Table 1.
Phenotypic characteristics of the movement disorder in patients within the study cohort with KMT2B-related dystonia (n = 44)
| Pt | Variant Inheritance How diagnosed | Age, y: Sex | AOO motor, y | Motor and other features at onset | Bilateral LL/UL age, y | Cranial / cervical / caryngeal age, y | Symptoms of cranial, cervical, laryngeal dystonia | MRI age, yGPi hypo. Additional features | Medications: response | GPI-DBS age, y |
|---|---|---|---|---|---|---|---|---|---|---|
| 1a |
Deletion: chr19:34521462–3819173 De novo Microarray |
F: 5 | 2.5 | Unilateral LL dystonia | 3.5/NR | NR/ND/4.25 | Dysarthria, dysphonia, swallowing difficulties |
4.9 Y |
BZD, l-DOPA, THY: no benefit |
Yesc 4.5 |
| 2 |
Deletion: chr19:3556008–35880945 Unknown Microarray |
6: M | 3 | Bilateral; LL dystonia | 3.25/4.75 | 5.75/NR/ND | Dysarthria→anarthria; mild rotary torticollis |
4.5 N |
NR | No |
| 3 |
c.12_24dup13 p.Ser9Glyfs*111 de novo Research WGS |
22: F | 5 | Unilateral LL dystonia | 6/11 | 15/17/18 | Dysarthria→anarthria; dysphagia; retrocollis; tridor |
8,9,11,13,17 Yb Less evident aged 17 compared to 13 |
BFN, CBZ, CPM, DPM, ITBFN, l-DOPA, THY: no benefit; TIZ: clinical benefit |
Yes 22 |
| 4 |
c.188delG p.Ala40Profs*6 de novo Diagnostic WGS +twin of Pt 5 |
19: M | 7-8 | Dysarthria; precocious puberty; deceleration of growth | 14/14–15 | 7–8/13/7–8 | Dysarthria→anarthria; drooling; swallowing difficulties; jaw-opening dystonia; torticollis |
12,16,18 Y |
BFN, CLO, CPM, TBZ, THY: no benefit; ARI, BTX: clinical benefit |
Yes 18 |
| 5 |
c.188delG p.Ala40Profs*6 de novo Diagnostic WGS +twin of Pt 4 |
19: M | 7-8 | Dysarthria; precocious puberty | 14/14–15 | 7–8/7–8/7–8 | Dysarthria; drooling; swallowing difficulties; torticollis |
12,13 Y |
BFN, THY, ARI: no benefit; BTX: clinical benefit |
Yes 18 |
| 6 |
c.816dupC p.Gly273Argfs*61 de novo Diagnostic WES |
12.75: F | 5–6 | LL dystonia; dysarthria | 6–7/9 | 5.5/ND/ND | Dysarthria; swallowing difficulties |
11 Yb |
NR | No |
| 7 |
c.850C>T p.Gln284* de novo Diagnostic Panel |
13: F | 6 | Cervical dystonia with febrile illness, followed by unilateral LL dystonia | 6.5/unilateral only 12 | 12/6/ND | Dysarthria |
10 Y |
l-DOPA: no benefit; CBZ: 10–20% reduction in exercise induced dystonia | No |
| 8 |
c.1107dupC p.Glu370Argfs*19 de novo Research SS |
26: M |
4 | Unilateral LL dystonia | 8/10 | 8/15/10 | Dysarthria→ anarthria; spasmodic dysphonia; swallowing difficulties; torticollis; jaw-opening dystonia |
15.75 Yb |
l-DOPA trial, ROP: no benefit | No |
Patients 1–8 are shown; details for Patients 9–44 are provided in the Supplementary material. NM_014727.2, GRCh38 (Chr 19). AOO motor = age at onset of motor symptoms; ARI = aripiprazole; BFN = baclofen; BTX = Botulinum toxin; BZD = benzodiazepine; CBZ = carbamazepine; CLO = clonidine; CPM = clonazepam; DPM = diazepam; F = female; hypo. = hypointensity; ITBFN = intra-thecal baclofen; l-DOPA = levodopa/carbidopa; LL = lower limb; M = male; N = no; ND = never developed; NR = not recorded; Pt = patient; ROP = ropinirole; SS = sanger sequencing; TBZ = tetrabenazine; THY = trihexyphenidyl; TIZ = tizanidine; UL = upper limb; VPA = sodium valproate; WES = whole-exome sequencing; WGS = whole-genome sequencing; Y = yes.
aIncluded in the DBS cohort. See Table 4 for further details; bReviewed by Neuroradiologist W.K.C; cLongitudinal GPI-DBS data are available.