Nonmotor Symptoms in Dopa‐Responsive Dystonia

Abstract

Background

Dopa‐responsive dystonia (DRD) is a rare inherited dystonia, caused by an autosomal dominantly inherited defect in the gene GCH1 that encodes guanosine triphosphate cyclohydrolase 1. It catalyzes the first and rate‐limiting enzyme in the biosynthesis of tetrahydrobiopterin, which is the essential co‐factor for aromatic amino acid hydroxylases. Mutation results in the typical scenario of a young‐onset lower‐limb dystonia with diurnal fluctuations, concurrent or subsequent development of parkinsonism and excellent response to levodopa. Given the myriad functions of tetrahydrobiopterin, it is reasonable that other systems, apart from motor, would also be impaired. So far, non‐motor symptoms have been overlooked and very few and often contrasting data are currently available on the matter.

Methods

Here by searching the Medline database for publications between 1971 to March 2015, we render an in‐depth analysis of all published data on non‐motor symptoms in DRD.

Results

Depression and subtle sleep quality impairment have been reported among the different cohorts, while current data do not support any alterations of the cardiologic and autonomic systems. However, there is debate about the occurrence of sleep‐related movement disorders and cognitive function. Non‐motor symptoms are instead frequently reported among the clinical spectrum of other neurotransmitter disorders which may sometimes mimic DRD phenotype, ie, DRD plus diseases.

Conclusions

Further studies in larger and treatment‐naïve cohorts are needed to better elucidate the extend of non‐motor symptoms in DRD and also to consider treatment for these.

Dopa‐responsive dystonia (DRD) or Segawa's syndrome1 is a rare inherited dystonia,2 with an estimated prevalence of 0.5 per million.3 It is caused by an autosomal dominantly inherited defect in the GCH1 gene (14q22.1–q22.2) that encodes guanosine triphosphate cyclohydrolase 1 (GTPCH1),4, 5, 6 resulting in tetrahydrobiopterin (BH4) deficiency.

The disease seems to be more prevalent among females,7, 8 and males appear more likely to have a milder phenotype.7, 8, 9 Penetrance of the genetic mutation is low3 and expressivity shows a marked intra‐ and interfamilial variability.10 Typically, the clinical scenario consists in young‐onset (7–14 years of age) lower‐limb dystonia, diurnal fluctuations, concurrent or subsequent development of parkinsonism, and excellent response to levodopa.7, 9 However, less frequently a number of atypical presentations have been reported.8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 A good and prompt response to a trial with l‐dopa is required. However, the diagnosis needs to be confirmed at biochemical or molecular levels. Taking into account the BH4 functions (Fig. 1), a reduction in its activity will impair dopamine synthesis, justifying the motor symptoms, but it will also decrease the activity of all the other aromatic amino acid hydroxylases putatively resulting in nonmotor symptoms (NMS).

Figure 1.

AADC, aromatic L‐amino acid decarboxylase; BH4, tetrahydrobiopterin; BPs, Biopterins (NH₂P₃ and 6‐PPH₄); DA, dopamine; DBH, dopamine beta‐hydroxylase; 5‐HIAA, 5‐hydroxyindole acetic acid; HVA, homovanillic acid; NA, norepinephrine; eNOS, endothelial nitric oxide synthase; EPI, epinephrine; GTP, guanine triphosphate; GTPCH‐1, GTP cyclohydrolase I; iNOS, inducible nitric oxide synthase; L‐arg, L‐arginine; MHPG, 3‐methoxy‐4‐hydroxyphenylglycol; MAO, monoamine oxidase; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; NP, neopterin; NH2P3, dihydroneopterin triphosphate; 5‐OH‐Tryp, 5‐hydroxytryptophan; PAH, phenylalanine hydroxylase; Phe, phenylalanine; 6PPH4, 6‐pyruvoyl‐tetrahydroptterin; PTPS, 6‐pyruvoyl‐tetrahydropterin synthase; SR, sepipterin reductase.TH, tyrosine hydroxylase; TPH, tryptophan hydroxylase; Tryp, tryptophan; Tyr, tyrosine; VMA, vanillylmandelic acid.

