A Systematic Review of Treatment Outcome in Patients with Dopa‐responsive Dystonia (DRD) and DRD‐Plus

Abstract

Background

Dopa‐responsive dystonia (DRD) and DRD‐plus are inherited metabolic disorders of the dopamine synthetic pathway that have considerable clinical, biochemical, and genetic heterogeneity. Dopamine is the main deficient neurotransmitter; however, a deficiency in norepinephrine and serotonin can coexist, depending on the gene and its degree of defect. Therefore, even though levodopa is the mainstay of therapy, response to levodopa can be suboptimal and, thus, other drugs are tried.

Methods and Results

The authors searched for reports of DRD and DRD‐plus and reviewed the drugs used, their response and side effects, and neurologic outcomes, including motor and cognition. Based on the current results, a recommended treatment plan is presented according to the type of enzyme defect in patients with DRD and DRD‐plus.

Conclusions

It is important to recognize the features of DRD and DRD‐plus, because many of them have a good clinical response to the appropriate treatment. The aim of this review is to help guide clinicians with planning treatment for patients with DRD and DRD‐plus.

Dopa‐responsive dystonia (DRD) is a rare disorder characterized by childhood onset of dystonia with diurnal fluctuation and improvement with sleep or rest.1 Dystonia in DRD commonly has a typical phenotype that presents with lower limb onset and subsequently generalizes.2 An autosomal dominant (AD) mutation in guanosine triphosphate (GTP) cyclohydrolase 1 (GCH‐1), which is the cofactor for tyrosine hydroxylase (TH) as well as the first rate‐limiting step in the biosynthesis of tetrahydrobiopterin (BH₄), is the most common and classic cause of DRD.3 On the other hand, DRD‐plus not only has some features of DRD but also has additional features that are not seen in DRD4, 5, 6 (Table 1). It also has other gene defects different from those in classic DRD.4, 5 Generally, enzyme defects related to the dopamine synthetic pathway, including autosomal recessive (AR) GCH‐1, TH, sepiapterin reductase (SR), 6‐pyruvoyltetrahydropterin synthase (PTPS), dihydropteridine reductase (DHPR), and aromatic L‐amino acid decarboxylase (AADC), can cause DRD‐plus with rare exception (Fig. 1).

Table 1.

What Are Dopa‐Responsive Dystonia (DRD) and (DRD)‐Plus?

	Definition	Cardinal Feature	Supportive Features
DRD	Selective nigrostriatal dopamine deficiency caused by genetic defects (AD GCH‐1 >>> TH, SR) in the dopamine synthetic pathway without nigral cell loss	Dystonia	Diurnal fluctuation
			Childhood or adolescent onset
			Excellent response to l‐dopa
			Normal dopamine transporter imaging
DRD‐plus	Selective nigrostriatal dopamine deficiency caused by genetic defects (AR GCH‐1, PTPS, SR, DHPR, TH, and AADC) in the dopamine synthetic pathway without nigral cell loss	Dystonia	At least one of three additional features that are not seen in DRD:
			Earlier onset than DRD, such as neonatal onset
			More severe motor features, such as truncal hypotonia, poor sucking, and swallowing difficulties
			Nonmotor manifestations, such as seizure, myoclonic attacks, psychomotor retardation, mental retardation, and autonomic dysfunction

AD, autosomal dominant; GCH‐1, guanosine triphosphate cyclohydrolase 1; TH, tyrosine hydroxylase, SR, sepiapterin reductase; l‐dopa, levodopa; AR, autosomal recessive; PTPS, 6‐pyruvoyltetrahydropterin synthase; DHPR, dihydropteridine reductase; AADC, aromatic L‐amino acid decarboxylase.

Figure 1.

