Table 1.
Clinical Findings in Four Affected Individuals with Truncating Variants in the NMD(−) Region of SEMA6B
| Individual 1 | Individual 2 | Individual 3 | Individual 4 | |
|---|---|---|---|---|
| Current age | 22 years | 28 years | 14 years | 11 years |
| Sex | male | female | male | female |
| Nationality | Japanese | Japanese | Israeli | Malaysian |
| Mutation | c.1950_1969dup | c.1976_1982del | c.1991del | c.1991del |
| Protein change | p.Arg657Profs∗35 | p.Ala659Valfs∗24 | p.Gly664Alafs∗21 | p.Gly664Alafs∗21 |
| Inheritance | de novo | de novo | de novo | de novo |
| Age at onset | 6 years | 11 months | 2 years | 4 years |
| Development milestones | rolling over: 12 months; meaningful words: 24–36 months | walking without support: 28 months | walking without support: 24 months | eye pursuit, 5 months; walking without support, 24 months; meaningful words, 30 months; |
| Initial symptom | seizure, developmental delay | seizure | seizure | seizure and developmental delay, |
| Initial walking | 1 year 5 months | 2 years 4 months | 2 years | 2 years, |
| Intellectual disability | severe (IQ = 25 at 17 years) | severe (IQ = 25 at 12 years) | severe | severe |
| Language | few words | few words | no words | few words |
| Microcephaly | − | + (−2.0 SD) | + (−2.5 SD) | + (2nd percentile) |
| Seizure type at onset | GTCS since 6 years, absence seizure since 9 years, atonic seizure since 11 years | GTCS since 11 months; loss of consciousness with abnormal eye movement since 5 years; complex partial seizure since 10 years; atonic seizure since 10 years, | absence seizure since 2 years | atonic seizure since 4 years |
| Response to therapy (seizure) | intractable | intractable | responsive | intractable, but improved by clobazam and sulthiame (responsive) |
| Regression | + (motor skill and dysarthria) | + (motor skill) | + (motor and verbal skills) | + |
| Ataxia | + | + | + | + |
| Intention tremor | + | + | + | + |
| Rigidity | + | + | ND | ND |
| Myoclonus | + | + | ND | + |
| Spasticity | + | + | ND | ND |
| Increased deep tendon reflex | + (upper and lower limbs) | + (upper and lower limbs) | ND | − |
| Pathogenic reflex | + (Rossolimo sign; positive, Mendel-Bechterew sign; positive) | − | ND | − |
| Dysmorphic features | − | − | − | − |
| Motor disturbance | wheelchair | wheelchair | wheelchair | walking with support |
| Brain MRI | normal | mild cerebellar atrophy; | small vermis | normal |
| EEG | abnormal discharge in right hemisphere (6 years); burst of diffuse irregular spikes and slow waves (9 years); diffuse spike and slow waves in frontal, parietal and temporal regions (14 years) | diffuse slow wave with 2–3 Hz and spike-and-wave in bilateral frontal region (3 years and 4 years); diffuse theta waves with 4–5 Hz and spike-and-wave burst with 2–3 Hz (9 years); multifocal spikes in left parietal region and bilateral frontal regions (12 years); multispikes in left occipital region (13 years); slow waves at baselines (23 years) | abnormal background activity (1 year); slow abnormal sleep features with paucity of sleep spindles (13 years) | focal bifrontal epileptiform discharges accentuated during sleep (4 years); frequent frontocentral discharges during awake state (5 years); frequent intermittent slow spikes in right posterior region (11 years) |
| SEP | prolonged N20 latency and high amplitude of P24-N33 | giant SEP | ND | ND |
| Other findings | ND | SLE | ND | ND |
SEMA6B variants are based on GenBank: NM_032108.4. Abbreviations are as follows: EEG, electroencephalogram; GTCS, generalized tonic-clonic seizures; ND, not described; MRI, magnetic resonance imaging; SEP, somatosensory evoked potential; SLE, systemic lupus erythematosus; +, present; and −, not present.