NMS are increasingly being recognized as an important feature of different movement disorders, for example, in Parkinson's disease21 or primary dystonia,22 and impact significantly on patients' quality of life (QoL). However, despite the biological plausibility of NMS in DRD, very little is currently known. Here, we provide a systematic review on the NMS in DRD, identifying what is known, but also pointing out areas where knowledge is lacking, which may be important for future research.

Methods

Search Strategy and Selection Criteria

References for the review were identified by searches in the Medline database (by means of PubMed: http://www.ncbi.nlm.nih.gov) for publications between 1971 (the year of the first report of DRD) to March 2015. The search terms were: dopa‐responsive dystonia, Segawa disease, autosomal dominant guanosine triphosphate cyclohydrolase 1 mutation, GCH1 gene* and sleep, neuropsychiatric/autonomic/sensitive symptoms. Only articles in English were selected, and reference lists of the articles retrieved by the electronic searches were checked for other relevant reports not indexed in the electronic database.

Literature researches retrieved 15 articles specifically reporting or investigating NMS in DRD. We excluded cases without proven GTPCH1 gene mutation. Indeed, molecularly proved DRD diagnosis (GCH1 gene mutation) was reported in all except the three first families described up to the year of 1995, and therefore these three pedigrees were not taken into account for the results (Table 1).

Table 1.

NMS in DRD: literature data

Article	Study Type	Population	Methods	Findings
Nitschke et al., J Neurol Neurosurg Psychiatry 1998	Case series	3 females with genetically proved DRD coming from the same family	Questionnaires for cognitive function: WAIS; WCST	In all patients, subtle cognitive abnormalities, which improved after l‐dopa treatment
Hahn et al., Arch Neurol 2001	Case series	13 patients with genetically proved DRD coming from the same family	History taking, BDI, STAI, MOCI	#6 psychiatric symptoms #4 depression #1 OCD 1 #6 anxiety #6 deafness (clinically reported)
Van Hove et al., J Neurol Neurosurg Psychiatry 2006	Case series	18 patients with biochemically or genetically proven DRD coming from 3 different families	Structured interview by a psychiatrist, using SCID‐I/P, Version 2.0, in 16 patients In 2 patients, psychiatric history was based on clinical records, PSQI, ESS, PSG, and MSLT.	44% depression (severe in 28%) 22% OCD 22% anxiety ESS normal PSG normal #5 recurrent tendonitis
Nagata et al., Mov Disord 2007	Case report	A 20‐year‐old female with biochemically proven DRD	WAIS‐R, HDS‐R, MMSE	Mild cognitive abnormalities: IQ: 44 HDS‐R: 22 MMSE: 23
Venna et al., N Eng J Med 2006	Case report	A 19‐year‐old female with genetically proven DRD	History taking	Intermittent emotional instability and depressed mood
Trender‐Gerhard et al., J Neurol Neurosurg Psychiatry 2009	Case series	34 patients with genetically proven DRD (32 patients coming from 16 different families and 2 isolated cases)	History taking	#12 depressed mood #6 severe depression #4 RLS
Dale et al., Develop Med Child Neurol 2010	Case series	3 patients with genetically proven DRD	History taking and psychiatric diagnosis	#2 major depression
Lopez‐Laso et al., J Neurol 2011	Case series	14 patients with genetically or biochemically proven DRD coming from 2 different families	Questionnaires: BDI; STAI; BIS‐11; OSQ; PSG WAIS‐III: CDI; STAI for children; MFF‐20; WPPSI; WISCR	#7 impulsivity #1 anxiety #9 IQ from borderline to mild impairment #4 of 7 sleep disturbances (anamnestic, mainly insomnia and disrupted sleep) #2 of 7 sleepwalking (anamnestic)
Ling et al., Mov Disord 2011	Case series	4 patients with genetically proven DRD coming from the same family	History taking, 1 patient PSG	#4 depression #4 migraine #1 panic attacks #4 RLS #1 of 1 PLM at PSG with increased arousal index
Tadik et al., Arch Neurol 2012	Case‐ control study	23 patients with genetically proven DRD	BDI	6 cases (32%) reported 1 or more NMF, among depression, anxiety, and migraine
Brüggemann et al., Parkinsons Related Disord 2014	Case‐control study	23 patients with genetically proven DRD	Questionnaires: BDI; STAI; ESS; SSS; FEPS‐II; WHO‐Qol BREF; #6 F PSG	#2 of 6: increased sleep latency #5 of 6: increased REM latency #2 of 6: reduced sleep efficiency #1 PLM >5 (with RLS)
Lin et al., J Chil Neurol 2014	Case‐report	A 14‐year‐old male with genetically proven DRD	History taking, laboratory test, and imaging	Low stature and GH, which normalized after l‐dopa

