Overview

The neurotransmitter deficiency in infants in this group arises as a result of defects in BH₄ metabolism (Figure 39-1). Patients are usually identified by elevated phenylalanine levels on newborn screening, as BH₄ is required for phenylalanine hydroxylation in the liver. The accompanying neurotransmitter deficiency results from the lack of BH₄, an obligatory co-factor required for the synthesis of catecholamines and serotonin. Although most academic biochemical genetics clinics that monitor children with phenylketonuria systematically perform the additional studies required to diagnose this group of disorders, children occasionally are not identified until they have progressive neurologic symptoms or clear evidence of developmental delay despite a phenylalanine-restricted diet. In the past, these patients were referred to as atypical phenylketonurics. In some cases, such afflicted infants are overlooked because screening is performed before an adequate interval of protein intake, resulting in a false-negative result on newborn testing.

Fig. 39-1 Synthesis and catabolism of catecholamine and indoleamine neurotransmitters.

AADC, aromatic l-amino acid decarboxylase; B₆, pyridoxine; COMT, catechol O-methyltransferase; DBH, dopamine β-hydroxylase; DHPG, dihydrophenyl glycine; DHPR, dihydropteridine reductase; DOPAC, dihydroxyphenylacetic acid; EPI, epinephrine; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HTP, 5-hydroxytryptophan; GTPCH, guanosine triphosphate cyclohydrolase; HVA, homovanillic acid; MAO, monoamine oxidase; MHPG, methoxy 4 hydroxyphenylglycol; NE, neoepinephrine; NOS, nitric oxide synthase; PAH, phenylalanine hydroxylase; PCD, pterin-4α-carbinolamine dehydratase; PTS, 6-pyruvoyltetrahydropterin synthase; qBH2, quinonoid dihydropterin; SPR, sepiapterin reductase; TH, tyrosine hydroxylase; TPH, tryptophan hydroxylase; VMA, vanillylmandelic acid.

Approximately 1–3 percent of patients with hyperphenylalaninemia have an associated BH₄ deficiency state. It is critical to identify such children so that BH₄ and neurotransmitter precursors can be supplemented as early as possible. The two most commonly identified disorders in children presenting with hyperphenylalaninemia in the newborn period are 6-pyruvoyltetrahydropterin synthase deficiency, accounting for 60 percent of mutations in atypical phenylketonurics, and dihydropteridine reductase deficiency, affecting 30 percent of cases [Longo, 2009]. 6-Pyruvoyltetrahydropterin synthase deficiency results in inadequate BH₄ synthesis; dihydropteridine reductase deficiency results in decreased regeneration of BH₄ from dihydrobiopterin (see Figure 39-1). Both are autosomal-recessive disorders in which hyperphenylalaninemia results from a deficiency of BH₄. Because of the involvement of BH₄ in catecholamine and serotonin synthesis, such infants also have a manifest deficiency of neurotransmitter metabolites in addition to hyperphenylalaninemia. Other conditions in this category include autosomal-recessive guanosine triphosphate cyclohydrolase (GTPCH) deficiency and primapterinuria (Table 39-2).

Role of BH₄ in the Central Nervous System

Because BH₄ is required for the hydroxylation of aromatic amino acids, its importance in the central nervous system (CNS) becomes immediately apparent. Tyrosine and tryptophan are required for the synthesis of catecholamines and serotonin. A BH₄-dependent process can be strongly suspected when plasma phenylalanine levels return to normal after BH₄ supplementation. A dose of 5–10 mg/kg of BH₄ is the usual recommended dose for correction of peripheral hyperphenylalaninemia, and 10–20 mg/kg per day has been recently advocated in classic phenylketonuria. Because BH₄ crosses the blood–brain barrier poorly, lifelong supplementation with the neurotransmitter precursors l-DOPA and 5-hydroxytryptophan, along with carbidopa to prevent peripheral decarboxylation, is necessary in most of the disorders mentioned earlier. A much higher dose of BH₄, approximately 20 mg/kg, can return BH₄ levels in the cerebrospinal fluid to normal, but it remains prohibitively expensive, and no studies exist as to the possible additional benefit of such a regimen. Dosing can be monitored by assessing clinical response and periodically measuring cerebrospinal fluid levels of neurotransmitter metabolites [Hyland, 2007]. Verifying normalization of serum prolactin levels has been advocated, but sensitivity is limited, as is detection of overadministration of precursors [Concolino et al., 2008]. The greater requirement of tyrosine hydroxylase for BH₄ in comparison with tryptophan hydroxylase may explain the more severe impairment in the catecholaminergic system compared with the serotonergic system.

