Table 1 Clinical, EEG and genetic features of our cohort affected by CELSR1 variants

From: Biallelic variants in CELSR1 cause brain malformations, neurodevelopmental disorders and epilepsy in humans

 

Patient #1a

Patient #2a

Patient #3

Patient #4a

Patient #5

Patient #6

Patient #7

Demographic

Age at last FUP/Gender

15 y/F

11 y/F

14 y/F

9 y/M

7 y/F

7 y/F

1 m (death)/M

Mutation

c.2935 C > T p.(Leu979Phe),

c.2935 C > T p.(Leu979Phe),

c.2018T>C p.(Val673Ala),

c.2935 C > T p.(Leu979Phe),

c.3601 G > A p.(Asp1201Asn)

c.3601 G > A p.(Asp1201Asn)

c.1210 G > A (p.Glu404Lys)

c.7456 G > C p.(Ala2486Pro)

c.7456 G > C p.(Ala2486Pro)

c.7012 G > A p.(Val2338Ile)

c.2935 C > T p.(Leu979Phe)

c.4436 T > A p.(Leu1479His)

c.4436 T > A p.(Leu1479His)

c.4415 C > G (p.Thr1472Ser)

Inheritance

Paternal/Maternal

Paternal/Maternal

Maternal/Paternal

Maternal/aternal

Maternal/de novo

Maternal/de novo

Maternal/Paternal

Family history

Consanguinity. ID.

Consanguinity. ID.

None known

Consanguinity. ID.

Mother: SVT. Lymphedema

Mother: SVT. Lymphedema

None known

Multiple miscarriages.

Neuroimaging

MRI scanning

7 y: pachygyria ( > F), several rounded subcortical WMA

6 y: pachygyria ( > F), several isolated subcortical WMA

3 y: coarse, small CC. Enlarged LV. PNHs.

3 y: unremarkable

n.p.

16 m: unremarkable

10 d: small pons, cerebral and cerebellar hypoplasia, mild enlargement of Fr subarachnoidal spaces, SPC. Enlarged LV.

Epilepsy

Epilepsy; age at Sz onset

Yes; 6 y

Yes; 2 y

Yes; 14 y

Yes; 3 y

No

No

No

Type of epilepsy/Sz

Staring, eyelid My

FS, staring, eyelid My

BTCS

AFS, BTCS, staring, ESES/DEE-SWAS

-

-

-

EEG

diffuse 3,5–5 Hz spike-polyspikes during hyperventilation and photostimulation

brief diffuse 3,5–5 Hz spike and polyspikes paroxysms and prominent photosensitivity

Slow BGA.

ESES/DEE-SWAS: maximum NREM-SWI 70%

-

-

Low BGA. No circadian activity

ASMs triedb

VPA, LEV, ESM

VPA, ESM, LEV

CBZ

VPA, LEV, ESM, STM

-

-

-

Current epilepsy status

Sz free (since the age of 13 y)

Sz free (since the age of 10 y)

Sz free (for 3 m)

ESES/DEE-SWAS remission: 8 y

-

-

-

Sz free (since 6 y of age) on STM

Development

Neurodevelopment

Mild NDD

Mild NDD

Moderate NDD

Moderate NDD

Mild NDD

Moderate NDD

Severe NDD

Gross motor delay

Mild

Mild

No

No

No

No

Severe. Akinesia, no active movements

Fine motor delay

No

Mild

No

No

No

No

-

Posture

2 y: walking

18 m: crawling

Normal

Normal achievement

Normal achievement

Normal achievement

-

2 y: walking

Intellectual disability

Mild. Attends special school

Cognitive executive deficit. Attends special school

Moderate/severe. No long-term memory

Moderate

Mild/Moderate

Moderate/severe

-

Understands commands

Yes

Yes

Yes

Yes

Yes

Yes

-

Expressive speech

Mild delay. Improving

Mild delay. Improving

Severe delay.

