Hyponatremia

The clinical effects of hyponatremia depend on the rapidity of the change, the absolute level of abnormality, and the effectiveness of cellular counter-regulatory responses. Acute decreases in sodium, occurring over hours or days, can cause mild symptoms at serum concentrations between 120 and 130 mEq/L, and severe symptoms at concentrations <120 mEq/L. Mild symptoms include irritability, apathy, excessive somnolence, and hypotonia. As the degree of hyponatremia worsens, seizures may occur, culminating in coma if uncorrected or if complicated by severe cerebral edema and intracranial hypertension. Osmotic demyelination, or central pontine myelinolysis, due to overly rapid correction of hyponatremia, has not been described in neonates. It would be difficult to isolate osmotic demyelination as a cause of white matter injury in neonates, most notably premature infants, who are vulnerable to white matter injury from other causes.

Hyponatremia occurs when sodium losses exceed sodium or water intake, or reabsorption exceeds water excretion, or both. Hyponatremia is common in sick neonates due to immature or damaged renal mechanisms of salt and water balance or to perturbations in the hypothalamic-pituitary mechanisms regulating volume and osmolar status. Hyponatremia during the first 1–2 weeks of life in sick neonates is most commonly due to excess arginine vasopressin (AVP) secretion in association with other diseases such as lung disease, intracranial hemorrhage, pain, and surgical procedures, and rarely is due to congenital adrenal insufficiency. Causes of hypo- or hypernatremia are summarized in Box 20-2.

Box 20-2 Causes of Hyponatremia and Hypernatremia in Neonates

Causes of Hyponatremia

Disorders causing positive water balance

Excessive AVP secretion

Systemic hypoxia, ischemia

Mechanical ventilation

Pneumothorax

Intracranial hemorrhage

Septic shock

Neonatal drug withdrawal

Hypothyroidism

Water intoxication

Inappropriately dilute intravenous fluids

Inappropriately dilute formula feedings

Disorders causing negative sodium balance

Abnormal renal salt handling

Chronic renal insufficiency

Adrenal insufficiency

Acute pyelonephritis

Acute obstructive uropathy

Urinary ascites

Insufficient salt intake relative to losses

High insensible fluid/electrolyte losses

Vomiting, diarrhea

Low-salt-containing infant formulas

Causes of Hypernatremia

Disorders causing negative water balance

Deficient AVP secretion (central diabetes insipidus)

Meningitis, encephalitis

Hypoxic-ischemic encephalopathy

Midline CNS malformations with pituitary insufficiency

Renal unresponsiveness to AVP

Obstructive uropathy

Renal dysplasia

Drugs

Excess water losses

Extensive skin disease

Osmotic diuresis

Disorders causing positive sodium balance

Administration of hypertonic salt solutions

Ingestion of hypertonic feedings

AVP, arginine vasopressin.

The management of hyponatremic encephalopathy in neonates depends on the cause, the chronicity, and the severity of symptoms. Subacute or chronic (days to weeks) hyponatremia of mild degree (>120 mEq/L) should be treated by determining and correcting the underlying cause. Controversy surrounds the treatment of acute severe hyponatremic encephalopathy, which is usually associated with serum sodium concentrations <120 mEq/L. In such cases, seizures are usually resistant to standard anticonvulsants, and the encephalopathy frequently depresses respiratory drive and airway protective reflexes, all of which constitute a degree of urgency in favor of rapid correction. Rapid correction of hyponatremic seizures in infants and young children can be accomplished without neurologic complications by the use of 3 percent saline [Sarnaik et al., 1991]. The fact remains, however, that very little is known about neurologic complications from rapid correction of acute symptomatic hyponatremia in premature infants and critically ill term neonates who are already at high risk for neurologic injury from other causes. Until better data are available in this population, treatment should proceed with caution.

Hypernatremia

Neurologic manifestations of hypernatremia arise from hypertonic dehydration of neurons and glia, and may be compounded by secondary ischemic injury from hyperviscosity, cerebral venous thrombosis, or intracranial hemorrhage. Mild symptoms accompany mild elevations of serum sodium, generally <160 mEq/L, while severe encephalopathy usually occurs with elevations >170 mEq/L. The causes of hypernatremia are the inverse of those causing hyponatremia: excess sodium intake relative to sodium losses, or excess water losses relative to water intake or reabsorption, or both (see Box 20-2). Excess sodium intake occurs with administration of hypertonic intravenous solutions or from hypertonic oral feedings. Negative water balance is the most common cause of hypernatremia, caused by excess losses of hypotonic body fluids, defective renal water absorption due to nephrogenic diabetes insipidus, deficient pituitary secretion of AVP, or cerebral salt wasting. Hypothalamic-pituitary insufficiency is caused by acquired brain insults, such as meningitis or hypoxic-ischemic encephalopathy, and by midline brain malformations. Management of hypernatremia begins with assessment and correction of intravascular volume deficits with normotonic solutions or plasma expanders in sufficient amounts to restore perfusion to normal levels and to maintain urinary output. The guiding principle in treatment is to prevent cerebral edema by correcting the hypernatremia over 48–72 hours, decreasing the serum sodium concentration at a rate not exceeding 10–15 mEq/L per 24 hours.

Maple Syrup Urine Disease

Maple syrup urine disease (MSUD) is an autosomal-recessive disorder due to deficient activity of branched chain keto-acid dehydrogenase (BCKAD); it causes accumulation in plasma of leucine, isoleucine, and valine, and their corresponding keto-acids (Figure 20-3). Of the five clinical phenotypes, the severe neonatal form is the most common [Morton et al., 2002]. After a normal interval of 4–7 days after birth, affected infants develop progressive lethargy and hypotonia, evolving to coma and decerebrate posturing, sometimes with seizures. Cerebral edema, particularly involving white matter, appears in the early stages, giving rise to a distinctive pattern of abnormalities on MRI, with pronounced T2 hyperintensity and restricted diffusion in the brainstem, cerebellar dentate nuclei, deep gray nuclei, and periventricular white matter [Jan et al., 2003]. Biochemical abnormalities include ketoacidosis, ketonuria, and hypoglycemia, often complicated by hyponatremia. Neuropathology consists of spongiform degeneration or delayed myelination of white matter with oligodendroglial cell loss, and cerebellar granular cell necrosis. The EEG during metabolic decompensation may show characteristic central sharp waves, or diffuse slowing to burst suppression as the symptoms progress. Diagnosis rests on the detection of marked elevations of plasma leucine (up to 1000–5000 μM during acute decompensation), isoleucine, and valine. Detection of l-alloisoleucine in plasma is pathognomonic for this disorder. An elevated ratio of leucine:alanine has been described as a sensitive and specific marker for MSUD, along with appreciation of the distinctive maple syrup odor in cerumen, allowing for earlier diagnosis of newborns in the presymptomatic stage. Urine organic acid profiles reveal elevated 3-hydroxyvaleric acid. BCKAD assay in cultured skin fibroblasts reveals activity at less than 2 percent of normal levels, and confirms the diagnosis. Treatment for acute severe decompensation requires metabolite removal via peritoneal dialysis or hemodialysis, along with supportive and nutritional measures to induce an anabolic state. Morton et al. reported that infants diagnosed in the first 72 hours of life, before becoming symptomatic, can be managed readily with enteral MSUD formula, thereby preventing acute metabolic decompensation and the associated neurologic injury [Morton et al., 2002]. Long-term management consists of dietary restriction of leucine, good nutritional support, and avoidance of catabolic stresses. Long-term outcome is related to the number and severity of metabolic decompensations.

