Carnitine palmitoyltransferase II deficiency
Jul. 15, 2022
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Aromatic L-amino acid decarboxylase (AADC) deficiency was identified as an autosomal recessively inherited disorder of biogenic amine metabolism resulting in combined generalized deficiency of serotonin and all catecholamines. The main clinical features typically present in infancy developmental delay, hypokinesia, truncal muscular hypotonia, often combined with limb rigidity, a progressive extrapyramidal movement disorder, especially parkinsonism-dystonia and chorea, oculogyric crises, as well as autonomic symptoms, sleeping difficulties, and irritability. Because the products of the defective enzyme, serotonin and dopamine, cannot pass through the blood-brain barrier, aromatic L-amino acid decarboxylase deficiency is 1 of the most difficult neurotransmitter disorders to treat. Adeno-associated virus vector-mediated gene delivery of the dopa decarboxylase (DCC) gene bilaterally into the putamen or to the substantia nigra plus the ventral tegmental area demonstrated safety and efficacy in first affected children. Three further clinical trials of gene therapy confirmed the promising results. It is to be hoped that with early detection by newborn screening and followed by optimized therapy (ie, gene therapy), the outlook of this often-devastating disorder will be changed.
The International Working Group on Neurotransmitter related Disorders has been instrumental in these positive developments with the first international, longitudinal patient registry and evidence-based guidelines for diagnosis and treatment (http://www.intd-online.org).
An international support group, the AADC Research Trust Children’s Charity, a nonprofit organization, has also been instrumental in helping to provide information and linking families and professionals involved in diagnosis, care, and research. The association’s board of directors and medical and scientific advisory board reviews contents, resources, and medical information posted on the website located at http://www.aadcresearch.org.
• Aromatic L-amino acid decarboxylase deficiency presents with severe autonomic developmental and neurologic dysfunction. It should be considered in infants and children with features suggestive of dystonic or athetoid cerebral palsy, hypotonia, developmental delay, and autonomic symptoms of unknown etiology.
• Aromatic L-amino acid decarboxylase deficiency leads to severe deficiency of serotonin as well as all catecholamines.
• Diagnosis relies on the measurement of neurotransmitters in CSF.
• Aromatic L-amino acid decarboxylase deficiency is inherited in an autosomal recessive manner, and some genotype-phenotype correlations have been described.
• Gene therapy is showing promising results.
For many years, disorders leading to severe deficiencies of biogenic amines (serotonin, dopamine, epinephrine, and norepinephrine) in infants and children were exclusively associated with biochemical defects of tetrahydrobiopterin metabolism (37). Tetrahydrobiopterin is the cofactor for tyrosine hydroxylase and tryptophan hydroxylase, the rate-limiting enzymes required for dopamine and serotonin biosynthesis. Fortunately, children with these disorders are often detected early because tetrahydrobiopterin is also the cofactor for phenylalanine hydroxylase, which causes hyperphenylalaninemia and is detected in newborn screening programs. The next step in the biosynthesis is decarboxylation by aromatic L-amino acid decarboxylase encoded by the DDC gene. Autosomal recessively inherited mutations in the DDC gene impair the synthesis of both serotonin and the catecholamines. Over 80 different pathogenic mutations have been published: http://www.biopku.org.
In 1988, monozygotic twins presented at the Hospital for Sick Children, Great Ormond Street, London, with the neurologic symptoms of biogenic amine deficiency, reminiscent of defects of tetrahydrobiopterin metabolism. Central and peripheral neurotransmitter deficiency was confirmed, but the children were not hyperphenylalaninemic, nor did they have any abnormality of tetrahydrobiopterin metabolism. The step after tyrosine hydroxylase and tryptophan hydroxylase in the biosynthetic pathway for dopamine and serotonin is common to both pathways and involves the vitamin B6 (pyridoxal 5’-phosphate) dependent decarboxylation of levodopa and 5-hydroxytryptophan to form dopamine and serotonin, respectively. These reactions are catalyzed by a single enzyme, aromatic L-amino acid decarboxylase (29). This enzyme is often named according to the substrate being metabolized (ie, levodopa decarboxylase or 5-hydroxytryptophan decarboxylase). Confirmation of a deficiency of the enzyme in the twins was established by measurement of levodopa decarboxylase activity in plasma and levodopa and 5-hydroxytryptophan decarboxylase activity in liver biopsy (21; 23).
Since the initial description of aromatic L-amino acid decarboxylase deficiency, about 200 cases have been tabulated in a database of pediatric neurotransmitter disorders (http://www.biopku.org) (17; 09), and several reviews have been published (31; 09; 18; 38). Additional patients are known, and it is most likely that many more cases exist, but diagnosis has not been made because of the absence of easily recognized markers in metabolic evaluations.
