Biomedical subjects
Publications and source records attributed to Harvey L Levy.
A patient with pericardial effusion and a complicated presentation of primary systemic carnitine deficiency (PSCD) is described. This is the first case of PSCD reported to have pericardial effusion. Compound heterozygosity for two mutations in the SLC22A5 gene, T440M and F23del, and four SLC22A5 polymorphisms (c.IVS3+6A>G, c.-77G>A, c.-78C>T, and p.S95S) were identified in the patient.
Subacute combined degeneration (SCD) of the spinal cord is a characteristic complication of vitamin B12 deficiency, but it has never been neuropathologically demonstrated in a B12-inborn error of metabolism. In this report SCD is documented in a 15-year-old boy with early-onset cobalamin C (cblC) disorder. The neuropathologic findings included multifocal demyelination and vacuolation with predilection for the dorsal and lateral columns at the mid-thoracic level of the spinal cord, confirming the similarity of SCD in cblC disorder to the classic adult SCD due to vitamin B12 deficiency. SCD developed in this boy despite treatment for cblC disorder that began at 3 months of age. There is clinical and experimental evidence to suggest that a deficiency in remethylation with concomitant reduction in brain methionine may be the cause of SCD. In this patient plasma methionine levels were low without betaine and/or l-methionine supplementation and in the normal range for only a 2-year period during compliance with therapy. In cblC disorder, a consistent increase in blood methionine to high normal or above normal levels by the use of betaine and l-methionine supplementation may be helpful in preventing SCD. This is especially important now that the presymptomatic detection of cblC disorder is possible through the expansion of newborn screening.
Elevation of homocysteine is implicated in multiple medical conditions, including classical homocystinuria, a variety of remethylation disorders, and most recently in coronary artery disease. Betaine is a methyl donor agent that is beneficial in lowering homocysteine through the remethylation of methionine. Betaine therapy alone has been shown to prevent vascular events in homocystinuria and may have clinical benefits in other hyperhomocysteinemic disorders when used as adjunctive therapy. Betaine does raise the methionine level and cerebral edema has occurred when plasma methionine exceeds 1000 micromol/L. Thus the plasma methionine as well as homocysteine must be monitored in patients receiving betaine.
The aim of newborn screening is to identify presymptomatic healthy infants that will develop significant metabolic or endocrine derangements if left undiagnosed and untreated. The goal of ultimately reducing or eliminating irreversible sequelae is reached by maximizing test sensitivity of the primary newborn screening that measures specific analytes by a number of methodologies. Differentiation of true from false negatives is accomplished by the test specificity. This review discusses disorders for which, in general, there are available therapies and that are detected by routine and expanded newborn screening. Recommendations are presented for evaluation by a primary care physician, with confirmation by a metabolic or endocrinology specialist. Disorders are organized in tabular format by class of pathway or analyte, with attention to typical clinical presentations, confirmatory biochemical and molecular tests, and therapies. There are numerous challenges in clinical follow-up, including diagnosis and appropriate understanding of the consequences of the disorders. The data required to meet these challenges can be acquired only by large scale longitudinal comprehensive studies of outcome in children identified by newborn screening. Only with such data can newborn screening fully serve families.
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OBJECTIVE: The objective was to evaluate the relationships between all types of fetal fatty acid oxidation defects and maternal liver disease, including acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. METHODS: This was a case-control study comparing fetal fatty acid oxidation defects to the outcome of maternal liver disease. Fifty case infants with fatty acid oxidation defects were identified, with 25 matched controls collected per case. This generated a total of 50 case infants and 1,250 control infants. Pregnancies were evaluated for the presence of maternal liver disease (comprised of acute fatty liver of pregnancy, HELLP syndrome, and preeclampsia evolving into HELLP syndrome) using a conditional logistic regression model. Subgroup analysis compared long chain to short and medium chain fatty acid defects. RESULTS: Maternal liver disease was noted in 16.00% of all fatty acid oxidation defect pregnancies compared with 0.88% in the general population (odds ratio 20.4, 95% confidence interval 7.82-53.2). These pregnancies demonstrated an 18.1-fold increase in maternal liver disease when compared with our matched population controls with unaffected fetuses. All classifications of fatty acid oxidation defects were at high risk of developing maternal liver disease. Long chain defects were 50 times more likely than controls to develop maternal liver disease and short and medium chain defects were 12 times more likely to develop maternal liver disease. CONCLUSION: Maternal liver disease is significantly higher across the entire spectrum of fatty acid oxidation defects pregnancies compared with the matched control population. Notably, there is significant risk to the pregnancies with fetuses affected with short and medium chain defects, not just those with fetal long chain fatty acid oxidation defects as previously reported. Future studies should examine the pathophysiology of all infant fatty acid oxidation defects and its implications for maternal liver disease for improved future health outcomes. LEVEL OF EVIDENCE: II-2.