Nitric oxide synthase is yet another enzyme with an absolute requirement for BH₄ for the oxidation of arginine to nitric oxide. The inability to replete normal levels of BH₄ in the CNS with oral administration in its currently used doses may be one reason that many children with BH₄-deficient disorders develop lifelong cognitive and developmental impairments despite other treatments. Nitric oxide also plays a critical role in CNS injury and neuroprotective mechanisms, and reduced efficiency of this enzyme may result in an imbalance of neuronal injury and vascular dysregulation and repair.

6-Pyruvoyltetrahydropterin Synthase Deficiency

6-Pyruvoyltetrahydropterin synthase catalyzes the elimination of inorganic triphosphate from dihydroneopterin triphosphate to form 6-pyruvoyltetrahydropterin. Patients have elevated neopterin to biopterin ratios in urine and plasma. Reduced 6-pyruvoyltetrahydropterin synthase activity can be documented in red blood cells. In the classic form of the disorder, patients have reduced catecholamine and serotonin metabolites and an increased neopterin to biopterin level in cerebrospinal fluid. Patients are usually detected by newborn screening, as with phenylketonurics. They exhibit progressive signs of neurologic involvement in the first few months of life, including extrapyramidal signs, axial and truncal hypotonia, hypokinesia, feeding difficulties, choreoathetotic or dystonic limb movements, and autonomic symptoms. Many of these patients, despite early diagnosis and supplementation with BH₄ and neurotransmitter precursors, continue to manifest delay in development [Dudesek et al., 2001]. A “peripheral” form of the disorder is associated with nearly one-third of known mutations with the human PTS gene [Thony and Blau, 2006], and is characterized by normal central neurotransmitter levels and less significant or transient hyperphenylalaninemia [Niederwieser et al., 1987]. Patients with the peripheral form have an excellent prognosis for normal neurologic development, provided the hyperphenylalaninemia is corrected by diet or BH₄ administration.

Dihydropteridine Reductase Deficiency

Dihydropteridine reductase deficiency manifests in a variety of phenotypes, all with hyperphenylalaninemia. The clinical presentation is similar to that of central 6-pyruvoyltetrahydropterin synthase deficiency. Without folinic acid to restore methyltetrahydrofolate status in the CNS, these patients can have progressive calcification of the basal ganglia and subcortical regions, despite treatment with BH₄ and neurotransmitter precursors [Woody et al., 1989]. A juvenile variant has been reported in which siblings were developmentally normal until 6 years of age, at which time they developed progressive encephalopathy, epilepsy, and pyramidal, cerebellar, and extrapyramidal features on clinical examination [Larnaout et al., 1998]. Diagnosis can be confirmed by the pattern of urine pterins and documentation of abnormal dihydropteridine reductase activity in skin fibroblasts [Milstien et al., 1980]. Results of phenylalanine loading tests are abnormal, and phenylalanine status improves or returns to normal with BH₄ supplementation. Cerebrospinal fluid neurotransmitter and pterin analysis reveals reduced concentrations of homovanillic acid and 5-hydroxyindoleacetic acid, decreased or normal BH₄ levels, and elevated dihydrobiopterin levels.

Autosomal-Recessive Guanosine Triphosphate Cyclohydrolase Deficiency

Although most mutations in GTPCH to date have been documented in association with autosomal-dominant dopa-responsive dystonia, or Segawa’s disease, these patients do not have hyperphenylalaninemia on routine plasma screening studies. Patients with the autosomal-recessive form of GTPCH deficiency, however, present in a fashion similar to patients with dihydropteridine reductase deficiency and 6-pyruvoyltetrahydropterin synthase deficiency. Such patients have severe global developmental impairment, marked hypotonia of the trunk and axial muscles, eye movement abnormalities, limb hypertonia, and convulsions; autonomic symptoms include temperature dysregulation, excessive diaphoresis, and blood pressure lability caused by the associated catecholamine deficiency. They typically have absent GTPCH activity in blood cells, liver, and skin fibroblasts. By contrast, patients with autosomal-dominant dopa-responsive dystonia have preservation of some GTPCH activity in liver because of their heterozygous status, enough to maintain normal phenylalanine levels under usual circumstances. Cerebrospinal fluid neurotransmitter metabolite analysis reveals low concentrations of homovanillic acid and 5-hydroxyindoleacetic acid, and low neopterin and biopterin levels.

Pterin-4α-Carbinolamine Dehydratase Deficiency (Primapterinuria)

Pterin-4α-carbinolamine dehydratase deficiency, or primapterinuria, is a cause of mild hyperphenylalaninemia [Blau et al., 1988; Adler et al., 1992]. These infants are usually identified on newborn screening but generally have a benign course with normal development. Phenylalanine hydroxylase catalyzes the conversion of phenylalanine to tyrosine, during which BH₄ is converted to the unstable carbinolamine 4α-hydroxytetrahydrobiopterin [Citron et al., 1993]. Carbinolamine dehydratase catalyzes the dehydration of carbinolamine to quinonoid dihydropterin (qBH2). The decreased rate of dehydration is responsible for the production of 7-biopterin in some mildly hyperphenylalaninemic individuals [Thony et al., 1998]. Urine studies reveal an excess of 7-substituted pterins, reduced biopterin levels, and an increased neopterin to biopterin ratio.

