An 18-year-old woman with sickle cell anemia presents with recurrent painful crises, and treatment with hydroxyurea is recommended. Hydroxyurea causes a shift toward the production of red cells ...containing fetal hemoglobin. A possible increase in the risk of acute leukemia due to hydroxyurea therapy remains the subject of debate.
An 18-year-old woman with sickle cell anemia presents with recurrent painful crises, and treatment with hydroxyurea is recommended. Hydroxyurea causes a shift toward the production of red cells containing fetal hemoglobin.
Foreword
This
Journal
feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author's clinical recommendations.
An 18-year-old woman with sickle cell anemia has had increasing symptoms, with painful crises and episodes of the acute chest syndrome. She was hospitalized three times in the past year. A hematologist recommends that hydroxyurea therapy be started.
The Clinical Problem
There are about 50,000 people in the United States who are homozygous for the sickle hemoglobin gene and thus have sickle cell anemia. Sickle cell anemia is primarily seen in persons of African heritage, about 1 in 14 of whom is an asymptomatic carrier (a heterozygote). One in 700 newborns of African heritage is affected.
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Although it is the most severe of the common sickle cell diseases (which include hemoglobin SC disease and sickle β
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-thalassemia), patients with sickle cell anemia have a wide spectrum of clinical manifestations. All patients with this disorder have a chronic hemolytic . . .
The causes of autism are largely unknown. This study establishes that aberrant dosage of a large genomic segment is associated with autism spectrum disorder. Deletion or duplication of the segment, ...which encompasses 25 known genes, was present in approximately 1% of case subjects and less than 0.1% of unscreened control subjects.
This study establishes that an aberrant dosage of a large genomic segment is associated with autism spectrum disorder. Deletion or duplication of the segment, which encompasses 25 known genes, was present in approximately 1% of case subjects and less than 0.1% of unscreened control subjects.
Autism is a pervasive developmental disorder defined by a neurobehavioral phenotype that includes social disability, communication impairment, repetitive behaviors, and restricted interests. The onset is generally before the age of 3 years, and the disorder has a prevalence of 0.6% in the population, affecting many more boys than girls.
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Results of twin and family studies have shown that the heritability of autism is approximately 90%, making it one of the most heritable complex disorders.
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In approximately 10% of patients, autism can be explained by genetic syndromes and known chromosomal anomalies (most of which have recognizable features in addition to autism), . . .
During the past decade a large body of experimental and clinical studies has focused on the hypothesis that nitric oxide (NO) depletion by plasma hemoglobin in the microcirculation plays a central ...role in the pathogenesis of many manifestations of sickle cell disease (SCD), particularly pulmonary hypertension. We have carefully examined those studies and believe that the conclusions drawn from them are not adequately supported by the data. We agree that NO depletion may well play a role in the pathophysiology of other hemolytic states such as paroxysmal nocturnal hemoglobinuria, in which plasma hemoglobin concentrations are often at least an order of magnitude greater than in SCD. Accordingly, we conclude that clinical trials in SCD designed to increase the bioavailability of NO or association studies in which SCD clinical manifestations are related to plasma hemoglobin via its surrogates should be viewed with caution.
Sickle cell disease (SCD) is the most common monogenic disorder in the world. Notably, there is extensive clinical heterogeneity in SCD that cannot be fully accounted for by known factors, and in ...particular, the extent to which the phenotypic diversity of SCD can be explained by genetic variation has not been reliably quantified. Here, in a family‐based cohort of 449 patients with SCD and 755 relatives, we first show that 5 known modifiers affect 11 adverse outcomes in SCD to varying degrees. We then utilize a restricted maximum likelihood procedure to estimate the heritability of 20 hematologic traits, including fetal hemoglobin (HbF) and white blood cell count (WBC), in the clinically relevant context of inheritance from healthy carriers to SCD patients. We report novel estimations of heritability for HbF at 31.6% (±5.4%) and WBC at 41.2% (±6.8%) in our cohort. Finally, we demonstrate shared genetic bases between HbF, WBC, and other hematologic traits, but surprisingly little overlap between HbF and WBC themselves. In total, our analyses show that HbF and WBC have significant heritable components among individuals with SCD and their relatives, demonstrating the value of using family‐based studies to better understand modifiers of SCD.
