Autosomal-Dominant GTPCH1 Deficiency (Segawa Disease, Dopa-Responsive Dystonia, DYT5a, DYT/PARK-GCH1)

GTPCH1 is a key enzyme of the BH₄ synthesis pathway. Genetic variants of the GCH1 gene cause drastically reduced dopamine and serotonin levels due to the reduced availability of BH₄ [3]. GTPCH1 deficiency presents either in an autosomal-dominant (AD) or autosomal-recessive (AR) manner.

The clinical spectrum of AD-GTPCH1 deficiency is wide with symptom onset during the first decade of life, mainly comprised of dystonia of the lower extremity. Typically symptoms show worsening during the day with rapid improvement after sleep, referred to as diurnal or circadian fluctuation [4]. Additional symptoms include “parkinsonian” symptoms, e.g. tremor and bradykinesia. Impaired fine motor skills can develop later in the clinical course and may be attributable to poor disease control [5]. Only a small subset of patients show impaired intellectual development, while neuropsychiatric features such as sleep disturbance and anxiety are more common [6].

Supplementation of low-dose levodopa in combination with a decarboxylase inhibitor (carbidopa or benserazid) improves motor function drastically in AD-GTPCH1-deficient patients; therefore, a treatment trial can be used as a diagnostic tool. Concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), biopterin, and neopterin are low in the CSF. Genetic testing is used to verify underlying variants in the GCH1 gene [7].

Sepiapterin Reductase Deficiency (DYT/PARK-SPR)

Variants of the SPR gene cause sepiapterin reductase (SPR) deficiency, a very rare autosomal-recessive disorder [8]. SPR deficiency leads to early-onset axial hypotonia, delayed achievement of developmental motor milestones, and prominent psychiatric features such as irritability and behavioral problems [9]. A constellation of motor symptoms has been described in the early stages, with hypokinetic rigidity including impairment of postural reactions, spasmodic dystonia of the trunk with oculogyric crises, and resting tremor of the limbs and head that can be inhibited by contact or spontaneous movement [10]. Growth-hormone deficiency and hypoglycemia are attributed to dopamine depletion in SPR-deficient patients [11]. The majority of patients with SPR deficiency show cognitive impairment [12]. Diagnosis may be challenging due to non-specific symptoms. Dystonic spasms and oculogyric crises may mimic epilepsy, delaying diagnosis [12]. Diagnosis depends on the determination of neurotransmitter metabolites in CSF. Here, low concentrations of HVA and 5-HIAA with elevation of sepiapterin and 7,8-dihyrobiopterin (BH₂) are typical.

Treatment consists of the supplementation of neurotransmitter precursors, levodopa and 5-hydroxytryptophan (5-HTP), in combination with the blockage of peripheral decarboxylation, in order to increase the dosage that crosses the blood–brain barrier. This is usually done in a 4:1 ratio of levodopa/decarboxylase inhibitor. Selective serotonin reuptake inhibitors (SSRIs), dopaminergic agonists, monoamine oxidase inhibitors, and dopamine/noradrenaline reuptake inhibitors have shown effects in single cases; however, so far there is no controlled clinical study or guideline available for the treatment of this disease [12].

Autosomal-Recessive GTPCH1 Deficiency (DYT/PARKGCH1)

Homozygous or compound heterozygous variants in GCH1 are the genetic cause for AR-GTPCH1 deficiency. With early neonatal onset and an often complex neurological phenotype, this disorder resembles the severe end of a continuous spectrum between the AR and AD form of GTPCH1 deficiency. Classic features at onset are neonatal rigidity, truncal hypotonia, and dystonia–parkinsonism, as well as oculogyric crises. Most cases present with HPA on newborn screening; however, this biochemical hallmark can be missing in rare cases of AR-GTPCH1 deficiency [13, 14].

Similar to AD-GTPCH1 deficiency, supplementation of levodopa/decarboxylase inhibitor represents the main treatment strategy. Compared to AD-GTPCH1 deficiency, the levodopa dose required to achieve an adequate treatment response is higher. 5-HTP can reduce neuropsychiatric symptoms. BH₄ supplementation can be used to normalize the HPA.

6-Pyruvoyltetrahydropterin Synthase Deficiency (DYT/PARK-PTS)

6-Pyruvoyltetrahydropterin synthase (PTPS) deficiency represents the most frequent disorder of BH₄ synthesis accompanied by HPA. It is caused by variants of the PTPS gene and comprises a highly variable clinical spectrum depending on the degree of residual enzyme activity [2]. The phenotype ranges from severe hypotonia with dystonia, dystonia–parkinsonism, cognitive impairment, and epileptic seizures to milder phenotypes with unaltered neurodevelopment [15]. HPA is usually present on newborn screening making it a key diagnostic marker for early diagnosis [13].

The treatment of patients with PTPS deficiency consists of the supplementation of neurotransmitter precursors and inhibition of peripheral decarboxylation. Similar to AR-GTPCH1 deficency, BH₄ supplementation helps control HPA. Some patients with PTPS deficiency benefit from BH₄ monotherapy. However, high doses need to be administered peripherally to achieve adequate concentrations in the central nervous system [2].

