Comprehensive dystonia panel
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
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.
- 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
- 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|
|ATM||607585||Breast cancer, susceptibility to; Ataxia-telangiectasia||AD, AR||73|
|ATP1A3||182350||Dystonia-12; CAPOS syndrome; Alternating hemiplegia of childhood 2||AD||12|
|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|
|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|
|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|
|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|
|TUBB4A||602662||Dystonia 4, torsion, autosomal dominant; Leukodystrophy, hypomyelinating, 6||AD||6|
Abbreviations: AD autosomal dominant; AR autosomal recessive; XLR X-linked recessive