Search

This chapter covers a broad range of disorders that can present in the newborn period including lysosomal and peroxisomal storage disorders, congenital disorders of glycosylation, and Smith-Lemli-Opitz syndrome. Lysosomal storage diseases (LSDs) have a variety of presentations including nonimmune hydrops fetalis, neurologic manifestations, cherry-red spot, dysmorphic features, organomegaly, and dysostosis multiplex. Diagnosis occurs via enzyme assay and/or molecular testing. Newborn screening for selected LSDs has begun, raising ethical and moral concerns. Many LSDs may be treated with enzyme replacement therapy (ERT) or hematopoietic stem cell transplantation (HSCT). The phenotypic presentation of congenital disorders of glycosylation is similarly broad ranging from mild to severe presentations and from single organ system to multisystem involvement. They should be considered in any unexplained clinical condition, but especially in multisystemic, neurologic conditions. Most diagnoses occur via molecular testing. Treatment is largely supportive with rare exceptions. Peroxisomal disorders are a heterogeneous group of disorders resulting from the absence or dysfunction of one or more peroxisomal enzymes. Features are varied, but include craniofacial dysmorphism, neurologic dysfunction, hepatodigestive dysfunction, renal cysts, and skeletal abnormalities. Diagnosis is best made by next generation sequencing following screening biochemical tests. Treatment is symptomatic and supportive. Smith-Lemli-Opitz (SLO) syndrome is a multisystemic, developmental and dysmorphic syndrome caused by a defect in cholesterol biosynthesis. Diagnosis is based on finding elevated 7-dehydrocholesterol and 8-dehydrocholesterol levels in the blood. Treatment involves cholesterol supplementation with supportive care.

Glutaric aciduria type I (GA-I) is an autosomal recessive organic aciduria resulting from a functional deficiency of glutaryl-CoA dehydrogenase, encoded by GCDH. Two clinically indistinguishable diagnostic subgroups of GA-I are known; low and high excretors (LEs and HEs, respectively). Early medical and dietary interventions can result in significantly better outcomes and improved quality of life for patients with GA-I. We report on nine cases of GA-I LE patients all sharing the M405V allele with two cases missed by newborn screening (NBS) using tandem mass spectrometry (MS/MS). We describe a novel case with the known pathogenic M405V variant and a novel V133L variant, and present updated and previously unreported clinical, biochemical, functional and molecular data on eight other patients all sharing the M405V allele. Three of the nine patients are of African American ancestry, with two as siblings. GCDH activity was assayed in six of the nine patients and varied from 4 to 25% of the control mean. We support the use of urine glutarylcarnitine as a biochemical marker of GA-I by demonstrating that glutarylcarnitine is efficiently cleared by the kidney (50-90%) and that plasma and urine glutarylcarnitine follow a linear relationship. We report the allele frequencies for three known GA-I LE GCDH variants (M405V, V400M and R227P) and note that both the M405V and V400M variants are significantly more common in the population of African ancestry compared to the general population. This report highlights the M405V allele as another important molecular marker in patients with the GA-I LE phenotype. Therefore, the incorporation into newborn screening of molecular screening for the M405V and V400M variants in conjunction with MS/MS could help identify asymptomatic at-risk GA-I LE patients that could potentially be missed by current NBS programs.

Newborn screening (NBS) is intended to identify congenital conditions prior to the onset of symptoms in order to provide early intervention that leads to improved outcomes. NBS is a public health success, providing reduction in mortality and improved developmental outcomes for screened conditions. However, it is less clear to what extent newborn screening achieves the long-term goals relating to improved health, growth, development and function. We propose a framework for assessing outcomes for the health and well-being of children identified through NBS programs. The framework proposed here, and this manuscript, were approved for publication by the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC). This framework can be applied to each screened condition within the Recommended Uniform Screening Panel (RUSP), recognizing that the data elements and measures will vary by condition. As an example, we applied the framework to sickle cell disease and phenylketonuria (PKU), two diverse conditions with different outcome measures and potential sources of data. Widespread and consistent application of this framework across state NBS and child health systems is envisioned as useful to standardize approaches to assessment of outcomes and for continuous improvement of the NBS and child health systems. Significance Successful interventions for newborn screening conditions have been a driving force for public health newborn screening for over fifty years. Organizing interventions and outcome measures into a standard framework to systematically assess outcomes has not yet come into practice. This paper presents a customizable outcomes framework for organizing measures for newborn screening condition-specific health outcomes, and an approach to identifying sources and challenges to populating those measures.

New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 Rtnol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 [tmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.

Patients with the RSH or Smith-Lemli-Optiz syndrome (SLOS) have an inborn error of cholesterol biosynthesis which results in a deficiency of cholesterol and an elevation of the cholesterol precursor, 7-dehydrocholesterol. A treatment protocol consisting of administration of cholesterol +/- bile acids was initiated in an attempt to correct the biochemical abnormalities seen. Fourteen patients (8 female, 6 male: ages 2 months to 15 years) have now been treated for 6-15 months. Three patients received cholesterol alone, while 11 patients received cholesterol and one or more bile acids. Biochemical improvement in sterol levels and in the ratio of cholesterol to total sterols was noted in all patients. The most marked improvement was noted in patients presenting with initial cholesterol levels < 40 mg/dl. No toxicity was observed. Clinical improvement in growth and neurodevelopmental status was also observed.

