Dystonic Disorders with Parkinsonism            Parkinsonian Disorders with associated dystonia

Distinguishing the dominant movement disorder in younger patients presenting with dystonia or Parkinson disease can be extremely difficult, and both conditions may be characterized by some degree of overlap.  It is unclear from the current knowledge of their pathophysiological changes in the basal ganglia how dystonia and parkinsonism can co-occur, and why they can both respond to lesion/DBS surgery.  To further emphasize how unclear the underlying mechanisms may be, chronic GPi DBS stimulation can sometimes paradoxically lead to parkinsonism in patients treated for dystonia¹.

Multiple causes of dystonia-parkinsonism have been identified, and some of these are associated with a complex phenotype with additional pyramidal signs or other features. Although the number of genetically proven reported cases for each disorder is still limited and there is overlap between the syndromes, information about age at onset, type and distribution of symptoms, ethnicity, and pattern of inheritance may help in the diagnostic workup².

Dystonia-parkinsonism syndromes encompass both common and rare conditions. Of particular importance are the following:

• Dopa-responsive dystonia (DRD)
• Wilson’s disease
• Parkin-, PINK1-, and DJ-1-associated Parkinsonism (PARK-Parkin, PARK-PINK1, PARK-DJ-1 respectively, formerly termed PARK2, 6, and 7 respectively)
• Rapid-onset dystonia-parkinsonism (DYT-PARK-ATP1A3 formerly termed DYT12)
• Neurodegeneration with Brain Iron Accumulation (NBIA, including PANK2- and PLA2G6-associated neurodegeneration, neuroferritinopathy, and others).
• Mutations in the POLG (polymerase gamma 1) gene may result in dystonia, associated with loss of substantia nigra neurons.

In some patients, parkinsonism dominates, whereas in others, dystonia prevails, particularly in the legs:

• Dystonia secondary to PD usually begins in the legs, is painful and is not relieved by sensory tricks.
• Dystonic slowness can resemble bradykinesia observed in PD, and dystonic tremor may be mistaken for parkinsonian tremor, particularly when it is observed at rest. Dystonic tremor is reviewed in the section of tremor.
• The differential diagnosis is predominantly with autosomal recessive parkinsonism, and it should be noted that both dystonia and parkinsonism may improve with dopaminergic medication³. 

1 Dystonic Disorders with Parkinsonism

Parkinsonism, with partial responsiveness to levodopa, is commonly seen with mutations in the genes listed below, which therefore all correspond to some form of dopa-responsive dystonia.  The response of early dystonia to the introduction of dopamine replacement therapy (levodopa, dopamine agonists) is also variable; it can worsen, improve or remain unchanged ; some have suggested a better response to dopamine agonists but this benefit is inconsistent¹.

1.1 Genetic mutations linked to parkinsonism and dystonia related to the dopamine synthesis pathway

DYT-PARK-GCH1 (DYT5a) (Dopa-responsive dystonia)  

DYT-PARK-TH (DYT5b) (Dopa-responsive dystonia)

Clinical heterogeneity of DRD is potentially a cause of diagnostic uncertainty. The DRD phenotype can include adult-onset parkinsonism with tremor and levodopa-induced dyskinesias, introducing the additional diagnostic issue of confusion with patients carrying mutations in the parkin gene⁴.

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.

Defects in dopamine pathways in dystonia are not limited to dopamine neurons themselves, but can also involve post-synaptic mechanisms, as seen in the figure of dopamine synthetic pathways above.

• the GNAL gene has been linked to isolated adult-onset dystonia and encodes the α-subunit of a G-protein, a GTP-binding protein involved in coupling dopamine receptors (and other receptors) on the post-synaptic membrane of striatal neurons to the adenylate-cyclase second messenger system.
• Similarly, dystonia is associated with mutations in the GNAO1 gene which encodes the α-subunit of another G protein, which also is involved coupling dopamine receptors (and other receptors) to the adenylate-cyclase second messenger system⁵.

1.2 Rarer genetic mutations associated with parkinsonism:

DYT-PARK-TAF1 (DYT3)

DYT-PARK-ATP1A3 (DYT12) (Rapid-onset dystonia parkinsonism)

DYT-PARK-PRKRA (DYT16) (Dystonia with mild parkinsonism)

DYT-TOR1A (DYT1) Atypical cases have been mistaken for PD (adult onset of task-specific tremor misdiagnosed as being benign tremulous PD; subsequently developed rest tremor of both arms, but had normal DAT scan⁴.
 

2 Parkinsonian Disorders with associated dystonia.

Around 10-15% of PD cases present with focal dystonia of the limbs.  In particular, dystonia affecting the foot in an adult should raise the possibility of PD.

Dystonia can be observed as part of the PD spectrum (e.g., blepharospasm and eyelid apraxia) and also following dopaminergic treatment or subthalamic nucleus stimulation, and may precede the development of parkinsonism from anywhere between 1 to 25 years.  

The response of dystonia to levodopa and dopamine agonists is variable.

Early dystonia in PD can have a variety of focal and segmental distributions, particularly involving the lower limb.  when dystonia affects the foot in an adult the possibility of PD should be considered as the cause of the foot dystonia. (There are several exceptions, however, to this clinical dictum, such as foot dystonia associated with lumbar canal stenosis and stiff-person syndrome⁴).

