Acta Neurologica Belgica

https://doi.org/10.1007/s13760-020-01574-1

REVIEW ARTICLE

Dopa‑responsive dystonia, DRD‑plus and DRD look‑alike: a pragmatic

review
Ajith Cherian1 · Naveen Kumar Paramasivan1 · K. P. Divya1

Received: 28 September 2020 / Accepted: 10 December 2020

© Belgian Neurological Society 2021

Abstract
Dopa-responsive dystonia (DRD) and DRD plus are diseases of the dopamine pathway with sizeable genetic diversity and
myriad presentations. DRD has onset in childhood or adolescence with focal dystonia, commonly affecting lower limb, diur-
nal fluctuations with evening worsening of symptoms and a demonstrable sleep benefit. DRD “plus” has “atypical features”
which include infantile onset, psychomotor delay, cognitive abnormalities, oculogyric crisis, seizures, irritability, spasticity,
hypotonia, ptosis, hyperthermia and cerebellar dysfunction. Neurodegeneration, however, is not a feature of either DRD
or DRD-plus disorders. Tetrahydrobiopterin (BH4), a key cofactor, deficiency leads to inadequate dopamine and serotonin
synthesis. Norepinephrine deficiency may coexist, depending on the enzyme defect. Hyperphenylalaninemia (HPA) is a clue
for BH4 paucity. However, HPA is conspicuously absent in autosomal-dominant guanosine triphosphate cyclohydrolase 1
deficiency and sepiapterin reductase deficiency. DRD look-alike is a group of neurodegenerative disorders involving the
nigrostriatal dopaminergic system, which could present with dystonia responsive to dopaminergic drugs or neurodegenera-
tive or non-neurodegenerative disorders without involving the nigrostriatal dopaminergic system yet responsive to levodopa.
Although levodopa is the mainstay of therapy, response to this drug can be unsatisfactory in DRD plus and DRD look-alike
and other drugs are tried. Simultaneous management of HPA leads to remarkable improvement in both motor and cogni-
tive functions. The aim of this review is to help neurology practitioners in treating patients with DRD, DRD-plus and DRD
look-alike as many of them have excellent outcome with appropriate therapy.

Keywords Tetrahydrobiopterin · BH4 · Neurotransmitter · Guanosine triphosphate · Sepiapterin · Hyperphenylalaninemia ·

Segawa · Fluctuating dystonia · Dopa-responsive dystonia

Introduction “hereditary progressive basal ganglia disease with marked

The earliest description of dopa-responsive dystonia (DRD)
was given by Beck et al. in 1947, when he described a young
girl with lower-limb predominant generalized dystonia and
tremor with a positive family history [1]. Corner noted
fluctuations in her dystonia and improvement with trihexy-
phenidyl several years later [2]. Segawa characterized the
clinical features more thoroughly in his classic report titled
Ajith Cherian and Naveen Kumar Paramasivan are joint first
authors and have contributed equally to the manuscript.
* K. P. Divya
drdivyakp01@gmail.com
1
Department of Neurology, Sree Chitra Tirunal Institute
for Medical Sciences and Technology, Thiruvananthapuram,
Kerala 695011, India
diurnal fluctuations” [3]. In 1988, Nygaard gave the term
“dopa-responsive dystonia” to reflect the core clinical char-
acteristics of dopamine responsiveness, by which name it is
known since then [4].
Materials and methods
We searched PubMed, Medline, JSTOR (journal storage)
and EMBASE electronically for articles from 1990 to
August 2020 using the MeSH terms “dopa responsive dys-
tonia,” “DYT 5,” “Segawa disease,” “GTP cyclohydrolase 1
deficiency,” “tyrosine hydroxylase deficiency,” “sepiapterin
reductase deficiency,” “6-pyruvoyltetrahydropterin synthase
deficiency,” “dihydropteridine reductase deficiency,” “aro-
matic L-amino acid decarboxylase deficiency,” and “Tet-
rahydrobiopterin.” For inclusion, articles written in English

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Vol.:(0123456789)

