Neurologic Assessment of Neonates with Metabolic Disease
As pointed out in Chap. 28, the neonate's nervous system functions essentially at a brainstem–spinal level. The pallidum and visuomotor cortices are only beginning to be myelinated and their contribution to the totality of neonatal behavior cannot be very great. Neurologic examination, to be informative, must therefore be directed to evaluating diencephalic–midbrain, cerebellar–lower brainstem, and spinal functions. The integrity of these functions in the neonate is most reliably assessed by noting the following, as was also described in Chap. 28:
Control of respiration and body temperature; regulation of thirst, fluid balance, and appetite–hypothalamus–brainstem mechanisms
Certain elemental automatisms, such as sucking, rooting, swallowing, grasping—brainstem–cerebellar mechanisms
Movements and postures of the neck, trunk, and limbs, such as reactions of support, extension of the neck and trunk, flexion movements, and steppage—lower brainstem (reticulospinal), cerebellar, and spinal mechanisms
Muscle tone of limbs and trunk—spinal neuronal and neuromuscular function
Reflex eye movements—tegmental midbrain and pontine mechanisms (a modified optokinetic nystagmus can be recognized by the third day of life)
The state of alertness and attention (stimulus responsivity and capacity of the examiner to make contact) as well as sleep–waking and electroencephalographic patterns—mesencephalic–diencephalic mechanisms
Certain reflexive reactions such as the startle (Moro) response and placing reactions of the foot and hand—upper brainstem–spinal mechanisms with possible cortical facilitation
Derangements of these functions are manifest as impairments of alertness and arousal, hypotonia, disturbances of ocular movement (oscillations of the eyes, nystagmus, loss of tonic conjugate deviation of the eyes in response to vestibular stimulation, i.e., to rotation of the upright infant), failure to feed, tremors, clonic jerkings, tonic spasms, opisthotonos, diminution or absence of limb movements, irregular or chaotic breathing, hypothermia or poikilothermia, bradycardia, circulatory difficulties, poor color, and seizures.
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.
Neonatal Metabolic Diseases and Their Estimated Frequency
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 37-1. Some of these disorders can be recognized by simple color reactions in the urine; these are listed in Table 37-2.
Table 37-1 Metabolic Disorders Detected by Neonatal Screening in New England ||Download (.pdf)
Table 37-1 Metabolic Disorders Detected by Neonatal Screening in New England
CASES PER 100,000
Maple syrup urine disease
Carnitine pamlityl transferase
Citrulinemia type I
Glutaric Aciduria-Type II
Very long chain acyl CoA dehydrogenase
Carnitine palmitoyl transferase type 2
Long chain hydroxyacyl CoA dehydrogenase
Table 37-2 Urinary Screening Tests for Metabolic Defects ||Download (.pdf)
Table 37-2 Urinary Screening Tests for Metabolic Defects
Maple syrup urine disease
Pale green (transient)
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.
It is important to note that the three most frequently identified hereditary metabolic diseases—phenylketonuria (PKU), hyperphenylalaninemia, and congenital hypothyroidism—do not become clinically manifest in the neonatal period and are therefore discussed in a later portion of this chapter and in Chap. 40 (in the discussion of congenital hypothyroidism). This is fortunate, for it allows time to introduce preventive measures before the first symptoms appear. A number of other metabolic disorders, which can be recognized either by screening or by early signs, are synopsized below.
Included under this heading is a group of diseases that respond not to dietary restriction of a specific amino acid but to the oral supplementation of a specific vitamin. Some 30 vitamin-responsive aminoacidopathies are known (they are all rare, but the more frequent ones are listed in Table 41-3), and many of them result in injury to the central nervous system (CNS).
Pyridoxine dependency is the prototypic example of a genetic, vitamin-dependent biochemical disorder, albeit a rare disease. It is inherited as an autosomal recessive trait and is characterized by the early onset of convulsions, sometimes occurring in utero; failure to thrive; hypertonia–hyperkinesia; irritability; tremulous movements ("jittery baby"); exaggerated auditory startle (hyperacusis); and later, if untreated, by psychomotor retardation. The specific laboratory abnormality is an increased excretion of xanthurenic acid in response to a tryptophan load. There are decreased levels of pyridoxal-5-phosphate and gamma-aminobutyric acid (GABA) in brain tissue. The mutation is of the ALDH7A1 gene.