Dihydropteridine Reductase Deficiency (DYT/PARKQDPR)

BH₄ is continuously recycled by a regenerative pathway using DHPR and pterin-4a-carbinolamine dehydratase (PCD) to reduce BH₂ and prevent the accumulation of potentially harmful intermediates (see Figure 21.1) [16]. Variants in the QDPR gene cause DHPR deficiency [8], resulting in a variety of biochemical features, such as the accumulation of BH₂ with the subsequent reduction of catecholamine and serotonin synthesis, dysregulation of nitric oxide synthase activity, and reduced 5-methyltetrahydrofolate (5-MTHF) formation [15]. Symptoms appear in early childhood, most frequently starting in the neonatal period, with microcephaly and developmental delay. Later in life, motor function is highly impaired in untreated children, characterized by a dystonia–parkinsonism phenotype with tremor as well as seizures [2].

Usually, after identification of HPA in newborn screening, the pterin pattern in dried blood spots or urine can further differentiate the underlying BH₄ disorder. But since pterins are normal in DHPR deficiency, it is crucial to determine the DHPR enzyme activity in dried blood to confirm this defect. Treatment is similar to other BH₄ synthesis defects based on the supplementation of neurotransmitter precursors. Based on the hypothesis that BH₄ supplementation may lead to increased 7, 8-dihydrobiopterin (BH₂) production resulting in aggravation of disease severity by inhibiting the aromatic L-amino acid hydroxylases or by increasing nitric oxide (NO) uncoupling and oxidative stress, this treatment approach is currently controversial in DHPRD. However, literature evidence for these potential harmful effects is scarce and based on cell experiments only. Therefore, there is no reliable justification to withhold this therapeutic intervention from patients with DHPRD. Due to folate depletion in the CSF, the administration of folinic acid should be initiated, having a positive effect on dopamine levels in the brain [18].

Pterin-4a-Carbinolamine Dehydratase Deficiency

PCD deficiency is caused by genetic variants in PCBD1, which lead to a milder and more benign phenotype compared to other BH₄ deficiencies. In newborn screening, only mild HPA is noted, whereas high urine levels of 7-biopterin (primapterin) confirms the diagnosis [19]. Therefore, PCD deficiency is often referred to as a mild form of HPA rather than a neurotransmitter deficiency. Interestingly, PCD deficiency is described as a dimerization cofactor for hepatocyte nuclear factor 1 (HNF1) [20]. Mutations in PCBD1 cause reduced transcriptional activity of HNF1 and are associated with the impaired development of liver and pancreatic cells causing early-onset diabetes [21, 22].

Treatment consists of dietary measures, and BH₄ is recommended to control HPA.

Tyrosine Hydroxylase Deficiency (TH-D, Dopa-Responsive Dystonia, DYT5b, DYT/PARK-TH)

TH catalyzes the rate-limiting step of dopamine synthesis, thus, TH deficiency leads to an isolated catecholamine deficiency (see Figure 21.1). TH deficiency is caused by genetic variants in the TH gene. Classic features of TH deficiency are caused by catecholamine depletion and include dystonia–parkinsonism, oculogyric crises, and non-specific features such as autonomic dysregulation and developmental impairment [23]. The phenotypic spectrum ranges from a mild form (type A) to a severe form (type B). The latter usually presents with early neonatal-onset encephalopathy and a hypokinetic–rigid movement disorder. In addition, severe developmental delay may be noted in type B patients [23]. CSF neurotransmitter measurements reveal reduced levels of HVA, normal 5-HIAA, and a low HVA:5-HIAA ratio [24].

Treatment is based on the supplementation of levodopa/decarboxylase inhibitor. Of note is that TH-deficient patients are highly sensitive to very low doses of levodopa. Furthermore, patients with long-standing dopaminergic deficiency are more likely to suffer from adverse medication-related effects, such as dyskinesia, nausea, or vomiting. This is not caused by a toxic effect of levodopa and should therefore not lead to the cessation of the medication. Reduced levodopa dosage is instead recommended until the side effects disappear [25].

Aromatic L-Amino Acid Decarboxylase Deficiency

Variants in the DDC gene cause aromatic L-amino acid decarboxylase (AADC) deficiency, which represents a rare disease with approximately 150 cases described in the medical literature, a fifth within an Asian subpopulation [26]. Similar to BH₄ disorders, a combined reduction of serotonin and dopamine-derived catecholamines leads to a complex movement disorder with predominating dystonia–parkinsonism and a progressive extrapyramidal movement disorder combined with autonomous dysregulation such as profuse sweating, nasal congestion, temperature instability, insomnia, and irritability. Many patients show signs of severe neurocognitive developmental delay [27, 28]. Diagnosis is established by reduced CSF concentrations of HVA and 5-HIAA in combination with elevated 3-orthomethyldopa, levodopa, and 5-HTP. Urine analysis of organic acids can reveal high concentrations of vanillylactate. The metabolic profile of pyridoxine-5’-phosphate oxidase (PNPO) deficiency can mimic the changes seen in AADC defciency, due to the role of pyridoxal 5’-phosphate (PLP) as an essential cofactor of AADC. However, the determination of AADC enzyme activity, vanillylactate concentration in the urine, or PLP concentrations in the CSF can be used to distinguish PNPO deficiency and AADC deficiency [27]. Due to high residual AADC activity in the renal parenchyma, the determination of catecholamine concentrations in the urine is not useful [29].

AADC deficiency represents the first neurotransmitter deficiency for which a consensus guideline was published [30]. This guideline suggests the first-line use of dopaminergic agonists as stand-alone therapy or in combination with monoamine oxidase (MAO) inhibitors to increase the availability of monoamine neurotransmitters. PLP can be used to increase the residual enzyme activity of the AADC enzyme [30]. A clinical trial is currently ongoing, which evaluates the use of adeno-associated viral-mediated gene therapy. Although the initial data reveal an improvement of motor function, long-term data evaluating the efficacy, safety, and stability of gene therapy are pending [31].