were retrieved. We screened titles, abstracts, or entire arti-
cles, and consequently, our systematic review identified 281
relevant articles. Directives according to the SIGN (Scottish
Intercollegiate Guidelines Network) methodology advised
by the International Working Group on Neurotransmitter
related Disorders were also incorporated [5].
DRD
The classic presentation of DRD consists of onset in
childhood or adolescence with focal dystonia, commonly
affecting lower limb. These patients have marked diurnal
fluctuations with evening worsening of symptoms and a
demonstrable sleep benefit. They have a dramatic and sus-
tained improvement of their symptoms with small doses of
levodopa with hardly any motor complications. These core
clinical characteristics are used to define the typical “DRD
phenotype.” The responsiveness to dopamine replacement
therapy is used as a diagnostic marker of this disease. It is a
practical recommendation that any childhood-onset dystonia
should be given a trial of levodopa, which is both diagnostic
and therapeutic [4].
Traditionally, DRD is defined as an entity characterized
by deficiency of nigrostriatal dopaminergic system due to
genetic defects in the dopamine synthetic pathway without
evidence of nigral cell loss [6]. Although nigrostriatal dopa-
minergic deficiency could lead to various neurologic symp-
toms, by convention only the motor manifestations, mainly
dystonia and mild parkinsonism, are considered.
DRD‑plus
DRD-plus is a group of disorders caused by genetic defects
in the dopamine synthesis pathway without nigral cell loss,
which have features of DRD, “plus” features that are atypical
for the classic DRD phenotype. These “atypical features”
include infantile onset, psychomotor delay, cognitive abnor-
malities, oculogyric crisis, seizures, irritability, spasticity,
hypotonia, ptosis, hyperthermia and cerebellar dysfunction
[7]. These disorders do not respond to levodopa therapy as
dramatically as the classic DRD and require higher doses
and often develop motor complications related to therapy.
The involvement of other parts of the neuraxis is often due
to the deficiency of neurotransmitters such as serotonin and
noradrenaline [5]. DRD and DRD-plus phenotypes have no
evidence of neurodegeneration.
DRD look‑alike
DRD look-alike is a group of:
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Acta Neurologica Belgica
• neurodegenerative disorders involving the nigrostriatal
dopaminergic system, which could present with dystonia
responsive to dopaminergic drugs or
• neurodegenerative or non-neurodegenerative disorders
without involving the nigrostriatal dopaminergic system,
yet show response to levodopa [7]
Accordingly, all neurodegenerative disorders with defects
in the dopamine synthesis are classified as DRD look-alike,
e.g., juvenile Parkinson’s disease (PD) [7], pallidopyramidal
syndrome [8], spinocerebellar ataxia 3 [9]. Disorders with-
out involvement of the dopaminergic system that have dopa
responsiveness are also included under the term DRD look-
alike, which could be again non-neurodegenerative-like glu-
cose transporter type 1 (GLUT1) deficiency [10], dystonic
cerebral palsy (CP), dystonia 1(DYT1) [11], myoclonus
dystonia [12] or degenerative-like ataxia telangiectasia [13]
and hereditary spastic paraplegia 11 [14]. Diseases that are
partially responsive to dopaminergic drugs but are not due
to disorders of dopamine synthesis are also included here,
e.g., transportopathies like dopamine transporter (DAT)
deficiency, vesicular monoamine transporter 2 (VMAT2)
deficiency [15, 16] as well as mutations in genes such as
SOX6 that play a vital role in the regulation of dopaminergic
neurons, cortical interneurons and oligodendroglial cells [6,
17, 18].
This classification has therapeutic and prognostic impli-
cations. DRD look-alike disorders like juvenile PD would
require escalating doses of levodopa, are prone to developing
wearing-off phenomenon and with time manifest levodopa-
induced dyskinesias. The response rates may decline with
worsening neurodegeneration. Classic DRD has a much bet-
ter prognosis than DRD-plus or look-alikes.
Etiopathogenesis of DRD and DRD plus
The manifestations of DRD are due to the deficiencies of
the monoamines and tetrahydrobiopterin (BH4), an essen-
tial cofactor of various enzymes in the dopamine synthesis
pathway. BH4 is also involved as a cofactor in phenylalanine
metabolism. The nature of the enzymatic defect, its severity
and the functional protein produced ultimately determine
the clinical manifestations, rather than the number or type
of mutations [19]. Depending on the severity of the enzy-
matic defect, the same mutation may present as DRD or
DRD-plus. The classical DRD is caused most commonly
due to deficiencies in guanosine triphosphate-cyclohydrolase
1(GTP-CH1), a rate-limiting enzyme in the synthesis of BH4
(Fig. 1a) [20]. There are, however, downstream enzymatic
defects that could lead to similar presentation, although they
are less common compared to the GTP-CH1 deficiency.
These rarer downstream enzymatic defects involve 6-pyru-
voyl tetrahydropterin synthase, sepiapterin reductase and
Acta Neurologica Belgica
Fig. 1  a. Synthesis and recycling of tetrahydrobiopterin (BH4).
b. Role of BH4 as a cofactor in the synthesis of monoamines and
phenylalanine metabolism. Dotted lines indicate the salvage path-
way. Green, blue and orange boxes denote cofactors, enzymes and
diagnostic metabolites, respectively. GTP Guanosine-5′-triphosphate;
PTP-6-pyruvoyl tetrahydropterin; SR sepiapterin reductase; CR car-
bonyl reductase; AR aldose reductase; DHFR dihydrofolate reductase;
BH4 tetrahydrobiopterin; 7,8-BH2 7,8-dihydrobiopterin; q-BH2 qui-
tyrosine hydroxylase [21]. Not all defects in the enzymes
involved in the pathway lead to DRD. Deficiency of pterin
4a-carbinolamine dehydratase is compensated by other
enzymes, and they do not develop DRD although they have
hyperphenylalaninemia at birth [22, 23].
Based on the nature of enzymatic defects in disorders
causing DRD, DRD-plus and DRD look-alike, they can be