Fig. 20-3 Biochemical pathways affected by defects in branched chain amino acid (BCAA) and organic acid metabolism.

Disorders and their corresponding enzyme defects: 1, Maple syrup urine disease, branched chain keto-acid dehydrogenase (BCKAD). 2, Isovaleric acidemia, isovaleryl CoA dehydrogenase. 3, Isoleucine defects, mitochondrial acetoacetyl CoA thiolase. 4, Propionic acidemia, proprionyl CoA carboxylase. 5, Methylmalonic acidemia, methylmalonyl. 6, CoA mutase or defective cobalamin metabolism.

The pathophysiology of the neurologic manifestations is incompletely understood, and is likely multifactorial and related to the roles of branched chain amino acids and their metabolites in cellular energetics, glutamate and GABA metabolism, fatty acid and cholesterol synthetic pathways, and the regulation of neuronal cytoskeleton development [Pessoa-Pureur and Wajner, 2007]. It has been suggested that acute symptoms reflect toxic effects of the keto-isocaproic acid (KIC) metabolite on glutamate, glutamine, and GABA signaling pathways and energy metabolism. Long-term effects of KIC may be related to altered phosphorylation of cytoskeletal proteins, which is influenced by glutamatergic and GABAergic receptor activation in a developmentally regulated manner. A further potential mechanism for toxicity of branched chain keto-aciduria (BCKAs) is via inhibition of glutamate reuptake (see Figure 20-3). Deficiencies in transmitter pools of glutamate, aspartate, and GABA, along with deficient GABA receptors, have been demonstrated in an animal model [Dodd et al., 1992], while human neuropathologic analysis has revealed reduced myelin lipids in untreated patients.

Organic Acidopathies due to Defects in Branched Chain Amino Acid Metabolism

BCKAs are autosomal-recessive disorders due to defects in the catabolism of branched chain amino acids. MSUD is a prominent example of an organic aciduria, as described in the preceding section. Defects in the downstream degradation of branched chain ketoacids of leucine, valine, and isoleucine cause accumulation of one or more branched chain organic acid intermediates (see Figure 20-3). While isovaleric, propionic, and methylmalonic aciduria are the best known of these disorders, several others have been described (Table 20-8). Clinical symptoms first appear from the neonatal period to early infancy, characterized by acute onset of severe metabolic acidosis with ketoacidosis, hypoglycemia, and hyperammonemia, which may progress to seizures and coma. Associated features may include growth failure, vomiting, diarrhea, hepatic dysfunction, circulatory collapse, neutropenia, and thrombocytopenia. Pathogenesis of clinical symptoms has been attributed to a combination of direct toxic effects of accumulated metabolites and compensatory responses. Energy metabolism may be compromised as a result of deficient substrates for gluconeogenesis and limited availability of free CoA for mitochondrial fatty acid oxidation. Accumulation of acyl-CoA intermediates inhibits the urea cycle, resulting in hyperammonemia.

Diagnosis should be suspected when first-stage screening reveals prominent metabolic acidosis with variable combinations of ketosis, lactic acidosis, hypoglycemia, and hyperammonemia. Specific diagnosis rests on specific urinary organic acid profiles, and can be confirmed by enzyme assay in cultured skin fibroblasts (see Table 20-8). Management consists of glucose administration, with insulin if necessary, to reverse catabolic states, and protein restriction, along with respiratory and circulatory support. Peritoneal dialysis may be necessary in the most severe cases with acute metabolic coma. l-carnitine and N-carbamylglutamate (NCG) supplementation respectively have been used to mitigate excessive ketogenesis and the inhibitory effects of high propionic acid levels on urea cycle function [Tuchman et al., 2008]. Carnitine and glycine supplementation may improve clearance of toxic metabolites in isovaleric acidemia. Co-factor supplementation can be helpful in subgroups characterized by primary defects in the co-factor metabolism using pharmacologic doses of cobalamin in some cases of methylmalonic acidemia, or biotin in some cases of propionic acidemia. Long-term management includes protein-restricted, high-carbohydrate diets and avoidance of catabolic stresses. Several case reports and case series have described improved long-term outcome following liver transplantation for some organic acidopathies [Morioka et al., 2007]. Long-term outcome can be normal if decompensations are minimized in frequency and treated aggressively when they occur.

Primary Lactic Acidosis due to Defects in Oxidative Phosphorylation

Primary lactic acidosis causes a severe metabolic encephalopathy in neonates with several types of defects in energy metabolism, including defects of pyruvate dehydrogenase complex, pyruvate carboxylase, and the respiratory chain. Figure 20-4 illustrates these pathways in relation to cellular energy and lactate metabolism. Secondary lactic acidosis is common in hypoxia or ischemia, and in other inborn errors of metabolism that secondarily affect energy metabolism, including organic acidopathies, urea cycle disorders, and fatty acid oxidation defects. Changes in the flux of citric acid cycle intermediates produce a multitude of downstream effects on energy substrate availability, precursors of neurotransmitters, and protein synthesis pathways. In the developing brain, these metabolic shifts have profound effects on immediate cellular functional integrity, as well as transcriptional and translational processes central to cell proliferation and differentiation. Advances in the understanding of the role of cellular energetics in the regulation of the cell cycle and differentiation have shed new light on the mechanisms of neurologic effects of these disorders (Figure 20-5). Energy substrate deficiency shifts the ratio of adenosine monophosphate (AMP):adenosine triphosphate (ATP), which is a key regulator of the intracellular signaling system involving mammalian target of rapamycin (mTOR). The state of activation of mTOR broadly modulates protein synthesis and cell proliferation [Fingar and Blenis, 2004]. Under conditions of energy substrate deprivation, changes in mTOR signaling shift protein metabolism from an anabolic to a catabolic state, initiating a cascade of events with major implications for subsequent growth and development.

Fig. 20-4 Schematic of intermediate metabolism.