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Krabbe disease, also known as globoid cell leukodystrophy, is a rare autosomal recessive disorder caused by a deficiency of a lysosomal enzyme, galactocerebrosidase. This defect prevents normal turnover of the galactolipids and results in progressive demyelination. In the infantile form, symptoms typically present at 3 to 6 months of age with subsequent neurologic deterioration. We report a case with presentation on day 7 of life and rapid progression culminating in death at 10 weeks. Galactocerebrosidase activity was absent in the leukocytes, and a 30 kb deletion in the GALC gene was found. To our knowledge, this is the earliest reported death from Krabbe disease. Several family members have multiple sclerosis, which is also a demyelinating disorder. We propose that the neonatal expression could be an example of complementary gene interaction in which coinheritance of a predisposition to multiple sclerosis led to the unusual early manifestation and rapid course of Krabbe disease in this infant.
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OBJECTIVE: To examine predictors of parenting stress in parents whose children were diagnosed with a biochemical genetic disorder clinically or through newborn screening. METHODS: Parents of 263 children with biochemical genetic disorders (139 identified by newborn screening, 124 identified clinically) completed interviews focused on child health, medical service use, satisfaction with services, parenting stress, and family functioning. RESULTS: Multiple regression analyses suggested that child adaptive functioning, parental satisfaction with support, and difficulties parents experienced meeting their child's health care needs were associated with scores on the Parenting Stress Index (R2 =.51). CONCLUSIONS: Initiatives to improve child adaptive functioning and parental support as well as practical assistance to help parents meet their child's health needs may reduce parental stress and family disruption in this population.
CONTEXT: Tandem mass spectrometry now allows newborn screening for more than 20 biochemical genetic disorders. Questions about the effectiveness and risks of expanded newborn screening for biochemical genetic disorders need to be answered prior to its widespread acceptance as a state-mandated program. OBJECTIVES: To compare newborn identification by expanded screening with clinical identification of biochemical genetic disorders and to assess the impact on families of a false-positive screening result compared with a normal result in the expanded newborn screening program. DESIGN: Prospective study involving an inception cohort of newly diagnosed children. SETTING: Massachusetts, Maine, and a private laboratory in Pennsylvania with expanded newborn screening; other New England states with limited screening. PARTICIPANTS: Families of 50 affected children identified through expanded newborn screening (82% of eligible cases); 33 affected children identified clinically (97% of eligible cases); 94 screened children with false-positive results (75% of eligible cases); and 81 screened children with normal results (63% of eligible cases). MAIN OUTCOME MEASURES: Child's health and development and the Parental Stress Index. RESULTS: Within the first 6 months of life, 28% of children identified by newborn screening compared with 55% of clinically identified children required hospitalization (P =.02). One child identified by newborn screening compared with 8 (42%) identified clinically performed in the range of mental retardation (P<.001). Mothers in the screened group reported lower overall stress on the Parental Stress Index than mothers in the clinically identified group (z = 3.38, P<.001). Children with false-positive results compared with children with normal results were twice as likely to experience hospitalization (21% [n = 20] vs 10% [n = 8], respectively; P =.06). Mothers of children in the false-positive group compared with mothers of children with normal screening results attained higher scores on the Parental Stress Index (z = 4.25, P<.001) and the Parent-Child Dysfunction subscale (z = 5.30, P<.001). CONCLUSIONS: Expanded newborn screening may lead to improved health outcomes for affected children and lower stress for their parents. However, false-positive screening results may place families at risk for increased stress and parent-child dysfunction.