grouped as:
a) Enzymatic defects in BH4 synthesis or recycling [GTP
cyclohydrolase 1 (GTP-CH1), sepiapterin reductase
nonoid dihydrobiopterin; DHPR dihydropteridine reductase; PCD
pterin 4a-carbinolamine dehydratase; PLP pyridoxal 5′-phosphate;
VLA vanillyl lactic acid; DOPAL 3,4-dihydroxy phenyl acetalde-
hyde; 5-HIAL 5 hydroxy indole acetaldehyde; VMA vanillyl mandelic
acid; HVA homovanillic acid; 5-HIAA 5-hydroxy indole acetic acid;
VMAT2 vesicular monoamine transporter 2; DAT dopamine trans-
porter (color figure online)
(SR), dihydropteridine reductase (DHPR), 6-pyruvoyl
tetrahydropterin synthase (PTPS), pterin-4a-carbinola-
mine dehydratase (PCD) deficiencies] (Fig. 1a)
b) Primary neurotransmitter synthesis defects [tyrosine
hydroxylase (TH), aromatic amino acid decarboxylase
deficiency (AADC) deficiencies] (Fig. 1b)
c) Monoamine transportopathies (DAT and VMAT2 defi-
ciencies) [24]. (Fig. 1b)
A) Enzymatic defects in BH4 synthesis or recycling
1) GTP cyclohydrolase 1 (GTP-CH1) deficiency
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GTP-CH1 is encoded by the gene GCH1 in chromosome
14q (14q22.1–2.2) [25]. Mutations in GCH1 gene can be
autosomal-dominant (AD) or autosomal-recessive (AR). The
dominant form of this deficiency is conventionally referred
to as Segawa’s syndrome. The AD form has mutation in one
GCH1 allele, accounting for a milder disease phenotype,
while the AR form has defects in both GCH1 alleles, leading
to severe disease phenotype with severe reduction in BH4
levels. GCH1 is a typical example of how mutations in the
same gene can give rise to DRD or DRD-plus phenotypes
depending on the severity.
AD form of GTP-CH1 deficiency results from a dominant
negative effect of the mutation in GCH1 leading to reduced
function of the wild-type GTP-CH1 protein [26]. In AD form
of GTP-CH1 deficiency, there is residual amount of enzyme
activity which is present as opposed to its total absence in
the recessive form. So there is no hyperphenylalaninemia
(HPA) in the AD form. However, if an oral loading test with
phenylalanine (100 mg/kg) is given, the partial enzyme
deficiency can be unmasked and HPA may result. This is
based on the fact that, due to the partial BH4 deficiency in
the liver, in loading conditions phenylalanine hydroxylase
is not able to convert phenylalanine to tyrosine at a normal
rate resulting in HPA. The AD form of disorder presents
as classic DRD phenotype, with childhood-onset focal limb
dystonia that subsequently generalizes and shows very good
response to levodopa. Diurnal fluctuations, often found in a
vast majority of patients, become less frequent with time
and disappear by third decade [27]. Childhood-onset forms
manifest as focal dystonia, whereas onset after 15 years
manifests as parkinsonism [28, 29]. Atypical presentations
like proximal weakness with waddling gait and generalized
hypotonia have been reported [30]. Though non-motor fea-
tures like depression, obsessive compulsive disorders and
anxiety have been documented, probably due to downstream
monoaminergic deficiencies [28], intellectual development
is affected only in a very small subset of patients.
In some parkinsonian patients (mean age of onset 43.2 ±
13.4 years), pathogenic GCH1 variants have been identified
with classic dopamine transporter imaging abnormalities,
suggesting nigrostriatal dopaminergic denervation as in idio-
pathic PD. Even if a family history for DRD is lacking, these
pathogenic GCH1 variants could contribute to the hazard of
developing PD. The frequency of GCH1 variants, in whole-
exome sequencing data, has revealed it to be significantly
higher in PD cases than in controls with an odds ratio of 7.5.
So rare GCH1 variants are associated with an increased risk
of PD, suggesting that it can bring about biochemical striatal
dopamine depletion and nigrostriatal cell loss leading to late
age idiopathic PD-like presentation [31].
AR form of GTP-CH1 deficiency leads to more severe
reduction of BH4 levels, HPA, serotonin and dopamine
depletion due to downstream effects, manifesting with
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Acta Neurologica Belgica
infantile axial hypotonia, rigidity, parkinsonism, chewing
and swallowing difficulties, oculogyric crisis, typical of
a DRD-plus phenotype. The amount of residual enzyme
activity often determines the clinical phenotype. This may
explain why mild homozygous and compound heterozy-
gous mutations have an intermediate severity of symptoms,
between AD and AR forms of GTP-CH1 deficiency [19].
2) Sepiapterin reductase (SR) deficiency
It is of AR inheritance with less severe deficiency in BH4.
SR deficiency occurs due to mutations in SPR gene on chro-
mosome 2p14-2p12 [32]. It does not cause HPA unlike other
defects due to compensation by the salvage pathway, which
restores BH4 levels in the liver but not in the brain, causing
only neurological dysfunction [22]. It can present as both
DRD [33] and DRD-plus phenotypes [34, 35] depending
on the severity of mutations. Common presentations include
infantile-onset axial hypotonia, motor and language devel-
opmental delay with oculogyric crisis which are highly
characteristic of this disorder [35]. Dystonia is not always
present, especially in infancy and was found only later in
about 50% of patients in a review [35]. In contrast to GTP-
CH1 deficiency, the vast majority of SR-defective patients
show signs of cognitive learning disabilities. Endocrinologi-
cal disturbances such as hypoglycemia and growth-hormone
deficiency have been identified as early symptoms of dopa-
mine depletion in SR deficiency. The disease has an excel-
lent response to levodopa, with 5-hydroxy tryptophan pro-
viding benefits in cognitive aspects [34]. Additional agents
including serotonin reuptake inhibitors (SSRI), monoamine
oxidase (MAO) inhibitors, dopamine/noradrenaline reuptake
inhibitors, have shown to have some benefits (Table 1).
3) 6-Pyruvoyl tetrahydropterin synthase (PTPS) deficiency
PTPS deficiency due to mutations in the PTPS gene is
the most common disorder of BH4 synthesis accompa-