Overview

Neurotransmitter deficiency disorders not associated with hyperphenylalaninemia span an increasingly complex spectrum of clinical phenotypes, ranging from ataxia and mental retardation to spastic diplegia to exercise-induced dystonia. The lack of ascertainment by way of newborn screening and increasingly broad phenotypic spectrum make these disorders as a group much more challenging to recognize. Other than autosomal-dominant dopa-responsive dystonia, the remaining disorders in this category are all inherited in an autosomal-recessive fashion with the exception of monoamine oxidase A deficiency, a rare X-linked recessive disorder. In general, heterozygous carriers for mutations in this group do not have a discernible phenotype, with rare exceptions in tyrosine hydroxylase deficiency and combined monoamine oxidase A and B deficiency.

Segawa’s Disease or Autosomal-Dominant Dopa-Responsive Dystonia

The best-described and most widely identified entity among this group of disorders is autosomal-dominant dopa-responsive dystonia caused by GTPCH deficiency, or Segawa’s disease [Segawa et al., 1976]. Identification and treatment of this disorder can be extremely rewarding because patients often benefit greatly from directed treatment of the associated dopamine deficiency state [Harwood et al., 1994]. Patients with a classic presentation of exercise-induced dystonia are not difficult to recognize. This diagnosis should also be considered in patients with spastic diplegia, especially when significant fluctuation in gait or worsening gait at the end of the day is noted, and in patients with more atypical presentations, including writer’s cramp, asymmetric limb dystonia, tremor, or restless leg-type symptoms. In patients with a classic presentation, many clinicians can make the diagnosis on a presumptive basis, after observing remission of symptoms with a trial of l-DOPA/carbidopa.

As of 2009 there are more than 85 known mutations of the GCH-1 gene, and in a large review of dopa-responsive dystonia, it was found that 60 percent are point mutations [Clot et al., 2009]. Although inheritance is autosomal-dominant, penetrance is incomplete, and variable expressivity among family members with the same mutation is well documented [Steinberger et al., 1998]. For instance, one might see spastic diplegia, writer’s cramp, restless leg syndrome, and more typical exercise-induced dystonia phenotypes among different members of the same family. The female to male ratio in sporadic cases is 4:1, and investigators have confirmed increased penetrance of GTPCH-I gene mutations in females [Ichinose et al., 1994; Furukawa et al., 1998]. Of note, a review of 47 patients with GCH-1 mutations or deletions found 40 patients manifested dystonic symptoms in the first decade of life [Clot et al., 2009].

Not surprisingly, mood and sleep disorders appear to be unusually prevalent in families with the disorder. Recent study of the neurologic and psychiatric phenotype of affected individuals within three extended families showed a higher frequency of major depressive disorder and obsessive-compulsive disorder, as well as disrupted sleep in 55 percent of patients [Van Hove et al., 2006]. These data help to support the idea that the disease carries an increased burden of attentional difficulties, anxiety, dysphoria, depression, and sleep disorders.

Cerebrospinal fluid neurotransmitter metabolite and pterin studies are helpful in confirming the diagnosis in these patients and can help characterize the degree of associated dopamine and serotonin deficiency. Phenylalanine loading is also valuable in confirming a suspected diagnosis but is not specific to the disorder, as phenylketonuria heterozygotes also manifest delayed phenylalanine clearance. GTPCH activity can be measured directly in skin fibroblasts. Urine pterin analysis serves as the first step in evaluation, with urine biopterin levels being low in autosomal-dominant GTPCH deficiency. Cerebrospinal fluid analysis should be performed before institution of a treatment trial of l-DOPA/carbidopa because treatment results in increased levels of homovanillic acid and 3-O-methyldopa. The typical pattern in cerebrospinal fluid in dopa-responsive dystonia resulting from GTPCH deficiency is a low homovanillic acid level, normal or low 5-hydroxyindoleacetic acid level, and reduced BH₄ level. Patients who are heterozygous for a GTPCH mutation, despite their normal blood phenylalanine levels on routine screening, have abnormal phenylalanine metabolism if they are stressed by administration of an oral phenylalanine load. If cytokine-stimulated fibroblast enzyme analysis of biopterin metabolism is not feasible or patients decline a cerebrospinal fluid examination and have an otherwise typical presentation, an oral phenylalanine loading test may be helpful in supporting the diagnosis. Phenylalanine is administered orally to the fasting patient at a dose of 100 mg/kg. Serum phenylalanine and tyrosine levels are obtained at baseline and 1, 2, and 4 hours after loading. An elevated phenylalanine to tyrosine ratio and delayed clearance of phenylalanine are typical in patients with GTPCH deficiency because BH₄ levels are typically reduced. Gene sequencing is available for confirmation of diagnosis, but has not yet supplanted biochemical studies as the diagnostic standard.