Selected disorders and their corresponding enzyme deficiencies are indicated as follows. Defects in oxidative phosphorylation include: 1, pyruvate dehydrogenase; 2, pyruvate carboxylase; 3, respiratory chain. Fatty acid oxidation defects include: 4, carnitine palmitoyl transferase (CPT); 5, malonyl CoA decarboxylase (MCD). ADP/ATP, adenosine monophosphate/triphosphate; GABA, gamma-aminobutyric acid; NADH, nicotine adenine dinucleotide.

Fig. 20-5 Schematic of intermediate metabolism, showing the potential role of anaplerotic therapy for inborn errors of metabolism affecting cellular energetics.

Energy status regulates anabolic vs. catabolic state of cellular systems via ratio of adenosine monophosphate (AMP):adenosine triphosphate (ATP), activation of AMP-mediated protein kinase (AMPK), and mammalian target of rapamycin (mTOR) activity. Anaplerotic therapeutic strategies may restore deficiencies in the supply of substrates for the Krebs cycle caused by some inborn errors, and indirectly affect downstream anabolic vs. catabolic state and cellular proliferation. C7 is heptanoin, a triglyceride, given as anaplerotic therapy; it is metabolized through the fatty acid oxidation pathway to produce acetyl-CoA and ketone bodies, restoring cellular metabolism toward an anabolic state.

Improved understanding of the molecular and cellular pathophysiology of metabolic disease has led to the development of “anaplerotic” therapeutic strategies [Roe and Mochel, 2006]. These interventions aim to restore a more physiologic state of cellular energetics and protein synthesis, and go beyond replacement of deficient metabolites or removal of toxins by providing alternative substrates for the citric acid cycle and respiratory chain. This approach is exemplified by use of the triglyceride triheptanoin as an alternative source of citric acid cycle substrates in the treatment of pyruvate carboxylase deficiency, further discussed below. As such, these strategies are most relevant for defects of oxidative phosphorylation and the respiratory chain, but can theoretically play a role in any metabolic disorder that disrupts energy metabolism.

Pyruvate dehydrogenase (PDH) defects are the most common of the primary congenital lactic acidoses, and include multiple subtypes depending on which component of this large enzyme complex is affected. E₁ component defects are the most common, and are inherited as X-linked dominants. The most severe form presents in newborns with permanent lactic acidosis, often >7 μM, which is maximal in the fed state, and a fulminant severe encephalopathy progressing to death in the first months of life. Intrauterine growth retardation, subtle facial and limb anomalies, and minor signs of brain dysgenesis (absent corpus callosum) illustrate the fetal effects of this disorder. Postnatal evolution of the neurologic symptoms is associated with necrotic changes and cavitation in cortical white matter, basal ganglia, and brainstem nuclei. Treatment options are limited, although some success has been reported with institution of a ketogenic diet and thiamine and carnitine supplements.

Pyruvate carboxylase (PC) converts pyruvate to oxaloacetate. It plays a critical role in hepatic gluconeogenesis and in maintaining a stable supply of citric acid cycle intermediates influencing energy metabolism, the function of the urea cycle, and substrate availability for neurotransmitter pools of glutamate and GABA. PC deficiency has several subtypes with a broad spectrum of clinical manifestations. PC deficiency type B (the French subtype) is the severe neonatal form, and presents with a fulminant neonatal encephalopathy with permanent severe lactic acidosis, hypoglycemia, citrullinemia, and hyperammonemia, and is usually fatal in early infancy. The neurologic symptoms include variably depressed mental status, hypotonia, high-amplitude tremors and dystonic movements, and a variety of paroxysmal eye movement abnormalities (gaze defects, pendular nystagmus) [Garcia-Cazorla et al., 2006]. Imaging shows cystic periventricular leukomalacia. Autopsies in these patients show widespread neuronal death and arrest of myelination, leading to cortical and white matter atrophy or cystic encephalomalacia. Treatment strategies with high carbohydrate diets have been used in these patients to avoid dependence on the defective gluconeogenic pathways. Early administration of triheptanoin as a form of anaplerotic therapy may rapidly reverse the metabolic crisis and ameliorate neurologic symptoms in symptomatic newborns.

Respiratory chain defects comprise a large spectrum of disorders in oxidative phosphorylation, which have a highly variable and rapidly expanding phenotype. The phenotypic complexity arises in part from the fact that both nuclear and mitochondrial genes determine these structures. This group of disorders should be considered in infants with either severe intractable lactic acidosis, or a cardinal clinical feature with or without lactic acidosis. Cardinal clinical features include external ophthalmoplegia, myopathy, or cardiomyopathy, often with variable encephalopathy. Involvement of other organs is common, such as hepatic dysfunction, renal tubular abnormalities, or growth failure. When lactic acidosis is present, the lactate:pyruvate ratio is increased (>25) in disorders of oxidative phosphorylation, as compared to PDH complex disorders where the lactate:pyruvate ratio is usually normal. The clinical course may be benign in cases with only skeletal muscle involvement (benign infantile mitochondrial myopathy), or intractable and fatal in cases with intractable acidosis (lethal infantile mitochondrial disease). Diagnosis is difficult because of the extreme phenotypic and genotypic variability, and because histologic and histochemical diagnostic techniques are difficult and not widely available. Treatment options are limited, and have generally relied on supportive strategies to minimize catabolic stresses, and administration of carnitine and the respiratory chain co-factors nicotinamide and riboflavin.

Glutamine Synthetase Deficiency

Glutamine synthetase (GS) forms glutamine from glutamate and ammonia (Figure 20-6). Glutamine is the most abundant amino acid in plasma, and functions as an amino-group donor in the synthesis of several amino acids and nucleotides. GS plays a critical role in the brain to detoxify ammonia and regulate the concentration and compartmentalization of neurotransmitter pools of glutamate and GABA (see Figure 20-6). GS deficiency has been described as a rare autosomal-recessive condition manifest as profound neonatal encephalopathy with coma, quadriparesis, severe bulbar dysfunction, lissencephaly, and death shortly after birth due to multi-organ failure [Haberle et al., 2006]. Diagnosis rests on the finding of moderate hyperammonemia, and very low or absent glutamine concentration in blood, cerebrospinal fluid (CSF), and urine, and is confirmed by severely deficient enzyme activity in cultured fibroblasts. There is no effective treatment.

Fig. 20-6 Urea cycle defects.

1, Argininosuccinate synthetase. 2, Argininosuccinase. 3, Ornithine transcarbamylase. 4, Carbamyl phosphate synthetase. 5, Glutamine synthetase.

Fructose-1,6-Biphosphatase Deficiency

Fructose-1,6-biphosphatase (FDPase) deficiency is an autosomal-recessive disorder causing a profound defect in gluconeogenesis. It presents as a severe acute metabolic encephalopathy in the first month of life, with fasting-induced marked lactic acidosis and ketoacidosis and hypoglycemia, usually without other organ involvement, except for hepatomegaly. The characteristic clinical and biochemical features should suggest the diagnosis, but confirmation rests on enzyme assay on a liver biopsy specimen. Treatment is similar to that for type I glycogenosis, in addition to restriction of fructose and sucrose intake.