nied by HPA. In PTPS deficiency, there is accumulation
of the immediate preceding metabolite dihydroneopterin
triphosphate (see Fig. 1a). Dihydroneopterin triphosphate
is non-enzymatically converted to neopterin, and its level
is increased. However, salvage pathway enzymes cannot
act on neopterin. Therefore, 6-PTPS deficiency leads to
severe BH4 deficiency and resultant HPA that is detected
during neonatal screening and can be treated with BH4 and
dopamine therapies to prevent the development of DRD or
DRD-plus later. Cognitive and neurological abnormalities
are seen in the severe form of the disease, and outcomes cor-
relate with CSF biogenic amine depletion [36]. PTPS often
causes poorer motor outcomes compared to other common
enzymatic defects [37], but early treatment has shown better
results [38].
Acta Neurologica Belgica
4) Dihydropteridine reductase (DHPR) deficiency
During hydroxylation by amino acid hydroxylases, BH4
is oxidized to pterin-4a-carbinolamine. The subsequent
regeneration of BH4 by pterin-4a-carbinolamine dehy-
dratase (PCD) and DHPR ensures a continuous supply of
reduced cofactor and prevents accumulation of harmful
metabolites (Fig. 1a). DHPR deficiency is due to muta-
tions in the QDPR gene. Though BH4 synthesis is sound,
the clinical outcome of this recycling enzyme deficiency
is poorer compared with primary BH4 synthesis defects.
Features include feeding problems during neonatal period,
hypersalivation, microcephaly, and developmental delay.
During infancy, truncal hypotonia with a complex dystonia
predominating movement disorder, parkinsonism, tremor,
as well as seizures occur [30]. CSF reveals reduced con-
centrations of serotonin and dopamine metabolites, namely
homovanillic acid (HVA) and 5-hydroxy indoleacetic acid
(5-HIAA). Treatment is mainly neurotransmitter precursor
replacement (Table 1). BH4 supplementation is avoided
due to the increased accumulation of potentially harmful
7,8-dihydrobiopterin. Guidelines recommend only a phe-
nylalanine-restricted diet to handle HPA associated with
DHPR deficiency [37]. Low CSF folate levels should be
corrected by administration of folinic acid, which has been
shown to increase L-dopa levels in the brain.
5) Pterin-4a-carbinolamine dehydratase (PCD) deficiency
PCD is the second enzyme in BH4 recycling catalyzing
the dehydration of pterin-4a-carbinolamine. PCD deficiency
is due to mutations in PCBD1 and results in mild HPA. PCD
deficiency is now thought to be a benign form of HPA more
than a neurotransmitter disorder. BH4 supplementation is
used as a therapeutic strategy to manage HPA. [37].
B) Primary neurotransmitter synthesis defects
1) Tyrosine hydroxylase (TH) deficiency
It is of AR inheritance and is due to mutations in TH gene
in chromosome 11p15.5 [39]. There are three variable types
of presentation. These include typical DRD [40], progressive
extrapyramidal movement disorder with parkinsonism and
dystonia (Type A) and progressive infantile encephalopa-
thy (Type B) [39]. The latter two types are classified under
DRD-plus phenotypes. The infantile parkinsonian variant
(Type A) has onset in infancy or childhood, shows levodopa
responsiveness and has diurnal fluctuations of dystonia.
Patients are often wheelchair bound as the disease advances.
Progressive infantile encephalopathy variant (Type B) has
onset in the neonatal period or early infancy, with features
of mental retardation, hypokinesia, rigidity, myoclonic jerks,
autonomic dysfunction with no diurnal fluctuations [39]. The
autonomic disturbances lead to lethargy irritability, dystonic
crisis and periods of pyrexia of unknown origin. Features
like oculogyric crisis, tremor, bilateral ptosis differentiate
this type from the infantile parkinsonian variant. Serotonin
is not deficient in patients with TH deficiency, but they have
deficiencies in dopamine, adrenaline and noradrenaline,
which explains the autonomic involvement. Dopamine defi-
ciency also leads to hyperprolactinemia and galactorrhea
[41, 42]. Although levodopa therapy controls the galactor-
rhea, hyperprolactinemia persists in these patients [41].
2) Aromatic amino acid decarboxylase deficiency
(AADC)
AADC enzyme, encrypted in the DDC gene, catalyzes
the metabolism of downstream metabolites in the synthesis
of dopamine and serotonin. They have an infantile onset
with a DRD-plus presentation with a higher prevalence
in the Asian population. Hypotonia is the most com-
mon manifestation followed by oculogyric crisis, marked
motor developmental delay and dystonia [43]. It can be
distinguished from other neurotransmitter deficiencies
by increased frequency of autonomic dysfunction. HVA
and 5-HIAA show dramatically decreased concentrations
in CSF. Combination treatment with dopamine agonists
activating postsynaptic dopamine receptors and MAO
inhibitors preventing the breakdown of dopamine and
serotonin, thereby increasing monoamine availability and
vitamin B6, are often used, although the response rate is
very poor. Majority of the patients often fail to achieve any
meaningful motor milestones, leading to bed-bound state,
feeding problems and frequent chest infections [44, 45].
C) Monoamine transportopathies
These are not disorders of dopamine synthesis but are
due to defects in dopamine reuptake from the synaptic
cleft or transportation of the neurotransmitters into the
vesicles. Two such entities are dopamine transporter defi-
ciency and vesicular monoamine transporter 2 deficiency.
These rare disorders have features of DRD- plus.
1) Dopamine transporter (DAT) deficiency
Dopamine reuptake is achieved by transmembrane
transporter proteins of solute carrier family 6 encoded by
SLC6A3 gene, and its mutations define the first inherited
dopamine “transportopathy” leading to dopamine dys-
homeostasis. A key step in the duration and intensity of
dopamine signaling is the reuptake of extracellular dopa-
mine that is principally mediated by the presynaptic dopa-
mine transporter, a ­Na+/Cl− dependent neurotransmitter
sodium symporter, expressed by dopaminergic neurons.
13