BIS‐11, Barratt Impulsiveness Scale‐11; CDI, Children's Depression Inventory; FEPS‐II questionnaire to assess specific personality traits of people with sleep problems; HDS‐R, Revised Hasegawa Dementia Scale; MFF‐20, Matching Familiar Figures Test‐20; MMSE, Mini–Mental State Examination; MOCI, Maudsley Obsessive–Compulsive; OSG, Oviedo Sleep Questionnaire; STAI, State‐Trait Anxiety Inventory; STAI for children, State‐Trait Anxiety Inventory for Children; WCST, Nelson's modified version of the Wisconsin Card Sorting Test; WHO‐Qol BREF, 26‐itemversion of the World Health Organization questionnaire; WISCR, Wechsler Intelligence Scale for Children‐Revised; WPPSI, Wechsler Preschool and Primary Scales of Intelligence.

By reviewing all those reports, we can identify different categories of NMS, namely, sleep‐related disorders, cardiac and autonomic disorders, neuropsychiatric disorders, cognitive disorders, and other less frequently reported or less investigated NMS.

For the sake of completeness, the article included also a brief paragraph reporting on NMS in “DRD plus.” By using the term DRD plus, we refer to other dopamine responsive conditions resulting from different mutations affecting the dopamine synthesis pathways (as, e.g., resulting from tyrosine hydroxylase [TH], sepiapterin reductase [SPR] deficiency, aromatic l‐amino acid decarboxylase [AADC], and autosomal recessive/compound heterozygote GCH‐1 deficiency), apart from the autosomal‐dominant mutation of the GCH1 gene.

Results

All the principal articles with population and methods' details are detailed in Table 1.

DRD and Sleep‐Related Disorders

BH4 synthesis impairment will result in lowering of dopamine and serotonin (Fig. 1). Both of them have a pivotal role in promoting waking and regulating slow‐wave sleep and rapid eye movement (REM) sleep.23, 24 Melatonin, as well, synthesized from serotonin, is implicated in the onset and persistence of sleep.25 Hence, an impairment of their synthesis would putatively result in an increase of daytime sleepiness along with the impairment of nocturnal sleep structure. Nonetheless, investigative studies analyzing nocturnal sleep and sleepiness in DRD patients are lacking.

Before genetic analysis was available, there were few studies analyzing sleep pattern by means of polysomnography (PSG) and reporting on the presence of periodic limb movements (PLMs) during non‐REM (NREM) sleep26, 27 and of gross body movements (GBMs) during REM sleep.27, 28, 29, 30 In these articles, the researchers do not give a clear description on the pattern of GBMs. Hence, it is difficult to speculate on the nature of these movements and whether they represent only an increase of the REM's physiological muscles phasic activity31 or a different sleep‐related movement disorder.

Since the time when genetic analysis became available, only a further two more PSG studies have been conducted in 18 and 6 patients, respectively,15, 32 but in none of them researchers reported details on movement analysis method.

