Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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This article includes discussion of abnormalities of tetrahydrobiopterin metabolism, atypical phenylketonuria, BH4 deficiency, dihydropteridine reductase deficiency, DNAJC12 deficiency, GTP cyclohydrolase deficiency, pterin-4 alpha-carbinolamine dehydratase deficiency, sepiapterin reductase deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Tetrahydrobiopterin (BH4) deficiencies, a group of rare inherited neurologic diseases with monoamine neurotransmitter deficiency, result in insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin. They may present with or without hyperphenylalaninemia (HPA). The same biochemical consequences are also caused by a sixth disorder, DNAJC12 deficiency. Tetrahydrobiopterin (BH4) is an essential cofactor not only for phenylalanine hydroxylase, but also for tyrosine and 2 tryptophan hydroxylases, 3 nitric oxide synthases, and glyceryl-ether monooxygenase. Defects of BH4 metabolism comprise a group of treatable pediatric neurotransmitter disorders. The major pathophysiology consists of disturbed phenylalanine degradation, as well as compromised catecholamine and serotonin biosynthesis. This heterogeneous group of disorders is caused by mutations in either 6-pyruvoly-tetrahydropterin synthase, GTP cyclohydrolase, pterin-4 alpha-carbinolamine dehydratase deficiency, sepiapterin reductase, or dihydropteridine reductase. Affected patients are usually clinically asymptomatic at birth and in early infancy. Without diagnosis and treatment they develop a progressive encephalopathy characterized by severe truncal hypotonia, decreased spontaneous movements, movement disorders, including chorea and dystonia, intellectual disability, and epileptic seizures. BH4 is also involved in cardiovascular and endothelial dysfunction and pain modulation.
Many patients present with hyperphenylalaninemia, which may be detected through newborn phenylketonuria screening programs, including DNAJC12 deficiency. Two forms of cerebral BH4 deficiency occur without hyperphenylalaninemia: the autosomal dominantly inherited form of GTPCH deficiency (dopa-responsive dystonia, initially described as Segawa disease, see also MedLink article, Dopa-responsive dystonia) and sepiapterin reductase deficiency. Treatment of tetrahydrobiopterin deficiencies relies on the use of a mixture of levodopa and carbidopa (ie, Sinemet®), 5-hydroxytryptophan, tetrahydrobiopterin, and, if necessary, a low-phenylalanine diet and an additional supplementation of folinic acid in the treatment of dihydropteridine reductase deficiency. Treatment should be initiated as early as possible and continued for life.
Since 2015, an international network of physicians and scientists, the International Working Group on Neurotransmitter Related Disorders (iNTD, www.intd-online.org), aims to more completely describe the initial and evolving clinical phenotypes of BH4 deficiency, including the development of guidelines for diagnostic and therapeutic interventions. Biochemical, clinical, and DNA data of patients with BH4 deficiencies are tabulated in the BIODEF and BIOMDB databases and are available on the internet (www.biopku.org).
• Tetrahydrobiopterin (BH4) deficiencies affect phenylalanine homeostasis, but most importantly impair catecholamine and serotonin biosynthesis.
• Five enzyme defects are all inherited in an autosomal recessive manner.
• DNAJC12 deficiency can have identical pathobiochemical consequences.
• Without early diagnosis and treatment, BH4 deficiencies result in progressive developmental impairment and severe neurologic dysfunction.
• Any baby presenting with any degree of hyperphenylalaninemia in the newborn screening program must be evaluated in a timely manner to exclude or diagnose one of the BH4 deficiencies, including DNAJC12 deficiency.
Phenylketonuria comprises a group of conditions that arise as a result of the inability to effectively convert phenylalanine to tyrosine. The first case was reported by Folling in 1934, and subsequent studies demonstrated that the majority of cases were due to defects of phenylalanine hydroxylase. Dietary control of the disease using a phenylalanine-restricted diet was introduced in 1953 by Horst Bickel and colleagues. In 1974, there were 2 independent reports of children with a form of phenylketonuria that was accompanied by a complex severe progressive neurologic illness unresponsive to dietary treatment (02; 40). It was already hypothesized that these children lacked tetrahydrobiopterin, the cofactor required for the phenylalanine hydroxylase reaction. Tetrahydrobiopterin is formed from GTP in a multistep pathway involving dihydroneopterin and tetrahydropterin intermediates. During the hydroxylation of phenylalanine, tetrahydrobiopterin is oxidized to quinonoid dihydrobiopterin by pterin-4 alpha-carbinolamine dehydratase, and then reduced back to tetrahydrobiopterin by the action of dihydropteridine reductase (45).
In addition to the phenylalanine hydroxylase reaction, tetrahydrobiopterin is also the cofactor for tyrosine hydroxylase and tryptophan hydroxylase, the rate-limiting enzymes required for the synthesis of the catecholamines and serotonin, the generation of nitric oxide from citrulline by nitric oxide synthases, and the production of an alkyl aldehyde and glycerol from a glycerol ether by glyceryl-ether monooxygenase (45). The continuing deficiency of all monamine neurotransmitters within the central nervous system explains why the neurologic symptoms in children with defects in tetrahydrobiopterin metabolism do not respond clinically to a low-phenylalanine diet alone.
