Miriam G. Blitzer

Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life

OBJECTIVE Fatty acid oxidation (FAO) disorders are frequently reported as the cause of sudden and unexpected death, but their postmortem recognition remains difficult. We have devised a biochemical protocol in which informative findings in liver tissue are microvesicular steatosis, elevated concentrations of C8-C16 fatty acids, glucose depletion, and low carnitine concentration. STUDY DESIGN We analyzed 27 cases representing five FAO disorders and compared the results with those obtained in a retrospective blinded analysis of 418 cases of sudden infant death (313 SIDS, 45 infections, and 34 accidents and abuse). RESULTS All cases of accidents and abuse correctly tested negative. Among the others, 25 (6%) showed at least two abnormal findings. Of these, 14 closely matched the biochemical profiles seen in specific FAO disorders. These included 2 cases with medium-chain acyl-CoA dehydrogenase deficiency, 4 cases consistent with glutaric acidemia type 2, 4 cases with either very long-chain acylcoenzyme A dehydrogenase deficiency or long-chain 3-hydroxy-acyl-coenzyme A dehydrogenase deficiency, and 4 cases predicted to be affected with carnitine uptake defect. CONCLUSION The results of this study support the view that approximately 5% of all cases of sudden infant death are likely caused by an FAO disorder.

Recommendations of core competencies in genetics essential for all health professionals

Genetic scientific discoveries made throughout the last decade already have a tremendous influence on health care. Understanding the role genetics plays in health and disease provides the means to integrate such information into prevention, diagnosis, and treatment of many common diseases to improve the health of society. Genetic information and technologies are increasingly making their way into health care.1 Yet, while patients are beginning to ask providers about—and even request— genetic services, primary care providers face economic and institutional barriers to incorporating genetic factors into management of patients.2 As outlined by the Institute of Medicine Report on the Future of Public Health,3 public health agencies will have an increasing role in assessing the health needs of populations, working with the private sector in ensuring the quality of genetic tests and services, and evaluating the impact of interventions on medical, behavioral, and psychosocial outcomes. The Department of Health and Human Services Secretary’s Advisory Committee on Genetic Testing (SACGT) is addressing the need to provide access to high-quality genetic testing when appropriate and effective.4 Ultimately health professionals, regardless of specialty area, role, or practice setting, will face questions about the implications of genetics for their patients and communities. The fast pace of genetics research advances, the paucity of professional training in genetics, and the widespread underestimation of the value of genetics in medical decision-making leaves many providers without up-to-date answers.5 The National Coalition for Health Professional Education in Genetics (NCHPEG) was founded by the American Medical Association, the American Nurses Association, and the National Human Genome Research Institute in an attempt to bridge this gap in genetic knowledge. This coalition of organizations constitutes an interdisciplinary, collaborative, and national effort to promote health professional education about application of human genetics information. NCHPEG members are representatives from more than 100 diverse organizations including consumer and voluntary groups, private industry, managed care organizations, government agencies, health professional societies, and genetics organizations (Appendix). Membership is voluntary, with representatives selected by their respective organizations. Read more about NCHPEG at the Web site (http://www.nchpeg.org/). NCHPEG seeks to gain from the diverse expertise and experience of member organizations working toward mutually identified goals. NCHPEG solicits group members to work together to address several priorities, including the identification of core competencies in genetics essential for all health professionals. Implicit goals of seeking consensus on basic genetics competencies among NCHPEG members were (1) to validate the importance of a basic foundation in genetics for health care, (2) to foster the use of common terminology, (3) to increase the consistency of genetics education efforts across the disciplines, (4) to facilitate active discourse about the relative role of the different professions in the provision of genetic services, and (5) to reduce duplication of effort. Achievement of each of these goals will require disciplines to recognize the need for genetics education, to integrate genetics concepts into their current educational resources, and to utilize these competencies to design new programs.

Multiple-marker screening in pregnancies with hydropic and nonhydropic Turner syndrome.

OBJECTIVE The combination of maternal serum alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin levels and maternal age has been used to increase the sensitivity of screening for fetal Down syndrome and trisomy 18 in early-second-trimester pregnancies. We hypothesized that a unique pattern of these analytes also may be characteristic of fetal Turner syndrome, with or without hydrops. STUDY DESIGN We studied preamniocentesis, second-trimester maternal serum specimens from seven hydropic and eight nonhydropic cases of fetal Turner syndrome. Clinical and pathologic records were reviewed. Statistical analysis of the data was performed by the rank sum test. RESULTS In both hydropic and nonhydropic cases, alpha-fetoprotein levels were slightly reduced, and unconjugated estriol levels were markedly reduced. In hydropic pregnancies human chorionic gonadotropin levels were elevated, and nonhydropic pregnancies had low human chorionic gonadotropin levels (p = 0.001). CONCLUSIONS The results suggest that the morphologic defect of hydrops, rather than the aneuploidy itself, is responsible for the elevation in human chorionic gonadotropin. In conjunction with the low unconjugated estriol levels, the elevation in human chorionic gonadotropin levels will result in the prenatal identification of hydropic fetal Turner syndrome pregnancies as being at increased risk for fetal Down syndrome.