The key to the evaluation of inborn errors of metabolism in the neonate is inclusion of these disorders in the differential diagnosis and intelligent use of selected laboratory tests that can increase or decrease suspicion of metabolic disorders (Table). Because the selection of appropriate tests and the interpretation of the results are based on a number of different clinical symptoms and the presence or absence of hypoglycemia, hyperammonemia, and acidosis, no simple flow diagram can replace the physician9s acumen and judgment in determining when and how to pursue the diagnosis.

Intrafamilial variability has not been reported previously in Hurler syndrome or Sanfilippo syndrome type A. We describe two families in which sibs with comparable deficiencies of α-iduronidase (Hurler) or sulfamidase (Sanfilippo type A) activities in vitro nonetheless have divergence in clinical severity and disease progression. These cases underscore the need for caution in counseling as well as the limitations of using sibs as controls in evaluating the outcome of treatment. © 1993 Wiley-Liss, Inc.

We describe a new case of molybdenum cofactor deficiency, an underrecognized inborn error of metabolism that results in neonatal seizures and neurologic abnormalities. Characteristic biochemical defects in affected individuals include hypouricemia, elevated urine sulfate (detectable by dipstick), and elevated S-sulfocysteine (detectable by anion exchange chromatography). This disorder should be considered in the differential diagnosis of neonatal seizures.

Article history: Received 16 March 2014 Received in revised form 18 March 2014 Accepted 18 March 2014 Available online 25 March 2014 and other neuro-psychologic and cognitive outcomes, and new pharmacological treatments for PKU were developed. To explore these new issues, an NIH State-of-the-Science Conference was convened in 2012. The two-day conference involved approximately 60 outside invited experts including professionals in the field of inborn errors of metabolism and representatives of patients and families, in addition to professional staff of the Department of Health and Human Services. This conference was just one part of a process that began with NIH

Summary: We report two children who presented with symptoms suggestive of biotinidase deficiency. Rather than deficiency, markedly elevated serum biotinidase activities were found. Based upon literature reports of elevated biotinidase activities in children with glycogen storage disease (GSD) type Ia, we considered the latter in our differential diagnosis and subsequently confirmed GSD type Ia in both patients by enzymatic testing. GSD type Ia should be considered in children with markedly elevated serum biotinidase activity.

Six infants and children with medium-chain acyl-coenzyme A dehydrogenase deficiency were found to have hyperuricemia during an acute episode. Hyperuricemia may be a clue to the diagnosis of medium-chain acyl-coenzyme A dehydrogenase deficiency.

Sir. —Phenylketonuria (PKU) is an inborn error of metabolism characterized by the inability to hydroxylate phenylalanine (PHE) to tyrosine (TYR). The condition is diagnosed by documentation of elevated serum PHE levels, and typically leads to moderate to severe mental retardation in its untreated form. Individuals with PKU who undergo early dietary PHE restriction usually achieve a full-scale IQ in the normal range. 1 Serum PHE levels of 120 to 480 μmol/L are the typical target values in treatment and constitute good dietary control. Current clinical recommendations and research findings support the need to maintain dietary control throughout childhood. 2-4 For various reasons, monitoring of serum TYR levels is not routine in many metabolic clinics. In our clinic, approximately 38% of patients with PKU who are younger than age 19 years have below-normal serum TYR concentrations (48 μmol/L). This is not clearly correlated with the kind of medical food or diet

3-Hydroxy-3-methylglutaric aciduria was found in a newborn infant whose parents are first cousins. The patient presented at 5 days of life with hyperammonemia, hypoglycemia, and metabolic acidosis. There was no ketonuria. Diagnosis was made by analysis of the pattern of organic acids excreted in the urine. A profound deficiency in activity of 3-hydroxy-3-methylglutaryl-coenzyme A lyase was found in cultured skin fibroblasts. The parents had intermediate levels of enzyme activity.

In a 9 month infant with the spinal fluid (CSF) NT abnormalities of biopterin synthesis defect we compared treatment with:BH4 high (20 mg/kg/d) dose only; BH4 low (3 mg/kg/d), moderate (10 mg/kg/d) or high dose with the NT precursors dopa/carbidopa (10/1 mg/kg/d) and 5-hydroxytryptophan (5 mg/kg/d); and NT precusors with phenylalanine (phe) restricted diet. Over 4 months we evaluated clinical status, CSF biopterin, CSF NT major metabolites homovanilic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol, and CSF NT minor metabolites 3,4-dihydroxy-phenylacetic acid, vanilmandelic acid, m-hydroxyphenylacetic acid (MHPAA), p-hydroxyphenylacetic acid (PHPAA) and indolacetic acid (IAA). Few control values for CSF biopterin and NT major metabolites and none for minor metabolites are known in children. Clinically the patient was well on NT precursors with or without BH4 and deteriorated on BH4 only. Liver enzymes, which were elevated at 4 months on BH4 only, remained normal and blood phe was in good control. CSF biopterin increased to at or above normal with moderate or high dose BH4 but virtually no response of HVA or 5-HIAA independent of NT precursors was seen. BH4 at any but low dose altered the IAA/5-HIAA ratio and BH4 at any dose increased PHPAA but not MHPAA. In this patient, the first in which NT minor metabolites have been measured on BH4, the CSF major metabolites could be maintained at normal levels only with NT precursors but BH4 modified the patterns of minor metabolites.