Dystonia

INDEX

Origin

GTP-cyclohydrolase1 (GCH1) is the first and rate limiting enzyme in the synthesis of tetrahydrobiopterin (BH4), which is a cofactor for tyrosine hydroxylase and other monoamine neurotransmitters. Dopamine signalling is important already for intra-uterine (brain) development, and dopamine deficiencies may manifest at birth with hemiatrophy or hypotonia.

Classically, heterozygous mutations results in GCH1 deficiency (the commonest cause of DRD) presenting with lower limb dystonia in children with diurnal variation and an excellent response to low doses of levodopa. Dominant GCH1 mutations result in a significant reduction of GCH1 activity through a dominant negative effect of the mutant protein on the normal enzyme.

However, there are also rarer enzymatic deficiencies which may result in a potentially similar clinical presentation (see section on differential diagnosis).  The dopa-responsive dystonia phenotype may also occur in association with genes involved in other steps in tetrahydropterin synthesis including:

SPR (sepiapterin reductase) SPR (sepiapterin reductase)

PTP (pyruvoyl-tetrahydropterin synthase)

PTP synthase

TH (tyrosine hydroxylase)
(rate-limiting step in dopamine synthesis)

 

 

In these disorders, dystonia is typically combined with other neurological features, presumably resulting from abnormalities that affect additional monoamine pathways; norepinephrine, epinephrine, and serotonin. All together, these disorders provide strong convergent evidence for a shared molecular pathway involving dopamine synthesis and metabolism for at least some types of dystonia.

Although mutations in GCH1 are the most striking example, many inherited forms of dystonia are underpinned by alterations in dopamine signalling. In addition, dystonia is a prominent feature of mutations in genes involved in the steps of dopamine synthesis and metabolism, including:

     DDC aromatic amino acid decarboxylase
     SLC18A2 (intracellular vesicular monoamine transporter 2)
     SLC6A3 (cell surface  monoamine transporter)1

 

Figure 1. Dopaminergic signalling in dystonia

 

 

BH4, tetrahydropterin, DDC, gene symbol for aromatic amino acid decarboxylase; GCH1, gene symbol for GTP cyclohydrolase
GNAL, gene symbol for Golf protein; PTPS, gene symbol for pyruvoyl-tetrahydropterin synthase;
SLC18A2, gene symbol for vesicular dopamine uptake transporter or VMAT2;
SLC6A3, gene symbol for dopamine transporter; SPR, gene symbol for sepiapterin reductase; TH, gene symbol for tyrosine hydroxylase.

From: Jinnah HA, Sun YV. Dystonia genes and their biological pathways. Neurobiol Dis. 2019 Sep;129:159-168. doi: 10.1016/j.nbd.2019.05.014. Epub 2019 May 18. PMID: 31112762.
 

Figure 2. Biosynthesis of BH4 and monoamine neurotransmitters.

Defects in the enzymes GTP cyclohydrolase 1 and sepiapterin reductase lead to DRD by reducing production of BH4, an essential cofactor in the production of dopamine. Defects in tyrosine hydroxylase also lead to DRD, as this enzyme catalyses the rate-limiting step in the synthesis of dopamine2.

 

AADC

Aromatic l -amino acid decarboxylase

5-HIAA

5-hydroxyindoleacetic acid

BH4

Tetrahydrobiopterin

PCD

Pterin-4-α-carbinolamine

DHPR

Dihydropteridin reductase

PTP

6-pyruvoyl tetrahydropterin

HVA

Homovanillic acid

qBH2

quinonoid dihydrobiopterin

From: Wijemanne S, Jankovic J. Dopa-responsive dystonia - Clinical and genetic heterogeneity. Nat Rev Neurol. 2015;11(7):414-424. doi:10.1038/nrneurol.2015.86

The same GCH1 mutations may result in two distinct phenotypes: a non-degenerative phenotype typically consisting of childhood-onset DRD, and a neurodegenerative phenotype of Parkinson’s disease. Intriguingly, none of the reported GCH1 mutation carriers with imaging evidence of dopaminergic degeneration have had dystonia in childhood. Conversely, no childhood-onset DRD cases with GCH1 mutations has been reported to have abnormal nigrostriatal dopaminergic imaging in adult life. This suggests that the degenerative and non-degenerative GCH1-associated phenotypes are mutually exclusive and that GCH1 mutation carriers with dystonia during childhood might be protected against dopaminergic degeneration in later life.