Fatty Acid Oxidation Defects

Fatty acid oxidation defects comprise a broad spectrum of disorders, most of which present beyond the neonatal period as acute encephalopathies with nonketotic hypoglycemia provoked by fasting or catabolic stress. In these disorders, one of several enzymes is deficient in the pathway for degradation of lipids to fatty acids to acetyl CoA or ketone body production (see Figure 20-4). Several of these disorders have been reported with prominent and distinctive presentations in neonates. These include carnitine palmitoyl transferase II (CPT II) deficiency, mitochondrial trifunctional protein deficiency (MTP) and malonyl CoA decarboxylase deficiency (MCD). Acyl CoA dehydrogenase deficiencies (long-chain or LCAD, medium-chain or MCAD, short-chain or SCAD) more typically present outside the neonatal period. These disorders share a constellation of clinical features, which include the rapid onset of a fulminant metabolic encephalopathy with hypoglycemia, moderate hyperammonemia, low or moderate ketonuria (disproportionately low for the degree of hypoglycemia), and metabolic acidosis. Associated clinical features may include hepatomegaly, cardiomyopathy, and myopathy. Patients with MCD deficiency have been reported to have cortical dysgenesis, manifest as pachygyria, white matter atrophy, and gray matter heterotopias. The pathogenesis of neurologic symptoms has been attributed to the combined effects of direct toxicity from accumulated free fatty acids, as well as insufficient glucose and ketones to fuel the Krebs cycle, and inhibition of mitochondrial energy production by the disturbed ratio of acyl CoA:free CoA. The characteristic clinical features should suggest the diagnosis, which can be further supported by finding decreased total plasma carnitine levels and specific patterns of elevated plasma acylcarnitine intermediates as follows: C16 and C18 species in CPT II deficiency; C14 species in LCAD; C6–C8 species in MCAD; C4 species in SCAD. MCD deficiency is identified by the finding of elevated urinary malonic acid. Definitive diagnosis rests on assay of enzyme activity from cultured skin fibroblasts, and identification of specific mutations by genomic sequence analysis. Treatment involves supportive measures, glucose administration, and carnitine supplementation, and modification of feeding schedules to minimize fasting states. Creatine supplements have been suggested for patients with MTP deficiency. Recurrent decompensations can be minimized by early initiation of intravenous glucose during intercurrent illnesses and avoidance of fasting. Long-term outcome depends on the frequency and severity of decompensations.

MTP is distinguished among these disorders by the high proportion of cases (about 50 percent) presenting in the neonatal period [den Boer et al., 2003]. It has two types of presentations:

Multisystem involvement has been reported, including retinopathy, peripheral neuropathy, myopathy, cardiomyopathy, and liver disease.

CPT II deficiency has several phenotypes, with onset in adulthood, infancy, or the neonatal period. The latter is the least common and most severe form [Sigauke et al., 2003], and is reported to be universally fatal. Affected infants often have prenatally detected cerebral lesions and malformations, including ventriculomegaly, agenesis of the corpus callosum, polymicrogyria, periventricular cystic leukomalacia, and subependymal hemorrhages. Neurologic symptoms appear at birth or within the first few days of life, including seizures, depressed consciousness, and hypotonia with myopathic features. Cardiomyopathy leading to circulatory failure is common. The metabolic findings are typical of fatty acid oxidation defects, as described above. Management is supportive and symptomatic, but ineffective in most cases. Definitive biochemical diagnosis is a prelude to genetic testing, which can provide a basis for family counseling and management of future pregnancies. A number of US states have incorporated CPT II in neonatal metabolic screening programs in hopes of promoting early diagnosis.

Urea Cycle Disorders

Urea cycle defects presenting in the neonate are characterized by the onset, between 1 and 4 days of age, of severe hyperammonemia with rapidly progressive lethargy and vomiting, progressing to coma with signs of cerebral edema [Summar et al., 2008]. Associated features may include respiratory alkalosis and hypothermia. First-stage laboratory assessments reveal no other major abnormalities. A presumptive diagnosis can be made from results of plasma amino acid, urine organic acid, and urinary orotate excretion profiles (see Figure 20-6). Elevated plasma glutamine levels are common to all the urea cycle disorders. Organic acidopathies and congenital lactic acid disorders that may cause hyperammonemia can be distinguished from urea cycle disorders by the presence in the former of acidosis, ketosis, or lactic acidosis, as well as by specific metabolites in urinary organic acid profiles, as described in previous sections. Transient hyperammonemia of the newborn is a poorly understood disorder, characterized by severe transient hyperammonemia associated with respiratory distress syndromes or herpes simplex infection. It is distinguished from the genetically determined enzyme defects by its earlier onset (first 24 hours of life) and its association with prematurity and pulmonary disease. The pathophysiology of hyperammonemic encephalopathy is complex, involving astrocyte swelling and dysfunction due to excessive glutamine accumulation [Takahashi et al., 1991] and disturbed regulation of nitric oxide synthesis [Nagasaka et al., 2009]. Treatment of acutely symptomatic infants includes administration of sodium benzoate, phenylacetate, and arginine. Infants unresponsive to these measures or those presenting with acute severe hyperammonemic coma are treated with hemodialysis to reduce plasma ammonia levels rapidly [Enns et al., 2007]. Use of pressors and volume to maintain adequate cerebral perfusion pressure is preferable to the use of hyperventilation or osmotic diuresis in managing intracranial hypertension. Careful protein restriction, providing adequate calories to prevent catabolic state, and administration of drugs to enhance excretion of excessive metabolites are tailored according to the specific enzyme defect. Orthotopic liver and liver cell transplantation have been reported with some success in stabilizing the disease process and improving outcome in some cases [Meyburg et al., 2009]. Long-term outcome is variable, with motor and cognitive deficits dependent on the severity and frequency of hyperammonemic decompensations.

