IllnessDystonia, childhood; differential diagnosis

NGS +

[Sanger]

Dystonias are associated with involuntary, repetitive, sustained muscle contractions/postures, typically beginning in a single limb, followed by progressive involvement of other limbs and the trunk. Early etiologic diagnosis is of great importance in childhood dystonia, as some of the possible underlying conditions are treatable. Numerous genetic (and nongenetic) causes are known. The genetic forms of dystonia, including inborn errors of metabolism, can be divided into two groups. The first group consists of the monogenic forms of dystonia with assigned genetic loci identified as DYT1-29, which have been termed primary dystonias and dystonia plus syndromes. These disorders are characterized by isolated dystonia or dystonia in combination with parkinsonism or myoclonus. The second group consists of genetic disorders in which dystonia is an important feature among several other neurological and systemic features. Important associated features in children are: ataxia, epilepsy, mental retardation, spasticity, hypotonia, abnormal eye movements, neuropathy, deafness, ophthalmologic signs, hepatosplenomegaly, psychiatric and dysmorphic features. These features are critical for accurate phenotyping and are prerequisites for correct interpretations of NGS results. The DNA diagnostic yield depends critically on the prior clinical case workup and the largest possible gene panel coverage, with the latter defining mutations in up to 30%. A negative molecular genetic result represents only the exclusion of the molecular genetically defined diagnoses. The yield appears higher in complex dystonia than in isolated, in particular in patients with intellectual deficits.