So the defect lies not in dopamine synthesis, but in dopa-
mine reuptake, and dopamine depletion with resultant
raised dopamine metabolites in CSF [15]. Postsynaptic D2
receptor over activity causes excess dopaminergic signal-
ing leading to hyperkinesia and sleep disturbance initially
and action on presynaptic dopamine synthesis regulater
auto receptors (D3), lead to decreased dopamine synthesis
in a negative feedback loop, earlier or later in the course.
Features include hyperkinetic movement disorders, which
shift towards parkinsonian symptoms with time. Infantile
dystonia-parkinsonism is the most common presentation,
with developmental delay and pyramidal signs reported
before 3 years. Eye movement abnormalities like saccadic
initiation delay and ocular flutter are characteristic of DAT
deficiency and serve to distinguish from disorders of dopa-
mine synthesis. CSF analysis shows increased HVA (dopa-
mine metabolite), to 5-HIAA (serotonin metabolite) ratios
varying from 5 to 13 much above the normal range of 1–4
and elevated urine HVA levels. CSF pterin profile is nor-
mal. Diagnosis is easily clinched with a DAT scan, which
shows virtually no uptake. DAT deficiency is only partially
responsive to dopa agonists [15]. Mutations in SLC6A3
lead to a continuum of phenotypes related to residual DAT
function, which determines the onset and severity of symp-
toms. Higher residual DAT activity may postpone the age
of disease onset [46].
2) Vesicular monoamine transporter 2 deficiency
(VMAT2) deficiency
It occurs due to mutations in SLC18A2, resulting in an
inability to transport neurotransmitters like dopamine, sero-
tonin, adrenaline and noradrenaline from the cytosol into the
synaptic vesicles, leading to depletion of the same [16]. The
clinical manifestations are often similar to AADC defects
as both have deficiencies in dopamine and serotonin. There
occurs no diurnal fluctuations of symptoms in VMAT2 defi-
ciency, and levodopa may worsen symptoms. Pramipexole
gives good benefit with improvement in parkinsonism and
amelioration of dystonic attacks.
Diagnosis
The first step would be to characterize the clinical phenotype
of the patients as classic DRD, DRD-plus or DRD look-
alike. This gives a clue to the underlying genetic abnormal-
ity. Patients with classic DRD phenotype often have defi-
ciencies in the GTP-CH1 activity, or less commonly in the
SR or TH enzymes. Those with DRD- plus phenotype could
be due to any of the enzyme deficiencies in the dopamine
synthesis pathway.
Clinically, the core feature of dopa responsiveness should
be established before labeling the disease as DRD spectrum.
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Acta Neurologica Belgica
This often involves small doses of 1–10 mg/kg/day of levo-
dopa given in divided doses along with a peripheral decar-
boxylase inhibitor such as carbidopa for children less than
6 years of age [14]. For children more than 6 years as well
as adults, higher doses are required, often up to 600 mg/day
of levodopa. Levodopa trial should be given for an adequate
period and response assessed before declaring as negative, in
which case the trial should be aborted [14]. Some infants and
children may show a delayed response, especially those with
DRD-plus phenotype. So it is prudent to continue the levo-
dopa trial for 3 months, before labeling the trial as negative.
After establishing levodopa responsiveness, it is essential to
differentiate between the various entities described above for
which ancillary investigations are available.
Neuroimaging
Routine magnetic resonance imaging (MRI) of the brain is
invariably normal in all patients with AD form of GTP-CH1
deficiency and almost all of SR and AR form of GTP-CH1
deficiency. Almost all patients with DHPR deficiency and
about 50% of PTPS deficiency had variable abnormalities
in the form of brain atrophy, periventricular white matter
changes, basal ganglia calcifications and delayed myeli-
nation [47]. As there was no specific pattern amongst the
BH4 deficiencies, routine MRI brain is indicated to rule out
other secondary causes of dystonia-like neuronal brain iron
accumulation. Dopamine transporter (DAT) and fluorodopa
positron emission tomography (PET) scans play a vital role
in differentiating DRD, which typically have normal uptake,
from juvenile and idiopathic PD which have a reduced
uptake [5, 48, 49] again reinforcing the fact that DRD is
a neurochemical disorder rather than a neurodegenerative
disorder.
Cerebrospinal fluid analysis (CSF) and blood testing
CSF analysis of metabolites and neurotransmitters plays
a crucial role in differentiating between various causes of
DRD. Defects in GTP-CH1, the most common cause, lead to
proximal synthesis defect, leading to low CSF neopterin and
biopterin levels. In symptomatic patients with classic DRD,
CSF neopterin levels are < 20% of normal values, whereas
in asymptomatic carriers, levels are about 20–40% of normal
values [50]. Defects in the latter part of the pathway such
as sepiapterin reductase(SR) can activate the salvage path-
way mediated by the carbonyl reductase (CR) and aldose
reductase (AR) enzymes and bypass the enzymatic steps
mediated by SR to produce BH4 (Fig. 1a). However, the
relatively low levels of dihydrofolate reductase (DHFR) in
the brain normally will impede the salvage pathway from
