65 research outputs found
Genotype- phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency
Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non- missense, including 20 stop- gain, 11 affecting splicing, five large deletions, four in- frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non- missense, and 17 for two non- missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty- five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non- missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non- missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154955/1/ajh25753.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154955/2/ajh25753_am.pd
L-leucine improves anemia and growth in patients with transfusion-dependent Diamond Blackfan anemia: Results from a multicenter pilot phase I/II study from the Diamond Blackfan Anemia Registry
Background: Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, short stature, congenital anomalies, and cancer predisposition. Most cases are due to mutations in genes encoding ribosomal proteins (RP) leading to RP haploinsufficiency. Effective treatments for the anemia of DBA include chronic red cell transfusions, long-term corticosteroid therapy, or hematopoietic stem cell transplantation. In a small patient series and in animal models, there have been hematologic responses to L-leucine with amelioration of anemia. The study objectives of this clinical trial were to determine feasibility, safety, and efficacy of L-leucine in transfusion-dependent patients with DBA.
Procedure: Patients â„2 years of age received L-leucine 700 mg/m2 orally three times daily for nine months to determine a hematologic response and any improvement in growth (NCT01362595).
Results: This multicenter, phase I/II study enrolled 55 subjects; 43 were evaluable. There were 21 males; the median age at enrollment was 10.4 years (range, 2.5-46.1 years). No significant adverse events were attributable to L-leucine. Two subjects had a complete erythroid response and five had a partial response. Nine of 25, and 11 of 25, subjects experienced a positive weight and height percentile change, respectively, at the end of therapy.
Conclusions: L-leucine is safe, resulted in an erythroid response in 16% of subjects with DBA, and led to an increase in weight and linear growth velocity in 36% and 44% of evaluable subjects, respectively. Further studies will be critical to understand the role of L-leucine in the management of patients with DBA
Characterization of the severe phenotype of pyruvate kinase deficiency
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162766/2/ajh25926.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162766/1/ajh25926_am.pd
Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1
Autosomal dominant dehydrated hereditary stomatocytosis (DHSt) usually presents
as a compensated hemolytic anemia with macrocytosis and abnormally shaped
red blood cells (RBCs). DHSt is part of a pleiotropic syndrome that may also exhibit
pseudohyperkalemia and perinatal edema. We identified PIEZO1 as the disease gene
for pleiotropic DHSt in a large kindred by exome sequencing analysis within the
previously mapped 16q23-q24 interval. In 26 affected individuals among 7 multigenerational
DHSt families with the pleiotropic syndrome, 11 heterozygous PIEZO1
missense mutations cosegregated with disease. PIEZO1 is expressed in the plasma
membranes of RBCs and its messenger RNA, and protein levels increase during in
vitro erythroid differentiation of CD341 cells. PIEZO1 is also expressed in liver and
bone marrow during human and mouse development. We suggest for the first time
a correlation between a PIEZO1 mutation and perinatal edema. DHSt patient red cells
with the R2456H mutation exhibit increased ion-channel activity. Functional studies
of PIEZO1 mutant R2488Q expressed in Xenopus oocytes demonstrated changes in
ion-channel activity consistent with the altered cation content of DHSt patient red
cells. Our findings provide direct evidence that R2456H and R2488Q mutations
in PIEZO1 alter mechanosensitive channel regulation, leading to increased cation transport in erythroid cells
Adenovirus-Associated Virus Vector-Mediated Gene Transfer in Hemophilia B
NIHR (RP-PG-0310-1001), the
Medical Research Council, the Katharine Dormandy Trust, the U.K.
Department of Health, NHS Blood and Transplant, the NIHR
Biomedical Research Centers (to University College London Hospital
and University College London), the ASSISI Foundation of
Memphis, the American Lebanese Syrian Associated Charities,
the Howard Hughes Medical Institute, the National Heart, Lung,
and Blood Institute (HL094396), the Royal Free Hospital Charity
Special Trustees Fund 35, the Royal Free Hospital NHS Trust, and
St. Jude Childrenâs Research Hospita
MECHANISM OF PHOSPHATE TRANSPORT ACROSS THE HUMAN ERYTHROCYTE MEMBRANE ASREVEALED BY PHOSPHORUS-32 RELEASE STUDIES.
MECHANISM OF PHOSPHATE TRANSPORT ACROSS THE HUMAN ERYTHROCYTE MEMBRANE ASREVEALED BY PHOSPHORUS-32 RELEASE STUDIES
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