With regard to subjective sleep quality and excessive daytime sleepiness, few studies are available.8, 32, 33

Lopez‐lazo et al.,33 by means of the Oviedo Sleep Questionnaire, the Pittsburg Sleep Quality Index (PSQI), and anamnestic interviews, performed in a cohort of 14 DRD‐patients reported on subjective complaining of nonrestorative sleep and insomnia in more than 50% of their cohort. Two of seven pediatric patients presented sleepwalking, which is known to be correlated with NREM sleep instability.34 Nearly half of the patients were on stable therapy with l‐dopa.

Van Hove et al.,15 in their cohort of 18 medicated DRD patients, reported that even if patients complained of poor sleep quality, the Epworth Sleepiness Scale (ESS) was normal in all the subjects and the PSQI resulted as impaired in only 2 patients. Instrumental examinations, including the Multiple Sleep Latency Test (MSLT), were normal.

Recently Brüggemann et al.,32 by performing either a questionnaire‐based interview (namely, PSQI, ESS, and Standford Sleepiness Scale [SSS]) in 23 genetically proven DRD as well as PSG recordings in 6 female patients, did not detect any abnormalities. Indeed, the researchers reported only slight sleep abnormalities (i.e., decreased sleep efficiency and increased sleep latency). Impaired sleep quality and depressive symptoms were associated with lower QoL.32

RLS as well seems not to be correlated to DRD given that it has been reported in 4 of 34 patients in the cohort of Trender‐Gerhard et al.8 and only in 1 of 23 in the cohort of Brüggemann et al.,32 showing percentages not different from that reported in the general population.31

To summarize, current data are insufficient in order to support any particular sleep abnormalities in DRD. The two PSG studies conducted on patients with genetically proven DRD disconfirmed any notable sleep disorder. Overall, the main finding is that of a slight alteration of the macrostructure of sleep. However, it is not clear what underlines such abnormalities, given that microstructure of sleep has never been analyzed. In light of this, it is difficult to speculate upon the nature of sleep abnormalities whether or not they are linked to biochemical alteration of neurotransmitters or if they are the result of concomitant features (such as an overlooked sleep‐related movement disorder or depression) or coincidental findings.

Lower subjective sleep quality has been reported to be associated with lower levels of the QoL and with depression.32 Given the retrospective nature of this finding, the causal‐effect link cannot be inferred, but it underlines that treatment of sleep impairment may putatively improve patients' QoL. Moreover, as reported in PD patients,35 to improve sleep quality may also have a positive effect on daytime motor functioning.

DRD and Neuropsychiatric Disorders

Both noradrenaline and serotonin also have a role in mood and behavioral regulation.36, 37 Neuropsychiatric symptoms are frequently reported in DRD patients, even if they have never been formally recognized.

Depression has been first reported to have a high prevalence in a large family of Texas with genetically proved DRD.14 Of note, mood disorders seemed to precede, or to be the sole clinical manifestation of the disease.14 Van Hove et al.,15 by means of a structured interview conducted by an experienced psychiatrist, using the Structured Clinical Interview for DSM‐IV Axis I Disorders (SCID‐I/P; Version 2.0), reported a high prevalence of depressive symptoms in almost 50% of their cohort (18 patients from three different families), with symptoms indicative of major depression in more than 20% of cases. Twenty percent of the cohort had obsessive‐compulsive disorders (OCDs), whereas anxiety symptoms where complained of only by 22% of patients. Peak incidence of the psychiatric symptoms was at 41 to 50 years of age, but can present also in childhood. Patients with psychiatric symptoms sometimes had a more severe motor syndrome. However, psychiatric symptoms seem not to be strictly correlated with the onset of the motor features given that they may precede, coincide with, or ensue the onset of the neurological signs. Patients showed a marked improvement of depressive symptoms after the introduction of selective serotonin reuptake inhibitors (SSRIs), serotonin‐noradrenaline reuptake inhibitor, and 5‐hydroxytryptophan (5‐OH‐Tryp) alone or in combination. However, the researchers did not comment on whether or not l‐dopa was nonetheless helpful for low mood. Moreover, in both the previous cohorts,14, 15 mutation‐negative family members were not examined, and this raises the question of a different comorbid disorder in the family.