normalizing the BH4 levels. The salvage pathway leads to
raised levels of dihydrobiopterin from which biopterin is
Acta Neurologica Belgica
derived, leading to normal CSF neopterin and high biopterin
levels [51]. Tyrosine hydroxylase deficiency has a low CSF
HVA with normal 5-HIAA, while AADC deficiency leads
to low CSF HVA, 5-HIAA and elevated 3-O-methyl dopa
[52]. Among transportopathies, DAT deficiency is associ-
ated with increased CSF ratios HVA to 5-HIAA levels and
also elevated urine HVA levels [19]. Among disorders of
BH4 synthesis/recycling, hyperphenylalaninemia in blood
is found in AR form of GTP-CH1, PTPS, DHPR deficien-
cies, while it is normal in AD form of GTP-CH1, TH and
SR deficiencies [24]. Phenylalanine levels are also normal
in monoamine transportopathies as they occur distally in the
enzymatic pathway.
Phenylalanine loading test
Since BH4 is a cofactor for phenylalanine hydroxylase, its
deficiency can reflect on phenylalanine (PA) blood levels.
This involves oral administration of 100 mg/kg of PA [53]
and subsequently measuring the blood levels of PA, phe-
nylalanine: tyrosine ratios about 1–2 h later. Patients with
AD form of GTP-CH1 deficiency have normal baseline PA
levels, as the GCH-1 mutation selectively affects the brain
sparing the liver; however, they cannot process the extra load
of PA given in the test, leading to elevated levels. Results are
also abnormal with SR deficiency but are normal with TH
deficiency, thereby enabling in the differentiation between
these. In TH deficiency, the enzymatic defect being distal in
the pathway, PA, is converted to tyrosine normally, causing
no elevation of phenylalanine-to-tyrosine ratios. It should
be borne in mind that this loading test can be positive in
heterozygotes of phenylketonuria [54]. Pretreatment with
BH4 can normalize the levels of PA and tyrosine levels,
and hence, patients should not be on BH4 supplementation
prior to the test. Despite its false-positive and false-negative
results, it is especially helpful in situations where CSF stud-
ies cannot be performed [47].
Enzyme activity assays
The enzyme GTP-CH1 is not expressed in blood cells and
fibroblasts [19]. However, cytokine-stimulated skin fibro-
blasts have been used to assess the enzymatic activity of
GTP-CH1 [55]. Assays of TH are limited by the fact that TH
is expressed only in the cells of brain and adrenal medulla
[19]. Enzymatic assays can serve as a surrogate marker when
genetic defects are not found but are not of much practical
utility for the clinician.
Genetic testing
Testing for GCH-1 mutations, which are the most common
cause of DRD, is limited by the fact that there are over a 100
pathogenically distinct mutations characterized by nonsense,
missense mutations, deletions and duplications [14]. Moreo-
ver, a significant number of mutations are sporadic [56].
About 17% of patients in a cohort had no identifiable muta-
tion despite clinical and ancillary investigations pointing to
the diagnosis of DRD [57]. These patients may have unde-
tected mutations in the promoter regions. In many patients,
the causative gene was not found, although linkage analysis
mapped it to chromosome 14p [58]. The problem is further
compounded by the fact that the penetrance of GCH1 muta-
tions is 30%, implying that the presence of a mutation does
not necessarily lead to DRD phenotype or a diagnosis [59].
A lot rests on the correlation with the clinical phenotype
and other ancillary investigations to support the diagnosis
in such cases. Caution should be exercised in employing
genetic testing, as large deletions, duplications and repeat
expansions can be missed by whole-exome sequencing
(WES). Hence, if a genetic test is negative for a patient with
a suspected DRD, then other tests like CSF neurotransmitter
profiles should be performed.
Neuropathology
Pathologically there is no evidence of nigral cell loss, but
there is reduction in melanin in DRD [60], in contrast to
juvenile and idiopathic PD where is there is evidence for
neurodegeneration. The nigrostriatal neurons of DRD
undergo depletion of dopamine in the nerve terminals,
whereas in PD it is due to the depletion of dopamine in the
nigrostriatal axon terminals as well as in the perikaryons
located in the substantia nigra pars compacta with associated
nigral cell loss that accounts for the different neuropathol-
ogy [27].
Treatment
Levodopa is the cornerstone of therapy in these patients
(Table 1). The doses required are small compared to con-
ventional dosing for PD, and the regimens, schedules and
titration have to be individualized depending on the degree
of severity of the underlying genetic defect. In view of the
deleterious effects of HPA on the brain leading to irrevers-
ible neuropsychiatric symptoms as evidenced in patients
with phenylketonuria (PKU), reducing the levels through
a PA-reduced diet or supplementation with BH4 is essen-
tial [61]. Hence, disorders with HPA such as AR form of
GTP-CH1, PTPS, PCD and DHPR deficiencies should be
given a PA-reduced diet or sapropterin (a synthetic BH4
analogue) supplementation, while AD form of GTP CH-1
and SR deficiencies does not require the same [47] (Table 1).
5-Hydroxytryptophan (5-HTP) has been shown to have
beneficial effects in AR form of GTP-CH1, SR, PTPS and
13
 Acta Neurologica Belgica