Treatment with l-DOPA/carbidopa leads to significant benefit or resolution of motor symptoms in the majority of patients with Segawa’s disease within a few weeks. However, compound heterozygotes or patients with long-standing or more severe motor manifestations, such as parkinsonism or long-standing spastic paraparesis, may require more careful titration of dosing, with gradual adjustment during a period of several months. Mood manifestations, such as depression and anxiety, often respond to l-DOPA treatment to some degree, but some patients have additional benefit from directed treatment of their associated serotonin deficiency, either with the serotonin precursor 5-hydroxytryptophan or with a serotonin reuptake inhibitor. Anecdotal evidence suggests that anticholinergic agents may also help ameliorate postural dystonia and tremor [Segawa et al., 1976].

Aromatic l-Amino Acid Decarboxylase or Dopa-Decarboxylase Deficiency

Aromatic l-amino acid decarboxylase is a pyridoxine-dependent enzyme that decarboxylates l-DOPA and 5-hydroxytryptophan to make dopamine and serotonin, respectively. Patients with this disorder typically present in the first few months of life with dystonia or intermittent limb spasticity, axial and truncal hypotonia, oculogyric crises, autonomic symptoms, and ptosis [Hyland et al., 1992]. Neonatal symptoms, including poor suck and feeding difficulties, ptosis, lethargy, and hypothermia, are common. Neurologic signs and symptoms are clearly evident within the first few months of life in all patients described to date. These patients demonstrate multisystemic involvement with a wide array of neurologic difficulties, including problems with sleep, attention, emotional regulation, and cognitive function that extend well beyond their motor difficulties. As they get older, gross motor delays with fluctuating tone, ataxia, and expressive speech impairment are prominent features, even in the patients with the best outcomes.

The phenomenology of the movement disorder is remarkably similar among the cases and, not surprisingly, shares a number of features in common with children with BH₄ deficiency disorders, such as 6-pyruvoyltetrahydropterin synthase deficiency and dihydropteridine reductase deficiency, and the autosomal-recessive form of GTPCH deficiency. Intermittent oculogyric crises and limb dystonia, generalized athetosis, and an overall paucity of voluntary movement become evident between 1 and 6 months of age. Tongue thrusting, ocular convergence spasm (Figure 39-2), myoclonic jerks, and episodes of sudden loss of head control or episodes resembling flexor spasms are common and frequently lead to a clinical diagnosis of epilepsy. Oculogyric crises, orofacial dystonia, torticollis, limb tremor with attempted voluntary movement, and blepharospasm are often the most compelling evidence supporting a defect in dopaminergic transmission. Breath-holding or apneic spells, paroxysmal sweating, nasal congestion, sudden respiratory or cardiorespiratory arrest, unresponsiveness associated with hypoglycemia, intermittent hypothermia, and feeding and gastrointestinal issues are manifestations of the often profound autonomic dysfunction these patients demonstrate [Swoboda et al., 2003]. First- and second-degree relatives of affected individuals have been shown to have a high incidence of psychiatric disorders, including depression, psychosis, suicide, or suicide attempts [Manegold et al., 2009].

Fig. 39-2 Episodic neurologic manifestations in aromatic l-amino acid decarboxylase deficiency.

A, Ocular convergence spasm, ptosis, and orofacial dystonia. B, Torticollis and limb dystonia. C, Torticollis and limb rigidity.

Cerebrospinal fluid neurotransmitter metabolites demonstrate a characteristic pattern: low homovanillic acid and 5-hydroxyindoleacetic acid levels; markedly elevated 3-O-methyldopa, 5-hydroxytryptophan, and l-DOPA; and normal biopterin and neopterin levels. Plasma l-DOPA is markedly elevated. Urine catecholamines may be reduced or elevated, specifically with vanillactic acid, despite normal preliminary organic acid results [Manegold et al., 2009; Abeling et al., 1998, 2000].

