Table 1.
Overlapping phenotypes in the CACNA1E patients
| Patient 1 | Patient 2 | Patient 3 | Patient 4 | Patient 5 | Patient 6 | Patient 7 | |
|---|---|---|---|---|---|---|---|
| Genetics | |||||||
|
CACNA1E variant (NM_000721.4) Coordinates in hg19 |
c.488T>C (p.Met163Thr) 1:181480622T>C |
c.1499A>G (p.Gln500Arg) 1:181686412 A>G |
c.2060C>T (p.Thr687Ile) 1:181690997 C>T |
c.2104G>T (p.Ala702Ser) 1:181693635 G>T |
c.2105C>T (p.Ala702Val) 1:181693636 C>T |
c.2108T>G (p.Val703Gly) 1: 181693639T>G |
c.3422+1G>A (p.?) 1:181705571 G>A |
| Inheritance | de novo | de novo | de novo | de novo | de novo | de novo | de novo |
| Localization | S3 of Domain I | Intersegment S1–S2 of Domain II | S6 of Domain II | S6 of Domain II | S6 of Domain II | S6 of Domain II | Beginning of Domain III |
| Age at genetics assessment | 6 yo | 8 yo | 18 mo | 31 yo | 6 yo | 4 yo 7 mo | 6 yo 6 mo |
| Clinical characteristics and history | |||||||
| Sex | M | M | M | F | M | F | M |
| Age at onset symptoms/parental concern | 14 mo (regression) | 8–10 mo | 12 mo | 6 mo | Shortly after birth | Neonatal GI symptoms related to sucrose isomaltase deficiency; DD at 6 mo | 24 mo (regression) |
| Age at last clinical evaluation | 7 yo | 10 mo | 25 mo | 31 yo | 6 yo | 4 yo | 8.5 yo |
| Seizures | No | No | No | IS at 6.5 mo—ACTH | No | No | No |
| EEG (age) | Left parieto sagittal discharges (6 yo) activated during sleep | Unremarkable (8 yo) | NA | NA | Multifocal spike and slow wave discharges (4.5 yo); bifrontal sharps activated during sleep | NA | NA |
| Neurological evaluation | |||||||
| Head circumference at last evaluation (Percentile) | 52 cm (P10–25) | 51.4 cm (P25–50) | 47.6 cm (P10–25) | 55 cm (P25–50) | 52 cm (P25–50) | 48.8 cm (P3–10) | 52 cm (P10–25) |
| Developmental regression number (age) |
2 (14 mo, 5 yo) Loss of communication skills, autonomy and diurnal bladder control at 5 yo |
1 (4 yo) Fine and global motor skills regression |
1 (12–18 mo) Language regression |
No | NA | No |
1 (24 mo) Language regression |
| GDD* | + | + | + | + | + | + | + |
| Intellectual disabilities (> 5yo)** | Moderate | Moderate to severe | NA | Severe | NA | NA | Severe |
| Language development |
Delayed Verbal, able to express complete sentences |
Delayed Speaks few words at 8 yo |
Delayed No words at 2 yo |
Delayed Some single-words |
Delayed Non-verbal |
Delayed Babbles at 4 yo |
Delayed Phrase speech at 48 mo; echolalia |
| Social behavior/impairment | Abnormal/ASD diagnosis | Abnormal/ ASD diagnosis | None reported at 2 yo | Abnormal | NA | Social: makes eye contact, smiles, giggles | Abnormal/ASD diagnosis |
| Sensory issues |
Produces loud sounds No reaction to pain |
Sensory seeking behavior (repetitive tapping) | – | – | Reduced pain sensitivity | Displayed sensory-seeking behaviors |
Picky eater Sensitive to noise and touch |
| Motor stereotypies | Body rocking, hand flapping | Hand flapping | NA | Hand flapping, hand stereotypies | NA | None | Persistent motor stereotypies |
| Tone disorder | Hypotonia | Hypotonia | Hypotonia | None | Hypotonia | Hypotonia | None |
| Motor development |
Delayed Ambulatory |
Delayed Ambulatory |
Delayed, Not walking at 2 yo |
Delayed Ambulatory |
Delayed Not walking, sat at 2.5 yo |
Delayed Not walking at 4 yo Apraxia |
Delayed Ambulatory |
ACTH adrenocorticotropic hormone, DD developmental delay, F female, GI gastrointestinal, IS infantile spasm, M male, mo months old, NA not available, S segment, yo year old. *No developmental quotient was available; **For patient 1 a WIPPSI IV was performed; the type of testing used for the IQ assessment was not available for the other patients