The state of the medical geneticist workforce: findings of the 2003 survey of American Board of Medical Genetics certified geneticists.

The state of the medical geneticist workforce: Findings of the 2003 survey of American Board of Medical Genetics certified geneticists

Partial biotinidase deficiency: Clinical and biochemical features

Neonatal screening for profound biotinidase deficiency (less than 10% of the mean normal activity level) has identified a group of children with partial biotinidase deficiency (10% to 30% of mean normal activity). Because partial biotinidase deficiency may result in clinical consequences that may be prevented by treatment with biotin, we evaluated such individuals and their family members (1) to determine whether partial biotinidase deficiency is associated with symptoms and (2) to determine the inheritance pattern. We quantified serum biotinidase activity levels and obtained medical histories of probands, their parents and siblings, and additional family members. All children with partial deficiency were healthy at the time of diagnosis. One child, who was not initially treated with biotin, later developed hypotonia, hair loss, and skin rash, which resolved with biotin therapy. Four adults and three children with partial biotinidase deficiency were identified among family members of infants identified by neonatal screening. All these individuals were healthy, although one sibling had elevated urinary lactate excretion. A fifth adult with partial deficiency, found among clinically normal adult volunteers, later showed minor symptoms that resolved after biotin therapy. Like children with profound biotinidase deficiency, children with partial biotinidase deficiency are symptoms free at birth. However, the subsequent occurrence of symptoms of profound biotinidase deficiency in some persons with partial deficiency suggests that biotin therapy for this condition may be warranted.

First‐trimester prediction of pre‐eclampsia: external validity of algorithms in a prospectively enrolled cohort

To evaluate the performance of published first‐trimester prediction algorithms for pre‐eclampsia (PE) in a prospectively enrolled cohort of women.

Molecular characterization of a unique patient with epimerase-deficiency galactosaemia

Inherited deficiencies of UDP-galactose 4-epimerase (GALE) havebeen associated with two distinct phenotypes. The vast majority of North American patients are clinically asymptomatic, are identified through newborn screening programmes for classical galactosaemia, and are of African-American descent. At least two symptomatic patients have been reported, one Pakistani and the other Asian Muslim, both with severe complications in the neonatal period and subsequent mental retardation. Through newborn screening, we have identified a GALE-deficient patient who is of mixed Pakistani/caucasian ancestry. He was clinically well in the neonatal period on a lactose-containing diet, and biochemical studies, including urine reducing sugars and galactitol, were consistent with a diagnosis of peripheral GALE deficiency. Although early developmental milestones were met normally, he now shows significant developmental delays in both motor and language skills. Mutational analysis revealed this patient to be a compound heterozygote at the GALE locus, with mutations N34S and L183P identified in the patient and confirmed in the parents. This report represents the first characterization of specific mutations ina GALE-deficient patient in conjunction with biochemical and clinical pheno-type, and facilitates further studies of the GALE enzyme and its role in the different clinical forms of epimerase-deficiency galactosaemia.

Profound biotinidase deficiency in two asymptomatic adults

Biotinidase deficiency is an autosomal-recessive disorder of biotin recycling. Children with profound biotinidase deficiency usually have neurological and cutaneous symptoms in early childhood, but they may not develop symptoms until adolescence. We now report on a man and a woman with profound biotinidase deficiency who are asymptomatic and who were diagnosed only because their biotinidase-deficient children were identified by newborn screening. These adults have never exhibited symptoms of the disorder and are homozygous for two different mutations resulting in different aberrant enzymes. There is no evidence of an increased dietary intake of biotin to explain why they have remained asymptomatic. Although these adults may still be at risk for developing symptoms, they could represent a small group of individuals with profound biotinidase deficiency who will never develop clinical problems. Their lack of symptoms suggests that there are probably epigenetic factors that protect some enzyme-deficient individuals from developing symptoms. These individuals broaden the spectrum of expression of biotinidase deficiency.

Inborn errors of metabolism and Reye syndrome: Differential diagnosis

Si, au debut, le diagnostic et le traitement du syndrome de Reye (SR) et des erreurs hereditaires du metabolisme (ECM) qui lui ressemblent sont identiques, ensuite, les recherches diagnostiques, le traitement, le pronostic varient avec la cause sous-jacente. Revue des caracteristiques cliniques et metaboliques pouvant faire suspecter une ECM devant un tableau de SR

Technical standards and guidelines for the diagnosis of biotinidase deficiency.

Abstract: Biotinidase deficiency is an autosomal recessively inherited disorder of biotin recycling that is associated with neurologic and cutaneous consequences if untreated. Fortunately, the clinical features of the disorder can be ameliorated or prevented by administering pharmacological doses of the vitamin biotin. Newborn screening and confirmatory diagnosis of biotinidase deficiency encompasses both enzymatic and molecular testing approaches. These guidelines were developed to define and standardize laboratory procedures for enzymatic biotinidase testing, to delineate situations for which follow-up molecular testing is warranted, and to characterize variables that can influence test performance and interpretation of results.