In a large cohort of patients, Trender‐Gerhard et al.8 reported the occurrence of various neuropsychiatric disorders in more than half of the cases. However, these symptoms have been mainly collected based on medical records. The most common reported symptoms were severe mood swings and treatment‐requiring depression that seemed to recur despite efficient and stable treatment with l‐dopa.8 Patients cannot pinpoint the onset of the psychiatric symptoms, but apparently, they were not reported to precede motor symptoms.

In the cohort of Lopez‐Lazo et al.,33 structured clinical interviews following the DSM‐IV‐TR's guidelines and ad‐hoc questionnaires highlighted that depression, anxiety, and OCD did not seem to be more common than that expected in the general population whereas the values in the scales testing for impulsivity were above the cut‐off point in all the adult patients. However, again, nearly half of the cohort was on stable therapy with l‐dopa.

Tadic et al.,9 by reviewing the published cases of genetically proved DRD, could find information on nonmotor signs only for 70 of 352 reported patients. Of these, 34% had depression, 19% anxiety, and 9% OCD. Moreover, they investigated by means of BDI and history taking the neurophsychiatric symptoms in a cohort of 23 medicated patients. Among those, 6 female patients (34%) complained of depressive mood and anxiety, but the natural history of these symptoms was not available.

However, in the more recent article by the same group,32 a questionnaires‐based interview could not reveal a significant increased frequency in depression or anxiety disorders when compared to a group of control. Again, we have to point out that all the patients were on stable therapy with l‐dopa.

There is only one report in which researchers reported a reduction in the efficacy of l‐dopa treatment on dystonia symptoms with SSRI,38 but we recommend caution in this regard.

To summarize, by reviewing all the studies dealing with neuropsychiatric features in DRD, it appears that they may be a feature among the spectrum of NMS. Among them, depression seems to be particularly frequent. A biochemical basis would support a primary association given that either basic researches or the therapeutic effect of SSRI support serotonin's implication in mood regulation.36 The decrease in noradrenaline induced by low l‐dopa may play an additional role.37

Apart from depression, there are little data about a possible association of DRD with impulsivity33 and this would also be supported by biochemical abnormalities.7, 33, 39

Interestingly, sometime the psychiatric symptoms seem to precede or be the only clinical manifestation of DRD.14, 15

Many of the above‐reported studies have a number of shortcomings. Not all the DRD patients have psychiatric symptoms,8, 14, 15, 32 and studies in other populations40 indicate that a specific vulnerability factor may contribute to expression of psychiatric symptoms in combination with serotonin depletion.40 Hence, presumably, additional trigger factors may be needed in order to develop depression also in patients with DRD. Further prospective studies taking into account the degree of severity of the biochemical profile and the association with motor and nonmotor feature as modifiers are needed. It should be also clarified whether or not l‐dopa may be useful for depressive symptoms as a first approach.

DRD and Cognitive Dysfunction

Dopaminergic, serotonin, and noradrenergic neurons are known to play a role in morphogenesis and in the development of neuronal networks for higher cortical functions, and their depletion has been implicated in the development of disorders of learning, such as autism or mental retardation.41

However, cognitive function in DRD is classically considered normal. There are few families in which cognitive abnormality has been reported.8, 33, 42

Nitschke et al.42 quantitatively investigated the neuropsychological abilities in three treatment‐naïve DRD patients, finding slight impairment. With treatment, patients improved clinically as well as on quantitative tests, mainly in concept formation and set‐shifting abilities.

Concentration problems and verbal memory deficits have also been seldom reported.8, 29 However, systematic studies investigating cognitive function are still lacking.

