Table 1.
Pathogenic Variants and Key Clinical Information of Individuals with Bi-allelic Mutations in ACTL6B
| Individual | R1 | R2 | R3 | R4 | R5 | R6 | R7 | R8a | R8b | R9 | R10 | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Inheritance | recessive, homozygous | recessive, compound heterozygous; similarly affected brother passed away at 5 y | recessive, homozygous; similarly affected brother passed away at 4 y | recessive, compound heterozygous | recessive, compound heterozygous | recessive, compound heterozygous | recessive, homozygous | recessive, homozygous | recessive, homozygous; sister of R8a | recessive, compound heterozygous | recessive, homozygous | |||||
| Coding change (NM_016188.4) | c.441_443delCTT | c.695delC | c.1275C>A | c.1279del | c.389G>A | c.556C>T | c.852C>G | c.740G>A | c.1231C>T | c.669+1G>A | c.289C>T | c.1045G>A | c.1045G>A | c.724C>T | c.617T>C | c.1279del |
| Protein change (NP_057272.1) | p.Phe147del | p.Pro232Glnfs∗24 | p.Cys425∗ | p.∗427Aspext∗33 | p.Arg130Gln | p.Gln186∗ | p.Tyr284∗ | p.Trp247∗ | p.Gln411∗ | splicing | p.Arg97∗ | p.Gly349Ser | p.Gly349Ser | p.Gln242∗ | p.Leu206Pro | p.∗427Aspext∗33 |
| gnomAD MAF | 0.00001444, no homozygotes | absent | absent | absent | 0.000008132, no homozygotes | absent | absent | absent | absent | absent | 0.000004064, no homozygotes | 0.00001219, no homozygotes | 0.00001219, no homozygotes | absent | absent | absent |
| Age at assessment | 3 y (F) | 5 y (M) (passed away at age 5) | 11 m (M) (passed away age 5) | 8 y (F) | 5 m (F) | 12 m (M) (passed away age 2) | 4 y (F) | 6 y (F) | 5 y (F) | 14 m (F) | 4.5 y (F) | |||||
| Head circum. (cm) | 43 (−3.5 SD) | NA | 44 (3rd) | 50.3 (10th %ile) | 38.4 (−3.0 SD) | 42 (−2.4 SD) | normal | 41.5 (−3.8 SD) at 18 m | 39 (7th %ile) at 4 m | 43 (−2.5 SD) | 47 (−2.8 SD) | |||||
| ID, DD | +, severe | + | + | +, severe | +, severe | +, severe | +, severe | +, severe | +, severe | +, severe | + | |||||
| Speech | − | − | NA | − | NA | − | NA | − | − | − | − | |||||
| Ambulation | − | − | NA | − | NA | − | NA | − | − | − | +, with support | |||||
| Axial hypotonia | + | + | + | + | + | + | + | + | + | + | + | |||||
| Limb spasticity | + | + | + | + | + | + | + | + | + | + | + | |||||
| Feeding difficulties | + | + | + | − | + | + | + | + | + | + | − | |||||
| Epilepsy | + | + | + | + | + | + | + | + | + | + | + | |||||
| Seizures (age at beginning) | 3 m | 3 y | NA | NA | 2 m | neonatal (25 days) | infancy | infancy | infancy | antenatal | 9 m, infantile spasms | |||||
| Seizure types | myoclonias 2–6 per day | complex partial | NA | NA | tonic and myoclonic | focal onset epilepsy, progressed to infantile spasms | NA | NA | NA | myoclonic and tonic seizures | tonic and myoclonic | |||||
| EEG anomalies | multifocal epileptic activity | NA | multifocal epileptic activity | NA | multifocal epileptic activity | multifocal interictal epileptiform spike discharges, lack of posterior dominant rhythm | multifocal EEG abnormalities | generalized slowing of background rhythms | generalized slowing of background rhythms | multifocal epileptic activity, esp. left hemisphere | multifocal epileptic activity, esp. left hemisphere | |||||
| MRI | prominent subarachnoid spaces and small corpus callosum | normal | mild T2 hyperintensity in frontal periventricular white matter | mild T2 hyperintensity in frontal periventricular white matter | 2 m: symmetric signal changes in the brainstem and in the dorsal medulla oblongata, possibly also around the dentate nucleus | 3 weeks: asymmetric ventricles, cortical dysplasia right parietal lobe; 9 m: cerebral atrophy, hypoplasia of corpus callosum | NA | 5 m: significantly decreased white matter throughout, extremely thin corpus callosum. Normal MR spectroscopy | 10 m: periventricular leukomalacia with white matter volume loss, overall brain volume loss, delayed myelination and thinning of corpus callosum. Normal MR spectroscopy | thin corpus callosum; high signal intensity doral globus pallidus/putamen; some asymmetry gyral patern | 3.5 y: cerebral and cerebellar atrophy, thin corpus callosum | |||||