PNDs with Normal Phenylalanine Levels

PNDs with Normal Phenylalanine Levels

Neurotransmitter deficiency disorders with normal blood phenylalanine levels 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 makes 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 MAO-A deficiency, a rare X-linked recessive disorder. Generally, heterozygous carriers for mutations in this latter group do not have a discernable phenotype, with rare exceptions in tyrosine hydroxylase deficiency and combined MAO-A and -B deficiency.

Segawa's SyndromeTH DeficiencyAADCSPR DeficiencyOther Rare, Specific Disorders

Autosomal Dominant Dopa-Responsive Dystonia (Segawa’s Syndrome)

The most well described and widely identified entity among this group of disorders is autosomal dominant dopa-responsive dystonia, caused by GTP cyclohydrolase deficiency, or Segawa’s disease. Identification and treatment of this disorder can be extremely rewarding because patients often benefit greatly with directed treatment of the associated dopamine deficiency state. 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.

Although inheritance is autosomal dominant, penetrance is incomplete and variable expressivity among family members with the same mutation are well-documented. 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 mutations in females.

Not surprisingly, mood and sleep disorders appear to be unusually prevalent in families with the disorder, although these issues have not been systematically studied. However, preliminary data in an ongoing study of prospectively ascertained family members supports an increased burden of attentional difficulties, anxiety, dysphoria, depression and sleep disorders. CSF 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 PKU heterozygotes also manifest delayed phenylalanine clearance. GTPCH activity can be measured directly in skin fibroblasts. CSF analysis should be performed before institution of a treatment trial of L-dopa/carbidopa, because treatment results in increased levels of HVA and 3-O-methyldopa.

The typical pattern in CSF in dopa-responsive dystonia due to GTPCH deficiency is a low HVA level, normal or low 5-HIAA level and reduced BH4 levels in CSF. Patients who are heterozygous for a GTPCH mutation, despite their normal blood phenylalanine levels on routine screening, can be shown to have abnormal phenylalanine metabolism if stressed by administration of an oral phenylalanine load (100 mg/kg). Therefore, if cytokine stimulated fibroblast enzyme analysis of biopterin metabolism is not feasible or patients decline a CSF examination and have an otherwise typical presentation, an oral phenylalanine load, with serial serum phenylalanine levels over the following four to six hours, can help confirm the clinical diagnosis. Gene sequencing is available for confirmation of diagnosis and may be a valuable adjunct to biochemical diagnostic studies, but will miss gene deletions, which are fairly common in this disorder.

Treatment with L-dopa/carbidopa leads to significant benefit or resolution of motor symptoms in the large majority of patients with Segawa’s disease within a few weeks’ time. However, compound heterozygotes or patients with longstanding or more severe motor manifestations, such as Parkinsonism or longstanding spastic paraparesis, may require more careful titration of dosing, with gradual adjustment over a period of several months. Mood manifestations such as depression or 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-HTP or a serotonin reuptake inhibitor.

Tyrosine Hydroxylase (TH) Deficiency

Facial DyskinesiaTyrosine 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. A wide range of symptoms can be associated with TH deficiency, associated with mild, moderate and severe phenotypes.

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 due to 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 speech articulation difficulties or delay. Children with mild symptoms generally respond quite well to treatment with medication.

In moderately affected cases, children demonstrate an abnormal gait (an abnormal walking pattern). Children may demonstrate dystonic posturing (involuntary twisting arm or foot movements) while walking, especially when attempting to walk on their heels or toes. Some children are uncoordinated or have poor balance or have tight leg muscles (referred to in medical terms as 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 tired or stressed or Frank oculogyric crises, where the eyes roll up and seem to get “stuck” for variable periods of time. The majority of these children have an excellent response to treatment, but full benefit may take many months and close monitoring for adjustment of medications and dosing.