Glycine Cleavage Defects

Glycine cleavage defects are a group of autosomal-recessive disorders that lead to accumulation of glycine (Figure 20-7). The most common form is a neonatal-onset progressive encephalopathy with depressed consciousness, apnea, and seizures, usually myoclonic, associated with a pattern of burst suppression on EEG. A transient form of nonketotic hyperglycinemia has been reported, in which symptoms similar to the classic form appear in the neonatal period, but which may resolve at 1–3 months of age when the glycine levels spontaneously normalize. In such children, enzyme activity measured from liver biopsy is normal, and long-term outcome is normal in the majority of individuals [Lang et al., 2008]. Glycine toxicity appears to be maximal in the neonatal period, and may spontaneously diminish after 1 month of age. Lifelong severe cognitive and motor handicap and intractable epilepsy are the rule among survivors, although there is considerable variability. Factors that predict a poorer outcome include earlier age of symptom onset, presence of cerebral dysgenesis, and degree of glycine elevation. Neurologic manifestations occur as a result of excessive stimulation of CNS glycine receptors, which are inhibitory in spinal cord and brainstem and excitatory in brain via a co-agonist effect at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors. Neuroimaging findings are varied, and may include cerebral dysgenesis of prenatal origin related to disturbed neuronal proliferation and differentiation, evolving to a progressive vacuolating myelinopathy in the postnatal period [Mourmans et al., 2006]. Biochemical abnormalities are limited to the finding of elevated glycine levels in plasma (1–8-fold above normal) and CSF (15–30-fold above normal). In cases with equivocal plasma elevations of glycine, the diagnosis can be made by finding a CSF:plasma ratio >0.06. Definitive diagnosis can be made by demonstrating absent or very low activity of the glycine cleavage system enzyme in liver biopsy or autopsy. Glycine cleavage defects can be distinguished from the hyperglycinemia that accompanies organic acidopathies by the presence of ketosis in the latter, and by characteristic organic acid excretion profiles. There are no proven therapies. Seizures have generally been resistant to standard anticonvulsants. Treatment with dextromethorphan, an NMDA-receptor antagonist, or with ketamine and benzoate has been reported in a small number of cases with limited success [Korman et al., 2006].

Fig. 20-7 Disorders of serine and glycine metabolism.

1, 3-phosphoglycerate dehydrogenase. 2, Serine hydroxymethyl transferase. 3, Glycine cleavage system. MTHF, methylenetetrahydrofolate; NMDA, N-methyl-d-aspartate.

Pyridoxine and Pyridoxal Phosphate Dependency Epileptic Encephalopathies

Pyridoxine is the precursor for pyridoxal-5-phosphate (PLP), an essential co-factor for multiple enzymes in brain metabolism. There are two known enzyme defects with distinct gene mutations that result in depletion or deficient production of PLP. These are pyridoxine-dependent epilepsy (PDE) and pyridoxal phosphate-dependency disorder, known as PNPO deficiency. The biochemical and genetic basis for PDE has been defined, and involves depletion of PLP as a result of binding with 1-piperideine 6-carboxylate, a byproduct of defective lysine metabolism (Figure 20-8). The defect in the lysine pathway enzyme, alpha-aminoadipic semialdehyde dehydrogenase (AASAD), arises from mutation of the gene antiquitin (ALDH7A1) [Mills et al., 2010]. Pyridoxal phosphate-dependency disorder involves mutations in the gene for pyridox(am)ine-5′-phosphate oxidase (PNPO), which converts pyridoxine to PLP [Bagci et al., 2008]. The pathophysiology of the encephalopathy is not fully defined, but likely involves multiple pyridoxine-dependent pathways in brain metabolism. Prominent among these is glutamic acid decarboxylase (GAD), which converts glutamate to GABA, the major inhibitory neurotransmitter in mammalian brain (Figure 20-9). A disruption of this pathway alters GABA-related neurotransmission, and may contribute to the clinical manifestations of intractable seizures and severe cortical dysfunction.

Fig. 20-8 Pyridoxine dependency/deficiency.

1, This is due to depletion of the active form of pyridoxine–pyridoxal-5′-phosphate (PLP), as a result of binding with 1-piperideine 6-carboxylate, a byproduct of lysine metabolism that builds up from deficiency of α-aminoadipic semialdehyde dehydrogenase (α-AASAD). *Effects of AASAD deficiency may be partially or wholly overcome by pyridoxine administration. 2, Pyridoxal phosphate-dependency disorder is due to deficient activity of pyridox(am)ine-5′-phosphate oxidase (PNPO), which converts pyridoxine to PLP.

Fig. 20-9 Schematic of interrelationships between intermediate metabolism and the major neuronal neurotransmitters glutamate and GABA.

Selected defects affecting neurotransmitter metabolism include: 1, pyridoxine dependency/deficiency, due to α-aminoadipic semialdehyde dehydrogenase (α-AASAD) deficiency; 2, pyridox(am)ine-5′-phosphate oxidase (PNPO) deficiency; 3, succinic semialdehyde dehydrogenase deficiency; 4, glutamate transporter defects; 5, glutamine synthetase defects. Alpha-AASAD may be partially or wholly responsive to pyridoxine or folinic acid administration.

Affected infants with either disorder have a similar clinical presentation, dominated by neonatal-onset seizures, or in some cases in utero-onset seizures, and chronic encephalopathy, with no other metabolic abnormalities. Seizures are usually unresponsive to standard anticonvulsants. EEG is typically severely abnormal, with any of several types of epileptiform patterns including hypsarrhythmia, burst suppression, or generalized spike-wave activity. The diagnosis of either disorder starts with clinical suspicion in the setting of refractory neonatal-onset seizures. Diagnosis of PDE can be confirmed by finding elevated levels of α-aminoadipic semialdehyde and pipecolic acid in urine, blood, and CSF. It can be further defined by mutation analysis of the antiquitin gene in affected children and their parents [Mills et al., 2006, 2010]. Diagnosis of pyridoxal phosphate-dependency disorder should be considered in infants with the clinical features of pyridoxine dependency, but who are unresponsive to pyridoxine, lack the confirmatory biochemical markers (elevated urinary AASA), and who respond to PLP.

Folinic acid-responsive neonatal epileptic encephalopathy resembles PDE clinically and electrographically. Gallagher et al. demonstrated that folinic acid-responsive epileptic encephalopathy is identical biochemically and genetically to PDE [Gallagher et al., 2009]. The biochemical basis for the favorable response to folinic acid is unknown.

Treatment recommendations for infants with clinically suspected or proven pyridoxine-dependency disorders include supplementation with both pyridoxine and folinic acid, as there is variable response to either agent. Institution of a lysine-restricted diet has also been suggested. For infants with clinical features resembling pyridoxine-dependency disorder, but who are not responsive to pyridoxine and folinic acid, a trial of pyridoxal supplementation may be considered while awaiting results of genetic testing for PNPO deficiency.

Sulfite Oxidase and Molybdenum Co-factor Deficiency

Molybdenum co-factor deficiency and isolated sulfite oxidase deficiency are closely related autosomal-recessive diseases involving defects in xanthine metabolism and sulfite degradation pathways [Schwarz et al., 2009]. Molybdenum co-factor (Moco) is essential for the function of xanthine dehydrogenase and sulfite oxidase. Synthesis of Moco involves conversion of guanosine triphosphate (GTP) to a pterin-containing intermediate (cPMP) (Figure 20-10). The mechanism of the brain injury is multifactorial, involving direct toxic effects of xanthines and sulfite metabolites on cellular architecture, damage to mitochondria, thiamine degradation, and impaired mucopolysaccharide synthesis. Moco deficiency leads to accumulation of S-sulfocysteine, which activates the glutamate receptor, and may contribute to the prominent epileptic features of affected patients.