We could find only one report33 in which the authors assessed cognition using the Wechsler Adult Intelligence Scale‐Third Edition (WAIS‐III) in adults and equivalent tests in pediatric patients, finding that 9 of 12 patients had an IQ in the range of borderline intellectual functioning to mild mental retardation. Interestingly, the 3 pediatric patients who were receiving l‐dopa treatment before the age of 10 had a normal IQ.

To summarize, even if there is some suggestions of possible mild cognitive dysfunction, there are only a few studies thus far and hence we cannot drawn clear conclusions. This is an important issue because one study33 suggests that early diagnosis and treatment may have a protective effect.

DRD and Cardiologic or Autonomic Dysfunctions

The pivotal role of BH4 in regulating endothelial nitric oxide (NO) synthase (eNOS) function has been dragged out in relation to its role in endothelial dysfunction,43 raising the question about possible cardiovascular comorbidities in DRD. However, the role of guanine triphosphate (GTP) on autonomic and cardiac function still needs to be clarified given that very large genome‐wide association studies have not identified GCH1 as a candidate locus for hypertension or cardiovascular outcomes.44

Cardiologic comorbidity has never been systematically assessed in DRD, apart from one study using self‐reported questionnaires,32 which showed a trend toward a lower frequency of arterial hypertension in 23 DRD patients when compared to 26 age‐matched controls (13% vs. 40%; P = 0.08), and, interestingly, an inverse relationship between plasma BH4 and endothelial function has been noted, with high plasma BH4 levels being associated with impaired endothelial function.45 Low epinephrine and norepinephrine levels may have an additional role.

There is only one study that conducted a comprehensive evaluation of autonomic function and cardiac structure in 16 DRD patients.46 The investigators indeed evaluated plasma biopterin and NO, endothelial function by brachial artery flow‐mediated dilation, sympathetic function by measurement of plasma norepinephrine, epinephrine, and heart rate and blood pressure in response to different tests. Cardiac function and structure were assessed by echocardiograph. The study reported reduced plasma biopterins, but normal NO levels; cardiac and endothelial functions were normal as well. At the same time, even if the plasma levels of epinephrine and norepinephrine were lower in supine positions and their rise in response to tilt was blunted, there was no difference between patients and controls in blood pressure or heart rate in response to different tests.

Mayahi et al.46 tried to explain this paradox, speculating that lifelong endogenous BH4 deficiency may elicit developmental adaptation mechanisms, for example, through the up‐regulation of other endothelial mediators.

To summarize, cardiac and autonomic abnormalities do not seem to be associated with DRD. On the contrary, one study reported that DRD seems to be somehow protective versus arterial hypertension. Larger epidemiological studies are required.

DRD and Pain

The GCH1 gene is one of few genes reported to be involved in the modulation of pain sensitivity in humans; hence, BH4 regulates the synthesis of catecholamine, serotonin, and NO, all involved in pain signaling. Lowering BH4 levels using 2,4‐diamino‐6‐hydroxypyrimidine, a selective but poor affinity GCH1 inhibitor, produces analgesia in rats after nerve injury and inflammation, confirming the pronociceptive action of excess BH4 production in the somatosensory system.47

Moreover, carriers of a particular haplotype of the GCH1 gene, associated with reduced inducibility of GTPCH1 expression, had been reported to have less pain postsurgery for chronic lumbar radiculopathy and a decreased sensitivity to some experimental mechanical pain stimuli.48 Recently, in a mouse model with partial or total loss of function of the GCH1 gene, a normal pain response, but a reduced inflammatory hypersensitivity, has been found,49 and in humans as well heat and pressure thresholds and tolerance to electrical stimulation in pain models without sensitization did not differ among the different haplotypes of the GCH1 gene.48

Based on the above‐reported studies, DRD patients may be more tolerant to pain after sensitization. However, to the best of our knowledge, pain functions in DRD have never been assessed.

Less commonly reported NMS (such as migraine, growth retardation, and tendonitis) are reported in Table 1.

NMS in DRD Plus

All the enzymes involved in the biosynthesis and recycling of BH4 can manifest with clinical syndromes responsive partly to dopamine. The most common forms of DRD plus are owing to TH and SPR deficiency. For these DRD‐mimicking disorders, the term DRD plus has been proposed50 and will be used here in this context.