Stroke in sickle cell anemia occurs in about 11 percent of patients under 20 years of age. Dr. Orah Platt writes that it appears that transfusion does not simply prevent stroke but actually reverses ...the stenotic lesion.
In the late 1930s, William Bosworth Castle and his colleague Thomas Hale Ham were studying blood samples obtained from patients with sickle cell anemia and found that the viscosity of the blood increased dramatically as its oxygen content decreased. As Castle later reflected, “It immediately occurred to us that this was because the elongated, sickled red cells had become tangled up `like haywire.'”
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Castle and Ham went on to hypothesize about the pathophysiology of organ damage in sickle cell anemia in a way that still drives much of our thinking today: “a vicious cycle of erythrostasis may be set up . . .
Mutations in the SLC26A4 gene are second only to GJB2 mutations as a currently identifiable genetic cause of sensorineural hearing loss. In most areas of China, genetic testing for sensorineural ...hearing loss is unavailable because of limited knowledge of the mutation spectrum. Although SLC26A4 c.919-2A>G (IVS7–2A>G) is a common mutation among some Asian populations, the mutation prevalence among various ethnic groups within China has not been studied.
DNA specimens from 3271 subjects with moderate to profound sensorineural hearing loss from 27 regions of China were genotyped for the c.919-2A>G mutation by polymerase chain reaction/restriction-fragment-length polymorphism. Normal hearing controls from Han (n = 185) and Uigur (n = 152) populations were also tested.
Overall, 408 subjects with sensorineural hearing loss (12.5%) carried at least one c.919-2A>G allele, with 158 (4.8%) homozygotes and 250 (7.6%) heterozygotes. Within the subpopulations examined, the rate varies from 0% to 12.2% for c.919-2A>G homozygotes and from 0% to 17.6% for heterozygotes. Based on this cohort, Chinese subjects with sensorineural hearing loss seem to have a relatively higher c.919-2A>G frequency than that of other Asian populations.
These results demonstrate that a simple and efficient genetic test for the c.919-2A>G mutation alone would identify the molecular cause in up to 8–12% of individuals with sensorineural hearing loss in a few eastern and central regions of China. Those who are negative for the c.919-2A>G mutation would be candidates for further mutational analysis of SLC26A4 or other deafness-related genes. This would greatly improve genetic diagnosis and counseling for a huge number of Chinese individuals and family members with sensorineural hearing loss in China, and many more ethnic Chinese in other countries, which might be up to one million.
The life expectancy of patients with sickle cell disease has improved considerably since 1960, when Sir John Dacie described sickle cell disease as “essentially a disease of childhood.” “Indeed,” he ...wrote, “the mortality is high and relatively few patients reach adult life, even when the standard of medical care is high”
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. In his 1973 review based on autopsies, Diggs estimated a median survival of 14.3 years, with 20 percent of the deaths occurring in the first 2 years of life, one third occurring before the fifth year of life, half between 5 and 30 years of age, and one . . .
As the overall health of patients with sickle cell anemia (SS) improves and diagnostic techniques become more sensitive, physicians are seeing patients with an increasingly wide range of subtle and ...not-so-subtle brain injury. The major breakthrough in the field of sickle-related brain injury has been the unprecedented success of transcranial Doppler ultrasonography (TCD) to identify asymptomatic patients at high risk of stroke, coupled with chronic transfusion therapy to prevent it. The evidence for TCD screening and preventive treatment is strong and compelling, but there are still important unanswered questions regarding the implications of "silent infarcts" found in the magnetic resonance images (MRIs) of asymptomatic individuals, and the growing awareness of the burden of neuropsychiatric dysfunction in otherwise apparently healthy individuals.
Sickle cell disease, a genetic red cell disorder inherited in an autosomal recessive manner, occurs throughout the world. Hepatic dysfunction and liver damage may be present in sickle cell disease, ...but the pathogenesis of these conditions is only partially understood.
