Figure 1
Pedigree of all four affected children presenting lingual dystonia. All children are homozygous for the two missense variants in MYH3 gene and both parents, which are asymptomatic, are heterozygous for the two variants. Each tongue picture is taken as the subject is requested to sit, at rest on the examination bench, with his mouth opened.
Video 1
Neurological examination of our patients’ dystonic features. Each tongue video shows the patient first at rest and then moving voluntarily the tongue. Segment 1: Isolated lingual dystonia examination in patient A. Lingual dystonia follows a torsion pattern inducing a curling of the tongue while opening the mouth. Segment 2: Examination of patient B with lingual dystonia (2–1). Pronator drift test reveals both hand dystonia and arthrogryposis of hands. There is no cerebellar dysfunction, but finger-to-nose test is difficult to achieve because of the torsion pattern resulting from hand dystonia (2–2) When sitting on the examination bench, a varus equine position of both feet is observed, but not during gait examination. Segment 3: Examination of patient C, presenting with lingual dystonia. Segment 4: Examination of patient D with lingual dystonia (4–1). Other dystonic features are also present, with cervical dystonia with a right torticaput pattern (4–2).
Figure 2
Clinical phenotype – 2A,B,C: Hand dystonia. Pictures A and C illustrate patient B and picture B illustrates patient D. In picture A and B, patients are asked to lift their hands while sitting at rest. In picture C, patient B is asked to put her hands facing each other; 2D – Foot dystonia in patient D while sitting at rest on the bench; 2E – Vertebral X-ray illustrating scoliosis in patient B; 2F,G – Feet and hands arthrogryposis in patient B.
Table 1
MYH3 variants classification.
| Variant cDNA (NM_002470.4) | c.3445G>A | c.4760T>C |
| Variant protein (NP_002461.2) | p.Glu1149Lys | p.Leu1587Pro |
| HGVS genomic (hg 19) | Chr17:g.10541644C>T | Chr17:g.10535989A>C |
| PM2: Rarity | GnomAD frequency = 0.00001067 with no homozygous | GnomAD frequency = 0.00001193 with no homozygous |
| PM3: already described | Described in Morali 2024 | Described in Morali 2024 |
| PP1: segregation | Family of 4 affected siblings | Family of 4 affected siblings |
| PP2: missense sensitive | Missense sensitive constraint score GnomAD = 4.67 | Missense sensitive constraint score GnomAD = 4.67 |
| PP3: in silico score | Highly conserved amino acid REVEL score = 0.777, CADD score = 5.5 | Moderately conserved amino acid REVEL score = 0.482, CADD score = 5.07 |
| PP4: phenotype | Patient B has typical distal arthrogryposis | Patient B has typical distal arthrogryposis |