The neuropathology has been studied in only a few cases. One patient of our colleague R.D. Adams, a 13.5-year-old boy affected in the neonatal period, was left in a state of mental retardation, with pale optic discs and spastic legs; the brain weight was 350 g below normal. There was a decreased amount of central white matter in the cerebral hemispheres and a depletion of neurons in the thalamic nuclei and cerebellum, with gliosis (Lott et al). Most importantly, in pyridoxine deficiency, the administration of 50 to 100 mg of vitamin B6 suppresses the seizure state, and daily doses of 40 mg permit normal development.
Some patients with increased concentrations of serum phenylalanine in the neonatal period are unresponsive to measures that lower phenylalanine. They are usually found to have a defect in biopterin metabolism. If this condition is unrecognized and not treated promptly, it leads to seizures of both myoclonic and, later, grand mal types, combined with a poor level of responsiveness and generalized hypotonia. Swallowing difficulty is another prominent symptom. Within a few months, developmental delay becomes prominent. Unlike in PKU, phenylalanine hydroxylase enzyme levels are normal, but there is a lack of tetrahydrobiopterin, which is a cofactor of phenylalanine hydroxylase. Treatment consists of administration of tetrahydrobiopterin in a dosage of 7.5 mg/kg/d in combination with a low-phenylalanine diet. It is important to recognize this condition early in life by the measurement of urine pterins and to institute appropriate therapy before irreversible brain injury occurs. A later onset form with diurnally fluctuating dystonia has also been described but its nature is not certain.
Inheritance of this disorder is autosomal recessive. The biochemical abnormality consists of a defect in galactose-1-phosphate uridyl transferase (GALT), the enzyme that catalyzes the conversion of galactose-1-phosphate to uridine diphosphate galactose. Several forms of galactosemia have been described, based on the degree of completeness of the metabolic block and some of these are due to mutations in other galactose pathway genes. In the typical (severe) form, the onset of symptoms is in the first days of life, after the ingestion of milk; vomiting and diarrhea are followed by a failure to thrive. Drowsiness, inattention, hypotonia, and diminution in the vigor of neonatal automatisms then become evident. The fontanels may bulge, the liver and spleen enlarge, the skin becomes yellow (in excess of the common neonatal jaundice), and anemia develops. In a small number, there is thrombocytopenia with cerebral bleeding. Cataracts form as a result of the accumulation of galactitol in the lens. Studies of the outcome of surviving infants have shown delayed psychomotor development (IQ about 85), visual impairment, osteoporosis, ovarian failure, and residual cirrhosis, sometimes with splenomegaly and ascites. This seems to happen even with treatment. However, it is not known whether, in such patients, the treatment is always maintained through a critical developmental period. In one such patient, who died at age 8 years, the main change in the brain was slight microcephaly with fibrous gliosis of the white matter and some loss of Purkinje and granule cells in the cerebellum, and also gliosis (Crome). The diagnostic laboratory findings are an elevated blood galactose level, low glucose, galactosuria, and deficiency of GALT in red and white blood cells and in liver cells. The treatment is essentially dietary, using milk substitutes; if this is instituted early, the brain should be protected from injury.
A late-onset neurologic syndrome has also been observed by Friedman and colleagues in galactosemic patients who had survived the infantile disease. By late adolescence, they were cognitively delayed; some showed cerebellar ataxia, dystonia, and apraxia. One of these patients was middle-aged.
Organic Acidurias of Infancy
These have been divided into ketotic and nonketotic types. Among the ketotic types, the main one is propionic acidemia. This is an autosomal recessive disease caused by a primary defect in organic acid metabolism that is expressed clinically by episodes of vomiting, lethargy, coma, convulsions, hypertonia, and respiratory difficulty. The onset is in the neonatal or early infantile period; in time, psychomotor retardation becomes evident. Death usually occurs within a few months despite dietary treatment. Propionic acid, glycine, various forms of fatty acids, and butanone are elevated in the serum. As with other ketotic organic acidurias, high protein intake induces ketotic attacks. Marked restriction of dietary protein (specifically leucine) may prevent attacks of ketoacidosis and permit relatively good psychomotor development.
