Chapter 11 Newborn Screening

Introduction Newborns can be screened for an increasing variety of conditions on the principle that early detection can lead to therapy that prevents severe, long-term medical problems. Technological advances are quickly expanding the scope of newborn screening. Disorders such as cystic fibrosis as well as endocrine, hematologic, immunologic, neurologic, and infectious disorders are being identified in the newborn period, in addition to inborn errors of metabolism.

Introduction cont. Screening of newborns for several inborn errors of metabolism is standard throughout the United States and in most of the developed world. The rationale is that identification of infants with inborn errors can lead to institution of treatment prior to the onset of clinical signs of the disorder. This can prevent otherwise irreversible neurologic damage and other medical problems

Introduction cont. The criteria for screening for a particular disorder are as follows: (1) The disorder produces irreversible damage if untreated early in life; (2) treatment prevents the damage but only if begun in the newborn period, when the infant is asymptomatic; (3) the natural history of the disease is known; (4) a suitable screening test is available; (5) facilities for diagnosis and treatment are available.

Children diagnosed with inborn errors of metabolism require lifelong care. Introduction cont.

There is a wide variety of pathophysiological mechanisms that underlie inborn errors of metabolism. These include defects in enzymes and coenzymes, with physiological consequences of product deficiency and/or substrate accumulation. Introduction cont.

A variety of approaches to the treatment of inborn errors of metabolism are in use or in development, including dietary management, coenzyme supplementation, removal of toxic metabolites, enzyme replacement, and gene therapy. Introduction cont.

Phenylketonuria The frequency of PKU is approximately 1 in births. Prior to the advent of newborn screening and treatment, PKU was one of the most common causes of intellectual disability. Children with untreated PKU exhibit profoundly delayed cognitive development. They also tend to have fair hair and skin owing to relative deficiency of melanin (normally derived, in part, from tyrosine).

Phenylketonuria A value greater than 20 mg/dL is indicative of classic PKU. Some newborns have phenylalanine values in an intermediate range (7–20 mg/dL), which is indicative of atypical or mild PKU. Either form of PKU is treated by reducing phenylalanine intake. Elevated levels of less than 7 mg/dL correspond with non-PKU benign hyperphenylalaninemia and require no treatment. Benign hyperphenylalaninemia mutations are mis-sense mutations. PKU mutations also are usually missense mutations but might be mutations that lead to deficient production of protein (e.g., stop codons, splicing mutations, and deletions)

Phenylketonuria An unexpected consequence of PKU is a risk of congenital anomalies in the child of an affected woman due to phenylalanine toxicity if the mother is not maintained on strict dietary control during pregnancy.

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) It is the most common of the fatty acid oxidation disorders and occurs with an estimated incidence of 1 in births. Patients with fatty acid oxidation disorders generally present clinically during periods of fasting and/or acute illness that result in an increased metabolic rate and energy requirement.

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) Unlike PKU, this condition does not require continuous treatment, but only at times of illness or metabolic stress. The majority of undiagnosed infants present with lethargy and hypoglycemia between 3 and 12 months of age (once the interval between feedings has lengthened, or nighttime feedings have been discontinued), or during an acute illness associated with decreased oral intake. Failure to recognize the signs and symptoms and institute glucose therapy promptly can result in coma and death. The ability to tolerate fasting improves with age and growth.

Lysosomal Storage Disorder Another major cellular dysfunction associated with some metabolic disorders is the gradual accumulation of substances within the cell due to hereditary deficiency of enzymes required for their breakdown. This occurs in lysosomal storage diseases, in which one or another of the enzymes required to metabolize cell membrane components in the lysosome is missing. A hallmark of these disorders is the progressive buildup of membrane debris in the lysosome, leading to progressive loss of cell function. An example of a lysosomal storage disorder is Tay–Sachs disease

Treatments Dietary manipulation. Alternative system to remove a toxic substrate. Organ transplantation. Enzyme replacement. Gene therapy protocols have also been tested on an experimental basis.