The dopamine biosynthesis pathway (modified from Lee and Jeon, 20145). Enzymes in which defects can cause dopa‐responsive dystonia (DRD) and DRD‐plus are shown in blue, and enzymes in which defects can only cause DRD‐plus are shown in red. GTP, guanosine triphosphate; GCH‐1, GTP cyclohydrolase 1; NH₂P₃, dihydroneopterin triphosphate; PTPS, 6‐pyruvoyltetrahydropterin synthase; 6‐PPH4, 6‐pyruvoyl‐tetrahydropterin; SR, sepiapterin reductase; BH₄, tetrahydrobiopterin; Tyr, tyrosine; Trp, tryptophan; Phe, phenylalanine; DHPR, dihydropteridine reductase; TH, tyrosine hydroxylase; TPH, tryptophan hydroxylase; PAH, phenylalanine hydroxylase; qBH₂, quinonoid dihydrobiopterin; l‐dopa, L‐dihydroxyphenylalanine; 5‐HTP, 5‐hydroxydryptophan; AADC, aromatic L‐amino acid decarboxylase; NE, norepinephrine; 5‐HIAA, 5‐hydroxyindolacetic acid.

Regarding treatment, low doses of L‐dihydroxyphenylalanine (levodopa [l‐dopa]) are known to produce a remarkable response without long‐term complications, such as motor fluctuations and dyskinesias, in patients with DRD.1 However, dyskinesia can occur on initial l‐dopa administration or dose titration, and there are cases in which the l‐dopa response is unsatisfactory.5 In DRD‐plus, the neurochemical deficit is more severe and extends into nondopaminergic systems, such as serotonin and norepinephrine. Thus, l‐dopa is known to show less motor benefit with severe dyskinesias.5 These findings make clinicians consider other therapeutic options that have yet to be systematically studied.

In this review, we searched for patients with DRD and DRD‐plus and summarized the drugs used, their response and side effects, and neurologic outcome, including motor and cognition. Based on this review, we present a recommended treatment plan according to the type of enzyme defect in patients with DRD and DRD‐plus.

Patients and Methods

This systematic review was performed according to the guidelines published by the Center for Evidence‐based Medicine (available at: http://www.cebm.net). We searched PubMed and EMBASE for articles published from January 1994 to December 2014 using the search terms “dopa responsive dystonia,” “DYT 5,” “Segawa disease,” “hereditary progressive dystonia,” “GTP cyclohydrolase 1 deficiency,” “tyrosine hydroxylase deficiency,” “sepiapterin reductase deficiency,” “6‐pyruvoyltetrahydropterin synthase deficiency,” “dihydropteridine reductase deficiency,” “aromatic L‐amino acid decarboxylase deficiency,” and “Tetrahydrobiopterin.” Articles were required to meet the following criteria for inclusion: (1) They reported on patients who had DRD and DRD‐plus with genetic confirmation by DNA analysis; (2) the information on individual data, treatment, and therapeutic response was included; 3) the full‐text article written in English was retrieved.

One author (R.K.) extracted general characteristics of the patients (type of genetic defect, medication, therapeutic dosage and response, side effect, neurologic outcome). This information was reviewed by the second author (B.J.), and any discrepancy was solved by agreement.

Results

An initial search identified 19,315 articles (13,183 from PubMed and 6,132 from EMBASE). After deleting duplicated articles, we screened titles, abstracts, or entire articles for the exclusion criteria. Consequently, our systematic review identified 1,142 cases suspected of DRD and DRD‐plus in 263 articles, of which we included only 575 patients who had DRD and DRD‐plus genetically confirmation by DNA analysis (Table 2, Fig.S1), complete references are available in the Appendix (Supporting e‐References), and more detailed information about treatment is provided in Table S1 (see online supporting information).

Table 2.

Summary of Treatment in Patients with Dopa‐responsive Dystonia (DRD) and DRD‐Plus

Enzyme Defect	Total No.	No. of Patients (%)
		Maintenance Treatment		Drug
		First Most Common	Second Most Common	l‐dopaa	DAs	MAOIs	5‐HTP	BH4	ACs
AD GCH‐1	408	l‐dopa: 393 (96.3)	ACs: 7 (1.7)	406 (99.5)	4 (1.0)	NR	1 (0.2)	1 (0.2)	16 (3.9)
AR GCH‐1	15	l‐dopa: 8 (53.3)	First + 5‐HTP + BH4: 6 (40)	15 (100)	NR	NR	6 (40)	7 (46.7)	NR
PTPS	18	l‐dopa + 5‐HTP + BH4:16 (88.9)	—	16 (88.9)	6 (33.3)	5 (27.8)	15 (83.3)	17 (94.4)	NR
SR	27	l‐dopa: 15 (55.6)	First + 5‐HTTP: 8 (29.6)	27 (100)	2 (7.4)	2 (7.4)	11 (40.7)	1 (3.7)	1 (3.7)
DHPR	5	—	—	5 (100)	2 (40)	2 (40)	5 (100)	3 (60)	NR
TH	70	l‐dopa: 45 (64.3)	First + MAOIs: 17 (24.3)	70 (100)	2 (2.9)	22 (31.4)	NR	NR	5 (7.1)
AADC	32	DAs + MAOIs: 24 (75)	First + ACs: 5 (15.6)	7 (21.9)	30 (93.8)	24 (75)	5 (15.6)	NR	11 (34.4)

