of age and progressed within months to a well-established maculopathy. Pseudocolobomas were documented in three patients. Measurable visual acuities ranged from 20/200 to 20/540. Nystagmus was present in 8/11 patients; 5/6 patients had normal ERGs; 1/6 had reduced rod-mediated responses. Spectral-domain OCT showed macular thinning, with severe ganglion cell layer (GCL) and outer nuclear layer (ONL) loss. Inner retinal thickening was observed in areas of total GCL/ONL loss. A normal lamination pattern in the peripapillary nasal retina was often seen despite severe central and/or retina-wide disease.
Patients with early-onset cblC and MMACHC mutations showed an early-onset, unusually fast-progressing maculopathy with severe central ONL and GCL loss. An abnormally thickened inner retina supports a remodeling response to both photoreceptor and ganglion cell degeneration and/or an interference with normal development in early-onset cblC.
The objective of this study was to evaluate the long-term clinical benefits and safety of recombinant human arylsulfatase B (rhASB) treatment of mucopolysaccharidosis type VI (MPS VI: Maroteaux-Lamy ...syndrome), a lysosomal storage disease. Fifty-six patients derived from 3 clinical studies were followed in open-label extension studies for a total period of 97–260 Weeks. All patients received weekly infusions of rhASB at 1
mg/kg. Efficacy was evaluated by (1) distance walked in a 12-minute walk test (12MWT) or 6-minute walk test (6MWT), (2) stairs climbed in the 3-minute stair climb (3MSC), and (3) reduction in urinary glycosaminoglycans (GAG). Safety was evaluated by compliance, adverse event (AE) reporting and adherence to treatment.
Results: A significant reduction in urinary GAG (71–79%) was sustained. For the 12MWT, subjects in Phase 2 showed improvement of 255
±
191
m (mean
±
SD) at Week 144; those in Phase 3 Extension demonstrated improvement from study baseline of 183
±
26
m (mean
±
SE) in the rhASB/rhASB group at Week 96 and from treatment baseline (Week 24) of 117
±
25
m in the placebo/rhASB group. The Phase 1/2 6MWT and the 3MSC from Phase 2 and 3 also showed sustained improvements through the final study measurements. Compliance was 98% overall. Only 560 of 4121 reported AEs (14%) were related to treatment with only 10 of 560 (2%) described as severe.
Conclusion: rhASB treatment up to 5 years results in sustained improvements in endurance and has an acceptable safety profile.
Williams syndrome (WS) affects 1 in 8,000 live births and has a high risk of sudden death. No previous studies have evaluated corrected QT (QTc) prolongation in WS. Retrospective review of all ...patients with WS evaluated at our institution from January 1, 1980 to December 31, 2007 was performed. WS was diagnosed by a medical geneticist and/or by fluorescence in situ hybridization. Patients with ≥1 electrocardiogram (ECG) with sinus rhythm and measurable intervals were included. Normal control ECGs were identified from a large clinical database. Corrected JT (JTc) interval was calculated when QRS and QTc intervals were prolonged. QTc interval ≥460 ms and JTc interval >340 ms were defined as prolonged. Prevalence comparisons were made using Fisher's exact test. Statistical probability of <0.05 was considered significant. Of 270 patients identified, 188 had ECGs for review. Complete data were present in 499 of 517 ECGs (patients' mean age 10.3 ± 9.9 years); 1,522 normal ECGs of age-similar patients composed the control group. QTc prolongation prevalences were 2.0% in controls and 13.6% in WS (p <0.0001); in those, JTc prolongation prevalences were 1.8% in controls and 11.7% in WS (p <0.0001). Four patients died during follow-up; 2 had QTc prolongation and 1 died during noncardiac surgery. Another patient with QTc prolongation sustained cardiac arrest during a procedure. In conclusion, cardiac repolarization is prolonged in WS. Presence of prolonged cardiac repolarization may contribute to the high incidence of periprocedural mortality in these patients. All patients with WS should be screened for cardiac repolarization abnormalities, especially before surgery.
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