Proof of a problem in cofactor metabolism came following demonstration of dihydropteridine reductase (DHPR) deficiency in the brain and liver of another child with phenylketonuria whose neurologic symptoms were unresponsive to diet (25). In 1976 evidence appeared for a defect affecting the biosynthesis of tetrahydrobiopterin (27). In this case, low concentrations of biopterins were found and an unusual pterin was detected (later identified as neopterin). Identification of low concentrations of biopterin in association with high concentrations of neopterin indicated a block after the formation of dihydroneopterin triphosphate. Additional reports soon confirmed that this new entity was due to a defect in the synthesis of tetrahydrobiopterin. At that time, the biosynthetic pathway for tetrahydrobiopterin was thought to occur via a dihydrobiopterin intermediate, and the new defects were classified as "dihydrobiopterin synthetase deficiencies." It is now known that tetrahydrobiopterin is synthesized via tetrahydropterin intermediates and the enzyme deficiency leads to blockage at the level of 6-pyruvoyltetrahydropterin synthase (PTPS).
Previous names for this enzyme have included dihydrobiopterin synthetase, phosphate eliminating enzyme and sepiapterin synthesizing enzyme-1. More than half of the patients with BH4 deficiencies suffer from a deficiency of this enzyme (33).
In 1984 a defect affecting GTP cyclohydrolase 1, the first enzyme in the biosynthetic pathway for tetrahydrobiopterin synthesis, was described (29). Since then several other cases have been reported (33). Not all cases of autosomal recessively inherited GTP cyclohydrolase deficiency have hyperphenylalaninemia; however, severe neurotransmitter deficiencies are detectable by CSF analyses. In several reported cases with well-defined, confirmed pathogenic mutations, progressive severe neurologic symptoms developed which responded well to L-dopa supplementation. These included neonatal-onset of rigidity, tremor, spasticity, oculogyric crises, and dystonia (04; 13; 19; 10). Abnormal phenylalanine metabolism could sometimes only be demonstrated after stressing the phenylalanine to tyrosine hydroxylation system by administering a phenylalanine loading challenge (34). The clinical spectrum of GTP cyclohydrolase 1 deficiency includes the classical dominant L-dopa-responsive dystonia without hyperphenylalaninemia, type Segawa, at the mildest, to neonatal onset of progressive spasticity, rigidity, tremor, dystonia, and hyperphenylalaninemia in autosomal recessive dopa-responsive dystonia at the other end of the continuum. Intermediate phenotypes with graded clinical symptoms can be related to compound heterozygous mutations resulting in different residual activities, again sometimes without overt hyperphenylalaninemia (34).
In 1988, a new type of defect affecting tetrahydrobiopterin metabolism was found (11). Dhondt and colleagues observed an unusual peak by HPLC used to screen for defects in tetrahydrobiopterin metabolism. This compound was later identified as 7-substituted biopterin (as opposed to the normal 6-substituted biopterin). It was shown to result from a deficiency of pterin-4 alpha-carbinolamine dehydratase, which functions as part of the phenylalanine hydroxylating system in the conversion of 4a-OH-tetrahydrobiopterin to quinonoid dihydrobiopterin.
In 1994, dopa-responsive dystonia was shown to be associated with dominant mutations in the gene for GTP cyclohydrolase 1 (22). This disorder was first described by Segawa, who named the disorder “hereditary progressive dystonia with marked diurnal fluctuation” (38). Unlike the other defects in tetrahydrobiopterin metabolism, this condition is inherited in an autosomal dominant fashion, and affected and asymptomatic carriers of the mutation do not have hyperphenylalaninemia under resting conditions (20; 35; 10).
In 1999, another defect in tetrahydrobiopterin metabolism was described that did not lead to hyperphenylalaninemia. It was first presumed to be a variant of dihydropteridine reductase deficiency (06) but was later shown to be due to sepiapterin reductase deficiency (08). Central nervous system catecholamine and serotonin metabolism were impaired leading to severe neurologic dysfunction.
Terminology for the group of defects that affect tetrahydrobiopterin metabolism has altered since the early descriptions. Initial cases were classified as forms of atypical phenylketonuria and then malignant hyperphenylalaninemia because they were unresponsive to classic dietary treatment. Currently, the term "tetrahydrobiopterin deficiencies" encompasses all of the disorders.
The BH4 deficiencies are clinically heterogeneous. There are variant forms of 6-pyruvoyltetrahydropterin synthase deficiency (transient cases, peripheral forms, and severe forms that affect both systemic and central systems) as well as several partial and mild cases of dihydropteridine reductase deficiency (05; 33).
Several different names have also been used to describe the autosomal dominantly inherited form of GTP cyclohydrolase 1. The condition was initially termed "hereditary progressive dystonia with marked diurnal fluctuation” or more commonly "Segawa syndrome." Since 1988, the term "dopa-responsive dystonia" has generally been applied to all dystonias responding to levodopa (31), which includes autosomal dominant dopa-responsive dystonia caused by mutations in the GTP cyclohydrolase 1 gene (22) (see also the MedLink article Dopa-responsive dystonia).
Since 2017, an additional disease has been included in the differential diagnosis of hyperphenylalaninemia with deficiency of monoamine neurotransmitters. It is caused by biallelic mutations in the DNAJC12 gene and associated with a variable neurologic phenotype (01).
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