The original description of the twins (21) encompasses most of the clinical features of this disease, with signs being virtually identical in many other reported cases (30; 40; 31; 18). For detailed description, see the clinical vignette section. Summaries of the clinical features in about 150 individuals with the disorder have been published (09; 36; 38). Patients typically show muscular hypotonia, poor sucking, feeding difficulties, and a tendency to hypoglycemia from birth. In the first few months of life, symptoms of dystonia or intermittent limb spasticity, axial and truncal hypotonia, extreme irritability, oculogyric crises, and psychomotor retardation develop. Head control is poor in infancy. Progressive neurologic dysfunction, especially extrapyramidal movement disorders comprising parkinsonism-dystonia, occurs in early childhood. Dystonia may be accompanied by athetosis or chorea. Eye fixation is poor. Voluntary movements are difficult. Physical examination may reveal brisk knee reflexes and extensor plantar responses. Speech is dysarthric and difficult. Associated features are sleep disturbances, labile temperature regulation, autonomic dysfunction, nasal congestion, irritability, and cognitive impairment.
Along with ptosis, miosis, and paroxysmal sweating, other autonomic symptoms in aromatic L-amino acid decarboxylase deficiency include chronic nasal congestion, temperature instability, hypotension, hypersalivation, and especially complex feeding difficulties related to disturbed intestinal motility, reflux, diarrhea, and constipation. One patient was not diagnosed until 15 years of age, with chronic diarrhea being his most prominent symptom resulting in dehydration and malnutrition (27). Patients may have difficulty swallowing or eating. This can be so severe that gastrostomy is necessary. Gastroesophageal reflux disease can require fundoplication. Providing enough energy and fluid is often problematic, and patients are at risk of becoming cachectic (40). Two patients also suffered from inflammatory bowel disease.
Sleep disturbances and episodes of excessive crying can be very troublesome and cause severe problems for families and caregivers. Endocrine abnormalities, including (tendency to) hypoglycemia, elevated prolactin levels, and growth (hormone) deficiency, have also been reported (40). Reduced catecholamine production puts patients at risk for apnea and/or sudden cardiac arrest, especially when exposed to stressful situations including hospitalization for diagnostic procedures or surgeries (04). Although most cases have presented at around 2 to 3 months of life, neonatal presentation can also occur with lethargy, hypotonia, metabolic acidosis, and hypoglycemia (01).
About a third of patients have single seizures with corresponding EEG abnormalities, but rarely develop severe epilepsy (40; 24; 31). Seizure types are grand mal or complex focal seizures. An ictal electroencephalographic study in an 11-year-old male demonstrated the presence of epileptic spasms and generalized tonic seizures together with involuntary nonepileptic movements. Epileptic attacks were controlled with antiepileptic drugs. This study demonstrates that differentiation between epileptic and nonepileptic episodes in aromatic L-amino acid decarboxylase deficiency is vital for appropriate treatment (24). Before the definitive diagnosis is established, oculogyric crises are often mistaken as seizures and many antiepileptic therapies initiated, all with little effect on these dopamine-deficiency phenomena.
About half of the patients diagnosed to date are of southeast Asian descent, especially from China, Taiwan, and Japan. They have a common mutation, IVS6+4A>T (26). The mutation is a splicing site alteration that leads to the insertion of 37 nucleotides into the DDC mRNA. Unfortunately, the clinical symptomatology of these patients is very severe.
Milder forms of the disease also exist. Those with the milder form predominantly exhibit autonomic symptoms (diarrhea, episodic hypoglycemia, nasal congestion), even without an evident movement disorder (05; 38). Psychomotor retardation was noted in a girl at 9 months of age. Hypotonia, short periods of hypertonicity, and oculogyric crises were also present. EEG and MRI of the brain were normal. By 2 years of age, the child could sit without support and could communicate nonverbally. Muscle tone still varied between hypo- and hypertonicity. Excessive sweating was noted, and oculogyric crises persisted (02). Two Chinese siblings were found to have aromatic L-amino acid decarboxylase deficiency at 10 and 12 years of age. At the time of diagnosis, both had excessive fatigability, hypersomnolence and dystonia. Early symptoms were mild in comparison to those observed in most other individuals with aromatic L-amino acid decarboxylase deficiency. First presentation was between 3 and 6 months with truncal hypotonia, bilateral ptosis, and mild developmental delay. Both siblings had appropriate speech development; 1 was able to walk independently and the other with assistance. Both functioned better in the morning. Treatment with selegiline, vitamin B6, and bromocriptine led to marked improvement in muscle strength and dystonic symptoms and to the ability to walk independently in the sibling who previously required assistance (41). Three patients (2 siblings and a cousin) have been diagnosed with syndromic intellectual disability. They showed craniofacial dysmorphisms, chronic diarrhea with or without recurrent hypoglycemia, gastroesophageal reflux, and progressive kyphoscoliosis, but were lacking specific clinical features, including oculogyric crises or severe hypotonia. Only as adults were they diagnosed with aromatic L-amino acid decarboxylase deficiency by whole exome sequencing (16). Two sisters were also diagnosed in adulthood with a stable to improving symptomatology, which was thought to be congenital myasthenia (28). A case has been described in which there was striking autistic behavior in an untreated boy by 4 years of age (10).