Although some children benefit in terms of the underlying movement disorder, treatment is complex, and these patients are vulnerable to an array of medication-related side effects. Instead of replacement of neurotransmitter precursors, as in the BH₄ deficiency-related disorders, the use of neurotransmitter receptor agonists or strategies to hinder reuptake or metabolism of endogenously produced neurotransmitters is necessary. Reported benefit has been noted in a subset of patients with monoamine oxidase inhibitors, dopamine receptor agonists, anticholinergic agents, pyridoxine, and, in rare cases associated with a defect in the gene encoding aromatic l-amino acid decarboxylase at the dopa-binding site, l-DOPA [Swoboda et al., 1999]. Dopamine receptor antagonists, such as clozapine, have been proposed as a new therapeutic option, given their increase in aromatic l-amino acid decarboxylase activity in a mouse model [Allen et al., 2009].

However, in spite of a variety of treatment interventions directed at ameliorating the effects of the associated neurotransmitter deficiency state, overall clinical outcomes in aromatic l-amino acid decarboxylase deficiency remain poor. All patients have had some degree of cognitive impairment, and there is increasing evidence of a gender-dependent discrepancy in severity, with females demonstrating the most severe phenotypes [Pons et al., 2004].

Sepiapterin Reductase Deficiency

Sepiapterin reductase catalyzes the (NADP) reduction of carbonyl derivatives, including pteridines, and plays an important role in BH₄ biosynthesis. Somewhat surprisingly, the first identified cases had normal plasma phenylalanine and urine pterin levels [Bonafe et al., 2001b]. Blau and colleagues have hypothesized that peripheral tissues can use alternative carbonyl, aldose, and dihydrofolate reductases to perform the last two steps in BH₄ biosynthesis. Therefore, BH₄ levels in the liver are likely to be normal, probably explaining the absence of hyperphenylalaninemia in these patients. In addition, it is likely that low dihydrofolate reductase activity in the brain allows accumulation of dihydrobiopterin that inhibits tyrosine and tryptophan hydroxylases and uncouples neuronal nitric oxide synthase, leading to neurotransmitter deficiency and neuronal cell death. Thus, identification of low cerebrospinal fluid neurotransmitter levels and the presence of elevated cerebrospinal fluid dihydrobiopterin is crucial for making the diagnosis in these patients.

Few patients have been described to date [Neville et al., 2005; Blau et al., 2001; Bonafe et al., 2001a]. Dystonic posturing, oculogyric crises, spasticity, tremor, ataxia, and psychiatric disturbances have been reported. The largest and most recent study reviewed clinical phenotypes in seven children, showing uniform early motor delay and diurnal variation in motor symptoms, with a high frequency of oculogyric crises, dystonia, and hypotonia [Neville et al., 2005]. All had cognitive delay to some extent, and some had parkinsonian symptoms and bulbar involvement. Also, in all cases, significant motor improvement resulted from low-dose l-DOPA/carbidopa therapy (range 1–6 mg/kg/day), although cognitive outcomes were not changed by therapy. In addition to l-DOPA/carbidopa therapy, there has been anecdotal improvement with the use of selegiline, a monoamine oxidase B inhibitor that prolongs the half-life of dopamine at the synapse. Cerebrospinal fluid neurotransmitter metabolite and pterin analysis reveals low levels of homovanillic acid and 5-hydroxyindoleacetic acid and high levels of biopterin, dihydrobiopterin, and sepiapterin. Diagnosis can be confirmed by documenting low sepiapterin reductase activity in skin fibroblast cultures.

Tyrosine Hydroxylase Deficiency or Autosomal-Recessive Dopa-Responsive Dystonia

Tyrosine hydroxylase deficiency, sometimes referred to as autosomal-recessive Segawa’s disease, displays a diverse phenotype ranging from exercise-induced dystonia to progressive gait disturbance and tremor in childhood to severe infantile parkinsonism [Bodeau-Pean et al., 1999; De Lonlay et al., 2000; de Rijk-Van Andel et al., 2000]. A wide range of symptoms can be associated with tyrosine hydroxylase deficiency, with mild, moderate, and severe phenotypes. In a large review of dopa-responsive dystonia, tyrosine hydroxylase defiency accounted for less than 5 percent of all cases [Clot et al., 2009].

In the mildest cases, walking or running may be clumsy, but little else may be noticed, at least initially. Abnormal posturing may be evident when the child is stressed or later in the day. These symptoms may progress slowly as the child gets older. Sometimes, one side of the body may seem weaker, or the child may begin to toe-walk because of hamstring or heel-cord tightness. Sometimes these children are diagnosed with cerebral palsy; other times, they are simply considered clumsy or uncoordinated. Some children demonstrate attentional difficulties or mild articulation disorders. Essentially, all children with mild symptoms are readily treated with medication.

In moderately affected cases, children demonstrate an abnormal gait. Children may demonstrate dystonic posturing while walking or with attempts to walk on their heels or toes. Some children are ataxic or have significant spasticity. Speech delay may be present. Many of these children are diagnosed with cerebral palsy. Some demonstrate involuntary eye movement problems, characterized either by brief upward eye-rolling movements when they are fatigued or stressed, or by frank oculogyric crises. The majority of these children have an excellent response to treatment, but full benefit may take many months.