Classification

  1. The commonest manifestation is that of the classical childhood presentation with slowly progressive dystonia.
  2. Severe manifestations may be at birth with initial hypotonia.
  3. At the opposite end of the age spectrum, late onset cases often present with pure parkinsonism with minimal dystonia, which may be levodopa responsive.  These cases may be difficult to distinguish from young onset PD. Such patients typically do not develop motor fluctuations or levodopa-induced dyskinesias, and the limited number of postmortem studies performed do not show nigral cell loss.  Some late onset cases present with very mild symptoms not requiring treatment, predominantly with dystonia of the legs.
  4. Other rare phenotypes include that of an MSA-like presentation (with other family members with DRD and PD), and some patients are shown to have features compatible with nigrostriatal degeneration on SPECT or PET imaging, suggesting that there may be two types of parkinsonism associated with GTP cyclohydrolase 1 deficiency3: is ‘benign’ parkinsonism (see #3 above), due to a phenotypic expression of autosomal dominant DOPA-responsive dystonia, who respond markedly to low doses of levodopa and, when treated with optimal doses, remain functionally normal for a long period of time without developing motor adverse effects of chronic levodopa treatment (motor response fluctuations and levodopa-induced dyskinesias); the other is ‘neurodegenerative’ parkinsonism, including Parkinson’s disease, in GCH1 mutation carriers3. Such cases are associated with nigral neurodegeneration at post mortem.
  5. Rare GCH1 coding variants may represent a risk factor for PD (WES of a large case-control cohort showed coding variants had a 7-fold increased risk of PD).  Similarly, a mega meta-analysis of genome-wide association data have highlighted GCH1 as a low-risk susceptibility locus for Parkinson’s disease5.

Clinical Features

There is a wide spectrum of phenotypes, including:

Dystonia

The classical childhood presentation of focal dystonia; this is an action dystonia which leads to an equinovarus posture.  During the first two decades of life, dystonia typically progresses to segmental or generalized dystonia, but remains most pronounced in the legs. About 2/3 of cases have evidence of cranio-cervical involvement, and half have truncal involvement. Hyperreflexia is frequently present.

Postural tremor may appear in a limb, and subsequently spread.

Tremor was the most prominent symptom in some adult onset cases6.

Diurnal fluctuation is characteristically present, with improvement following sleep. In 70% of patients, symptoms worsen towards the end of the day.

Writer’s cramp, guitarist’s finger, spasmodic dysphonia

Cerebral Palsy mimic

Parkinsonism

Infantile hypotonia

Nonmotor symptoms, such as depression, anxiety and obsessive–compulsive disorder, are increasingly recognized as belonging to the clinical spectrum of DRD. The tetrahydrobiopterin deficiency that results from GCH-1 deficiency leads to reduced serotonin synthesis, possibly implicated in these psychiatric symptoms. Complaints of fidgetiness and restless legs syndrome are common6.

 

Examination

Age of onset

The mean age of onset is about 10 years, with a wide range, and adult onset is not rare, perhaps more common in males.  DRD presents more commonly in girls, and, conversely, there is a significant excess of men amongst asymptomatic carriers. 

Distribution

Typical onset is with lower limb dystonia, which is then followed by spread generally.

Diagnosis

Genetic Testing

To date, more than 100 different mutations have been reported including missense, nonsense, frameshift, and splice-site mutations throughout the gene, as well as whole-exon or whole-gene deletions. GCH1 mutation carriers show a penetrance of around 50% which is considerably higher in women compared to men. Biallelic mutations in GCH1 result in a much more severe clinical phenotype including developmental delay and infantile onset.

If commercially available genetic testing is unavailable, or in cases with negative results but a suggestive phenotype, additional analysis of cerebrospinal fluid levels of neurotransmitters and a phenylalanine loading test may be useful to reach a diagnosis

 

Levodopa Challenge1

1–10 mg/kg levodopa daily, administered in multiple doses, in combination with a peripheral decarboxylase inhibitor; eg Carbilev 25/100: half a tablet twice daily for a 20 Kg child.

Trial of half a tablet of Carbilev 25/100, one to three times daily with meals for 1 week, increasing over the 2nd week, and by the onset of the 3rd week: two tablets of Carbilev 25/100 three times daily. If no response is seen after 1 month, the trial may be stopped.

0.5–10.0 mg/kg levodopa daily, administered in multiple doses and combined with a peripheral decarboxylase inhibitor, and continued for at least 2–3 months. The extended trial length in these patients reflects the time taken to show a response in some patients.

Differential Diagnosis

Common misdiagnoses included cerebral palsy, hereditary spastic paraplegia and early onset Parkinson disease. 

Parkin gene mutations: The major diagnostic issue is that of confusion with patients carrying mutations in the parkin gene: the age of onset is similar, although age of onset is typically in the 3rd decade for Parkin mutations. Generally, the presence of early prominent parkinsonism and severe dyskinesias favours parkin mutations.

autosomal recessive juvenile parkinsonism with abnormalities in the parkin

gene shows diurnal fluctuation.59,60

Cerebral Palsy

One of the most common questions that arises in patients with early onset dystonia combined with spasticity is whether it is due to cerebral palsy. Cerebral palsy itself is a syndrome rather than a disease, implying a static encephalopathy caused by an acquired perinatal or early infantile, monophasic cerebral insult. Although dystonia is usually present from early childhood, delayed-onset dystonia can occur.

 

The diagnosis of cerebral palsy is supported by:

 

A levodopa trial in all patients with dystonia and in cases of spastic paraplegia with severe gait abnormalities and discrete pyramidal signs should be considered.