Fig. 20-10 Defects in purine metabolism and sulfur-containing amino acids.

These are caused by deficiencies in: 1, molybdenum co-factor (Moco); 2, isolated sulfite oxidase deficiency. Enzymes in purine metabolism are shown as: 3, 5′-nucleotidase; 4, purine nucleoside phosphorylase; 5, xanthine dehydrogenase, which requires molybdenum as a co-factor. Synthesis of Moco involves conversion of guanosine triphosphate (GTP) to a pterin-containing intermediate (cPMP). *Administration of cPMP in animal models of Moco deficiency has been effective in normalizing the phenotype. AMP, adenosine monophosphate; GMP, guanosine monophospate; IMP, inosine monophosphate.

These two distinct genetic defects share a similar clinical presentation, consisting of acute or subacute evolution of a severe neonatal-onset epileptic encephalopathy with diffuse severe cavitary leukomalacia. Infants are usually born at term uneventfully, and develop seizures in the first week of life that progress over the ensuing weeks in association with arrested development, acquired microcephaly, and early appearance of generalized hypertonicity, evolving to a severe mixed motor and cognitive handicap in survivors. Most children do not survive infancy. The clinical and radiographic features in the early stages mimic those seen in children with hypoxic-ischemic encephalopathy. The absence of a history of severe peripartum hypoxia or circulatory decompensation should prompt a search for other diagnoses. The severe cavitary leukomalacia seen in these patients is very distinctive and not typically seen after perinatal hypoxia-ischemia. It is more severe in isolated sulfite oxidase deficiency than in Moco deficiency. There are no associated malformative anomalies, systemic metabolic perturbations, or abnormalities affecting other organ systems.

Diagnostic biochemical characteristics include increased urinary excretion of sulfites, thiosulfate, S-sulfocysteine, and taurine. Patients with Moco deficiency have low serum and urinary uric acid levels, and increased urinary xanthine and hypoxanthine levels. These findings may vary according to protein intake and nutritional status. Patients with isolated sulfite oxidase deficiency have normal uric acid metabolite levels. The diagnosis may be confirmed by enzyme assay of biopsied liver or cultured skin fibroblasts. Treatment is supportive with an emphasis on optimizing anticonvulsant therapy. Dietary intervention with cysteine and thiamine supplementation and methionine restriction has been reported to be beneficial in isolated cases [Boles et al., 1993]. Administration of cPMP in animal models of Moco deficiency has been effective in normalizing the phenotype, but has not been evaluated in humans [Schwarz et al., 2004].

Menkes’ disease

Menkes’ disease is an X-linked recessive disorder of the ATP7A gene, which results in defective function of the intestinal copper transport protein [Tumer and Moller, 2010]. This causes low tissue levels of copper and secondarily deficient function of numerous enzymes for which copper is a co-factor, including dopamine-β-hydroxylase, cytochrome c oxidase, and lysyl oxidase. The clinical phenotype invariably consists of severe neonatal-onset chronic encephalopathy with refractory epilepsy. Infants typically have central hypotonia and developmental arrest with microcephaly. Distinguishing findings on examination, outside of neurologic abnormalities, include redundant and hyperelastic skin, coarse brittle hair, thin or absent eyebrows and eyelashes, and poor temperature stability. When examined under a microscope, hair fibers display the classic appearance of pili torti. Non-neurologic manifestations include vasculopathy with excess tortuosity and fragility, leading to thromboembolic stroke or subdural hemorrhage. This disease should be suspected in the setting of early infantile epileptic encephalopathy with the characteristic physical stigmata, and is supported by the biochemical findings of low ceruloplasmin level and low serum copper. Confirmation of the diagnosis based on serum ceruloplasmin and copper markers is unreliable in the newborn period. Distinctive abnormalities in serum profiles of catecholamines, on the other hand, provide a sensitive and specific diagnostic approach in the presymptomatic neonates [Kaler et al., 2008]. Correction of serum copper levels with dietary supplements may be helpful if started in presymptomatic infants. Otherwise, treatment is supportive with an emphasis on anticonvulsant management.

Glucose Transporter Defects

DeVivo et al. characterized a disorder arising from mutations in the neuronal glucose transporter, known as GLUT1 deficiency syndrome (GLUT1 DS) [De Vivo et al., 2002]. The disease manifests as early infantile-onset epileptic encephalopathy associated with a low CSF glucose concentration (mean 30 mg/dL). Seizures have their onset from age 4 weeks to 18 months, with a mean of 5 months, include all clinical seizure types (focal, generalized, myoclonic), and are resistant to anticonvulsant drugs. Affected infants have neurodevelopmental impairment of variable severity, and acquired microcephaly. The cardinal biochemical feature is a decreased ratio of CSF glucose relative to plasma glucose, typically <33 percent, which contrasts with the relatively high ratio of CSF/blood glucose seen in term and premature newborns of 70–80 percent, accompanied by low levels of the GLUT1 glucose transporter assayed in red blood cells. Conventional anatomical neuroimaging with CT or MRI is typically normal, while metabolic imaging with ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) reveals a distinctive pattern of hypometabolism in the thalami and mesial temporal regions [Pascual et al., 2002]. The ketogenic diet is the mainstay of treatment, resulting in good control of seizures in most patients but limited benefit for the neurodevelopmental disability. Long-term outcome is variable, with most children affected by some degree of cognitive impairment.

Serine Biosynthesis Defects

Defects in serine biosynthesis have been described that present as neonatal-onset chronic encephalopathies with prominent refractory epilepsy [de Koning and Klomp, 2004]. Affected infants are neurologically abnormal at birth with intrauterine growth retardation (IUGR), congenital microcephaly, cataracts, seizures, and neurodevelopmental impairment. A distinctive pattern of leukoencephalopathy is seen on MRI, characterized by hypomyelination, vacuolar changes, and gliosis, which may improve after treatment with serine and glycine supplementation. The disease involves defective serine biosynthesis due to 3-phosphoglycerate dehydrogenase deficiency (see Figure 20-7). Clinical manifestations have been attributed to multiple mechanisms, including loss of neurotrophic effects of serine, impaired synthesis of glycine, which acts as a glutamate receptor co-agonist, and impaired synthesis of 5-methyltetrahydrofolate (5-MTHF), which is a co-factor for numerous brain enzyme pathways. Diagnosis can be made by finding low CSF concentrations of serine, glycine, and 5-MTHF. In contrast to many inborn errors of metabolism, this disorder is potentially treatable by high-dose dietary supplementation of serine (200–600 mg/kg/day) and glycine (200 mg/kg/day).