^aThis was levodopa (l‐dopa) with decarboxylase inhibitor.

Das, dopamine agonists; MAOIs, monoamine oxidase inhibitors; 5‐HTP, 5‐hydroxytrytophan; BH₄, tetrahydrobiopterin; ACs, anticholinergics; AD, autosomal dominant; GCH‐1, guanosine triphosphate cyclohydrolase 1; NR, not reported; AR, autosomal recessive; PTPS, 6‐pyruvoyltetrahydropterin synthase; SR, sepiapterin reductase; DHPR, dihydropteridine reductase; TH, tyrosine hydroxylase, AADC, aromatic L‐amino acid decarboxylase.

Treatment: Response and Side Effects

AD GCH‐1 Deficiency

Of 408 patients who had an AD GCH‐1 deficiency, ^e1–e96 all but 2 patients^e14,e92 used l‐dopa/decarboxylase inhibitor (DCI), and benefit was reported in 403 of 406 patients. Because of substantial improvement to l‐dopa monotherapy, it was the most commonly used maintenance treatment (96.3%) Reported doses of l‐dopa/DCI ranged from 25 to 1800 mg daily, but most of them were managed with less than 600 mg daily. Among 3 patients without benefit from l‐dopa,^e25,e62,e72 1 experienced an aggravation in stiffness during l‐dopa treatment and thus did not get any benefit.^e62 Twenty‐two patients (5.4%) had l‐dopa induced dyskinesias (LIDs),^{e8,e12,e13,e18,e26,e28,e30,e35,e46,e53,e59,e62,e71,e72,e76,e80,e88} which were well controlled by reducing the l‐dopa dose, or by a gradual escalation to a higher dose, or by increasing the frequency of the dosing. Of the patients with LIDs, 3 patients showed spontaneous improvement of LIDs without any changes in medications.^e8,e12,e63 Two patients received amantadine for LIDs, which produced a beneficial effect at a dose from 4 to 5 mg/kg daily.^e59 Only 1 patient changed from l‐dopa to trihexyphenidyl due to LIDs.^e71 In addition, 2 patients changed from l‐dopa to dopamine agonists because of l‐dopa–induced nausea and headache.^e25,e48

Anticholinergics like trihexyphenidyl were the second most commonly used drugs.^{e14,e17–e19,e26,e28,e53,e57,e71–e73,e79,e82,e88,e92} Reported doses of trihexyphenidyl ranged from 2 to 20 mg daily, and benefit was reported in 15 of 16 patients. Among those patients, 7 patients used trihexyphenidyl monotherapy as a maintenance treatment,^{e14,e17,e28,e71,e92} of which 4 patients responded better to trihexyphenidyl than to l‐dopa.^e28,e71 Four patients were treated with a combination of trihexyphenidyl and l‐dopa because their symptoms were not completely controlled with l‐dopa monotherapy.^{e18,e19,e26,e28,e53} Dopamine agonists, 5‐HTP, and BH₄ were only rarely used.^{e18,e25,e26,e34,e48,e53,e88,e95}

AR GCH‐1 Deficiency

In 15 patients who had an AR GCH‐1 deficiency,^{e24,e58,e88,e89,e97–e104} l‐dopa monotherapy (53.3%) was the most commonly used maintenance treatment,^{e24,e58,e98–e100,e102,e103} followed by l‐dopa combined with 5‐HTP and BH₄ (40%).^{e89,e97,e101,e104} All patients received l‐dopa/DCI at doses that ranged from 1 to 16 mg/kg daily. LIDs were reported in 2 patients (13.3%).^e24,e88 Almost half of patients received 5‐HTP and BH₄, but independent benefits from them were not definite, because all of patients received a combination of l‐dopa. The reported doses of 5‐HTP and BH₄ were from 1 to 8 mg/kg daily and from 1 to 10 mg/kg daily, respectively.