Psychiatric disorders in carriers. In several case series there was a high incidence of psychiatric disorders in first- and second-degree relatives (40; 31). These psychiatric disorders were depression, psychosis, suicide, or suicide attempts. The extreme stress related to the very demanding care for patients must, however, be considered.
Until now, the overall prognosis is guarded. About half the patients stabilize with a combined therapy of pyridoxine, dopamine agonists, and monoamine oxidase inhibitors acquiring different degrees of motor and psychosocial skills. The others do not show any sustained improvements (31; 09; 44; 38). About 20% clearly improve to the point that they successfully manage regular schooling as long as some help is provided for the remaining motor handicap. Despite all therapeutic interventions, the disease course is often severe and can be fatal at a young age or any time.
Gene therapy has been developed as a novel therapeutic approach for aromatic L-amino acid decarboxylase deficiency (20; 15; 25; 42; 39). With the aid of targeted neurosurgical procedures, viral vector-mediated gene transfer of the human DDC gene into the putamen or into the substantia nigra plus the ventral tegmental area has become possible. The first clinical results of this exciting technique seem promising and the therapy is becoming licensed in several countries.
Male identical twins of normal birth weight were born following a normal pregnancy and delivery. No neonatal problems were reported. Generalized hypotonia was present at 2 months, together with developmental delay and paroxysmal movements consisting of a cry followed by extension of arms and legs, eyes rolling up, and cyanosis. Anticonvulsant therapy was ineffective. Social smiling developed at 3 months, and babbling speech at 9 months.
At 9 months, the twins were within the normal range for weight (10th percentile), length (10th percentile), and head circumference (50th percentile). Thereafter, linear growth, growth in head circumference, and weight gain had virtually ceased until 1 year of age. Clinical signs included irritability, incessant crying, poor head control, and skin pallor. Despite normal muscle bulk, they were floppy with central and peripheral hypotonia; there was paucity of spontaneous movements and flattening of the occiput. There was fine chorea of the distal limbs when the twins were awake. Direct tendon reflexes were brisk, and superficial reflexes were present. Both twins produced excessive sweat, had normal tear production, and had unstable temperature in the absence of any obvious infection. There was miosis, ptosis, and a reverse Argyll Robertson pupil. Extraocular movements and the ocular fundi were normal. ECG showed normal beat-to-beat variation. Postural drop in blood pressure was not present at 9 months but was noted at 1 year. Motor and sensory peripheral nerve conduction velocities were normal; EMG showed no spontaneous activity; and recruited potentials were normal. CT and MRI of their brains demonstrated cerebral atrophy.
Two distinct paroxysmal movements occasionally occurred. The first commenced with a cry, followed by extension of the legs and ankles, extension of the arms with internal rotation at the shoulder, flexion and ulnar deviation at the wrists, finger extension, and abdominal rigidity. The second also began with a cry but was followed by deviation of the eyes either up or down for up to 30 seconds. The limb and eye movements could occur simultaneously. The eye movements were conjugate when upward but convergent when downward. Doll's head maneuvers did not affect the eye position. EEG showed normal awake and asleep activities, and the awake pattern was not affected during the paroxysmal movements. The abnormal eye movements disappeared on treatment with bromocriptine (a dopamine D2 receptor agonist) and were considered extrapyramidal in nature.
After 1 year of treatment with pyridoxine (100 mg twice daily), tranylcypromine (4 mg twice daily), and bromocriptine (2.5 mg twice daily) in combination, weights and lengths were at the 10th percentile, and head circumferences were at the 50th percentile. The twins crawled at 4 years of age and walked at 5 years. They were saying only a few words, but were adept at nonverbal communication and had good comprehension. At 8 years of age, fine hand coordination allowed the tying of shoes, writing, and feeding with utensils. Language comprehension was good, but speech was limited to about 10 words, and academic function was 3 years behind grade level. There was absence of bowel and bladder control. A striking diurnal fluctuation in motor function and tone was apparent with the twins becoming floppy, weak, parkinsonian, dystonic, and ataxic and with development of ptosis of the eyelids and postural instability during the progression of the day. A short nap was sufficient to restore motor function to near that seen in the morning. There were no signs of major autonomic failure. Head circumference was at the 50th percentile. Over the following 25 years the clinical picture did not change significantly.