References: https://www.ncbi.nlm.nih.gov/books/NBK1155/

https://jnnp.bmj.com/content/86/7/774

https://pubmed.ncbi.nlm.nih.gov/32334381/

• Aicardi-Goutieres syndrome 6 (ADAR)
• Alias: Early-onset (generalized) torsion dystonia
• Alias: Early-onset isolated dystonia
• Alias: Early-onset primary dystonia
• Alias: Idiopathic torsion dystonia
• Alias: Oppenheim dystonia
• Allelic: Adenocarcinoma of lung, somatic (PRKN)
• Allelic: Amyotrophic lateral sclerosis, susceptibility to, 13 (ATXN2)
• Allelic: Breast cancer, susceptibility to (ATM)
• Allelic: Dyschromatosis symmetrica hereditaria (ADAR)
• Allelic: Hemosiderosis, systemic, due to aceruloplasminemia (CP)
• Allelic: Hyperferritinemia-cataract syndrome (FTL)
• Allelic: Hypoceruloplasminemia, hereditary (CP)
• Allelic: L-ferritin deficiency, AD + AR (FTL)
• Allelic: Lymphoma, B-cell non-Hodgkin, somatic (ATM)
• Allelic: Lymphoma, mantle cell, somatic (ATM)
• Allelic: Migraine, familial basilar (ATP1A2)
• Allelic: Migraine, familial hemiplegic, 2 (ATP1A2)
• Allelic: Ovarian cancer, somatic (PRKN)
• Allelic: Parkinson disease 13 (HTRA2)
• Allelic: Parkinson disease, late-onset, susceptibility to (ATXN2)
• Allelic: T-cell prolymphocytic leukemia, somatic (ATM)
• 3-methylglutaconic aciduria, type VIII (HTRA2)
• Allelic: Seizures, benign neonatal, 1 (KCNQ2)
• Alternating hemiplegia of childhood (ATP1A3)
• Alternating hemiplegia of childhood 1 (ATP1A2)
• Aromatic L-amino acid decarboxylase deficiency (DDC)
• Arthrogryposis multiplex congenita 5 (TOR1)
• Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (APTX)
• Ataxia-telangiectasia (ATM)
• Basal ganglia calcification, idiopathic, 1 (SLC20A2)
• Basal ganglia calcification, idiopathic, 1 (SLC39A14)
• CAPOS syndrome (ATP1A3)
• Cerebellar ataxia (CP)
• Choreoacanthocytosis (VPS13A)
• Deafness, dystonia + cerebral hypomyelination (BCAP31)
• Developmental + epileptic encephalopathy 17 (GNAO1)
• Developmental + epileptic encephalopathy 53 (SYNJ1)
• Developmental and epileptic encephalopathy 7 (KCNQ2)
• Developmental and epileptic encephalopathy 98 (ATP1A2)
• Dyskinesia, familial, with facial myokymia (ADCY5)
• Dystonia 11, myoclonic (SGCE)
• Dystonia 12 (ATP1A3)
• Dystonia 25 (GNAL)
• Dystonia 26, myoclonic (KCTD17)
• Dystonia 28, childhood-onset (KMT2B)
• Dystonia 30 (VPS16)
• Dystonia 4, torsion, AD (TUBB4A)
• Dystonia 6, torsion (THAP1)
• Dystonia musculorum deformans 1
• Dystonia, DOPA-responsive, due to sepiapterin reductase deficiency (SPR)
• Dystonia, DOPA-responsive, with or without hyperphenylalaninemia (GCH1)
• Dystonia, childhood-onset, with optic atrophy + basal ganglia abnormalities (MECR)
• Dystonia-1, modifier of (TOR1)
• Dystonia-1, torsion (TOR1)
• Dystonia-Parkinsonism, XL (retroposon insertion in TAF1)
• Epilepsy, progressive myoclonic 1A [Unverricht + Lundborg] (CSTB)
• Fetal akinesia, respiratory insuff., microcephaly, polymicrogyria, dysmorphic face (ATP1A2)
• Frontotemporal dementia and/or amytrophic lateral sclerosis 7 (CHMP2B)
• Gabriele-de Vries syndrome (YY1)
• Galloway-Mowat syndrome 1 (WDR73)
• Glutaricaciduria, type I (GCDH)
• Huntington disease-like 2 (JPH3)
• Hypermanganesemia with dystonia 1 (SLC30A10)
• Hyperphenylalaninemia, BH4-deficient, B (GCH1)
• Hyperuricemia, HRPT-related (HPRT1)
• ID, autism, abnormal behavior, dystonia, ataxia, chorea, myoclonus (CAMK4)
• Kufor-Rakeb syndrome (ATP13A2)
• Lesch-Nyhan syndrome (HPRT1)
• Leukodystrophy, hypomyelinating, 6 (TUBB4A)
• Machado-Joseph disease (ATXN3_CAG)
• McLeod syndrome with/-out chronic granulomatous disease (XK)
• Mental retardation, XL, syndromic 3 (TAF1)
• Mitochondrial DNA depletion syndrome 5, encephalomyopathic +/- methylmalonic aciduria (SUCLA2)
• Myokymia (KCNQ2)
• Neurodegeneration with brain iron accumulation 3 (FTL)
• Neurodegeneration with brain iron accumulation 4 (C19orf12)
• Neurodegeneration with brain iron accumulation 5 (WDR45)
• Neurodegeneration with brain iron accumulation 6 (COASY)
• Neurodevelopmental disorder with dystonia [panelapp] (IMPDH2)
• Neurodevelopmental disorder with involuntary movements (GNAO1)
• Neurodevelopmental disorder, spasticity, cataracts, cerebellar hypoplasia (MED27)
• Parkinson disease 15, AR (FBXO7)
• Parkinson disease 20, early-onset (SYNJ1)
• Parkinson disease, juvenile, type 2 (PRKN)
• Paroxysmal nonkinesigenic dyskinesia 1 (PNKD)
• Pettigrew syndrome (AP1S2)
• Pontocerebellar hypoplasia, type 12 (COASY)
• Pyruvate dehydrogenase E2 deficiency (DLAT)
• Spastic ataxia 8, AR, with hypomyelinating leukodystrophy (NKX6-2)
• Spastic paraplegia 35, AR (FA2H)
• Spastic paraplegia 43, AR (C19orf12)
• Spastic paraplegia 78, AR (ATP13A2)
• Spinocerebellar ataxia 2 (ATXN2_CAG)
• Spinocerebellar ataxia, AR 29 (VPS41)
• Striatonigral degeneration, childhood-onset (VAC14)
• Thiamine metabolism dysfunction syndrome 2, biotin-/thiamine-resp. encephalopathy type 2 (SLC19A3)
• Wilson disease (ATP7B)
• Woodhouse-Sakati syndrome (DCAF17)