PTPS Deficiency

In 18 patients with PTPS deficiency,^e105–e112 BH₄ combined with l‐dopa and 5‐HTP was the most commonly used maintenance treatment (88.9%).^{e105,e106,e108–e110} The reported doses of l‐dopa, 5‐HTP, and BH₄ ranged from 0.1 to 18 mg/kg daily, from 0.1 to 20 mg/kg daily, and from 0.45 to 40 mg/kg daily, respectively. LIDs were frequently reported (8 patients; 44.4%).^{e107,e109,e110} Dopamine agonists were received by 5 patients in whom concurrent administration of pramipexole with l‐dopa was effective in reducing the l‐dopa dose and the number of administrations as well as improving the clinical course.^e107

SR Deficiency

In 27 patients with SR deficiency,^{e33,e113e−127} l‐dopa monotherapy was the most commonly used maintenance treatment (15 patients; 55.6%),^{e33,e113,e117,e118,e121,e125,e126} followed by l‐dopa combined with 5‐HTP, which was used in 8 patients (29.6%).^{e33,e114,e115,e117,e119,e120,e123,e124,e127} All patients received l‐dopa/DCI with beneficial effect. Reported doses of l‐dopa/DCI ranged from 0.16 to 20.0 mg/kg daily. LIDs were frequently reported (10 patients; 37%)^{e33,e113,e115,e116,e118,e119,e122–e125}; however, titration of the l‐dopa dose or increasing the frequency of the dosing improved LIDs in all but 1 patient,^e116 who added a dopamine agonist with decrement of the l‐dopa dose due to a wearing‐off phenomenon as well as LIDs. 5‐HTP was the second most commonly used drug.^{e33,e114,e115,e117,e119,e120,e122–e124,e127} Reported doses of 5‐HTP ranged from 0.75 to 16.0 mg/kg daily with benefit reported in 8 of 10 patients. Dopamine agonists, anticholinergics, monoamine oxidase inhibitors (MAOIs), and BH₄ were only rarely used.^{e116,e122,e127}

DHPR Deficiency

Treatment of DHPR deficiency was limited due to a very small number of patients. In 5 patients with DHPR deficiency,^e128–e130 all used l‐dopa/DCI combined with 5‐HTP. The reported doses of l‐dopa/DCI and 5‐HTP ranged from 1 to 15.8 mg/kg daily and from 0.9 to 11 mg/kg daily, respectively. BH₄ was used in 3 patients,^e128–e130 2 of whom stopped it due to economic problems.^e128,e130 The reported dose of BH₄ ranged from 2.5 to 40 mg/kg daily.

TH Deficiency

In 70 patients with TH deficiency,^{e9,e33,e38,e131–e162} l‐dopa monotherapy (64.3%) was the most commonly used maintenance treatment.^{e9,e33,e38,e131,e132,e134,e135,e137–e139,e141,e144,e145,e147,e148,e150–e153,e155,e156,e159,e161,e162} One patient received bilateral subthalamic nucleus deep brain stimulation, which produced a remarkable improvement with l‐dopa treatment.^e139 Reported doses of l‐dopa/DCI ranged from 0.1 to 52.1 mg/kg daily or from 25 to 1000 mg daily, with benefit reported in 61 of 70 patients. LIDs were frequently reported (24 patients; 34.3%) (Appendix: e‐References^{e33,e132,e135–e137,e139–e141,e143,e144,e146,e149,e150,e152–e154,e157–160}; see online supporting information). Among these patients, 2 used amantadine with improvement in LIDs.^e132,e137 Monoamine oxidase B (MAO‐B) inhibitors like selegiline were used in 22 patients who had a partial response or side effects from l‐dopa^{e133–e136,e140–e143,e146,e149,e152,e154,e157,e158,e160}; of these, 17 patients were treated with a combination of l‐dopa and selegiline.^{e133,e136,e140–e142,e146,e149,e152,e154,e157,e158,e160} This regimen was the second most commonly used treatment (24.3%). Reported doses of selegiline ranged from 0.2 to 0.4 mg/kg daily or from 0.5 to 15 mg daily, with benefit reported 17 of 22 patients. Dopamine agonists and anticholinergics were rarely used with little beneficial effect.^{e134,e135,e139,e141,e152,e158,e160}