Another instructive case of aromatic L-amino acid decarboxylase deficiency was well documented, undiagnosed, and untreated until 5 years of age. From birth, there were muscle hypotonia, poor sucking, and feeding difficulties. At 4 months of age, paroxysmal episodes of inconsolable crying developed together with rolling of the eyes, temperature instability, and extension of the extremities. At 10 months of age, global developmental delay and profound muscle hypotonia were present. Brain MRI was normal, and head circumference was at the 25th percentile. At 5 years of age, brain MRI was again found to be normal, and head circumference remained at the 25th percentile. Episodes of eye-rolling continued, and there were persistent and profound axial hypotonia and increased muscle tone of the extremities, with brisk deep tendon reflexes and extensor plantar responses. Spontaneous movements were choreoathetoid in nature. This male child was socially interactive and appeared to understand verbal commands, but was unable to vocalize. He was noted to sweat excessively (30). At baseline, patients are predominantly hypotonic-hypokinetic, but with stress (eg, febrile illness), dystonic or dyskinetic crises may occur, and rhabdomyolysis has been reported (33).
Aromatic L-amino acid decarboxylase deficiency is an autosomal recessive disorder. Many variants in the DDC gene have been described that account for the decreased enzyme activity (41; 17; 26; 09; 18; 38). The human DDC gene is encoded by a single-gene copy that is over 85 kb in length. It is located on chromosome 7p12.1-p12.3 and contains 15 exons (03). The enzyme requires pyridoxal phosphate as a cofactor and is a homodimer composed of identical subunits with a molecular mass of 53.9 kDa. Differential splicing leads to 2 forms of aromatic L-amino acid decarboxylase mRNA that code for a single amino acid sequence. These mRNAs differ in their 5’ untranslated regions and are encoded by 2 distinct exons, exon N1 being designated the neuronal type and exon L1 the nonneuronal type. The 2 forms of mRNA are produced by alternative use of these 2 first exons. Alternative splicing also exists in the coding region of the human aromatic L-amino acid decarboxylase mRNA. Differential splicing in this area leads to the formation of a short-version transcript that lacks exon 3 and appears not to have any enzyme activity (11). Genomic sequencing of the DDC gene has revealed more than 80 different variants (http://www.biopku.org) (09; 18). Detailed studies of the structural and functional consequences of different mutations delineate varying consequences that lead to specific enzymatic phenotypes (35; 18). It is hoped that these studies will help to guide therapeutic decisions including the prevention of individually inappropriate therapy.
More patients appear to have been diagnosed in Taiwan and usually suffer from a severe phenotype. A fairly common splice site mutation, IVS6+4A>T, was detected in Taiwanese children with aromatic L-amino acid decarboxylase deficiency (26), leading to the insertion of an additional 37 nucleotides into the dopa decarboxylase mRNA. This variant also occurs in Southern China and Japan.
In 1 family, 3 patients had an L-DOPA-responsive movement disorder. Sequencing revealed a homozygous G-to-A substitution converting glycine to serine at position 102 (G102S) in exon 3. Kinetic studies and analysis of the enzyme structure revealed that the mutation increased the apparent Km for L-DOPA, altering the protein configuration near the substrate-binding site (12). Optimal clinical response was achieved after additional treatment with pyridoxal phosphate. The pyridoxal phosphate forms a Schiff base, rearranges the substrate pouch, and may act as a chaperone (35).
Decreased activity of aromatic L-amino acid decarboxylase leads to reduced synthesis of catecholamines and serotonin and an accumulation of 3-O-methyldopa, 5-hydroxytryptophan, and levodopa in CSF, plasma, and urine. The methylation of levodopa to form 3-O-methyldopa reduces the levels of S-adenosylmethionine within the central nervous system and sometimes the level of 5-methyltetrahydrofolate (18).
The clinical symptoms are attributed to severe deficiency of biogenic amine neurotransmitters. Dopamine deficiency results in progressive extrapyramidal movement disorders, especially hypokinesia, parkinsonism-dystonia, and chorea. Dopamine not only plays a central role in the control of movement, but also is important for cognition and emotion/affect, and neuroendocrine, pituitary gland hormones (prolactin and growth hormone) (18; 38). Under physiological circumstances, dopamine concentrations are also high in the kidney, where it is involved in control of sodium and water transport. In the gastrointestinal tract, dopamine controls motility. Reduction or inappropriately low response of norepinephrine and epinephrine can lead to hypoglycemia, ptosis, and autonomic disturbances with loss of regulation of body temperature, vascular tone and blood flow, decreased blood pressure, and inappropriate stress response. It also affects attention, mood, sleep, and cognition. Deficiency of serotonin does not appear to lead to the severe neurologic symptoms, but affects appetite, sleep, memory, learning, mood, modulation of pain mechanisms, as well as cardiovascular and endocrine functions. This description outlines the pathophysiology of the complex, severe, and difficult to treat consequences of aromatic L-amino acid decarboxylase deficiency (18).