In the most severe cases, children are severely disabled and affected from early infancy. This is referred to as the infantile Parkinson’s disease variant. Infants may demonstrate muscle tightness and rigidity, arching, tremor and poor muscle control, and involuntary eye movements. They may have ptosis. They usually have speech delay and often demonstrate difficulties in feeding, chewing, or swallowing. Constipation is common. Whereas most children tend toward increased muscle tone and even rigidity, there are children who have generalized low muscle tone, with poor head control and inability to sit unsupported. They often demonstrate torticollis. They may have difficulty directing their hands to a toy, generating a flinging hand motion. Occasionally, children suffer from intermittent color changes, unexplained low body temperature or fevers, low blood glucose level, and difficulty regulating blood pressure. These symptoms are more likely to occur during another illness the child may be experiencing. Children in the more severely affected group of patients are more difficult to treat, and several medications may be needed to modulate symptoms. They are unusually vulnerable to side effects of dopaminergic agonists or precursors, which can result in excessive movement and irritability. Response may be slow, with some continued benefit during months to years, but it may not result in the complete resolution of all symptoms. Some children have had persistent mental retardation, encephalopathy, and motor disability in spite of directed treatment of their underlying dopamine deficiency state.

Low tyrosine hydroxylase activity results in significant cerebrospinal fluid catecholamine deficiency, as demonstrated by low homovanillic acid concentrations; cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid, neopterin, and biopterin are normal. It is more difficult to distinguish these children from those with secondary neurotransmitter deficiency states because phenylalanine loading studies are normal, and enzymatic assays for confirmation of a suspected diagnosis are not presently available. Confirmation by molecular testing is extremely helpful, particularly in providing adequate counseling for parents about recurrence risks with future pregnancies. Children have a paucity of autonomic features, suggesting a compensatory peripheral mechanism, except in children with the severe infantile parkinsonism variant. In four patients whom the author has observed, including one patient with the severe infantile parkinsonism variant, peripheral plasma catecholamine levels have been normal, although reduced urine homovanillic acid levels have been noted. Caution should be taken to monitor blood glucose concentration in the setting of prolonged fasting, such as before a magnetic resonance imaging (MRI) study.

Patients variably respond to l-DOPA/carbidopa, and some have complete reversal of symptoms. The exception to this is the patient with the severe infantile parkinsonism form. These patients sometimes tolerate l-DOPA poorly, with excessive dyskinesia, irritability, and reflux, or have incomplete or inadequate response with regard to their motor manifestations of the disorder [Brautigam et al., 1999; Dionisi-Vici et al., 2000]. When diagnosis occurs late in such patients, motor development must be recapitulated, and continued slow improvement during months is to be expected. Typical features in infants affected by the severe infantile parkinsonism variant include rigidity, tremor, bradykinesia, oculogyric crises, and severe psychomotor delay.

Treatment with l-DOPA/carbidopa alone may lead to severe dyskinesias with marked on-off effects in such patients. Addition of dopamine agonists such as selegiline or anticholinergic agents like trihexyphenidyl can provide significant benefit and help promote the gradual on-going attainment of motor skills and ability to ambulate independently, but such achievements may occur over years, rather than months or weeks, in the most severely affected patients. Whereas more mildly affected patients may tolerate 1–3 mg/kg of l-DOPA per dose, 2–4 times per day, severely affected infants and younger children require l-DOPA quantities as low as 0.2 mg/kg/dose. Breaking standard formulations of l-DOPA/carbidopa into more than two doses per tablet is not advisable because the amount of carbidopa will then be insufficient to help enhance transport of l-DOPA across the blood–brain barrier and to minimize peripheral side effects, such as nausea, reflux, decreased appetite, and vomiting. Carbidopa should be maintained at a minimum of approximately 1 mg/kg/dose up to 25 mg per dose, no matter the l-DOPA requirement. Slow institution of small, compounded doses of l-DOPA/carbidopa, along with selegiline (monoamine oxidase B inhibitor) and an anticholinergic agent such as trihexyphenidyl, may be more beneficial than l-DOPA/carbidopa alone [Haussler et al., 2001]. Selegiline doses may also require compounding because low-dose formulations are not available for use in infants. Frequent side effects of excessive dosing include eating disorders, nightmares, and insomnia. Dosing should be started in the range of 0.1 mg/kg and increased as tolerated. Patients with a mild form of the disorder, such as an isolated gait disorder or exercise-induced dystonia, respond well to monotherapy with l-DOPA/carbidopa and rarely develop dyskinesia.

