17 research outputs found
The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial
The aim of this prospective study was to evaluate the long-term efficacy and safety of hydroxyurea (HU) in patients with sickle cell disease (SCD). Thirty-four patients with sickle cell anemia (hemoglobin S [HbS]/HbS), 131 with HbS/ 0 -thal, and 165 with HbS/ ؉ -thal participated in this trial. HU was administered to 131 patients, whereas 199 patients were conventionally treated. The median follow-up period was 8 years for HU patients and 5 years for non-HU patients. HU produced a dramatic reduction in the frequency of severe painful crises, transfusion requirements, hospital admissions, and incidence of acute chest syndrome. The probability of 10-year survival was 86% and 65% for HU and non-HU patients, respectively (P ؍ .001), although HU patients had more severe forms of SCD. The 10-year probability of survival for HbS/ HbS, HbS/ 0 -thal, and HbS/IVSI-110 patients was 100%, 87%, and 82%, respectively, for HU patients and 10%, 54%, and 66%, for non-HU patients. The multivariate analysis showed that fetal hemoglobin values at baseline and percentage change of lactate dehydrogenase between baseline and 6 months were independently predicted for survival in the HU group. These results highlight the beneficial effect of HU, which seems to modify the natural history of SCD and raise the issue of expanding its use in all SCD patients. (Blood
Expansion of the neurodevelopmental phenotype of individuals with EEF1A2 variants and genotype-phenotype study
Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 pathogenic missense variants affecting EEF1A2 have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2 variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2 variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations.</p
239-kb Microdeletion Spanning KMT2E in a Child with Developmental Delay: Further Delineation of the Phenotype
Pathogenic KMT2E variants underly O'Donnell-Luria-Rodan syndrome, a
recently described neurodevelopmental disorder characterized by global
developmental delay, variable degrees of intellectual disability, and
subtle facial dysmorphism. Less common findings include autism,
seizures, gastrointestinal (GI) problems, and abnormal head
circumference. Occurrence of mostly truncating variants as well as the
similar phenotype observed in individuals with deletions spanning KMT2E
suggest haploinsufficiency of this gene as a common mechanism for the
disorder, while a gain-of-function or dominant-negative effect cannot be
ruled out for some missense variants. Deletions reported in the
literature encompass several additional known or presumed
haploinsufficient genes, thus leading to more complex phenotypes. Here,
we describe a male with antenatal onset hydronephrosis, hypotonia,
global developmental delay, prominent GI symptoms as well as facial
dysmorphism. Chromosomal microarray revealed a 239-kb de novo
microdeletion spanning KMT2E and LHFPL3. Clinical presentation of our
proband, harboring one of the smallest deletions of the region confirms
the core features of this disorder, suggests GI symptoms as a prominent
finding in affected individuals while expanding the phenotypic spectrum
to abnormalities of the urinary tract
TRIO-related neurodevelopmental disorder
Clinical characteristics.TRIO-related neurodevelopmental disorder (TRIO-NDD) is characterized by two phenotypes: TRIO-NDD due to gain-of-function variants and TRIO-NDD due to loss-of-function variants.TRIO-NDD due to gain-of-function variants within the spectrin repeat domain is characterized by moderate-to-severe developmental delay, intellectual disability, macrocephaly (or relative macrocephaly), neurobehavioral manifestations (poor attention, stereotypies, obsessive-compulsive behavior, aggressive behavior, and autism spectrum disorder), and early feeding difficulties with poor weight gain and growth deficiency. Seizures, constipation, scoliosis, dental abnormalities, and cardiac anomalies are also reported.TRIO-NDD due to loss-of-function variants is characterized by mild-to-moderate developmental delay and intellectual disability, microcephaly, neurobehavioral manifestations (poor attention, aggressive behavior, autism spectrum disorder, obsessive-compulsive traits, and stereotypies), early feeding difficulties with poor weight gain, dental abnormalities, and digit anomalies, including 2-3 toe syndactyly in some individuals. Seizures, constipation, scoliosis, and cardiac anomalies are also reported.Diagnosis/testing.The diagnosis of TRIO-NDD is established in a proband with a heterozygous TRIO pathogenic variant identified by molecular genetic testing.Management.Treatment