Transgenic mice with sickle cell disease (SAD mice) and wild-type mice were exposed to an ischemic/reperfusion stress. The following parameters were evaluated: hematologic profile, transaminase and bilirubin levels, liver histopathology, and mRNA levels of nuclear factor-κB p65, endothelial nitric oxide synthase, inducible nitric oxide synthase, heme oxygenase-1 and phosphodiesterase-1, -2, -3, and -4 genes in hepatocytes obtained by laser-capture microdissection. Immunoblotting was used to analyze the expression of the following proteins: nuclear factor-κB p65 and phospho-nuclear factor-κB p65, heme oxygenase-1, biliverdin reductase, heat shock protein-70, heat shock protein-27 and peroxiredoxin-6. A subgroup of SAD mice was treated with the phosphodiesterase-4 inhibitor rolipram (30 mg/Kg/day by gavage) during the ischemic/reperfusion protocol.
In SAD mice the ischemic/reperfusion stress induced liver damage compatible with sickle cell disease hepatopathy, which was associated with: (i) lack of hypoxia-induced nuclear factor-κB p65 activation; (ii) imbalance in the endothelial/inducible nitric oxide synthase response to ischemic/reperfusion stress; (iii) lack of hypoxia-induced increased expression of heme oxygenase-1/biliverdin reductase paralleled by a compensatory increased expression of heat shock proteins 70 and 27 and peroxiredoxin-6; and (iv) up-regulation of the phosphodiesterase-1, -2, -3, and -4 genes. In SAD mice the phosphodiesterase-4 inhibitor rolipram attenuated the ischemic/reperfusion-related microcirculatory dysfunction, reduced the inflammatory cell infiltration and induced the heme oxygenase-1/biliverdin reductase cytoprotective systems.
In SAD mice, sickle cell hepatopathy is associated with perturbed nuclear factor-κB p65 signaling with an imbalance of endothelial/inducible nitric oxide synthase levels, lack of heme oxygenase-1/biliverdin reductase expression and up-regulation of two novel cytoprotective systems: heat shock protein-27 and peroxiredoxin-6.
1 Department of Otorhinolaryngology Head and Neck Surgery and Genetic Testing Center for Deafness, PLA General Hospital, Beijing, People's Republic of China
2 Renal Division and Molecular and ...Vascular Medicine Unit, Beth Israel Deaconess Medical Center, Boston, Massachusetts
3 Department of Pediatrics, Rambam Medical Center and Department of Physiology and Biophysics, Technion School of Medicine, Haifa, Israel
4 Department of Laboratory Medicine
5 Department of Otolaryngology
6 Division of Genetics, Children's Hospital Boston
7 Harvard Medical School, Boston, Massachusetts
8 Institutes of Biomedical Science, Fudan University, Shanghai, People's Republic of China
Mutations of the human SLC26A4/PDS gene constitute the most common cause of syndromic and nonsyndromic hearing loss. Definition of the SLC26A4 mutation spectrum among different populations with sensorineural hearing loss is important for development of optimal genetic screening services for congenital hearing impairment. We screened for SLC26A4 mutations among Chinese and U.S. subjects with hearing loss, using denaturing HPLC (DHPLC) and direct DNA sequencing. Fifty-two of 55 Chinese subjects with deafness accompanied by enlargement of the vestibular aqueduct (EVA) exhibited at least one mutant SLC26A4 allele, whereas SLC26A4 mutations were found in only 2 of 116 deaf Chinese patients without EVA. The spectrum of SLC26A4 mutations differed among Chinese and U.S. subjects and included 10 previously unreported SLC26A4 variants: 4 in the Chinese population (p.E303Q, p.X329, p.X467, p.X573) and 6 in the U.S. population (p.V250A, p.D266N, p.F354S, p.D697A, p.K715N, p.E737D). Among the seven novel in-frame missense mutations, five encoded SLC26A4 proteins with substantially reduced Cl – /anion exchange activity as expressed and measured in Xenopus oocytes, but four of these were sufficiently active to allow study of anion selectivity. The only mutant polypeptide exhibiting complete loss of anion exchange function, p.E303Q, was expressed at or near the oocyte surface at near-wild-type levels. Two variants, p.F354S and p.E737D, displayed selective reduction in relative rate of Cl – /HCO 3 – exchange compared with similarly measured rates of Cl – /Cl – and Cl – /I – exchange. Our data show that mutation analysis of the SLC26A4 gene is of high diagnostic yield among subjects with deafness and bilateral EVA in both China and the U.S. However, the pathogenicity of monoallelic SLC26A4 gene variants in patients with hearing loss remains unclear in many instances.
Pendred syndrome; chloride/bicarbonate exchange; iodide transport; enlargement of vestibular aqueduct; goiter
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