A number of other ketotic acidurias also occur in infancy. The most important of these are methylmalonic acidemia, isovaleric acidemia, beta-keto acidemia, and lactic acidemia. Each of these disorders can become manifest with profound metabolic acidosis and intermittent lethargy, vomiting, tachypnea, tremors, twitching, convulsions, and coma, with early death in about half the patients and developmental retardation in those who survive. Rare subtypes of methylmalonic acidemia respond to vitamin B12. Isovaleric acidemia is characterized by a striking odor of stale perspiration, which has given it the sobriquet "sweaty foot syndrome." Numerous metabolic defects, most commonly of pyruvate decarboxylase and pyruvate dehydrogenase, are responsible for the accumulation of lactic and pyruvic acids. The enzymatic defect of isovaleric acidemia also has been demonstrated in a recurrent form of episodic cerebellar ataxia and athetosis and in a persistent form in mitochondrial encephalopathies (Leigh disease), as described further on in this chapter.
A separate and rare deficiency of aromatic L-amino acid decarboxylase has been described; the chemical signature is low levels of almost all catecholamines. This defect is associated with a peculiar movement disorder of oculogyric crises, dystonia and athetosis, and autonomic failure (see Swoboda et al).
A type II glutaric acidemia has also been observed in the neonatal period and causes episodes of acidosis with vomiting and hyperglycemia. Multiple congenital anomalies of brain and somatic structures and cardiomyopathy are conjoined. A diet low in the specific toxic amino acid and supplements of carnitine and riboflavin are recommended, but the effects are unclear.
In the nonketotic form of hyperglycinemia, there are high levels of glycine but no acidosis. The notable diagnostic finding is an elevation of the CSF glycine, several times higher than that of the blood. The effects on the nervous system are more devastating than in the ketotic form. In reported cases (the authors and our colleagues have seen several), the neonate is hypotonic, listless, and dyspneic, with dysconjugate eye movements, opisthotonic posturing, myoclonus, and seizures. A few such neonates survive to infancy but are extremely cognitively impaired and helpless. Spongy degeneration of the brain has been reported both in this disease and in the ketotic form (Shuman et al). No treatment has been effective in severe cases. In an atypical milder form, with neurologic abnormalities that appear in later infancy or childhood, reduction of dietary protein and administration of sodium benzoate in doses up to 250 mg/kg/d have been beneficial. The use of dextromethorphan, which blocks glycine receptors, is said to be effective in preventing seizures and coma.
These are a group of six diseases caused by inborn deficiencies of the enzymes of the Krebs-Henseleit urea cycle; they are designated as N-acetyl glutamate synthetase, carbamoyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinic acid synthetase (citrullinemia), argininosuccinase deficiency, and arginase deficiency. Hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) and intrinsic protein intolerance are closely related disorders. They are identified by the finding of a persistent or episodic elevation of ammonia levels in the blood. A detailed account of these inherited hyperammonemic syndromes is contained in the review by Brusilow and Horwich.
The pattern of inheritance of each of these disorders is autosomal recessive except for OTC deficiency, which is X-linked dominant. Their clinical manifestations are a common expression of an accumulation of ammonia or of urea cycle intermediates in the brain; they differ only in severity, in accordance with the degree of completeness of the enzymatic deficiency and with the age of the affected individual. The one exception is arginase deficiency, which commonly appears during later childhood as a progressive spastic paraplegia with mental retardation. Clinically, it has been convenient to divide the hyperammonemias into two groups—one that presents in the neonatal period and another that becomes evident in the weeks or months thereafter. This division is somewhat artificial, the clinical presentation being more in the nature of a continuous spectrum governed by the biologic factors mentioned above and even extending to rare cases that have their first symptoms during adulthood.
In the most severe forms of the hyperammonemic disorders, the infants are asymptomatic at birth and during the first day or two of life, after which they refuse their feedings, vomit, and rapidly become inactive and lethargic, soon lapsing into an irreversible coma. Profuse sweating, focal or generalized seizures, rigidity with opisthotonos, hypothermia, and hyperventilation have been observed in the course of the illness. These symptoms constitute a medical emergency, but even with measures to reduce serum ammonia, the disease is usually fatal.