Specific and logistically challenging investigations of neurotransmitters or molecular analyses are necessary to make the diagnosis of aromatic L-amino acid decarboxylase deficiency. These analyses are not available in many countries. Because most pediatricians and neurologists are not familiar with the broad clinical spectrum, disorders, or the diagnostic approach for identifying neurotransmitter disorders, extended time periods usually pass between the clinical presentation of patients and reaching the correct diagnosis. A substantial number of patients, if not most, are likely to remain undiagnosed. About 200 cases of aromatic L-amino acid decarboxylase deficiency have been identified since the initial description of the index family in different ethnicities. A larger cohort of patients has been described from Taiwan where newborn screening has now been started as a pilot project by measuring 3-O-methyldopa in dried blood spots of newborns (26; 14). Four newborns with elevated 3-O-methyldopa were identified out of 130,000 newborns and were confirmed as having aromatic L-amino acid decarboxylase deficiency, giving an estimated incidence of aromatic L-amino acid decarboxylase deficiency in Taiwan of 1 in 32,000 (95% confidence interval: 1 in 12,443 to 1 in 82,279).
Whitehead and colleagues used whole-genome sequencing and whole-exome sequencing data to probe genomic DNA sequence databases for the frequency of pathogenic DDC variant alleles in the United States, European Union, and Japan (45). Variants already described in patients with aromatic L-amino acid decarboxylase deficiency and known to be pathogenic as well as variants predicted to be pathogenic based on the impact of missense mutations and splice site variants were found. Based on analysis of approximately 200,000 individual genomes, 33 previously known and 183 predicted pathogenic variants were identified. The predicted birth rates of newborns with aromatic L-amino acid decarboxylase deficiency are 1 in 90,000 in the United States, 1 in 118,000 in the European Union, and 1 in 182,000 in Japan, respectively. These birth rates translate into a current estimate of about 1800 living patients with aromatic L-amino acid decarboxylase deficiency in the United States (estimated n = 840), European Union (estimated n = 853), and Japan (estimated n = 125).
Using a different approach of screening biological samples from 19,684 United States patients with neurologic deficits of unknown origin, Hyland and Reott estimated the newborn prevalence of aromatic L-amino acid decarboxylase deficiency to approximately 1 in 42,000 (22). This estimate is not so different from the estimate of Whitehead and colleagues (1 in 42,000 vs. 1 in 90,000) considering that they used completely different approaches and populations. In summary, aromatic L-amino acid decarboxylase deficiency is a rare to ultrarare disorder and the majority of patients remain undiagnosed.
No method is known for preventing aromatic L-amino acid decarboxylase deficiency; however, prenatal diagnosis is available using biochemical or DNA techniques in informative families. Prenatal diagnosis for this condition is available by measuring levodopa decarboxylase activity in fetal liver or by fetal DNA analysis where the mutations are known. Preimplantation and prenatal genetic diagnosis has also been accomplished using an amplification refractory mutation system-quantitative polymerase chain reaction technique (13).
Aromatic L-amino acid decarboxylase deficiency can mimic many neuromuscular disorders. Often patients were initially labeled as having cerebral palsy; therefore, aromatic L-amino acid decarboxylase deficiency should be considered in infants and children with features suggestive of neuromuscular disorders, dystonic or athetoid cerebral palsy, hypotonia, developmental delay, and autonomic symptoms of unknown etiology (40; 44; 18; 38).
Although many of the symptoms of aromatic L-amino acid decarboxylase deficiency are nonspecific, as a group they resemble those seen in other inborn errors affecting dopamine metabolism. In addition to defects in tetrahydrobiopterin metabolism and DNAJ12 deficiency, these include tyrosine hydroxylase deficiency, the dopamine transporter deficiency syndrome, and the vesicular monoamine transporter 2 deficiency (19; 36). Aromatic L-amino acid decarboxylase deficiency results in a severe central and peripheral deficiency of catecholamines and serotonin. Neonatal symptoms include lethargy, hypotonia, metabolic acidosis, and hypoglycemia. Later symptoms include developmental delay, oculogyric crises, generalized hypotonia, irritability, fine chorea of distal limbs, excessive sweating, miosis and ptosis, a reverse Argyll Robertson pupil, temperature instability, and other autonomic signs. CT and MRI scans show a normal brain or only cerebral atrophy.
