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 10
ANO3 610110 Dystonia 24 AD 16
ARSA 607574 Metachromatic leukodystrophy AR 71
ATM 607585 Breast cancer, susceptibility to; Ataxia-telangiectasia AD, AR 73
ATP1A3 182350 Dystonia-12; CAPOS syndrome; Alternating hemiplegia of childhood 2 AD 12
ATP7B 606882 Wilson disease AR 23
CACNA1B 601012 ?Dystonia 23 AD 23
CIZ1 611420 30
COL6A3 120250 Bethlem myopathy 1; Ullrich congenital muscular dystrophy 1; Dystonia 27 AD, AR 31
GCDH 608801 Glutaricaciduria, type I AR 18
GCH1 600225 Dystonia, DOPA-responsive, with or without hyperphenylalaninemia; Hyperphenylalaninemia, BH4-deficient, B AD, AR 22
GNAL 139312 Dystonia 25 AD 8
HPCA 142622 Dystonia 2, torsion, autosomal recessive AR 0
KCNMA1 600150 Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy; ?Cerebellar atrophy, developmental delay, and seizures AD, AR 25
KCTD17 616386 Dystonia 26, myoclonic AD 2
PANK2 606157 Neurodegeneration with brain iron accumulation 1; HARP syndrome AR 21
PLA2G6 603604 Infantile neuroaxonal dystrophy 1; Neurodegeneration with brain iron accumulation 2B; Parkinson disease 14, autosomal recessive AR 51
PNKD 609023 Paroxysmal nonkinesigenic dyskinesia 1 AD 12
PRKN 602544 Adenocarcinoma, ovarian, somatic; Adenocarcinoma of lung, somatic; Parkinson disease, juvenile, type 2; Leprosy, susceptibility to AR 39
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 (Norman-Roberts type); Epilepsy, familial temporal lobe, 7 AD, AR 48
SGCE 604149 Dystonia-11, myoclonic AD 23
SLC2A1 138140 Dystonia 9; GLUT1 deficiency syndrome 1, infantile onset, severe; Stomatin-deficient cryohydrocytosis with neurologic defects; GLUT1 deficiency syndrome 2, childhood onset; Epilepsy, idiopathic generalized, susceptibility to, 12 AD, AR 35
SLC6A3 126455 Nicotine dependence, protection against; Parkinsonism-dystonia, infantile AR 10
SPR 182125 Dystonia, dopa-responsive, due to sepiapterin reductase deficiency ?AD, AR 10
TH 191290 Segawa syndrome, recessive AR 37
THAP1 609520 Dystonia 6, torsion AD 16
TIMM8A 300356 Mohr-Tranebjaerg syndrome XL R 3
TOR1A 605204 Dystonia-1, torsion AD 15
TUBB4A 602662 Dystonia 4, torsion, autosomal dominant; Leukodystrophy, hypomyelinating, 6 AD 6

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