Metabolic disorder

One of the largest population-based disease intervention programs in the United States is newborn metabolic screening. Since the mid- to late 1970s, newborns have been screened routinely for one or more metabolic disorders [1-4]. The goal of early identification and treatment of metabolic disorders is prevention of the serious medical and developmental consequences of the disorders (e.g., mental retardation [MR]). Despite this goal, the United States has no mechanism for systematic surveillance of the developmental status of children who screen positive for and subsequently have metabolic disorders diagnosed. To determine the number of selected developmental disabilities attributable to metabolic disorders detected by newborn screening, CDC conducted a preliminary investigation of children with developmental disabilities and metabolic disorders in the metropolitan Atlanta area using data from the Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP). This report summarizes the results of this investigation, which indicate that newborn screening is highly effective in reducing the burden of MR associated with these disorders.

Since 1991, CDC has conducted MADDSP, an ongoing, population-based surveillance system for selected developmental disabilities (i.e., MR. cerebral palsy, hearing impairment, and vision impairment) among children aged 3-10 years in the five-county metropolitan area. MADDSP identifies children with one or more of these conditions by reviewing existing records at multiple sources, including the public school systems serving the surveillance area; three pediatric specialty-care hospitals and their associated clinics; and other agencies serving children with sensory, motor, or mental impairments. The prevalence of the selected disabilities in metropolitan Atlanta is comparable with other published population-based rates (5).

The records of children with developmental disabilities who were born from 1981 through 1991 to a resident of the Atlanta area were reviewed to identify the presence of associated medical conditions. Medical data for children in MADDSP include pregnancy and birth history, data on congenital malformations, diagnostic information, and data on general medical conditions associated with the children's disability. In addition to narrative information on medical conditions from MADDSP, data are reviewed from nonmedical sources (e.g., schools and social service agencies), and hospital discharge data (discharge diagnoses identified by selected International Classification of Diseases, Ninth Revision, Clinical Modification, codes). For this report, a pediatric geneticist and a developmental pediatrician independently reviewed medical data from MADDSP and identified a subset of children for whom the primary etiology of their developmental disability appeared to be a metabolic disorder.

Thirteen children in MADDSP were identified as having possible metabolic disorders. Some indication of abnormal metabolic status--such as a positive screening result or mention of a metabolic disorder--was noted in these children's records. These 13 children included nine with positive screening test results for congenital hypothyroidism, two with classic galactosemia (galactose-1-phosphate uridyl transferase deficiency), one with maple syrup urine disease (MSUD), and one with tyrosinuria. In the judgement of study physicians, two of the 13 children (one with galactosemia and one with MSUD) appeared to have developmental disabilities, specifically MR, that could be attributed to a metabolic disorder.

Cases were excluded based on individual assessments. Of the nine children reported with congenital hypothyroidism, three had Down syndrome, and the other six were born prematurely, had other medical conditions, and most likely had transient hypothyroxinemia of prematurity. For the child reported with tyrosinuria, no confirmatory information was available in the MADDSP records, and no additional information about this child was located by searching records of the genetics programs in the area. One child reported with galactosemia was a carrier for the condition and did not have MR.

Of the two children with developmental disabilities attributable to metabolic disorders, one had galactosemia resulting in MR, and the other had MSUD with MR. The child with galactosemia was born in the early 1980s and was identified in school records as having MR at age 8 years. The result of the initial screening test for galactosemia for this child was normal; however, galactosemia subsequently was diagnosed when the child was aged 1 month. The child with MSUD also was born in the early 1980s and was detected as having MSUD by the newborn screening test for MSUD. According to medical records, that child had cerebral palsy diagnosed at age 5 years and MR at age 6 years.

Assuming that a child with an untreated metabolic disorder associated with MR will develop MR, CDC and the Emory University School of Medicine estimated the expected number of children with MR attributable to these disorders in the metropolitan Atlanta area (Table 1) (1,7). This calculation was based on the estimated incidence of each metabolic disorder in Georgia and the number of live-born infants in the five-county metropolitan Atlanta area [6]. Of the 362,390 live-born infants of residents of metropolitan Atlanta from 1981 through 1991, an estimated 148 children would have screened positive for at least one of six metabolic disorders and would have been at risk for having MR if left untreated. However, only two children from these birth cohorts were identified in MADDSP as having MR associated with one of these underlying metabolic disorders.