Although inheritance to date in most families seems to be recessive, at least one family has been described in which the father of the affected proband had mild exercise-induced dystonia responsive to therapy, raising the possibility that tyrosine hydroxylase deficiency could present in an autosomal-dominant fashion in some families with a milder phenotype [Furukawa et al., 2001].

Tryptophan Hydroxylase Deficiency

Tryptophan hydroxylase catalyzes the BH₄-dependent hydroxylation of tryptophan to 5-hydroxytryptophan, which is then decarboxylated to form serotonin. Tryptophan hydroxylase expression is limited to certain cells in the CNS and periphery, including raphe neurons, pinealocytes, mast cells, mononuclear leukocytes, beta cells of the islets of Langerhans, and enterochromaffin cells of the gut. Patients with presumed tryptophan hydroxylase deficiency have been described, although it is not yet certain that their symptoms result from tryptophan hydroxylase deficiency [Raemaekers et al., 2001]. Clinical features, consisting of ataxia, speech delay, mild psychomotor retardation, and hypotonia, are nonspecific. Cerebrospinal fluid neurotransmitter metabolite and pterin studies demonstrate the expected low 5-hydroxyindoleacetic acid with normal homovanillic acid, neopterin, and biopterin levels. Mutations in the gene encoding tryptophan hydroxylase have not yet been identified, although identification of isoforms specific to nervous tissue will likely facilitate future research [Invernizzi, 2007].

Dopamine β-Hydroxylase Deficiency

Dopamine β-hydroxylase is the enzyme that converts dopamine to norepinephrine. Presenting symptoms of this disorder have been largely attributed to the importance of this enzyme in postganglionic sympathetic neurons [Robertson et al., 1986]. Patients with severe deficiency of this enzyme, however, cannot synthesize norepinephrine, epinephrine, and octopamine in CNS or peripheral autonomic neurons. Dopamine acts as a false neurotransmitter for noradrenergic neurons. Neonates with dopamine β-hydroxylase deficiency can have episodic hypothermia, hypoglycemia, and hypotension, leading to early death. Survivors do fairly well until late childhood, when overwhelming orthostatic hypotension profoundly limits their activities. The hypotension can be so severe as to lead to convulsive syncope with recurrent clonic seizures [Robertson et al., 1991].

Most patients have been identified as young adults. Observation of severe orthostatic hypotension in a patient whose plasma norepinephrine/dopamine ratio is much less than 1 supports the diagnosis. Orthostatic hypotension, particularly after exercise, and ptosis are constant features. General lethargy and lassitude improve dramatically and blood pressure becomes normal with treatment with d,l-threo-dihydroxyphenylserine, a synthetic amino acid that is converted to norepinephrine by aromatic l-amino acid decarboxylase. Whether these patients suffer from attention problems or other subtle cognitive deficits has not been adequately studied. Patients may undergo personality change, becoming more “aggressive” with treatment.

Monoamine Oxidase Deficiency

Monoamine oxidase is a mitochondrial enzyme involved in the catabolism of biogenic amines. Monoamine oxidase A, the primary type in fibroblasts, preferentially degrades serotonin and norepinephrine. Monoamine oxidase B, the primary type in platelets and in the brain, preferentially degrades phenylethylamine and benzylamine. These enzymes are critical in the neuronal metabolism of catecholamine and indoleamine neurotransmitters. The genes are closely linked on the X chromosome, near the Norrie’s disease locus, and only affected boys have been identified to date [Schuback et al., 1999]. Comparisons of the neurochemical characteristics of previously described patients with combined monoamine oxidase A and B deficiency and selective monoamine oxidase A deficiency have led to an improved understanding of the roles of monoamine oxidase A and monoamine oxidase B in the metabolic degradation of catecholamines and other biogenic amines, including serotonin and the trace amines.

Gamma-Aminobutyric Acid Transaminase Deficiency

GABA is the major inhibitory neurotransmitter of the brain, derived primarily from glutamate, the major excitatory neurotransmitter. The first step of the GABA degradation pathway involves GABA transaminase, which removes an amino group from GABA and adds it to alpha-ketoglutarate, thus replenishing glutamate and re-establishing the closed loop system known as the GABA shunt. GABA transaminase deficiency is a rare, autosomal-recessive disorder characterized by abnormal development, seizures, and high levels of GABA in serum and cerebrospinal fluid [Pearl and Gibson, 2004]. Publications to date have presented limited family and case studies, all of which have had poor outcomes. Definitive diagnosis can be made by measurement of GABA transaminase activity in liver, lymphocytes isolated from whole blood, or Epstein–Barr virus-transformed cultured lymphocytes [Gibson et al., 1985].