All inborn errors of dopamine metabolism including L-amino acid decarboxylase deficiency have many similar clinical characteristics, but the diseases are easily separated by biochemical indices. The final effect of tetrahydrobiopterin deficiency, DNAJ12 deficiency, and aromatic L-amino acid decarboxylase deficiency is a lack of catecholamines and serotonin, and these conditions lead to lowered levels of HVA and 5HIAA in CSF; however, a tetrahydrobiopterin deficiency or DNAJ12 deficiency, in general, also leads to accumulation of plasma phenylalanine and to phenylketonuria (37; 36). Elevation of phenylalanine is not seen in aromatic L-amino acid decarboxylase deficiency. In addition, no abnormality is present in tetrahydrobiopterin metabolism, as demonstrated by normal levels of tetrahydrobiopterin and neopterin in CSF (23; 31; 44; 18). In tyrosine hydroxylase deficiency, phenylalanine, serotonin, and tetrahydrobiopterin metabolism are not affected, but an isolated deficiency of HVA in CSF does occur. The opposite, extremely elevated dopamine metabolites in cerebrospinal fluid are the hallmark of the dopamine transporter deficiency syndrome, whereas neurotransmitter determinations are usually unremarkable in the vesicular monoamine transporter 2 deficiency (19; 36). The accumulation of 3-O-methyldopa, 5-hydroxytryptophan, and levodopa in peripheral and central fluids in aromatic L-amino acid decarboxylase deficiency is not seen in any of the defects that affect tetrahydrobiopterin metabolism or in tyrosine hydroxylase deficiency. Similarly, elevations of these metabolites are not seen in conditions in which there might be nonspecific destruction of serotonergic or catecholaminergic neuronal pathways; such conditions would also lead to reduced levels of HVA and 5HIAA in CSF.
Several reports of aromatic L-amino acid decarboxylase deficiency arising secondarily to pyridoxal 5’-phoshate deficiency have been described (34). These patients presented in infancy with a severe seizure disorder. Cerebrospinal fluid neurotransmitter metabolite profiles suggested aromatic L-amino acid decarboxylase deficiency, but primary deficiency of this enzyme was excluded by molecular analysis and by a finding of normal enzyme activity in plasma. In 2005, this disorder was shown to be caused by mutations in the PNPO gene encoding pridox(am)ine 5’-phosphate oxidase (34).
The presence of generalized hypotonia associated with oculogyric crises, ptosis, temperature instability, and sweating after about 2 months of age should suggest the possibility of aromatic L-amino acid decarboxylase deficiency. Neonatal symptoms include lethargy, hypotonia, metabolic acidosis, and hypoglycemia. Dehydration, temperature instability, and reflux are hallmarks in the young infant. Measurement of neurotransmitter metabolites HVA and 5HIAA in CSF is required to document a central deficiency of dopamine and serotonin. The concentrations of HVA and 5HIAA are markedly reduced in CSF. Unfortunately, neurotransmitter metabolites are still rarely investigated in children with suspected (neuro-) metabolic disease. A CSF profile of reduced concentrations of HVA and 5HIAA, together with elevated concentrations of 3-O-methyldopa, is highly suggestive of the condition, but a similar profile has been seen in patients with a defect in the synthesis of pyridoxal 5'-phosphate (34). Further metabolite proof may be obtained by finding elevated 3-O-methyldopa in plasma, urine, or dried blood spots (08). Concentrations of 3-OMD are increased in dried blood spots of aromatic L-amino acid decarboxylase deficient patients and hence are a diagnostic biomarker that appears suitable for newborn screening programs (08). Additionally, L-DOPA and 5-hydroxytryptophan are elevated in plasma and CSF. In urine, there is a variable elevation of vanillactic acid. The ratio of vanillactic acid/vanillylmandelic acid in urine is a reliable diagnostic marker (07). Peripheral deficiency of the biogenic amines can be confirmed by measurement of catecholamines in plasma and of serotonin in whole blood. Measurement of the urinary concentrations of the neurotransmitters themselves may lead to (paradoxical) normal findings. Low concentrations of HVA and 5HIAA are also present in CSF, as well as low whole blood serotonin in defects affecting tetrahydrobiopterin metabolism and the clinical symptoms are similar; however, no accumulation of 3-O-methyldopa or elevation of 5-hydroxytryptophan or levodopa occurs in these conditions. The presence of normal plasma phenylalanine and a normal profile of urinary or CSF biopterin and neopterin in a potential case of aromatic L-amino acid decarboxylase deficiency will exclude the possibility of a defect of tetrahydrobiopterin metabolism.
Confirmation of the diagnosis can be made by measurement of levodopa decarboxylase activity in plasma (44; 18). In all patients in whom activity of the aromatic L-amino acid decarboxylase enzyme in plasma has been measured, the activities were very low or undetectable (40; 09; 38). The activity of levodopa decarboxylase in the plasma of parents has varied between 16% and 58% of that found in controls. Levodopa decarboxylase measurement in plasma can also differentiate between a primary aromatic L-amino acid decarboxylase deficiency and a secondary deficiency due to altered pyridoxal 5'-phosphate metabolism. In the latter, levodopa decarboxylase activity is either normal or elevated (34).
