Table 4.
Summary of the Clinical Features of Individuals with DNMs in CLTC (GenBank: NM_004859.3)
| Individual | Gender | Age at Last Examination | DNM (Detection) | Cognitive and Behavioral Features | Epilepsy Diagnosis | Age at Seizure Onset | Seizure Types | AEDs | EEG | Brain MRI | Associated Neurological Features and Seizure Outcome |
|---|---|---|---|---|---|---|---|---|---|---|---|
| PBSD | female | 11 years, 2 months | c.977_980delCAGT (p.Ser326Cysfs∗8) (cWESa) | GDD, borderline IQ at 5 years | no seizures | NA | NA | NA | NA | T2 hypersignal in white matter (hypomyelination) | ADHD, impulsivity, poor socialization skills, mild hypotonia, wide-based gait |
| 5289183 | male | 20 years, 5 months | c.1660_1668del (p.Met554_Tyr556del) (cWESa) | borderline IQ, learning disabilities | NA | 14 years | one seizure | LEV | normal | normal | progressive paraparesis with lower-limb spasticity, ataxia, myoclonus, one seizure without recurrence under LEV, no seizures for 4 years off meds |
| indvAA | male | 3 years, 2 months | c.2669C>T (p.Pro890Leu) (cWESb) | GDD | no seizures | NA | NA | NA | normal | normal | mild ataxia, possible myoclonus |
| CAUSES1 | male | 4 years, 7 months | c.2669C>T (p.Pro890Leu) (WES) | GDD, suspected ID | no seizures | NA | NA | NA | NA | normal | mild hypotonia, oral and motor apraxia, suspected ADHD |
| 18052017 | female | 30 years | c.2669C>T (p.Pro890Leu) (WESc) | moderate ID | no seizures | NA | NA | NA | normal | normal | bradykinesia, bradypsychism, hypomimia, hypokinesia, clumsiness, attention instability |
| indvPAR | male | 16 years | c.3140T>C (p.Leu1047Pro) (trio cWES) | severe ID | DEE | 1 year | suspected FIA | VPA | non-specific irritative pattern, no foci | thin and short CC with hypoplasia of its posterior part, wide Virchow-Robin spaces | neonatal-onset hypotonia, no speech, acquired microcephaly, severe gastroinstestinal reflux, no seizures under VPA |
| 273692 | male | 4 years | c.3322T>C (p.Trp1108Arg) (WESd) | severe GDD, suspected severe ID | DEE | 2 years | M, GTC, possible gelastic seizures | LEV | abnormal | pontocerebellar atrophy, delayed myelination | nonambulation, spasticity, dystonia, myoclonus, neonatal feeding difficulties, visual impairment, seizure control with LEV |
| DDD261801 | male | 10 years, 7 months | c.3595C>T (p.Gln1199∗) (WESd) | mild GDD, mild ID | no seizures | NA | NA | NA | NA | normal | neonatal-onset hypotonia, congenital ptosis, poor social skills |
| indvMB | female | 7.5 years | c.3621_3623del (p.Asp1207del) (WES) | GDD, severe ID | DEE | 3 years | febrile GTC, M, To | VPA, LTG, CLB, CZP, LEV, TPM, LCM | MSW, biF | thin CC, T2 hypersignal in white matter, enlarged LVs | acquired microcephaly, severe hypotonia, ataxia, oral and motor apraxia, intractable seizures |
| HSC0054 | female | 23 years | c.4575dupA (p.Glu1526Argfs∗18) (WGSe) | GDD, moderate ID | DEE | 5 months | A, M, To, GTC, Fo | CLB, VPA,HCTZ, LEV, LTG, KD | gen. SW and PSW | delayed myelination, normal at 20 years | neonatal hypotonia, scoliosis, intractable seizures until puberty, no seizures under LEV and LTG |
| LDKQS | male | 12 years, 10 months | c.4605+2T>C (cWESa) | GDD, moderate ID | no seizures | NA | NA | NA | NA | normal | hypotonia, neonatal feeding difficulties, sensorineural hearing loss |
| DDD0280 | female | 6 years | c.4663C>T (p.Gln1555∗) (WESd) | GDD, moderate to severe ID | no seizures | NA | NA | NA | NA | ND | hypotonia |
| 281177 | male | 11 years | c.4667G>A (p.Trp1556∗) (WESd) | moderate ID | no seizures | NA | NA | NA | NA | ND | neonatal hypotonia |
Underlining indicates treatment with clinical response (decreased seizure frequency or severity). Abbreviations are as follows: NA, not applicable; ND, not done; cWES, clinical whole-exome sequencing; WGS, whole-genome sequencing; GDD, global developmental delay; IQ, intelligence quotient; ID, intellectual disability; DEE, developmental and epileptic encephalopathy; FIA, focal impaired awareness; M, myoclonic; GTC, generalized tonic-clonic; To, tonic; A, absence; Fo, focal; AED, anti-epileptic therapy; LEV, levetiracetam; VPA, valproic acid; LTG, lamotrigine; CLB, clobazam; CZP, clonazepam; TPM, topiramate; LCM, lacosamide; KD, ketogenic diet; HCTZ, hydrochlorothiazide; EEG, electroencephalography; MSW, multifocal spike-wave; biF, bi-frontal predominance; gen. SW, generalized spike-wave; PSW, poly-spike and wave; MRI, magnetic resonance imaging; WM, white-matter tracts; CC, corpus callosum; LV, lateral ventricle; and ADHD, attention-deficit hyperactivity disorder.
GeneDx.
Radboud University Medical Center.
Ospedale Pediatrico Bambino Gesù.
DDD study.
CENet.