Table 1  Overview of the treatment approach of selected inherited neurotransmitter disorders

Disorder Enzyme or Inheritance Treatment
protein defi-
ciency

Biopterin synthesis or recycling defects
Primary neurotransmitter synthesis defects TH
Monoamine transportopathies
AD GTP-CH1 AD L-Dopa starting at 1 mg/kg/d titrated up to 10 mg/kg/d combined with
carbidopa in 4:1 ratio,
AR GTP-CH1 AR L-Dopa starting at 1 mg/kg/d titrated up to 10 mg/kg/d combined with
carbidopa in 4:1 ratio; 5-HTP starting at 1 mg/kg/d titrated up to
6 mg/kg/d; BH4 at 1 to 10 mg/kg/d titrated according to PA levels
PTPS AR L-Dopa starting at 0.5–1 mg/kg/d titrated up to 10 mg/kg/d combined
with carbidopa in 4:1 ratio; 5-HTP starting at 1 mg/kg/d titrated up
to 8 mg/kg/d; BH4 1 to 10 mg/kg/d titrated according to PA levels
SR AR L-Dopa starting at 1 mg/kg/d titrated up to 10 mg/kg/d combined with
carbidopa in 4:1 ratio; 5-HTP starting at 1 mg/kg/d titrated up to
8 mg/kg/d; consider selegiline 0.03 to 0.2 mg/kg/d
DHPR AR L-Dopa starting at 0.5–1 mg/kg/d titrated up to 10 mg/kg/d;5-HTP
starting at 3 mg/kg/d titrated up to 11 mg/kg/d; PA level control only
by dietary measures; folinic acid 10–20 mg/d
PCD AR Consider BH4 titrated according to PA levels, early screening for
diabetes
AR L-Dopa starting at 0.5–1 mg/kg/d titrated up to 10 mg/kg/d combined
with carbidopa in 4:1 ratio; selegiline 0.1–0.4 mg/kg/d (max. dose
10 mg/d)
AADC AR Dopamine agonists: pramipexole base 5–10 μg/kg/d (max. 75 μg/
kg/d), ropinirole 0.25 mg/d (max. 24 mg/d), transdermal rotigotine
2 mg/d, increased weekly up to 8 mg/d, bromocriptine 0.1 mg/kg/d
up to 0.5 mg/kg/d
MAO inhibitors: selegiline 0.1 mg/kg/d increased every 2 weeks up to
0.3 mg/kg/d
Cofactors: pyridoxine 100 to 200 mg/d, pyridoxal
5′-phosphate 100–200 mg/d
SLC6A3 AR Pramipexole base 5–40 μg/kg/d, ropinirole 0.5 to 4 mg/d, transdermal
(DAT) rotigotine 6 mg/kg/d
SLC18A2 AR Pramipexole base 5–40 μg/kg/d
(VMAT2)