2.1 The dystonic syndromes of PD
These syndromes are typical of dystonia, as found in idiopathic torsion dystonia, and may be task specific. In particular, dystonia of the upper limb in PD may be task specific although non-task specific dystonia is more common. Both task and non-taslk specific dystonias preceding the development of overt Parkinson’s disease have been described.
Different types of dystonia seen include:

The following forms of dystonia are seen in PD:

 Focal dystonias

  Cervical dystonia

  Oro-mandibular dystonia

  Limb dystonia

• Unilateral equinovarus 
• Upper arm-forearm or forearm-hand flexion
• Writer’s cramp
• Musician’s dystonia
• Task- specific writing tremor

  Hemidystonia

  Blepharospasm

  Striatal foot/hand

 Axial dystonia

  Scoliosis, kyphoscoliosis

  Camptocormia

  Freezing gait

2.2 Striatal limbs
The striatal’ foot is characterized by a uni- or bilateral equinovarus dystonic posture of the foot and extension of the big toe (sometimes confused with the Babinski sign), associated with flexion of the toes and ankle inversion.  Isolated striatal toe is a subtype.

The ‘striatal’ hand deformity, with flexion of the metacarpophalangeal (MCP) joint and extension of the interphalangeal (IP) joints, may be seen up to 10% of untreated PD patients with advanced disease, and, if untreated may progress to contractures.  The striatal hand is classically seen in advanced PD but can also be seen in early stages typically associated with mild flexion of metacarpophalangeal joints of the hand.

These ‘striatal’ limbs are unusual for dystonia, and controversial as a consequence: they persist during sleep, do not respond to antiparkinsonian medication, and were more common in the pre-levodopa era. Both botolulinum toxin and DBS have been used successfully in their treatment¹.

2.3 Dystonia and early onset PD
In particular, dystonia affects more than half of patients in sporadic early onset Parkinson’s disease, 20% of patients with onset at age <55 years, and another 10% within two years of onset. Although, in most cases, parkinsonism will dominate, dystonia of the legs or exercise-induced dystonia can be the presenting symptom of early onset PD, especially in autosomal recessive genetic parkinsonism such as PARK-Parkin (PARK2).

Dystonia in young-onset PD most commonly involves the foot:

• A “pseudo-foot drop gait” secondary to the action dystonia of the plantar flexors and the foot invertors triggered while walking.
• Unilateral equinovarus foot
• Patients can also develop fixed painless contractures of limbs, which are also thought to be dystonic.

2.4 PD mutations strongly associated with dystonia
The following mutations result in PD and have a strong association with dystonia:

• Parkin (PARK-Parkin, PARK2).  Mutations in this gene are currently the commonest cause of early-onset PD. The disorder is characterized by early dystonia, before the initiation of levodopa, which is the initial symptom in 40% of cases. Rarely, this may present as paroxysmal exercise-induced dyskinesia/dystonia.
  Occasionally, this may mimic either DYT-TOR1A (DYT1) or DYT/PARK-GCH1 (DRD). The foot dystonia is usually task-specific, brought out and worsened by walking or exercise and sometimes this can progress to involvement at rest. Occasional patients can present with foot drop dystonia.
• PINK1 (PARK-PINK1, PARK6). This presents in a similar manner to mutations in the Parkin gene, although dystonia is less common.  Cognitive and psychiatric features may also be present. 
  Both parkin and PINK1-associated parkinsonism are characterized by a benign course reflected by a slow annual reduction rate of striatal dopamine uptake that is significantly slower compared with the late-onset PD patient².
• DJ-1-associated Parkinsonism (PARK-DJ-1 respectively, formerly termed PARK7). Lower limb dystonia and blepharospasm have been reported.
  Early onset cases are rare.
• LRRK2 (PARK-LRRK2, PARK8). Off period foot dystonia appears to be particularly common.
• PARK9—Kufor-Rakeb Disease.  The clinical phenotype comprised of parkinsonism with supranuclear gaze palsy, oculogyric dystonic spasms, facial-oropharynx-finger mini-myoclonus, and pyramidal tract signs in some. Cognitive features include dementia and visual hallucinations.  Disease onset was in adolescence, around the ages of 12– 15 years.  A good response to levodopa has been noted, but, as in PLA2G6-associated NBIA levodopa-induced choreiform dyskinesias developed early. Brain CT and MRI revealed diffuse moderate cerebral and cerebellar atrophy. Iron deposition within the basal ganglia may be present. Kufor-Rakeb disease is due to mutations in the ATP13A2 gene on chromosome 1p².

In particular, patients with foot involvement may develop exercise-induced cramp-like discomfort, first noticed in the toes and later evolving into inversion of the affected foot.  This has been called kinesigenic foot dystonia, and is induced by exercise of progressively less intensity. Hand and neck dystonia, as well as hemidystonia are also associated⁵.

2.5 Dystonia related to PD treatment
Treatment with levodopa may induced motor fluctuations and dyskinesias, which typically are made up of a combination of chorea and dystonia.

Isolated dystonia is typically an off period phenomenon (off-period dystonia) but can present as peak dose dystonia, or diphasic dystonia.  The dystonias seen in the ‘off’ period are often painful and tend to occur in the wearing-off phase of levodopa cycle or early after levodopa intake, but before full benefit or choreiform dyskinesias appear.  

• Off dystonias typically involve the lower limb, classically the foot (early morning dystonia). This can be precipitated by anxiety or attempts to walk.  They often start on the side with initial or most severe signs of parkinsonism.
• Peak dose dyskinesias typically are associated with dystonia of the neck and face.

 

 

 

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