In most instances of neonatal metabolic disease, the pregnancy and delivery proceed without mishap. Birth at full term is usual. The infant is of a size and weight expected for the duration of pregnancy, and there are no signs of a developmental abnormality (in a few instances the infant is somewhat small, and in GM1 gangliosidosis there may be a pseudo-Hurler appearance; see further on). Furthermore, function continues to be normal in the first few days of life. The first hint of trouble may be the occurrence of feeding difficulties: food intolerance, diarrhea, and vomiting. The infant becomes fretful and fails to gain weight and thrive—all of which should suggest a disorder of amino acid, ammonia, or organic acid metabolism.
The first definite indication of disordered nervous system function is likely to be the occurrence of seizures. These usually take the form of unpatterned clonic or tonic contractions of one side of the body or independent bilateral contractions, sudden arrest of respiration, turning of the head and eyes to one side, or twitching of the hands and face. Some of the ill-formed seizures may become generalized. They occur singly or in clusters and, in the latter instance, are associated with unresponsiveness, immobility, and arrest of respiration.
The other clinical abnormalities in the motor realm, according to authorities such as Prechtl and Beintema, can be subdivided roughly into three groups, each of which constitutes a kind of syndrome: (1) hyperkinetic–hypertonic, (2) apathetic–hypotonic, or (3) unilateral or hemisyndromic. Prechtl and Beintema, from a study of more than 1,500 newborns, found that if clinical examination consistently discloses any one of the 3 syndromes, the chances are 2 in 3 that by the seventh year the child will be manifestly abnormal neurologically. They found also that certain neurologic signs—such as facial palsy, lack of grasping, excessive floppiness, and impairment of sucking—while sometimes indicative of serious disease of the nervous system, are less dependable; also, being rare, these signs will identify but few brain-damaged infants. It is not the single neurologic sign but groups of them that are held to be the most reliable indices of brain abnormality, and the 3 syndromes mentioned above are the important ones, even though their anatomic and physiologic bases are not completely known.
In cases of hypocalcemia–hypomagnesemia, the hyperkinetic–hypertonic syndrome prevails. Although most of the other diseases tend to induce the apathetic–hypotonic state, the hyperactive–hypertonic syndrome may represent the initial phase of the illness and always carries a less ominous prognosis than the apathetic– hypotonic state, which represents a more severe condition regardless of cause. The third putative group of unilateral abnormalities in the metabolic diseases is less common and more difficult to recognize. These syndromes frequently overlap and seizures may occur in all of them. The anatomic correlate for some of these neurologic abnormalities can be observed by MRI. Clearly what is needed is a more definitive neonatal neurologic semiology utilizing numerous stimulus–response tests, including those described by Andre Thomas and Dargassis.
In New England, screening of all newborns for metabolic disorders has been practiced for almost 50 years. Data on the diseases with neurologic implications were in the past collated by our colleague, H.L. Levy of Boston Children’s Hospital, and are summarized in Table 36-1. In the past, some of these were identified by colorometric chemical tests of urine (Table 36-2). This has been largely replaced by tandem mass spectroscopy.
To this group should be added the inherited hyperammonemic syndromes and vitamin-responsive aminoacidopathies (such as pyridoxine dependency and biopterin deficiency), as well as certain nonfamilial metabolic disorders that make their appearance in the neonatal period—hypocalcemia, hypothyroidism and cretinism, hypomagnesemia with tetany, and hypoglycemia.