AADC Deficiency

In 32 patients who had AADC deficiency,^e163–e172 dopamine agonists combined with MAOIs (75%) constituted the most commonly used maintenance treatment.^{e163,e167,e169,e171} Unlike in other enzyme defects, l‐dopa was rarely used in patients with AADC deficiency. Although the response to l‐dopa was poor compared with that produced by other enzyme deficiencies, 4 of 7 patients had a beneficial effect without LIDs.^{e165,e167,e168,e172} Dopamine agonists were the most commonly used drug. The dopamine agonists used in AADC deficiency included pergolide, bromocriptine, pramipexole, ropinirole, and rotigotine patches; but the response to each drug varied.^e163–e172 MAOIs were the second most commonly used and showed beneficial effects in 8 of 24 patients.^{e163,e165,e167–e169,e171,e172} Nonselective MAOIs like tranylcypromine were used more frequently than selective MAO‐B inhibitors. Anticholinergics were used in 11 patients,^{e163,e166–e168,e170,e171} but only 3 of those patient had a minimal beneficial effects from trihexyphenidyl.^{e166,e167,e170} In all patients who used anticholinergics, it was combined with dopamine agonists and MAOIs.

Neurological Outcome

Motor outcome is graded as “excellent,” “good‐fair,” and “poor” according to clinical impression, degree of disability, and dependence in daily activities. An “excellent” outcome is defined as a remarkable improvement upon adequate treatment, which results in usual activities without assistance. A “good‐fair” outcome is defined as a partial or moderate improvement, which might result in usual activities with some help. A “poor” outcome is defined as a very small or no improvement despite the appropriate treatment, which results in severe disability or a bedridden state. Cognitive outcome is evaluated based on test results, school performance, social functioning and clinical impression.

Motor

Motor outcome differed according to the type of enzyme defect (Fig. 2). Patients with AD GCH‐1 deficiency mostly had excellent motor outcomes. Of the 319 patients who had AD GCH‐1 deficiency,^{e1–e13,e15–e24,e26–e33,e35–e51,e53–e59,e61–e63,e65–e69,e71–e77,e79–e93,e95,e96} 301 patients (93.4%) had an excellent motor outcome,^{e1–e13,e15–e17,e19–e24,e26–e33,e35–e47,e49–e51,e53–e59,e61,e63,e65–e69,e71–e77,e79–e93,e95,e96} and 16 patients (5%) had a good‐fair motor outcome.^{e3,e17–e19,e26,e35,e36,e45,e48,e53,e55,e68,e69,e72} Only 2 patients had a poor motor outcome despite receiving the appropriate treatment.^e62,e72 Interestingly, patients with SR deficiency had motor outcomes similar to those reported in patients with AD GCH‐1 deficiency. Of the 24 patients who had SR deficiency,^{e33,e113–e125,e127} 22 (91.7%) had an excellent and sustained motor response to treatment.^{e33,e113–e119,e121–e123,e125,e127} Patients who had TH, AR GCH‐1, PTPS, and DHPR deficiencies had less favorable motor outcomes compared with those who had AD GCH‐1 and SR deficiencies. However, these results were limited due to the low number of patients who had AR GCH‐1, PTPS, and DHPR deficiencies. Those who had AADC deficiency had very limited success with treatment. Of the 32 patients who had AADC deficiency,^e163–e172 only 1 had an excellent motor outcome,^e167,e169 whereas 17 patients (53.1%) had a poor motor outcome despite various therapeutic trials.^{e163,e165,e167,e168,e171,e172}

Figure 2.