 

 

The recessively inherited disorders of dopamine metabolism usually present in infancy, and are usually severe, with a complex phenotype with combinations of dystonia (often with oculogyric crises), hypotonia, parkinsonism (including rest tremor of the cranial region, trunk, or limbs), pyramidal signs, intellectual delay, and autonomic, sleep, and endocrine disturbances. The presence of ptosis (due to bilateral Horner syndrome) and facial hypomimia can lead to the misdiagnosis of a muscle disorder.

Table 1. Characteristics of dopa-responsive dystonia with different causes.

Other than dominant GTP-CH1 deficiency, these conditions typically present at birth or in infancy. Note that HSP type 11 (caused by mutations in SPG11), SCA3, and ataxia telangiectasia may also present with DRD.

From: Wijemanne S, Jankovic J. Dopa-responsive dystonia - Clinical and genetic heterogeneity. Nat Rev Neurol. 2015;11(7):414-424. doi:10.1038/nrneurol.2015.86

It should be noted that L-aromatic acid decarboxylase deficiency and dopamine transporter deficiency do not respond to treatment with levodopa.

 

Diagnostic Tests

Imaging: typically SPECT (DAT) or L-dopa PET studies are normal in DRD, reflecting an intact nigrostriatal pathway.

Parkinsonian features may even be associated with a presynaptic dopaminergic deficit as seen on F-Dopa PET or SPECT, although this is atypical, and conversely, normal PET or SPECT might prompt a search for DRD in a patient with mild parkinsonism.

 

A key investigation when a disorder of dopamine metabolism is suspected is measurement of CSF neurotransmitters and pterins.

However, a decrease of pteridin metabolites, neopterin as well as biopterin, in cerebrospinal fluid (less than 20% of normal values detected by Fujita and Shintaku33 and by Furukawa and colleagues34) is the most characteristic finding for autosomal dominant GCH-I deficiency. Hyland and colleagues35 showed abnormalities in the pheynylalanine loading test.

Table 2. Use of CSF and serum testing in order to identify the type of DRD

Abbreviations: 5‑HIAA, 5‑hydroxyindoleacetic acid; CSF, cerebrospinal fluid; DRD, dopa-responsive dystonia; GTP‑CH‑I, GTP cyclohydrolase 1; HVA, homovanillic acid; PTP, 6‑pyruvoyl tetrahydropterin.

From: Wijemanne S, Jankovic J. Dopa-responsive dystonia - Clinical and genetic heterogeneity. Nat Rev Neurol. 2015;11(7):414-424. doi:10.1038/nrneurol.2015.86

Phenylalanine loading

Autosomal dominant GCH1 mutation selectively affects the brain and does not affect the liver, so does not cause baseline hyperphenylalaninaemia. However, blood phenylalanine levels do become abnormal in patients with the autosomal dominant condition following a phenylalanine challenge, which can, therefore, be used to detect this condition. This test can also identify other forms of DRD, as results are abnormal with sepiapterin reductase deficiency but normal with tyrosine hydroxylase deficiency.

The phenylalanine loading test is conducted by administering 100 mg/kg phenylalanine and subsequently measuring the phenylalanine:tyrosine ratio in the blood at different time intervals, for example at 0, 1 ,2 4 and 6 hours. Quite likely that single sample at 4 hours is sufficient. Samples need to be taken to the laboratory immediately for processing and freezing.

In patients with mutations in GCH1 or SPR, this phenylalanine challenge results in an increased phenylalanine:tyrosine ratio in the blood at 1–2 h after phenylalanine administration: following the load, phenylalanine is typically higher than controls, and tyrosine lower than controls. This test is particularly useful when lumbar puncture and CSF analysis are not possible. However, false-negative and false-positive results have been reported.

In infants with encephalopathy or an atypical presentation of DRD, CSF neurotransmitter analysis is often used as one of the initial diagnostic screening tests.

 

Treatment

Due to the enzymatic defect in the levodopa biosynthesis, there is a life-long response of DRD to levodopa therapy.

DRD is usually treated with levodopa, but the exact doses, regimens and resulting response depend on the precise nature and severity of the condition. Some patients have residual symptoms, and some can develop levodopa-induced dyskinesia (about 10%). The latter are rarely described to limit treatment.

Levodopa treatment in patients with GCH1 mutations typically produces a dramatic response. 50–200 mg levodopa daily, usually combined with a peripheral decarboxylase inhibitor (carbidopa), is often sufficient for almost complete resolution of neurological deficits, and some patients have an excellent response at less than 100 mg daily.

Even if levodopa therapy is delayed for many years, most patients still respond to low doses of this agent. Controlled-release levodopa, dopamine agonists and anticholinergic drugs, can also be effective. Despite the dramatic response to levodopa treatment in most patients, some (most frequently females) have residual motor symptoms, including dystonia and parkinsonism1. Many patients respond very well but many do require dose adjustments.

Exceptional patients fail to respond well to levodopa therapy or dopamine agonists.

 

 

References