Purine Biosynthesis Defects

Defects of purine biosynthesis have recently been described, with clinical presentation in the neonatal period involving adenylosuccinate lyase, or riboside transformylase enzyme deficiencies [Jurecka, 2009] (Figure 20-11). These infants are typically born uneventfully at term, and manifest a severe neonatal encephalopathy with hypotonia, seizures, and mildly dysmorphic facies. Neuroimaging initially may be normal, and over time discloses diffuse atrophy. The long-term course is characterized by persistent severe static encephalopathy with profound mental retardation, blindness due to optic atrophy, refractory epilepsy, and growth failure. The cardinal biochemical features include massive urinary excretion of the riboside metabolites 5-amino-4-imidazolecarboxamide ribosiduria (AICA) and succinyl-5-amino-4-imidazolecarboxamide ribosiduria (SAICA) in urine and CSF. These metabolites give a positive result on the Bratton–Marshall test, which screens for high concentrations of succinyl purines. Diagnosis is confirmed by high-resolution thin-layer chromatography analysis of urine for succinyl purines. In addition, affected infants may have disturbed glucose and lipid metabolism as a result of impaired hepatic gluconeogenesis, fatty acid, and cholesterol synthesis. Management is symptomatic and supportive, as there is no definitive or curative treatment.

Fig. 20-11 Defects in purine biosynthesis.

These are caused by deficiencies in: 1, adenylosuccinate lyase; 2, 5-amino-4-imidazolecarboxamide riboside transformylase. AICAR, 5-amino-4-imidazolecarboxamide riboside; AMP, adenosine monophosphate; FAICR, formyl-5-amino-4-imidazolecarboxamide riboside; GMP, guanosine monophosphate; IMP, inosine monophosphate; S-Ado, succinyladenosine; SAICAR, succinyl-5-amino-4-imidazolecarboxamide riboside.

l-Amino Acid Decarboxylase Deficiency

l-ADD is a defect of biogenic amine neurotransmitter metabolism, causing a combined deficiency of brain dopamine, serotonin, norepinephrine, and epinephrine [Swoboda et al., 2003] (Figure 20-12). Patients commonly present in the first weeks of life with a progressive disorder affecting multiple levels of the nervous system. Symptoms and signs include lethargy, hypotonia, suck/swallow dysfunction, and seizures, sometimes associated with hypoglycemia and acidosis. Autonomic dysfunction leads to ptosis, hypotension, gastric and intestinal dysmotility, and poor temperature regulation. With advancing age, a distinctive movement disorder appears, consisting of dystonia, athetosis, oculogyric crises, and nonepileptic myoclonus. Diagnosis rests on evaluation of CSF neurotransmitter profiles, which show increased levels of biogenic amine precursors L-DOPA and 5-hydroxytryptamine, and decreased levels of the neurotransmitter metabolites homovanillic acid (HVA) and 5-hydroxy-indole-acetic acid (5-HIAA). Similar profiles of neurotransmitter amino acids are measured in plasma and urine. A clue to this disorder would be the finding on a urine organic acid profile of elevated vanillactic acid (VLA), a breakdown product from an alternate degradative pathway for L-DOPA. Management is symptomatic and supportive. Attempts to treat by replacing deficient neuroactive amines have been hindered by the lack of an effective targeted delivery system. Outcome is poor in most patients, who develop mixed severe motor and cognitive disability and chronic movement disorders that are refractory to symptomatic treatment.

Fig. 20-12 Defects in biogenic amine neurotransmitter metabolism.

1, Tyrosine hydroxylase + BH₄. 2, Aromatic l-amino acid decarboxylase + B₆. 3, Dopamine β-hydroxylase. 4, Phenylethanolamine-N-methyl-transferase. 5, Tryptophan hydroxylase + BH₄. 6, Catechol-ortho-methyl transferase (COMT). Affected metabolites and co-factors include homovanillic acid (HVA), vanillylmandelic acid (VMA), vanillactic acid (VLA), 5-hydroxytryptamine (5-HT), 5-hydroxy-indole-acetic acid (5-HIAA), and tetrahydrobiopterin (BH₄).

Hyperphenylalaninemia

Hyperphenylalaninemia causes a chronic encephalopathy with neonatal onset due to one of several defects in the metabolism of phenylalanine. These include phenylalanine hydroxylase (PAH) deficiency, tetrahydrobiopterin (BH₄) synthesis deficiency, and GTP cyclohydrolase deficiency (Figure 20-13). In classical phenylketonuria (PKU) caused by PAH deficiency, plasma phenylalanine levels exceed 1000 μM, and PAH activity in liver biopsy is severely deficient (<1 percent of normal). In a milder form of the disease, designated non-PKU hyperphenylalaninemia, plasma phenylalanine levels are <1000μM and PAH activity is less severely deficient (5–30 percent of normal). Clinical symptoms in untreated classical PKU evolve with age to include irritability, hyperkinesis, acquired microcephaly, and severe cognitive deficiency. Infants with GTP cyclohydrolase deficiency have a neonatal-onset chronic encephalopathy with severe hypotonia, bulbar dysfunction, and seizures. Symptoms may evolve over time to a pattern of rigidity, hyperkinesia, and oculomotor abnormalities. Treatment with L-DOPA has been beneficial in some patients [Nardocci et al., 2003]. Diagnosis is made by newborn metabolic screening in most countries. After identification of newborns with hyperphenylalaninemia, further quantitation of plasma phenylalanine and tyrosine, and of urinary and CSF biopterin metabolites at baseline and after phenylalanine loading is necessary to distinguish classical PKU from BH₄ and GTP cyclohydrolase disorders. Treatment consists of the use of a semisynthetic diet low in phenylalanine that is carefully titrated according to plasma amino acid levels. Patients with BH₄ disorders require folate and BH₄ replacement. A subset of patients with milder forms of PKU, and some residual PAH enzyme activity, may respond to BH₄ supplementation. In these patients, BH₄ responsiveness is associated with missense mutations of PAH [Sarkissian et al., 2009]. A trial of L-DOPA and 5-hydroxytryptophan replacement to restore brain monoamine levels may prove helpful in some patients for symptoms of the dystonia and rigidity. Gene therapy and enzyme replacement therapy, while conceivable, are not yet clinically available, and are the focus of intensive experimental study.

Fig. 20-13 Defects in amino acid metabolism leading to hyperphenylalaninemia.

1, Phenylalanine hydroxylase. 2, Dihydropterin reductase. 3, GTP cyclohydrolase. 4, 6-pyruvoyltetrabiopterin synthase. BH₂, dihydrobiopterin; BH₄, tetrahydrobiopterin.

