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Table 1 Overlapping phenotypes in the CACNA1E patients

From: De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures

 

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

  1. 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