Succinic Semialdehyde Dehydrogenase Deficiency

Succinic semialdehyde dehydrogenase deficiency is an autosomal-recessive inborn error of metabolism associated with a defect in the metabolism of GABA [Gibson et al., 1998]. Phenotypic features range from nonspecific global developmental delay and hypotonia to ataxia, severe mental retardation, visual impairment, and seizures. The course of the disease is somewhat unique in regard to other neurotransmitter abnormalities in that it is not intermittent or episodic, making distinction from static encephalopathies challenging [Pearl et al., 2009]. Neuropsychiatric symptoms are prominent and include sleep disorders, inattention, hyperactivity, and anxiety [Pearl et al., 2009]. Generalized epilepsy affects nearly half of patients, with over half having abnormal electroencephalograms (EEGs) [Pearl et al., 2009]. MRI is commonly abnormal in patients with succinic semialdehyde dehydrogenase deficiency, with increased T2-weighted signal in the globus pallidi, subcortical white matter, cerebellar dentate nucleus, and brainstem [Pearl et al., 2009].

Urine organic acid screening to detect elevated 4-hydroxybutyric acid is the most easily available screening strategy, but GABA levels in cerebrospinal fluid and urine are also elevated. Improvement of seizures in a mouse model of the disorder was demonstrated with treatment with vigabatrin or a GABA B receptor antagonist [Hogema et al., 2001]. Unfortunately, this medicine has not been consistently helpful in humans and there is considerable risk involved with its administration. Investigations into other potential therapies, including taurine, the ketogenic diet, and GABA B receptor antagonists is currently under way in mouse models [Pearl et al., 2009].

Glycine Encephalopathy

Glycine encephalopathy, formerly referred to as nonketotic hyperglycinemia, is a heterogeneous disorder associated with insufficient activity of various components of the mitochondrial glycine cleavage system. The enzyme system for cleavage of glycine is composed of four protein components: P protein, a pyridoxal phosphate-dependent glycine decarboxylase; H protein, a lipoic acid-containing protein; T protein, a tetrahydrofolate-requiring enzyme; and L protein, a lipoamide dehydrogenase. Nonketotic hyperglycinemia may be caused by a defect in any one of these enzymes. It is an autosomal-recessive disorder with several reported phenotypes, including the classic severe neonatal form, an infantile variant, a mild-episodic childhood variant, a late-onset form, and a benign reversible form [Hamosh and Johnston, 2001].

Most patients described to date have the neonatal and most severe phenotype, likely because it is the most distinctive phenotype. These patients present shortly after birth with lethargy, encephalopathy, hypotonia, myoclonic jerks, and apnea. EEG generally reveals a burst-suppression pattern. Those who survive the neonatal period generally develop intractable seizures and profound mental retardation. Patients with the infantile form have seizures and variable cognitive impairment after a short period of apparently normal development. In the mild-episodic form, patients typically present some time after infancy with mild psychomotor retardation, and may manifest episodes of delirium, chorea, and vertical gaze palsy during febrile illness. In the late-onset form, children present with progressive spastic diplegia and optic atrophy. They generally do not have seizures, and intellectual function is preserved.

Diagnosis is best made by documenting an increased cerebrospinal fluid to plasma glycine ratio [Applegarth and Toone, 2001]. In the neonatal form of nonketotic hyperglycinemia, cerebrospinal fluid glycine level can be 30 times normal. Plasma glycine level is also typically high, but it can be in the normal range. A cerebrospinal fluid to plasma ratio above 0.08 is usually considered diagnostic, but mildly affected cases can have ratios of 0.04–0.1 [Applegarth and Toone, 2001]. (In rare cases, cerebrospinal fluid to plasma ratios are normal, and only elevations in plasma glycine occur [Jackson et al., 1999].) Confirmation of diagnosis requires enzyme analysis in liver or transformed lymphoblasts [Christodoulou et al., 1993]. Treatment with dextromethorphan and sodium benzoate has led to variable improvement in seizure control and behavioral problems in some patients [Boneh et al., 1996; Hamosh et al., 1998].

Leukoencephalopathy with Vanishing White Matter

Leukoencephalopathy with vanishing white matter (also known as childhood ataxia with central white matter hypomyelinization) is a heterogeneous autosomal-recessive leukodystrophy characterized by progressive ataxia, motor impairment, and encephalopathy, in which episodic deterioration is associated with infection or minor head trauma [van der Knaap et al., 1997]. A wide range of onset has been reported in the dozen patients described to date. Cerebrospinal fluid glycine is elevated and can be helpful in confirming the diagnosis [van der Knaap et al., 1999]. At least two genes have been noted to have mutations in patients with this disorder: EIF2B5 and EIF2B2, the first translation initiation factors implicated in human disease [Leegwater et al., 2001]. This disorder is described in more detail in Chapter 71.