Overall, DRD plus syndromes have an earlier onset and a more severe motor phenotype.51 These disorders are inherited in an autosomal‐recessive fashion. Autosomal‐dominant (AD)‐DRD and DRD plus have different cerebrospinal fluid (CSF) neurotransmitters levels and hence they may be distinguished by CSF examination. If biopterin levels are low, one must consider AD‐DRD; otherwise, one should consider the other neurotransmitters disorders as shown in Figure 1.

TH deficiency is, together with AADC, a disorder of monoamine synthesis. Thus far, nearly 40 patients with this condition have been reported. It presents either as a neonatal‐onset progressive encephalopathy52, 53, 54 or as a childhood‐onset hypokinetic‐rigid syndrome with dystonia, l‐dopa responsiveness, and l‐dopa‐induced dyskinesia.54, 55, 56, 57, 58 Patients with a phenotype mimicking AD‐DRD have been rarely reported on.59, 60, 61 Cognitive deficits are common, and it is unknown whether or not a prompt diagnosis and treatment with l‐dopa can be somehow protective.58 Autonomic dysfunctions resulting from norepinephrine deficiency are also frequent and consist mainly in ptosis, paroxysmal temperature dysregulation with excessive drooling, sweating, and paroxysmal pyrexia.58, 62 Growth delay owing to growth hormone (GH) deficiency and galactorrhea owing to hyperprolactinemia have been reported as well.53, 62, 63, 64, 65

SPR deficiency is, as with AD‐DRD, a disorder of BH4 synthesis. Thus far, less than 50 patients have been described. The main features are neonatal childhood‐onset of hypotonia, oculogyric crises, developmental delay, and cognitive impairment.66 Milder phenotypes have been rarely reported.67, 68, 69 Additional NMS are quite frequent. Particularly, more than 50% of reported cases had hypersomnia, altered circadian rhythm, and fragmented sleep,66, 70 and above 50% of patients had behavioral/psychiatric abnormalities such as irritability, inattention, anxiety, hyperactivity, and obsessive‐compulsive features. Yet, 40% of patients presented symptoms of autonomic imbalance, such as excessive sweating, ptosis, temperature instability, and nasal congestion.66, 71 Sleep and behavioral and cognitive abnormalities seemed to respond l‐dopa alone or in association with 5‐HT (serotonin).66, 70, 72

Finally, conditions such as AADC deficiency73, 74, 75 or autosomal‐recessive GCH‐1 deficiency or the compound heterozygote mutations would frequently have NMS.76, 77 The subtypes of NMS are broad, ranging from those related to monoamines' deficit (cognitive, behavioral, and sleep problems) or catecholamines' deficit (autonomic imbalance) to those linked to serotonin's deficit (sleep and behavioral disorders). However, the clinical spectrum of these disorders is much more severe and only few mutations determining a milder clinical phenotype have been reported.78, 79

It appears that NMS are integral parts of the clinical spectrum of DRD plus and likely related to the most severe serotonin neurons' impairment.51

Conclusions and Future Directions

By reviewing all the published literature on NMS in DRD, the most consistent data may be summarized as follows:

• 1Neuropsychiatric features, and, particularly, depression, have been reported in nearly all the available cohort studies.14, 15, 32, 33

Biochemical basis together with the fact that sometimes they may precede motor signs14, 15 or may be the only clinical manifestation14 would support that they are a primary feature. However, data on their occurrence and prevalence are still poor, given that, for example, the same researchers, in two different cohorts,9, 32 failed to reproduce the same results. Moreover, a role of trigger factors or modifiers (motor signs and the related psychosocial impairment) has never been investigated. One must acknowledge that all the studies have been conducted in patients under l‐dopa medication. Consequently, prospective studies in treatment‐naïve patients are needed. Of note, neuropsychiatric symptoms may precede, succeed the motor symptoms, or be the only clinical manifestation, and information regarding response to l‐dopa and/or SSRIs is mixed and limited.14, 15, 32, 33 This implies the necessity of an accurate assessment of the latter through all the family members and monitoring patients through the course of the disease.

