Publications about genetic testing for neurological disorders
  1. Comprehensive Dystonia Panel

Comprehensive Dystonia Panel

October 04, 2018

Disease summary:

Dystonias are a diverse spectrum of neurological movement conditions characterized by sustained muscle contractions (spasms) causing repetitive twisting movements or abnormal postures 1,2.  Dystonia can be a chronic and disabling condition, localized to areas such as the head and neck or individual limbs or affecting the whole body (generalized). The most severe, generalized cases of dystonia begin in early childhood3. Clinical presentation varies widely in age of onset, localization, temporal pattern and presence of specific features or associated conditions, and careful diagnosis and then classification is important for prognosis and treatment selection5,6.

There are currently over 12 types (or sub-types) of dystonia linked to genetic mutations, including primary generalized dystonia (DYT-TOR1A), segmental dystonia with laryngeal involvement (DYT-THAP1), myoclonus dystonia (DYT-SGCE)8 and several genes causing paroxysmal dystonia. Most of these exhibit autosomal dominant inheritance, though the list of autosomal recessive forms, X-linked and mitochondrial is continuously growing4. DYT1 mutations are the most important genetic cause of early-onset generalized, isolated dystonia worldwide9


Autosomal dominant, autosomal recessive, X-linked

16/100,000 for primary dystonia9

3/100,000 for early onset torsion dystonia10

1/100,000 for cervical dystonia11

1/1,000,000-1/200,000 for Dopa-responsive dystonia

Major clinical symptoms 1-3

  • Sustained muscle contractions causing twisting and repetitive movements and abnormal postures either generalized or localized to one or more areas such as head and neck or individual limbs.
  • Dyskinesia
  • Additional specific features such as gestes antagoniste, overflow to other body parts and mirror movements
  • Initial tremors

Less common symptoms

  • Clinical presentation may show less typical features of dystonia sometimes intermixed with additional clinical signs. Dystonia is the only physical sign of primary dystonia syndromes, whereas in non-primary cases, it is associated with other movement disorders(1-3).
  • Clinical confirmation/assessment and classification of dystonia into sub-type using a validated rating scale3
  • Response to administration of oral L-Dopa3
  • Neurophysiological tests 3
  • Conventional or structural MRI studies 3

There is no cure; however, there are different types of treatment that can help.

  • A diagnostic L-Dopa trial is warranted in every patient with early-onset dystonia without an alternative diagnosis3,12
  • Botulinum toxin treatment for focal dystonia3
  • Deep brain stimulation 3, 13,14
  • Physical therapy 15

 

  • Essential tremor>
  • Parkinson’s disease
  • Myoclonus
  • Chorea
  • Tics
  • Adverse side effects, especially neuroleptic treatment

 

Genetic testing should be performed after establishing the clinical features and diagnosis of dystonia.

To confirm a diagnosis and classification of Dystonia, CENTOGENE offers the following tests:

  • Comprehensive dystonia panel NGS panel or panel plus (see list of genes in Table 117)
  • Comprehensive dystonia panel NGS panel or panel plus + CNV which includes sequencing of the genes listed in Table 1 and additionally detection of large deletions and duplications from the NGS data
  • Comprehensive dystonia panel NGS panel genomic

    • Step 1: whole genome locus sequencing with analysis of only panel genes for sequencing (exonic and intronic) and deletion/duplication variants
    • Step 2: if no variant is detected, reflex to bioinformatics analysis of whole genome based on phenotype.
  • Comprehensive dystonia panel deletion/duplication testing using MLPA/qPCR
  • Individuals with a positive family history of dystonia
  • Individuals with (early onset) symptoms of dystonia (regardless of family history)

Confirmation of a clinical diagnosis through genetic testing for dystonia can allow for genetic counseling and may direct medical management.


Table 1. Overview of the genes in CENTOGENE´s Comprehensive Dystonia Panel:

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
ADCY5 600293 Dyskinesia, familial, with facial myokymia AD 11
ANO3 610110 Dystonia 24 AD 16
ARSA 607574 metachromatic leukodystrophy AR 72
ATM 607585 familial breast cancer; ataxia-telangiectasia AD, AR 75
ATP1A3 182350 Dystonia 12; Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss; Alternating hemiplegia of childhood 2 AD 12
ATP7B 606882 Wilson disease AR 24
CACNA1B 601012 dystonia 23 AD 23
CIZ1 611420 30
COL6A3 120250 Bethlem myopathy type 1; Ullrich congenital muscular dystrophy; dystonia 27 AD, AR 30
GCDH 608801 glutaric academia type I AR 20
GCH1 600225 dopa-responsive dystonia; Hyperphenylalaninemia, BH4-deficient, B AD, AR 22
GNAL 139312 dystonia 25 AD 8
HPCA 142622 dystonia 2 AR 0
KCNMA1 600150 Generalized epilepsy and paroxysmal dyskinesia AD, AR 25
KCTD17 616386 Dystonia 26, myoclonic AD 2
PANK2 606157 neurodegeneration with brain iron accumulation type 1; HARP syndrome AR 22
PLA2G6 603604 infantile neuroaxonal dystrophy; neurodegeneration with brain iron accumulation 2B; Parkinson disease 14 AR 53
PNKD 609023 dystonia 8 AD 12
PRKN 602544 Ovarian Cancer; Lung Cancer; Parkinson disease 2 AR 40
PRKRA 603424 dystonia 16 AR 7
PRRT2 614386 Episodic kinesigenic dyskinesia 1; Convulsions, familial infantile, with paroxysmal choreoathetosis; Seizures, benign familial infantile, 2 AD 18
RELN 600514 lissencephaly 2; familial temporal lobe epilepsy, 7 AD, AR 47
SGCE 604149 myoclonus-dystonia AD 21
SLC2A1 138140 Dystonia-9; GLUT1 deficiency syndrome; dystonia 18; Epilepsy, idiopathic generalized, suscpetibility to, 12 AD, AR 37
SLC6A3 126455 Tobacco Addiction, Susceptibility To; Parkinsonism-dystonia, infantile AR 10
SPR 182125 Dystonia, dopa-responsive, due to sepiapterin reductase deficiency ?AD, AR 9
TH 191290 Segawa syndrome AR 37
THAP1 609520 dystonia 6 AD 16
TIMM8A 300356 Mohr-Tranebjaerg syndrome XLR 3
TOR1A 605204 dystonia 1 AD 17
TUBB4A 602662 dystonia 4; hypomyelinating leukodystrophy-6 AD 6

Abbreviations: AD autosomal dominant; AR autosomal recessive; XLR X-linked recessive