Studies were carried out to identify the cause of combined severe hypermethioninemia and moderate hyperhomocysteinemia in a cluster of 10 infants ascertained between 1999 and early 2001. Although several were thought initially to have cystathionine beta-synthase (CBS) deficiency and treated accordingly, CBS deficiency and other known genetic causes of hypermethioninemia were ruled out by assay of CBS activity in fibroblasts of four patients and by assays of plasma cystathionine and S-adenosylmethionine. Retrospective data on dietary methionine intakes and plasma concentrations of methionine and related metabolites established that the hypermethioninemia in nine of the 10 babies was related to ingestion of an infant protein hydrolysate formula, the methionine content of which had been increased from May 1998 to February 2001. The formula in question has now been reformulated and is no longer available. The 10th infant manifested similar metabolic abnormalities while receiving TPN containing excessive methionine. Brain MRI abnormalities indicative of cerebral edema, most marked in the cerebral cortex and posterior brainstem, occurred in two patients near times of extreme hypermethioninemia. Metabolic and MRI abnormalities resolved when the methionine intake decreased. A third infant had a normal MRI 1 day after the formula was changed. The possible relationship between extreme hypermethioninemia and cerebral edema is discussed and a working hypothesis offered to explain the relative sensitivity of the inferior colliculi, based upon the facts that this is the region most active in glucose utilization and that Na(+),K(+)-ATPase is inhibited by methionine and related metabolites.
A defect in the P-protein component of the glycine cleavage system has been the most frequent abnormality found in patients with glycine encephalopathy (NKH). In a retrospective study of a more specific group of NKH patients, however, we found that >50% had T-protein mutations. The patients studied had one or more of the following unusual biochemical findings: residual glycine cleavage system activity in liver assayed by the standard method or a newly developed micromethod, residual glycine cleavage system activity in lymphoblasts, and/or increased amniotic fluid glycine/serine ratio with a normal amniotic fluid glycine level in prenatal diagnosis. The selected patients had a much higher incidence of T-protein defects than expected in the general NKH patient population. We report, here, three novel mutations and five polymorphisms in the T-protein gene, PCR/restriction enzyme methods for one mutation (R296H) and two polymorphisms (E211K and R318R), and an estimation of their frequency in normal controls. The co-occurrence of the polymorphism E211K with the mutation R320H in patients with a severe phenotype is discussed.
We describe a rare and lethal case of arginase deficiency in a 2-day-old female infant with encephalopathy and cerebral edema. The levels of glutamine and arginine but not ammonia were markedly elevated, lending support to the "glutamine hypothesis" as the mechanism of cerebral edema in urea cycle defects.
It is safe to predict that we are still at an early stage of newborn screening. There is a high probability that in the future, MS/MS or a similar technology will be applied to screening for many additional disorders, both metabolic and non-metabolic. The ability to examine DNA in the Guthrie specimen, currently used in second-tier screening, has opened up opportunities for primary screening of a huge array of potential disorders that previously could not be identified in the newborn. Among the possibilities under current discussion are type I diabetes, severe combined immunodeficiency, fragile X syndrome, hereditary hemochromatosis, and lymphoblastic leukemia. The major problems with these considerations, however, are that preventive treatment is not yet possible for most of these disorders, and for many, the abnormal finding determines only susceptibility for and not certainty of disease. Our experiences in the past with such newborn screening as that for histidinemia, which was found not to produce disease, and alpha 1-antitrypsin deficiency, which was not medically beneficial and had negative psychological effects, are lessons that must be taken seriously when considering new avenues of screening. Beyond further application to the Guthrie blood specimen and testing in a centralized laboratory is the broader concept of newborn screening exemplified by universal screening for hearing impairment. This screening is conducted directly on the newborn in the newborn nursery. This type of in-hospital universal screening may have wider application in the future. Much activity is underway to develop a consensus on appropriate newborn screening. This activity has been led by the Genetic Disease Branch of the federal Maternal and Child Health Bureau (MCHB), Health Resources and Services Administration (HRSA), in collaboration with the American Academy of Pediatrics and, currently, in collaboration with the American College of Medical Genetics through a committee to promulgate criteria for inclusion in newborn screening. The aphorism, "good judgment comes from experience, and experience comes from bad judgment," may be applied to newborn screening. Our challenge now is to use the experience we have from the previous bad judgements to guarantee future good judgements.
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OBJECTIVE: To provide information on the history of maternal phenylketonuria. METHODS: A review of the literature and personal observations were conducted. RESULTS: Compilation of sequential information about the development of our understanding of maternal PKU was produced. CONCLUSIONS: The history of maternal PKU reflects continuous additions to our understanding of this teratogenic syndrome.