Few single words

Severe delay.

Mild mixed receptive-expressive language disorder

Moderate mixed receptive-expressive language disorder

-

2 y: first single words

9 y: few single repetitive words

Behavioral problems

No

ADHD

ADHD. Auto and hetero- aggressivity

ADHD. ASD

ASD. 4 y: ARFID

ASD. 4 y: ARFID

-

Regression/loss of psychomotor function

No

No

No. Progressive improvement

Yes. After Sz onset

No

No

-

Clinical Feature

Neurological features

Poor gait balance

Mild imbalance gait.

Walks on front part of the feet

None

None

None

Severe hypotonia

Hand dyspraxia

Eye

Right eye dyspraxia, reduced color detection

Normal

Normal

Normal

Normal

Normal

-

Hearing

Normal

Normal

Normal

Normal

Normal

Normal

-

Head circumferencec

15 y: <−1.3 SD

11 y: <−1.3 SD

Birth: <−2.44 SD

wnl

wnl

wnl

wnl

7 y: <−4 SD

Facial dysmorphic features

None

None

Upslanting palpebral fissures, medial sparseness of eyebrows, flat nasal bridge and retrognathia

None

Deep-set hooded eyelids, epicanthal folds, broad nasal tip, thick lips, narrow palate, diastema of teeth, short neck, unilateral hockey-stick crease

Deep-set hooded eyelids, epicanthal folds, broad nasal tip, full lips, narrow palate, diastema of teeth, short neck, unilateral hockey stick crease

None

Weight/staturec

15 y: 75–90°ile/10°ile

10 y: <10°ile/15–25°ile

Birth: wnl

9 y: <10°ile/15–25°ile

2 y: 50–75°ile/50–75°ile

2 y: 75–90°ile/50–75°ile

Birth: 25–50°ile / 25–50°ile

Other features

-

-

-

Asthma

Recurrent otitis, VUR, lower UTIs, eczema

Recurrent otitis, VUR, upper UTIs, eczema. Meningitis (4 y)

Contractures of large joints and fingers, hip dysplasia, arthrogryposis, hirsutism, cryptorchidism

  1. ADHD attention deficit hyperactivity disorder, AFS atypical febrile seizures, ARFID avoidant restrictive food intake disorder, ASD autism spectrum disorder, ASMs anti-seizure medications, BGA background activity, BTCS bilateral tonic-clonic seizures, CBZ carbamazepine, CC corpus callosum, d days, EEG electroencephalogram, ESES/DEE-SWAS encephalopathy related to status epilepticus during slow sleep/developmental epileptic encephalopathy with spike-wave activation during sleep, ESM ethosuximide, F female, Fr: frontal, FS febrile seizures, FUP follow-up, ID intellectual disability, LEV levetiracetam, LV lateral ventricles, m months, M male, MRI magnetic resonance imaging, My myoclonias, NDD neurodevelopmental delay, n.p. not performed, NREM non-rapid eye movement sleep, PNH periventricular nodular heterotopia, PV periventricular, SD standard deviation, SPC septum pellucidum cyst, STM sulthiame, SVT supraventricular tachycardia, SWI spike-wave index, Sz seizures, UTI urinary tract infection, VPA valproate, y years, VUR vesicoureteral reflux, WMA white matter abnormalities; wnl: within normal limit.
  2. aSee pedigree for more information (Supplementary Fig. 1).
  3. bASMs with reported best efficacy are highlighted in bold. Current ASMs at last available evaluation are underlined.
  4. cReference values from the CDC growth charts for term newborns, infants, and children, online at WWW.CDC.GOV/GROWTHCHARTS/CLINICAL_CHARTS.HTM and from the Fenton growth charts for premature newborns, online at WWW.MSDMANUALS.COM/PROFESSIONAL/PEDIATRICS/PERINATAL-PROBLEMS/GROWTH-PARAMETERS-IN-NEONATES.
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