Motor outcomes are illustrated according to the enzyme defect in patients with dopa‐responsive dystonia (DRD) and DRD‐plus. AD, autosomal dominant; GCH‐1, guanosine triphosphate cyclohydrolase 1; AR, autosomal recessive; PTPS, 6‐pyruvoyltetrahydropterin synthase; SR sepiapterin reductase; DHPR, dihydropteridine reductase; TH, tyrosine hydroxylase; AADC, aromatic L‐amino acid decarboxylase.

Cognition

Unlike motor outcomes, cognitive outcomes were unfavorable. Regardless of the type of enzyme defect, most patients with cognitive impairment had little or no response to treatment. Of 408 patients with AD GCH‐1 deficiency,^e1–e96 six reported cognitive impairment that was not improved despite treatment, whereas their motor symptoms were remarkably improved.^e26,e35,e53 In patients with DRD‐plus, long‐term cognitive development commonly was subnormal. Despite early therapeutic intervention, mental retardation was reported in 10 of 27 patients (37%) with SR deficiency,^{e33,e116,e118,e123,e125}, in 28 of 70 patients (40%) with TH deficiency,^{e33,e133,e135,e136,e140–e143,e148,e149,e152,e154,e157–e160} and in 21 of 32 patients (65.6%) with AADC deficiency.^{e164–e168,e171,e172} Cognitive outcomes in patients who had AR GCH‐1, PTPS and DHPR deficiencies were limited because of low patient numbers.

Therapeutic Recommendations

We present therapeutic recommendations for the treatment of DRD and DRD‐plus. The recommendations are based on case series, clinical experience, and molecular pathways. First‐line treatment, second‐line treatment, and recommended doses are proposed (Table 3). In all types of DRD and DRD‐plus, early therapeutic intervention is very important, because it is associated with favorable outcomes.

Table 3.

Recommended Treatment in Patients with DRD and DRD‐Plus

Enzyme Defect	First‐line Treatment	Second‐line Treatment	Drug	Recommended Dose, mg/kg/Day
				Starting	Maintenance
AD GCH‐1	l‐dopaa	Anticholinergics	l‐dopaa	25–50 mg/day	100–300 mg/day
			Trihexyphenidyl	2 mg/day	6–10 mg/day
AR GCH‐1/PTPS/DHPR	l‐dopaa + 5‐HTP + BH4	DAs	l‐dopaa	1–2 (PTPS, 0.5–1)	10–15
			5‐HTP	1–2	5–10
	Plus folic acid (only DHPR)		BH4	1–2	5–10 (keep serum Phe below 120 μM)
			Pramipexole	Undetermined	0.02–0.04
			Folic acid	5	15–20
SR	l‐dopaa + 5‐HTP	Undetermined	l‐dopaa	0.5–1	2–5
			5‐HTP	1	2–4
TR	l‐dopaa	MAOIs	l‐dopaa	0.5–1 (25–50 mg/day)	4–10 (200–400 mg/day)
			Selegiline	0.1 (0.5–1 mg/day)	0.2–0.4 (5–10 mg/day)
AADC	DAs + MAOIs	Anticholinergics	Rotigotine	1–2 mg/day	6–8 mg/day
			Bromocriptine	1–2 mg/day	5–10 mg/day
	Plus pyridoxine		Tranylcypromide	5 mg/day	10–15 mg/day
			Pyridoxine	100 mg/day	200–400 mg/d
			Trihexyphenidyl	Undetermined	Undetermined

^aThis was levodopa (l‐dopa) with decarboxylase inhibitor.

AD, autosomal dominant; GCH‐1, guanosine triphosphate cyclohydrolase 1; AR, autosomal recessive; PTPS, 6‐pyruvoyltetrahydropterin synthase; DHPR, dihydropteridine reductase; 5‐HTP, 5‐hydroxytryptophan; BH₄, tetrahydrobiopterin; DAs, dopamine agonists; Phe, phenylalanine; SR, sepiapterin reductase; T, tyrosine hydroxylase; MAOIs, monoamine oxidase inhibitors; AADC, aromatic L‐amino acid decarboxylase.

l‐Dopa

l‐dopa is used as first‐line treatment in all types of DRD and DRD‐plus except for AADC deficiency. According to the current review, almost half of patients who had DRD‐plus caused by AADC deficiency had a beneficial effect from l‐dopa. However, it is not recommended, because l‐dopa may result in the depletion of S‐adenosylmethionine, which is enhanced by AADC deficiency and can lead to a deficiency in 5‐methyltetrahydrofolate.7 Thus, dopamine agonists are preferred for the treatment of AADC deficiency, as described below.