5-HTP 5-hydroxytryptophan; AADC aromatic L-amino acid decarboxylase; AD autosomal-dominant; AR autosomal-recessive; BH4 tetrahyd-
robiopterin; DBH dopamine β-hydroxylase; DHPR dihydropteridine reductase; DTDS dopamine transporter deficiency syndrome; GTP CH1
guanosine-5′-triphosphate cyclohydrolase1; MAO A/B monoamine oxidase A/B; PA phenylalanine; PCD pterin-4a-carbinolamine dehydratase;
PTPS 6-pyruvoyltetrahydropterin synthase; SR sepiapterin reductase; SSRI selective serotonin reuptake inhibitor; TH tyrosine hydroxylase;
VMAT2 vesicular monoamine transporter 2

DHPR deficiencies, although evidence is lacking for other
enzymatic defects [47]. Second-line therapies include dopa-
minergic agonists, monoamine oxidase (MAO) inhibitors for
treatment of AADC or VMAT2 deficiency, residual symp-
toms non-responsive to levodopa, or to manage motor com-
plications like dyskinesias or wearing-off phenomena. Third-
line agents include anticholinergics, catechol-O-methyl
transferase (COMT) inhibitors in patients with incomplete
response [47].
GTP‑CH1 deficiency
AD forms of GTP-CH1 deficiency respond very well
to doses of 50-200 mg of levodopa per day, given in
combination with a peripheral decarboxylase inhibitor [14].
Although, by definition, they are expected to show complete
and sustained response to levodopa, a small percentage do
not experience complete resolution of symptoms and have
residual dystonia or parkinsonism [28]. AR forms of GTP-
CH1 deficiency also respond well to levodopa, although
they require much higher doses of levodopa (6-10 mg/kg)
and have incomplete responses too. They often require con-
comitant supplementation with BH4 and 5-HTP, to replen-
ish the deficiencies. Patients with GTP-CH1 deficiencies
rarely develop levodopa-induced dyskinesias, which how-
ever may scarcely occur when initiated in higher doses [62]
and respond to reduction in the dosages or to treatment with
amantadine [56]. Levodopa is also shown to be safe in preg-
nant patients [29].

13
Acta Neurologica Belgica
SR deficiency
These patients also show excellent responses to levodopa,
although the incidence of dyskinesias rises to about 45%,
which subsides on reduction of dosages. Often they require
dosages ranging from 0.1 to 16 mg/kg/day of levodopa, with
a mean of 3.9 mg/kg/day [35].
TH deficiency
Type A variants have excellent responses to levodopa, while
Type B variants are poorly responsive and often have hyper-
sensitivity to levodopa necessitating initiation at extremely
low doses [39]. Levodopa responsiveness depends on the
severity of the disorder. Levodopa-induced dyskinesias are
more common in TH deficiency than in GTP-CH1 defi-
ciency, often occurring within a few months of starting the
therapy irrespective of the age of the patient [63].
AADC deficiency
They are often the most difficult to treat among enzymatic
defects of dopaminergic system as levodopa supplementa-
tion is an ineffective therapy due to this enzyme deficiency.
Combination treatments with dopamine agonists like prami-
pexole and ropinirole, use of enzyme cofactors pyridoxal
5′-phosphate and pyridoxine, MAO inhibitors like selegiline
often have been used in the vast majority of patients [43].
Transportopathies
Dopaminergic agonists have been show to improve symp-
toms in both DAT and VMAT2 deficiencies, and levodopa
is not of much benefit.
Specific role of BH4 and other vitamins
BH4 is an effective drug for DRD-plus due to paucity of
AR form of GCH-1, PTPS and DHPR. Suggested initial
dosage of BH4 is 1—2 mg/kg/day, slowly escalated up to
5—10 mg/kg /day. Isolated BH4 therapy fails in rectifying
neurotransmitter deficiencies due to poor blood brain bar-
rier permeability and is therefore used in combination with
levodopa and 5-HTP. BH4 doses are adjusted to maintain
the serum phenylalanine level below 120 µmol/L. Treatment
with folic acid and pyridoxine especially should be consid-
ered certain DRD-plus syndromes. Folinic acid is recom-
mended for DRD- plus caused by DHPR deficiency, because
DHPR has an important role in maintaining the folate level
in its active form. Recommended maintenance doses of
folinic acid are 10–20 mg daily. Pyridoxine is advised in
DRD-plus due to AADC deficiency to boost residual enzyme
activity through cofactor excess. Suggested starting dose is
100 mg/day slowly escalated up to 200 to 400 mg/day [5].
Conclusion
The spectrum of DRD has expanded with the recognition
of novel entities having myriad clinical features in addition
to the key feature of dopa responsiveness. The classifica-
tion into DRD, DRD-plus and DRD look-alike has a strong
clinical basis and is helpful in the segregation of possible
underlying conditions, which in turn can serve as a clue in
making the final diagnosis. Genetic testing will help in the
confirmation although its limitations are to be borne in mind.
In such instances, the utility of ancillary investigations like
functional imaging using DAT scans or fluorodopa PET as
well as CSF neurotransmitter profiles cannot be overempha-
sized. Whole-exome sequencing will enable identification
of novel genetic mutations in future, further expanding the
disorders under this spectrum. Early diagnosis will pre-
vent undue treatment delays, which could have prognostic
implications.
Funding None.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflicts of
interest.
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