If the mutation can be detected, this provides an ideal method for prenatal diagnosis and heterozygote detection (44; 18; 38).
Treatment should be commenced as soon as possible following diagnosis. The therapeutic management is very challenging, and the response to treatment for most patients cannot be predicted. All medication has to be prescribed “off-label” and without established pediatric dosage regimens (19; 44; 36). A detailed guideline for all aspects of treatment of aromatic L-amino acid decarboxylase deficiency has been published and should be consulted (44). Treatment is aimed at correcting the peripheral and central deficiency of serotonin and catecholamines. This has been attempted using dopamine agonists (eg, bromocriptine, pramipexole, and ropinirole), anticholinergic treatment (trihexiphenidyl), and/or nonselective MAO inhibitors (eg, tranylcypromine, selegiline, and phenelzine). Response to treatment is variable, but often poor (31; 09; 44; 38). Pergolide should not be used because of the risk of fibrotic complications. Most cases have had residual low levels of enzyme activity in plasma and presumably some activity in the brain, as low concentrations of HVA and 5HIAA were present in CSF. In 3 patients, administration of a nonspecific monoamine oxidase inhibitor (tranylcypromine, 4 mg twice daily) raised plasma norepinephrine and whole blood serotonin levels, reduced sweating, and improved spontaneous movement, tone, and color (40). In another case, it had no obvious effect (40).
Aromatic L-amino acid decarboxylase requires pyridoxal 5’-phosphate as a cofactor, and pyridoxal 5’-phosphate deficiency decreases aromatic L-amino acid decarboxylase activity (34). Pyridoxine (up to 400 mg daily) has had, however, no clinical effect on most patients (30; 40; 44; 38); however, future cases of aromatic L-amino acid decarboxylase deficiency may be cofactor-responsive. Molecular modeling suggests an increase in the expression of the enzyme by pyridoxine plus L-DOPA for several mutations, including the frequently occurring mutation S250F (35). A trial of B6 and L-DOPA monotherapy and not the usual combination of L-dopa with a decarboxylase inhibitor, such as carbidopa, may be considered in patients with aromatic L-amino acid decarboxylase deficiency. The response should be monitored clinically, but also by CSF analysis of neurotransmitters.
Optimum treatment has resulted from bromocriptine (0.5 mg/kg, start 0.1 to 0.2 mg/kg) or pramipexole (5 µg/kg/day to start, up to 35 µg/kg/d of base) followed by a monoamine oxidase inhibitor, such as selegiline (0.2 mg/kg/d, range 0.03 to 1.5 mg/kg/d) or tranylcypromine (0.4 to 0.8 mg/kg/d) (19; 36). The younger the patient the greater the tolerance of anticholinergic treatments. In pediatric patients we, therefore, often exceed the dosages recommended for adults if they are well tolerated. However, the process of dose titration has to be very slow and tapering should be performed with caution. Essentially, the occurrence of side effects is what defines the dosage, which is then chosen at just below the threshold for producing side effects. Amantadine with 4 mg/kg/d helps prevent drug-induced dyskinesias.
Sustained oculogyric crisis, or even status dystonicus, is potentially life threatening, with hyperthermia and rhabdomyolysis as major complications (44; 33). Benzodiazepines are helpful with a continuous midazolam perfusion. The current medication should be optimized if dosages are changed. Tone reduction, sedation, and pain killers are necessary. In some cases, intubation and inhalative anesthesia is sometimes the only way to maintain body temperature and minimize rhabdomyolysis. Physical cooling, avoidance of constipation with discomfort, physiotherapy for mobilization of pulmonary secretions, regular checks for urinary tract infections (discomfort), etc., are important. It is essential to maintain hydration and provide extremely high caloric intake because dystonic muscles have excessive energy consumption. For example, 130 kcal/kg/day in a school-age child may be necessary to reverse the catabolic state.
Mutation analysis is recommended in aromatic L-amino acid decarboxylase deficiency to confirm the diagnosis. A glycine to serine conversion at amino acid 102 in exon 3 has been shown to affect the binding of the levodopa substrate to the enzyme. Three siblings carrying homozygous mutations at this site were shown to be responsive to levodopa and pyridoxine (12; 35).
It is also necessary to examine folate metabolism in aromatic L-amino acid decarboxylase deficiency because there is a report of the secondary changes in plasma homocysteine and low concentrations of CSF 5-methyltetrahydrofolate in children with this condition (06). Folinic acid supplementation in doses of 10 to 20 mg/day may be necessary if elevated plasma homocysteine is found or if central concentrations of 5-methyltetrahydrofolate are low.