In less severely affected infants, hyperammonemia develops some months later, when protein feeding is increased. There is a failure to thrive, and attempts to enforce feeding or during periods of constipation (both of which increase ammonia production in the bowel) may result in bouts of vomiting, lethargy, hyperirritability, and screaming. Respiratory alkalosis is a consistent feature. Other manifestations are periods of alternating hypertonia and hypotonia, seizures, ataxia, blurred vision, and of confusion, stupor, and coma. During episodes of stupor, often precipitated by dehydration, an alimentary protein load, or minor surgery, brain edema may be seen by CT and MRI; with repeated relapses, the brain edema gives way to atrophy, which appears as symmetrical areas of decreased attenuation in the cerebral white matter. Between attacks, some patients with partial deficiency may be normal or show only a slight hyperbilirubinemia (DiMagno et al; Rowe et al). With decompensation, the bilirubin rises, as does ammonia, but neither reaches exceedingly high levels. After repeated attacks, signs of developmental delay with motor and mental retardation become evident, and the patient is vulnerable to recurrent infections. Two adult male patients in our care, who were married (but with azoospermia, which is common) and working at technically demanding jobs, came to medical attention because of bouts of visual blurring followed by stupor that evolved over hours (Shih et al, 1999). They had displayed an aversion to protein and milk products as children; in later life, after meals high in protein, they became encephalopathic, one with severe brain swelling. There are few phenotypic differences among the late-onset hyperammonemias except for argininosuccinic aciduria, in which excessive dryness and brittleness of the hair (trichorrhexis nodosa) are notable features, and the aforementioned arginase deficiency with spastic diplegia.
Diagnosis is established by the finding of hyperammonemia, often as high as 1,500 mg/dL. The precise biochemical diagnosis requires testing of blood and urine for amino acids or assays for specific enzymes in red cells, liver, or jejunal biopsies. The primary hyperammonemias must be distinguished from the organic acidurias, including methylmalonic aciduria (see above), in which hyperammonemia can occur as a secondary metabolic abnormality.
In all the neonatal hyperammonemic diseases, the liver is often enlarged and liver cells appear to be inadequate in their metabolic functions, but how the enzymatic deficiencies or other disorders of amino acid metabolism affect the brain remains uncertain. It must be assumed that in some the saturation of the brain by ammonia impairs the oxidative metabolism of cerebral neurons, and when blood levels of ammonium increase (from protein ingestion, constipation, etc.), episodic coma or a more chronic impairment of cerebral functions occurs—as it does in adults with cirrhosis of the liver and portal-systemic encephalopathy. In the acutely fatal cases, the brain is swollen and edematous, and the astrocytes are diffusely increased in number and enlarged. The neurons are normal. Astrocytic swelling has been attributed to the accumulation of glutamate secondary to a suppression of glutamate synthetase. These changes have been reproduced in animals by the injection of ammonium chloride. When the hyperammonemia is abrupt in onset and severe, the resulting combination of encephalopathy, brain swelling, and respiratory alkalosis simulates the Reye syndrome (see "Reye-Johnson Syndrome" in Chap. 40).
As in all forms of liver disease, valproic acid and other hepatic toxins may cause hepatic coma by further impairing the urea cycle enzymes. Notable are a few cases of inherited hyperammonemia that come to light in childhood or adulthood only after the administration of one of these drugs.
Ornithine Transcarbamylase Deficiency and Argininosuccinic Aciduria
Most cases present in the neonatal period with hyperammonemia but milder forms may appear later in life with episodic symptoms such as episodic stupor, ataxia, and seizures. The other features have been mentioned above.
Treatment of the Hyperammonemic Syndromes
The treatment of acute hyperammonemic syndromes is directed at lowering ammonia levels by hemodialysis, exchange transfusions, and administration of arginine and certain organic acids. With subsidence of the acute symptoms, a systematic form of management should be undertaken, as outlined by Brusilow and colleagues and by Msall and colleagues. Sodium benzoate should be given in doses up to 250 mg/d, supplemented by sodium phenylacetate or sodium phenylbutyrate, which, on theoretical grounds, should divert nitrogen from the ureagenesis cycle. Arginine (50 to 150 mg/kg) should be added to the diet, as a deficiency of this substance may be responsible for the mental retardation and skin rashes. In more chronic cases, treatment consists of decreasing the ammonium load by the use of dietary protein restriction and by administration of oral antibiotics and lactulose. In infants with inborn errors of ureagenesis, there is a constant danger of recurrent episodes of hyperammonemia and coma, particularly in response to infections. In a few instances, careful management of the metabolic error has resulted in normal psychomotor development.