In general, l‐dopa is used with DCIs like as carbidopa or benserazide to block the peripheral conversion to dopamine. This coadministration not only increases bioavailability but also reduces peripheral side effects.8 The recommended therapeutic dose of l‐dopa varies according to the type of enzyme defect. In DRD caused by AD GCH‐1 deficiency, the recommended starting dose of l‐dopa is from 25 to 50 mg daily and thereafter is titrated up to 100 to 300 mg daily. In DRD‐plus, a higher recommended maintenance dose of l‐dopa is needed for patients who have AR GCH‐1, PTPS, and DHPR deficiencies compared with those who have SR deficiency.

Clinicians should be cautious, because LIDs can occur commonly in patients with DRD‐plus, especially because of SR, TH, and PTPS deficiencies. The current study showed that LIDs were reported in 37%, 34.3%, and 44.4% of patients who had SR, TH, and PTPS deficiencies, respectively. In such patients, a very low starting dose of l‐dopa with from 0.5 to 1 mg/kg daily divided into 4 to 6 doses is recommended.

Amantadine

Amantadine is a drug that functions both as a partial dopamine agonist and as a partial N‐methyl‐D‐aspartic acid receptor antagonist. If dose adjustment of l‐dopa is insufficient to treat LIDs in patients with DRD and DRD‐plus, then amantadine should be considered. The recommended dose of amantadine is from 4 to 6 mg/kg daily.9

Dopamine Agonists

Dopamine agonists are considered first‐line treatment for patients who have DRD‐plus caused by AADC deficiency, and it is a second‐line treatment for those who have DRD‐plus caused by deficiencies in AR GCH‐1, PTPS, and DHPR. Pergolide, bromocriptine, pramipexole, ropinirole, and rotigotine were used to treat DRD and DRD‐plus. Based on the therapeutic response and frequency of use, rotigotine and bromocriptine are recommended in AADC deficiency, and pramipexole is recommended in AR GCH‐1, PTPS, and DHPR deficiencies. The recommended starting doses of rotigotine and bromocriptine are 1 or 2 mg daily and are titrated up to 6 to 8 mg daily and 5 to 10 mg daily, respectively. The recommended maintenance dose of pramipexole is from 0.02 to 0.04 mg/kg daily.

MAOIs

Nonselective MAOIs like tranylcypromine are the first‐line treatment for DRD‐plus caused by AADC deficiency, whereas selective MAO‐B inhibitors like selegiline are the second‐line treatment for DRD‐plus caused by TH deficiency. Selective MAO‐B inhibitors in AADC deficiency are not recommended, because they do not block the breakdown of serotonin. The recommended starting dose of tranylcypromine is 5 mg daily and is titrated up to 10 to 15 mg daily. However, clinicians should be careful, because tranylcypromine can lead to hypertensive crisis due to raised tyramine levels, which might be fatal.8 On the other hand, the recommended starting dose of selegiline is 0.1 mg/kg daily or 0.5 to 1 mg daily and is titrated up to 0.5 to 1 mg daily or 5 to 10 mg daily, respectively.

BH₄

BH₄ is used to reduce phenylalanine levels in a hyperphenylalaninemia state caused by deficiencies in AR GCH‐1, PTPS, and DHPR. Although the patients with AR GCH‐1 and DHPR deficiencies had insufficient data to prove the efficacy and safety of BH₄, it is recommended as a supplement to treatment.10 Thus,BH₄ is considered a first‐line treatment for DRD‐plus caused by deficiencies of AR GCH‐1, PTPS, and DHPR. The recommended staring dosage of BH₄ is 1 or 2 mg/kg daily and is titrated up to 5 to 10 mg/kg daily. In general, BH₄ is used in combination with l‐dopa and 5‐HTP, because it is ineffective in correcting neurotransmitter deficiencies due to poor permeability through the blood‐brain barrier.11 During treatment, the recommendation is to adjust the BH₄ dose to maintain the serum phenylalanine level below 120 μmol/L.12