• 2Subjective poor sleep quality is frequently reported, but the two PSG studies conducted in patients with genetically proved AD‐DRD did not report any relevant sleep abnormality.15, 32

Therefore, it is unclear whether or not the complain of nonrestorative sleep is a primary feature or if it is related to an associated condition, such as the neuropsychiatric comorbidity or to an overlooked sleep‐related movement disorder.

• 3Impairment in cognition in a small percentage of patients, but not in those who were receiving l‐dopa since childhood, has been reported in one study.33

This finding points to the need of cognition assessment in a fashionable way. It should be important, of course, to correlate cognitive abnormalities with biochemical profile, ongoing treatment, disease severity, and, particularly, with neuropsychological features.

• 4With regard to the autonomic functions, the only study addressing this issue in DRD46 disconfirmed any abnormality.

Of course, epidemiological studies on larger cohorts are needed in order to draw a firm conclusion on the matter.

• 5Finally, with regard to sensory functions, biochemical48 and experimental studies47, 49 would support a role of GTP in pain modulation.

Response to inflammation and pain perception has never been investigated in DRD patients, and both clinical and neurophysiological assessments of pain and sensory function may be of some interest.

Based on current data, NMS appear to be not so common in DRD, despite the fact that all the metabolites of BH4 are impaired. The cause of this is unknown. It may be speculated that GCH1 gene mutation mainly affects dopamine (DA) neurons rather than the serotonin (5‐HT) neurons.80, 81 Indeed, as reported on murine models,80, 81 it is possible that, also in humans, GCH1 may have a different regulation in different parts of the brain so that neurotransmitter synthesis within the nigrostriatal DA neurons may be much more vulnerable to deficit in BH4 biosynthesis, thus resulting mainly in motor symptoms.80, 81 Moreover, the same animal models presented different degrees of expression of mutant messenger RNA (mRNA) in different brain regions,80, 81 and it appears that the amount of GTPCH protein within nigrostriatal DA neurons is even lower than would be predicted based on corresponding GTPCH mRNA.82 Hence, it may be speculated that mutations in the GTPCH1 gene may further impair already low levels of GTPCH1 gene expression. Yet another explanation may take into account the fact that, as proposed previously,83, 84 BH4, while stimulating TH gene expression, has only a role of control on the steady‐state levels of the other proteins for which it acts as a cofactor.83, 84

To clarify, whether or not NMS represent part of the clinical spectrum of DRD would be important, given that the awareness of these symptoms can allow their diagnosis and guarantee a more comprehensive care of patients.

Overall, it should be acknowledged that, currently, overt NMS would suggest a diagnosis of DRD‐plus rather than of AD‐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 of the First Draft, B. Review and Critique.

E.A.: 1A, 1B, 1C, 3A, 3B

M.S.: 3B

R.L.: 3B

K.P.B.: 1A, 1B, 3B

Disclosures

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

Financial Disclosures for previous 12 months: E.A. holds grants from the COST foundation (ref. no.: COST‐STSM‐ECOST‐STSM‐BM1101‐070115‐053783). K.P.B. has received honoraria/financial support to speak/attend meetings from GlaxoSmithKline (GSK), Boehringer‐Ingelheim, Ipsen, Merz, Sun Pharma, Allergan, Teva Lundbeck, and Orion pharmaceutical companies. K.P.B. holds grants from a MRC Welcome Strategic grant (ref. no.: WT089698) and PD UK (ref. no.: G‐1009). M.S. serves on the editorial boards of Movement Disorders and Frontiers in Movement Disorders; received travel and speaker honoraria from Actelion and Lundbeg Pharmaceuticals; and receives research support from the Hellenic Ministry of Education (THALIS) and from the Michael J. Fox Foundation (Prodromal PPMI).