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 feeding, chewing or swallowing. Constipation is common. While 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. Oftentimes they demonstrate torticollis. They may have difficulty directing their hands to a toy, generating a flinging hand motion. Occasional children suffer from intermittent color changes, unexplained low body temperature or fevers, low blood sugar 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 over months to years, but 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 CSF catecholamine deficiency as demonstrated by low HVA concentrations; CSF concentrations of 5-HIAA, neopterin and biopterin are normal. It is more difficult to distinguish these children from secondary neurotransmitter deficiency states, since phenylalanine loading studies are normal, and enzymatic assays for confirmation of a suspected diagnosis are not presently available. Thus, confirmation via molecular testing is extremely helpful, particularly in providing adequate counseling for parents regarding recurrence risks with future pregnancies. Children reported to date seem to have a paucity of autonomic features, suggesting a compensatory peripheral mechanism. In four patients that we have observed, including one patient with the severe infantile Parkinsonism variant, peripheral plasma catecholamine levels have been normal, although reduced urine HVA levels have been noted.

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, reflux or have incomplete or inadequate response with regard to their motor manifestations of the disorder. Slow institution of small doses of L-dopa/carbidopa, along with selegiline (MAO-B inhibitor) and an anticholinergic agent such as trihexyphenidyl, may be more beneficial than L-dopa/carbidopa alone. When diagnosis occurs late in such patients, motor development must be recapitulated, and continued slow improvement over months is to be expected. Typical features in the one infant affected by the severe infantile Parkinsonism variant included 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 ongoing 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. 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/carbide 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.

Download A Parents’ Guide to TH Deficiency

Aromatic L-amino Acid Decarboxylase (AADC)

Uliano ConvergenceAromatic L-amino acid decarboxylase is a pyridoxine dependent enzyme that decarboxylates L-dopa and 5-HTP 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. (See references page, 15). 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 reported to date. These patients demonstrate multi-systemic 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 PTS and DHPR deficiency and the autosomal recessive form of GTP cyclohydrolase deficiency. Intermittent oculogyric crises and limb dystonia, generalized athetosis and an overall paucity of voluntary movement become evident between one to six months of age. Tongue thrusting, ocular convergence spasm, 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.

While some children have demonstrated 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 AADC gene at the dopa-binding site, L-dopa. (See references page, 19.) However, in spite of a variety of treatment interventions directed at ameliorating the effects of the associated neurotransmitter deficiency state, overall clinical outcomes in AADC deficiency remains poor.
All patients reported to date 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.

Sepiapterin Reductase (SPR) Deficiency

episodic ocular abnormalitiSepiapterin reductase catalyzes the NADPH-dependent 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. Blau and others 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 nitric oxide synthase (nNOS), leading to neurotransmitter deficiency and neuronal cell death. Thus, identification of low CSF neurotransmitter levels and the presence of elevated CSF dihyrobiopterin is crucial for making the diagnosis in these patients.

Few patients have been reported to date. Dystonic posturing, oculogyric crises, spasticity, tremor and ataxia with recurrent falls were reported in one 9-year-old boy. He also had a depressed affect, aggressive behavior and psychomotor retardation. Another child had psychomotor retardation, microcephaly, growth deficiency, spasticity and dystonia. Blau and others recently confirmed this diagnosis in a 22-year-old woman with cerebral palsy and lifelong cognitive impairment and a gait disorder, who had been having increasing difficulties with head control, excessive fatigue and dystonia, with associated Parkinsonian features including gait instability, hypophonia and pallilalia. She had significant diurnal variation of symptoms, with symptoms much worse in the evenings. She benefited greatly with supplemental 5-hydroxytryptophan (HTP) and L-dopa/carbidopa but later discontinued both due to side effects. She remains on treatment with selegeline, an MAO-B inhibitor which prolongs half-life of dopamine at the synapse.

CSF neurotransmitter metabolite and pterin analysis reveals low levels of HVA and 5-HIAA, and high levels of biopterin and dihydrobiopterin. Diagnosis can be confirmed by documenting low SPR activity in skin fibroblast cultures.

Tryptophan hydroxylase deficiency

Tryptophan hydroxylase (TPH) catalyzes the BH4-dependent hydroxylation of tryptophan to 5-HTP, which is then decarboxylated to form serotonin. TPH 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 TPH deficiency have recently been reported, although it is not yet certain that their symptoms result from TPH deficiency. (See references, 31.) Clinical features, consisting of ataxia, speech delay, mild psychomotor retardation and hypotonia, are nonspecific. CSF neurotransmitter metabolite and pterin studies demonstrate the expected low 5-HIAA with normal HVA, neopterin and biopterin levels. Mutations in the TPH gene have not yet been identified.