Succinic Semialdehyde Dehydrogenase Deficiency

Succinic semialdehyde dehydrogenase deficiency is a defect of GABA degradation that results in elevated brain GABA levels (see Figure 20-9). The clinical presentation is variable. Some patients present in the neonatal period with a chronic encephalopathy and later symptoms of diffuse hypotonia, neurodevelopmental impairment, and epilepsy. An important clue to the diagnosis in this otherwise nonspecific clinical pattern is the finding on brain MRI of T2 hyperintensity in the globus pallidus. Diagnosis rests on the finding of elevated urinary 4-hydroxybutyric acid, and is associated with high levels of GABA in CSF and urine. Treatment with vigabatrin, a selective inhibitor of GABA transaminase, has been suggested, though results are mixed [Pearl et al., 2009].

Glutaric Aciduria

Glutaric aciduria (GA) is an autosomal-recessive defect in degradation of 2-keto-adipic acid, a metabolite in lysine and tryptophan degradation pathways. The neonatal and early infantile presentation occurs in type I GA, which is due to glutaryl-CoA dehydrogenase deficiency. Affected infants have a chronic progressive encephalopathy of neonatal or early infantile onset with macrocephaly, hypotonia evolving to rigidity and dystonia, developmental regression, and epilepsy. There may be episodic decompensations with vomiting, ketotic hypoglycemia, acidosis, hyperammonemia, hepatomegaly, and depressed consciousness triggered by intercurrent illness. MRI abnormalities are distinguished by the finding of selective frontotemporal atrophy, especially involving subcortical white matter, with prominent extra-axial CSF collections, and in some cases subdural hemorrhage. Metabolic crises are associated with acute bilaterally symmetric striatal necrosis in a large proportion of these patients, leading to permanent neuromotor disability. Diagnosis rests on the finding of elevated urinary glutaric acid and 3-OH-glutaric acid, and confirmed if needed in equivocal cases by enzyme assay in cultured fibroblasts. Treatment involves dietary protein restriction, in particular l-lysine and tryptophan, and supplementation with l-carnitine and riboflavin. Timely supportive care with intravenous fluids and dextrose during intercurrent illness can minimize the risk of metabolic decompensations and striatal necrosis. Type II GA involves multiple acyl-CoA dehydrogenase deficiencies, which lead to elevations of multiple organic acids (glutaric, lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric). The clinical picture in the neonatal-onset form of type II GA is typically severe, with nonketotic hypoglycemia, metabolic acidosis, vomiting, depressed consciousness, and multi-organ dysfunction.

Congenital Disorders of Glycosylation

Congenital disorders of glycosylation (CDG) comprise a group of genetically determined metabolic diseases characterized by abnormalities in protein glycosylation, which is a cotranslational modification step in the synthesis of most secretory and membrane-bound proteins (see Chapter 35). The nervous system is prominently affected, in association with abnormalities in multiple other organ systems, including liver, kidney, heart, and bone [Haeuptle and Hennet, 2009]. Two main subgroups have been described: type I, involving defects in assembly of the oligosaccharide precursors; and type II’ involving processing of the oligosaccharide. CDG Ia is the most common and best described of these disorders, and has two types of presentations: a neurologic and a multisystem pattern. The neurologic presentation is one of chronic severe neurologic disability punctuated by episodic acute deterioration resembling stroke. There is usually prominent cerebellar dysfunction, with severe cerebellar atrophy detected on brain MRI. Usually normal at birth, some patients present with hypotonia and oculomotor abnormalities. Over time, patients display persisting ataxic hypotonic motor impairment and severe cognitive deficiency, retinopathy, epilepsy, acquired microcephaly, thromboembolic strokes, and weakness due to polyneuropathy. Associated non-neurologic findings include growth failure, protein-losing enteropathy, obstructive cardiomyopathy, nephrotic syndrome, deficient antithrombin III or protein C or S. Inverted nipples and subcutaneous fat pads are distinctive physical stigmata that may serve as clues to the disorder. Diagnosis is made by measuring transferrin isoelectric focusing using mass spectrometry, which may not become abnormal until the second or third week of life. Associated biochemical findings include elevated liver transaminases, low serum proteins, anemia, leukopenia, and low serum cholesterol. Treatment with high-dose mannose supplementation may ameliorate systemic symptoms, but the benefit for neurologic and neuromuscular manifestations is uncertain [Sparks and Krasnewich, 2009].

Peroxisomal Disorders

Peroxisomal disorders comprise a group of progressive neurologic diseases with variable age of onset and severity (see Chapter 38). Neonatal forms with prominent neurologic involvement include Zellweger’s syndrome and neonatal adrenoleukodystrophy, both of which are inherited as autosomal-recessive disorders [Steinberg et al., 2006]. Infants with classic Zellweger’s syndrome have multi-organ involvement with typical facial dysmorphic features, ocular anomalies (cataracts, glaucoma, pigmentary retinopathy), hepatic fibrosis, cystic kidney disease, subclinical adrenocortical insufficiency, and cardiac anomalies. Neurologic features include seizures, cranial nerve dysfunction, optic atrophy, and diffuse myopathic weakness. Survivors are multiply and profoundly handicapped. Neuroimaging and pathologic studies have revealed cortical and cerebellar migrational abnormalities and a central white matter demyelinating process. The pathogenesis relates to near-complete failure of peroxisomal function as a result of defective transport of proteins into the peroxisomal matrix. This results in defective oxidation and abnormal accumulation of very long chain fatty acids (VLCFAs), phytanic acid, pipecolic acids, and deficient synthesis of plasmalogens. The typical clinical features should suggest the diagnosis, which is supported by finding markedly elevated plasma VLCFA and decreased plasmalogen levels. Neonatal adrenoleukodystrophy resembles Zellweger’s syndrome in many respects, but is less severe. There are no proven definitive treatments. Trials are under way to evaluate strategies aimed at modifying lipid and fatty acid composition of the diet.

Cholesterol Biosynthesis Defects (Smith–Lemli–Opitz Syndrome)

The molecular defect in Smith–Lemli–Opitz syndrome was recently characterized as a disorder of cholesterol biosynthesis. This condition presents in the neonatal period with a constellation of multiple congenital anomalies and a chronic static encephalopathy [Herman, 2003]. Infants present with microcephaly, abnormal facies with ptosis and micrognathia, genital anomalies, and growth retardation. Less frequent abnormalities include cataracts, congenital heart defects, digital anomalies, and cleft palate. Neurologic features include hypotonia, sensorineural deafness, feeding and swallowing dysfunction, and severe cognitive deficiency. Cerebral malformations are common, including holoprosencephaly, agenesis of the corpus callosum, frontal hypoplasia, and cerebellar hypoplasia. Serum cholesterol is low in 90 percent of cases, but definitive diagnosis rests on finding elevated serum levels of 7- and 8-dehydrocholesterol measured by GC mass spectrometry. Treatment is supportive and symptomatic. Enteral supplements of cholesterol may mitigate some of the symptoms.