Liver transplantation may prove to be a therapeutic option.
Branched-Chain Aminoacidopathies (Maple Syrup Urine Disease)
These conditions are caused by a deficiency of α-keto acid dehydrogenase, resulting in the accumulation of the branched-chain amino acids leucine, isoleucine, and valine and the corresponding branched-chain α-keto acids. Maple syrup urine disease may be taken as the prototype. The pattern of inheritance is autosomal recessive. With the most-severe neonatal type, the infant appears normal at birth, but toward the end of the first week, poor feeding, intermittent hypertonicity, opisthotonos, and respiratory irregularities appear. These are followed by diminished neonatal automatisms, convulsions, severe ketoacidosis, and often coma and death toward the end of the second to fourth week. This disease is one of the causes of the malignant epileptic syndrome of early infancy (Brett). Four milder forms of the disease have been described. In these more chronic cases, feeding difficulties begin somewhat later in the early infantile period. They are manifest as recurrent infections, episodic acidosis, coma, and retarded growth and psychomotor development. Some of these patients, toward the end of the first year, may become quadriparetic or ataxic; or there may be only a nonspecific mental retardation. The disease derives its name from the maple syrup odor of the child's urine that tests positively for 2,4-dinitrophenylhydrazine (DNPH).
Other important laboratory findings are increased plasma and urine concentrations of leucine, isoleucine, valine, and keto acids. Secondary accumulation of a derivative of α-hydroxybutyric acid probably accounts for the maple syrup odor. The neuropathologic findings are uncertain. In the first acute case described, only interstitial edema was observed; but in more chronic cases, pallor and loss of myelin and gliosis of parts of the cerebral white matter that myelinate after birth may be found. This can be visualized in CT and MRI scans.
Treatment by restriction of foods containing branched-chain amino acids (leucine, isoleucine, and valine) allows reasonably normal mental development, but only if such restriction is begun in the neonatal period and maintained lifelong. A thiamine-responsive variant with a slightly different pattern of keto acids described by Prensky and Moser responds variably to 30 to 300 mg of thiamine. The acute episodes, which threaten life, may require peritoneal dialysis to remove the putative toxic metabolites; they respond to the administration of glucose amino acid mixtures that are free of branched-chain keto acids.
In addition to maple syrup urine disease, there are a number of other metabolic disturbances, some of them of mitochondrial origin, that appear in the neonatal period or later and are marked by an organic acidemia. If they are severe, the infant develops a metabolic (lactic) acidosis soon after birth, with lethargy, feeding problems, rapid respirations, and vomiting. Or there may be irritability, jerky limb movements, and hypertonia. Later presentations take the form of feeding difficulties, repeated vomiting, hypotonia, and failure to thrive. With the passage of time, psychomotor retardation and drug-resistant seizures become evident. Metabolic stress—e.g., intercurrent infection or surgical procedures—may precipitate an episode of lactic or ketoacidosis.
Biochemical studies may disclose a biotinidase deficiency, methylmalonic aciduria, glutaric acidemia, methylglutaconic acidemia, or any number of other organic acid abnormalities. The precise abnormality is determined by measuring enzyme activity in white blood cells or cultured skin fibroblasts. As remarked above, some of these enzymes act in conjunction with a specific vitamin cofactor, so that exact diagnosis is imperative. The biotinidase deficiency may respond to 10 mg of biotin per day; the methylmalonic acidemia to 1 to 2 mg of vitamin B12 per day; maple syrup urine disease to 10 to 20 mg of thiamine per day; and glutaric acidemia types I and II to 300 mg of riboflavin per day. The administration of carnitine may increase the elimination of toxic metabolites.
The care of these patients during an acute illness is of extreme importance. See Lyon and colleagues for a more complete description.