of manifestations: Treatment is symptomatic and includes routine management of developmental delays, intellectual disability, neurobehavioral manifestations, seizures, feeding difficulties, gastroesophageal reflux, constipation, spine abnormalities, and dental abnormalities, as well as for rarely occurring cardiovascular anomalies and recurrent infections.Surveillance: At each visit, monitor developmental progress and educational needs; behavioral assessments for attention, aggression, and/or social communication difficulties; growth and feeding assessments to ensure optimal nutritional status; assessment for seizures, constipation, spine deformities, and frequent infections; regular dental evaluations.Genetic counseling.TRIO-NDD is an autosomal dominant disorder. The majority of individuals diagnosed with TRIO-NDD have the disorder as a result of a de novo pathogenic variant; approximately 15% have inherited the TRIO pathogenic variant from an affected parent. TRIO gain-of-function missense variants (affecting the spectrin repeat domain) and TRIO loss-of-function missense variants (within the GEFD1 domain) are typically de novo. TRIO loss-of-function truncating variants may occur de novo or be inherited from an affected parent. Each child of an individual with TRIO-NDD has a 50% chance of inheriting the TRIO pathogenic variant. Once the TRIO pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible
Pontine Tegmental Cap Dysplasia:A rare case in pediatric neurology and the search of the genetic etiology
Pontine Tegmental Cap Dysplasia:A rare hindbrain malformation and the search of the genetic etiology
Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration
Dickkopf-1 is an inhibitor of Wnt signaling, which is crucial for osteoblast differentiation. This study shows that serum levels of Dicckopf-1 are increased in patients with thalassemia and osteoporosis. Interestingly, in a placebo-controlled, randomized therapeutic trial a 12-months treatment with zoledronic acid reduced serum Dickkopf-1 levels and increased bone mineral density in these patients
Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration
Dickkopf-1 is an inhibitor of Wnt signaling, which is crucial for
osteoblast differentiation. We evaluated serum levels of Dickkopf-1 in
66 patients with thalassemia-induced osteoporosis who received therapy
with zoledronic acid in a placebo-controlled, randomized trial. At
baseline, thalassemia patients had increased serum levels of Dickkopf-1
that correlated with reduced bone mineral density of the lumbar spine
and the distal radius. High Dickkopf-1 also correlated with increased
bone resorption and reduced bone formation markets. Zoledronic acid
produced a reduction in serum Dickkopf-1, which was associated with bone
mineral density increase after 12 months of therapy. On the contrary,
placebo group showed a borderline increase of Dickkopf-1, which was
higher in patients who showed deterioration in pain scores. These
results suggest that Dickkopf-1 is implicated in the pathogenesis of
osteoporosis in thalassemia and reveal Dickkopf-1 as a possible target
for the development of novel agents for the management of
thalassemia-induced osteoporosis (ClinicalTrials. got., Identifier:
NCT00346242)
The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS)
The aim of this prospective study was to evaluate the long-term efficacy
and safety of hydroxyurea (HU) in patients with sickle cell disease
(SCD). Thirty-four patients with sickle cell anemia (hemoglobin S
[HbS]/HbS), 131 with HbS/beta(0)-thal, and 165 with HbS/beta(+)-thal
participated in this trial. HU was administered to 131 patients, whereas
199 patients were conventionally treated. The median follow-up period
was 8 years for HU patients and 5 years for non-HU patients. HU produced
a dramatic reduction in the frequency of severe painful crises,
transfusion requirements, hospital admissions, and incidence of acute
chest syndrome. The probability of 10-year survival was 86% and 65%
for HU and non-HU patients, respectively (P = .001), although HU
patients had more severe forms of SCD. The 10-year probability of
survival for HbS/HbS, HbS/beta (0)-thal, and HbS/IVSI-110 patients was
100%, 87%, and 82%, respectively, for HU patients and 10%, 54%, and
66%, for non-HU patients. The multivariate analysis showed that fetal
hemoglobin values at baseline and percentage change of lactate
dehydrogenase between baseline and 6 months were independently predicted
for survival in the HU group. These results highlight the beneficial
effect of HU, which seems to modify the natural history of SCD and raise
the issue of expanding its use in all SCD patients. (Blood. 2010; 115:
2354-2363