5‐HTP

5‐HTP, a biosynthetic precursor of serotonin, is a first‐line treatment for deficiencies of AR GCH‐1, PTPS, SR, and DHPR. Because 5‐HTP increases serotonin levels, it may have a beneficial effect on psychomotor dysfunction, sleep disturbances, and gastrointestinal problems in patients with DRD‐plus.13 A higher recommended maintenance dose of 5‐HTP is needed in patients who have AR GCH‐1, PTPS, and DHPR deficiencies compared with those who have SR deficiency. Clinicians should be cautious, because 5‐HTP has a variety of side effects, such as nausea, vomiting, anxiety, abdominal pain, diarrhea, and sleepniess.13

Anticholinergics

Anticholinergics are considered second‐line treatment for DRD caused by AD GCH‐1 deficiency and for DRD‐plus caused by AADC deficiency. However, response to anticholinergics in our systematic review was much better in patients who had AD GCH‐1 deficiency than in those who had AADC deficiency. In DRD caused by AD GCH‐1 deficiency, the recommended staring dose of trihexyphenidyl is 2 mg daily and is titrated up to 6 to 10 mg daily. In DRD‐plus caused by AADC deficiency, the recommended starting and maintenance doses of selegiline are not determined due to a lack of data.

Vitamin B

Treatment with folic acid and pyridoxine especially should be considered in patients who have DRD‐plus. Folic acid is recommended for DRD‐plus caused by DHPR deficiency, because DHPR has an important role in maintaining the folate level in its active form.14 Recommended starting and maintenance doses of folic acid are 5 mg daily and from 15 to 20 mg/kg daily, respectively. Pyridoxine is recommended for DRD‐plus caused by AADC deficiency to boost residual AADC activity through cofactor excess, although patients with AADC deficiency do not have a depletion of pyridoxine 5′‐phosphate.15 The recommended staring dose of pyridoxine is 100 mg daily and is titrated up to 200 to 400 mg daily.

Conclusions

DRD and DRD‐plus have considerable heterogeneity with clinical, biochemical, and genetic features. They are important to recognize, because many have a good clinical response to the appropriate treatment. Therefore, it is our hope that this review will help clinicians plan treatment for their patients with DRD and DRD‐plus.

Because therapeutic strategies differ according to the type of enzyme defect, genetic studies should be done for diagnostic confirmation. Analysis of neurotransmitters in cerebrospinal fluid or measurement of enzyme activity will also help to make the diagnosis. However, there is controversy about treatment for patients who have DRD and DRD‐plus with an undetermined genetic defect, because several disorders, such as early onset Parkinson's disease with parkin gene and dopamine transporter deficiency syndrome, can have clinical features that are similar to dopaminergic responsiveness. Thus, it is very important to exclude mimicking disorders in patients with a clinical suspicion of DRD or DRD‐plus.

The current study has several limitations. First, the data associated with outcomes, including motor and cognition, were heterogeneous, because the patients were not evaluated by the same tests, and the follow‐up period was significantly different. Second, although it was reported that outcomes might differ in relation to the promptness of treatment,16 we could not confirm a correlation between the onset of treatment initiation and neurologic outcome, because those data were missing in many of the included articles. Third, treatment outcomes and recommendations for patients who had DRD‐plus caused by PTPS and DHPR deficiencies were limited because of the low patient numbers. Although there were many patients with PTPS and DHPR deficiencies who had genetic confirmation, many of them were not included, because dystonia was not described in the reports. However, we believe that dystonia could be overshadowed by other neurologic symptoms and signs from a depletion of serotonin and norepinephrine in DRD‐plus, which might be underestimated compared with the actual incidence. Therefore, detailed physical examination in further studies will be required to help establish evidence‐based treatment for patients with DRD‐plus as well as DRD.

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

R.K.: 1B, 1C, 3A

B.J.: 1A, 3B

W.W.L.: 1A, 3B

Disclosures

Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for the previous 12 months: The authors report no financial disclosures.

Supporting information

Appendix S1. Supporting e‐References.

Figure S1. Flowchart of the literature review.

Table S1. Benefit, reported dose, and side effects of used drugs in DRD and DRD‐plus patients.