The use of pressors in patients with aromatic L-amino acid decarboxylase deficiency should only be conducted with close cardiac monitoring. An adult male with the disorder developed serious cardiac rhythm disturbances during treatment with intravenous dopamine and norepinephrine for severe hypotension and later died (04).
Nasal congestion is a frequent problem for patients probably because of their deficit in catecholamines. Topical application of oxymetazoline or xylometazoline is necessary in most cases. Application should be accompanied by local care (eg, with dexpanthenol containing ointments). The package insert and major textbooks warn of use of the combination of MAO inhibitors and topical alpha-adrenoreceptor agonists nose drops because severe hypertensive crises may occur. In aromatic L-amino acid decarboxylase deficient patients, however, catecholamines are reduced and in practice, we are not aware of such complications using this combination in most of our patients (19; 44; 36).
In addition to pharmacotherapy, physiotherapy is important to prevent the development of progressive contractions. Gastrostomy is often necessary. Many patients suffer from constipation and some from diarrhea. Gastroesophageal reflux can occur requiring fundoplication.
Specific gene therapy for aromatic L-amino acid decarboxylase deficiency has been developed. Adeno-associated virus vector-mediated gene delivery of DDC by stereotactic surgery into both putamina has demonstrated safety and efficacy (20). In the first trial of 4 individuals with aromatic L-amino acid decarboxylase deficiency in Taiwan, the choreic dyskinesia resolved after several months of therapy in all. In addition, motor function improved with 6 to 16 months of treatment (20). In 2 further open-label phase 1/2 studies in 10 Taiwanese children (aged 1 to 8 years) (15) and 6 patients in Japan (aged 4 to 19 years) (25) with aromatic L-amino acid decarboxylase deficiency, both confirmed safety as well as beneficial effects of gene therapy. Later in this trial, improvement in motor function could be associated with improvement in white matter microstructural integrity following gene therapy (42). All patients achieved significant continuous sustained improvement of motor as well as cognitive and language functions. Most patients also experienced an increase of HVA but not of 5-HIAA concentrations in CSF. The success of gene therapy was greater in children treated at younger ages (ie, with less permanent damage). As in other neurometabologic disorders, early and accurate diagnosis by newborn screening will be essential for optimal outcome using gene therapy (15; 08). All these improvements could also be achieved by submitting a viral vector expressing aromatic L-amino acid decarboxylase into the substantia nigra plus the ventral tegmental area (38).
Overall, response to treatment is variable, but outcome appears to be slightly better in males than in females (31; 09; 18). Monitoring of therapy with respect to the complex movement disorder, as well as weight gain, swallowing problems, communication issues, arising orthopedic complications, etc., requires repeated careful clinical evaluation by a (pediatric) neurologist, ideally including video documentation (44). Despite all therapeutic interventions, the disease course is often severe and may be fatal at a young age. It is hoped that together with early detection by newborn screening (15; 07), optimized therapy, especially gene therapy (42; 39), will change the outlook of this often-devastating disorder.
In patients with aromatic L-amino acid decarboxylase deficiency the synthesis of epinephrine and norepinephrine is also compromised, which likely requires admission to the ICU. Hypoglycemia is often reported and careful monitoring of glucose concentrations in conditions leading to increased glucose demand or fasting is indispensable. There appears to be a dangerous impairment of sympathotonic stress reaction, which can result in sudden apneas, arterial hypotension, and/or dysrhythmias such as atrial fibrillation (40; 04; 43). Patients should, therefore, receive an emergency card including a summary about the disorder, possible complications, and drugs to avoid (44).
A successful pregnancy was reported in a 26-year-old woman with aromatic L-amino acid decarboxylase defect who was treated with low doses of pramipexole (0.26 mg/day) and selegiline (5 mg/day) (32).
Patients with aromatic L-amino acid decarboxylase deficiency must be carefully monitored during intercurrent illnesses, especially during severe illnesses, surgeries, ICU admissions, and/or anesthesia. Stressful situations, including hospital admission for diagnostic procedures and stimuli, eg, venous puncture, can lead to severe bradycardia or cardiopulmonary arrest (40). Opioids can result in severe bradycardia and hypotension. On the other hand, patients were reported to react very sensitively to dopamine with an unusually marked increase of blood pressure and heart rhythm (43). Apparently, there is a deficiency of catecholamines in the periphery combined with upregulated receptors and consequently increased sensitivity to pharmacotherapy with catecholamines, which must be administered carefully with possibly lower dosages than usually.
Georg F Hoffmann MD
Dr. Hoffmann of the University Center for Child and Adolescent Medicine in Heidelberg has no relevant financial relationships to disclose.See Profile
Barry Wolf MD PhD
Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.See Profile
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