Reported by: PM Fernhoff, MD, Div of Medical Genetics, Dept of Pediatrics, Emory Univ School of Medicine, Atlanta, Georgia. Div of Child Development, Disability, and Health (proposed), National Center for Environmental Health, CDC.

Editorial Note: The findings in this report underscore the importance of early identification and treatment of children with metabolic disorders to prevent or lessen the severity of serious neurodevelopmental sequelae. Screening for metabolic disorders does not ensure complete detection of affected infants. Some infants with metabolic disorders will be missed because of individual genetic variations, administrative or laboratory errors, or low sensitivity of screening tests (4,8). Surveillance for developmental disabilities among children who have metabolic disorders would facilitate efforts to determine the effectiveness of treatment and metabolic control. The finding that metropolitan Atlanta children have a low occurrence of serious developmental disabilities attributable to these rare and serious metabolic disorders supports the effectiveness of the newborn screening program. However, the presence of two cases of MR attributable to MSUD and galactosemia suggests a need to conduct surveillance or other ass essments of children with metabolic disorders identified by newborn screening to monitor the effectiveness of this intervention program.

The findings in this report are subject to at least three limitations. First, to be identified by MADDSP, a child with a metabolic disorder must have survived to age 3 years and must have lived in the five-county ascertainment area at that age or later. Second, the data did not allow researchers to evaluate the effect of treatment for metabolic disorders on the severity of associated developmental disabilities. Although treatment of some metabolic disorders may not prevent completely a developmental disability, it may lessen its severity. Therefore, treated children may not meet the MADDSP case definition for MR but may still have some cognitive impairment. Finally, a metabolic disorder diagnosis may not have been in the medical records that were reviewed by the MADDSP staff.

The specific panel of newborn screening tests varies by state (3). With the advent of tandem mass-spectrometry and the decreasing costs of DNA technology, the screening panel for any given state potentially could be expanded to include up to 50 different organic acid and amino acid disorders (9,10). As these technologic advances are implemented to establish a more thorough system for early identification and diagnosis, surveillance systems and other assessments of children with metabolic disorders will help gauge the effectiveness of screening and treatment during infancy. CDC is initiating an effort to link data from MADDSP with data on newborns in metropolitan Atlanta who have had a metabolic disorder diagnosed.

References

(1.) Taeusch WH, Ballard RA, Avery ME. Diseases of the newborn. Philadelphia, Pennsylvania: WB Saunders Co., 1991:111-46.

(2.) Fisher DA, Dussault JH, Foley TP Jr, et al. Screening for congenital hypothyroidism: results of screening 1 million North American infants. J Pediatr 1979;94:700-5.

(3.) American Academy of Pediatrics. Newborn screening fact sheets. Pediatrics 1996;98:467-72.

(4.) Fernhoff PM, Fitzmaurice N, Milner J. Coordinated system for comprehensive newborn metabolic screening. South Med J 1982;75:529-32.

(5.) Boyle CA, Yeargin-Allsopp M, Doernberg NS, et al. Prevalence of selected developmental disabilities in children 3-10 years of age: the Metropolitan Atlanta Developmental Disabilities Surveillance Program. MMWR 1996;45(no. SS-2):1.-13.

(6.) Grinzaid KA, Breen S, Fernhoff PM. Comprehensive newborn metabolic screening annual report--1997. Atlanta, Georgia: State of Georgia, Division of Medical Genetics, Department of Pediatrics, Emory University School of Medicine, 1998.

(7.) Nelson WE, Behrman RE, Kleigman RN, et al, eds. Textbook of pediatrics. 15th ed. Philadelphia, Pennsylvania: WB Saunders Co., 1996.

(8.) American Academy of Pediatrics. Issues in newborn screening. Pediatrics 1992;89:345-9.

(9.) Rashed MS, Ozand PT, Bucknall MP, Little D. Diagnosis of inborn errors of metabolism from blood spots by acylcarnitines and amino acids profiling using automated electroscopy tandem mass spectroscopy. Pediatr Resear 1995;38:324-31.

(10.) Levy H. Newborn screening by tandem mass spectrometry: a new era. Clin Chem 1998;44:2401-2.

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