Sulfite Oxidase Deficiency with or Without Molybdenum Cofactor Deficiency (See also "Sulfite Oxidase Deficiency")
These are extremely rare autosomal recessive disorders of sulfur metabolism, manifest clinically during the neonatal period by seizures, axial hypotonia, reduced level of responsivity, and spasms with opisthotonos. There may be added dislocation of lenses, blindness, coloboma, and enophthalmos in combination with severe mental retardation and dysmorphic facial features (widely spaced eyes, long face and philtrum, puffy cheeks). There are no differences between pure sulfite oxidase deficiency and that associated with molybdenum cofactor deficiency. With survival into infancy, episodic confusion and stupor give way to seizures, mental retardation, and ataxia. In one of our cases, described by Shih and colleagues (1977) a stroke-like syndrome of hemiplegia and aphasia appeared during a relapse at the age of 4.5 years, and in one case, subluxation of the lenses and choreoathetosis appeared at 8 months of age.
The biochemical abnormality is the accumulation of sulfite and possibly sulfatase as a result of the enzyme deficiency. Shih and colleagues (1977) have identified sulfite, thiosulfate, and S-sulfocysteine in the urine. Cerebral atrophy with loss and destruction of white matter and gray matter (cerebral cortex, basal ganglia, and cerebellar nuclei) was observed in one postmortem examination. Increasing the intake of molybdenum or lowering the dietary intake of sulfur amino acids is a therapeutic possibility not yet fully evaluated.
Diagnosis of Neonatal Metabolic Diseases
An important clue, of course, is provided by the history of a neonatal disease or unexplained death earlier in the same sibship or in a male maternal relative. A history that protein foods are rejected by the infant, or even a history among relatives of a dislike of protein or feeding difficulties in infancy, should raise the suspicion of an inherited hyperammonemic disorder or an organic acidemia. Measurements of blood ammonia and lactate and of the urine for ketones and reducing substances (that react with cupric sulfate) are the key laboratory tests. A wide-spectrum screening program may disclose a biochemical abnormality; this is the optimal state of affairs, especially when this type of screening provides the information before symptoms appear.
A number of nonhereditary metabolic diseases must be distinguished from the hereditary ones in this period of life. Hypocalcemia is one of the most frequent causes of neonatal seizures; tetany, spasms, and tremulous movements are usually present. Its cause is unknown, but the disorder is easily corrected, with excellent prognosis. Symptomatic hypoglycemic reactions are frequent in neonates. Premature infants are the most susceptible. Seizures, tremulousness, and drowsiness occur with blood sugar levels of less than 30 mg/dL in the mature infant, and less than 20 mg/dL in the premature. Maternal toxemia and diabetes mellitus also predispose to hypoglycemia. Other causes of hypoglycemia are adrenal insufficiency, galactosemia, an idiopathic pancreatic islet-cell hyperplasia, the treatable fatty-acid beta-oxidation disorders, and a congenital deficiency of CSF glucose transport—causing persistent hypoglycorrhachia and refractory seizures unless blood glucose levels are kept high. The damaging effects of untreated hypoglycemia were well documented by Koivisto and colleagues. Also now identified is a disorder of CSF serine transport causing failure to thrive, severe developmental disability with spasticity and intractable epilepsy. The diagnosis is made by measuring CSF amino acids; treatment is with high-dose oral serine. Cretinism and idiopathic hypercalcemia are other recognizable entities that appear during this age period.
Aicardi has described a neonatal myoclonic syndrome, and Ohtahara has described a malignant neonatal seizure disorder. In some of the cases, the neonatal syndrome merged later with the West type of infantile spasms and the Lennox-Gastaut syndrome (see Chap. 16). Some of the cases had developmental abnormalities of the cerebrum, and severe mental retardation was the outcome. In other cases of this type, a familial coincidence was a feature; a metabolic defect has been suspected in these cases but never proved.
The hereditary metabolic diseases must also be distinguished from a number of other catastrophic disorders that occur at or soon after birth, such as asphyxia, perinatal ventricular hemorrhage with the respiratory distress syndrome of hyaline membrane disease, other hypotensive–hypoxic states, erythroblastosis fetalis with kernicterus, neonatal bacterial meningitis, meningoencephalitis (herpes simplex, cytomegalic inclusion disease, listeriosis, rubella, syphilis, and toxoplasmosis), and hemorrhagic disease of the newborn. These are described in Chap. 38, on the developmental diseases.