Dopamine beta-hydroxylase deficiency

Dopamine beta-hydroxylase (DBH) 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. Patients with severe deficiency of this enzyme, however, cannot synthesize norepinephrine, epinephrine and octopamine in either the CNS or the peripheral autonomic neurons. Dopamine acts as a false neurotransmitter for noradrenergic neurons. Neonates with DBH deficiency can have episodic hypothermia, hypoglycemia and hypotension, but survivors then 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.

Most patients reported to date have been identified as young adults. Observation of severe orthostatic hypotension in a patient whose plasma norepinephrine/dopamine ratio is much less than one supports the diagnosis. Orthostatic hypotension, particularly after exercise, and ptosis are constant features. General lethargy and lassitude improve dramatically and blood pressure normalizes with treatment with d-l-threo-dihydroxyphenylserine, a synthetic amino acid that is converted to norepinephrine by aromatic L-amino acid decarboxylase. Whether or not 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 (MAO-A), the primary type in fibroblasts, preferentially degrades serotonin and norepinephrine. Monoamine oxidase B (MAO-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 disease locus, and only affected boys have been identified to date. Comparisons of the neurochemical characteristics of previously described patients with combined MAO-A and MAO-B deficiency and selective MAO-A deficiency have led to an improved understanding of the roles of MAO-A and MAO-B in the metabolic degradation of catecholamines and other biogenic amines, including serotonin and the trace amines.

Monoamine oxidase A deficiency

Brunner reported a family with an X-linked nondysmorphic mild mental retardation and a tendency to aggressive or violent behavior including arson, attempted rape, exhibitionism and attempted suicide. Urine studies revealed marked disturbance of monoamine metabolism. Normal platelet MAO-B activity suggested that the unusual behavior pattern in this family might be caused by isolated MAO-A deficiency, which was later confirmed by identification in all affected males of a point mutation leading to premature termination of the protein.

Measurement of MHPG (3-methoxy, 4-hydroxyphenolglycol, a metabolite of norepinephrine) in plasma is the most sensitive index of MAO-A activity in humans and can be used to screen potential cases. MAO-A enzyme activity can be measured directly from fibroblasts, however. The inability to identify additional patients despite screening in at-risk males with a mental retardation or behavioral phenotype makes it likely this disorder is rare. (See references, 10.) Interestingly, a high activity MAO-A promoter allele has been found with increased frequency in women with panic disorder. A possible association of decreased enzyme activity in women with bipolar disorder has also been reported.

Monoamine oxidase B deficiency

Isolated MAO-B deficiency has not yet been reported in a patient. Two brothers with a microdeletion including the Norrie locus and MAO-B, however, had features consistent with Norrie disease alone, with congenital blindness and progressive hearing loss caused by cochlear degeneration in adolescence. These patients had neither abnormal behavior nor mental retardation, leading us to conclude that MAO-A plays a more significant role than MAO-B in the metabolism of biogenic amines and MAO-B deficiency alone may have a primarily neurochemical phenotype: that of increased phenylethylamine in urine.

Monoamine oxidase A and B deficiency

Conclusions regarding the phenotype of individuals with combined deficiency of MAO-A and MAO-B come primarily from a study of a single boy with a microdeletion at Xp14 involving the Norrie locus and documented severe deficiency of MAO-A and MAO-B activity. He was severely mentally retarded, blind and had other neurologic features including myoclonus and tendency for motor stereotypies. Because Norrie disease is an X-linked recessive disorder, obligate carriers would not be expected to have symptoms. In this family, two obligate carriers had normal IQ testing. The proband’s mother had psychiatric symptoms characterized by “chronic hypomania and schizotypal features,” however, and both carriers had low MAO activity.

Succinic semialdehyde dehydrogenase deficiency

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive inborn error of metabolism associated with a defect in the metabolism of 4-gamma-aminobutyric acid or GABA. Phenotypic features range from nonspecific global developmental delay and hypotonia to ataxia, severe mental retardation, visual impairment and seizures. Urine organic acid screening to detect elevated 4-hydroxybutyric acid is the most easily available screening strategy, but GABA levels in CSF and urine are also elevated. Recently, improvement of seizures in a mouse model of the disorder was demonstrated with treatment with vigabatrin or a GABA B receptor antagonist. The relevance of these findings to treatment of patients, if any, is not yet known.