Background
Methods
Patients
Patient
|
CASK
mutation
|
Birth OFC/W/L (SD)
|
Age
|
OFC
a
(SD)
|
Height
a
(SD)
|
Weight
a
(SD)
|
DD/ID
|
Tonus
|
Seizures EEG
|
Other neurologic anomalies
|
Eye findings
|
Sensorineural hearing loss
|
Other anomalies
|
Face
|
MRI
|
Overall phenotype
|
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Pat 1
| c.704_708del p.K236Efs*10 ex 7 dn | w 37 +3 -4.2/-3.2/? | † at 7 m | −5.9 (4.5 m) | −4.8 (6 m) | −1 (6 m) | profound, no development | severe hypotonia | intractable seizures | apnoeas, inability to swallow | optic atrophy | + | ASD, bil. clubfeet | dolichocephaly, puffy eyelids, broad nasal bridge, bulbous tip of nose, severe retromicrognathia, ear dysplasia, fleshy ear lobes | severe hypo CBL + pons + medulla, simplified gyri, cortical atrophy |
MICPCH Severe epilepsy
|
Pat 2
| Dup ex 10–16 dn | w 37 +3 -2.5/-1.9/-1.5 | 10 m † at 21 m | progressive microcephaly | −2.4 | −2.8 | profound | severe hypotonia | probably Ohtahara s., burst suppression | macropapilla, optic atrophy? | +? | long convex fingernails, overriding 2nd toes, linear blisters right leg, needed PEG | retrognathia, fleshy uplifted ear lobules | significant hypo CBL + pons |
MICPCH Severe epilepsy
| |
Pat 3
| c.1A > G ex 1 dn | −1.3/-0.3/? | 5 y | −5 (3 y) | −3 | −2 | profound, no development | severe hypotonia | intractable seizures | opticus hypoplasia | – | AVSD, tapering fingers, edema of the dorsum of hands and feet, needed PEG | long eyelashes, short nose, large ears with fleshy uplifted ear lobules | small brain, hypo CBL + pons |
MICPCH Severe epilepsy
| |
−3.7 (5 y) | ||||||||||||||||
Pat 4
| c.79C > T p.R27* ex 2 dn | w 33 +2 -2.57/-1.14/-1.73 | 15 m | −9.0 | −3.0 | −1.67 | profound | severe hypotonia | intractable seizures, burst suppression | apnoea-bradycardy-syndrome, inability to swallow | optic atrophy? | VSD, short limbs, contractures of fingers | plagiocephaly, metopic ridge | severe hypo CBL + pons, progressive cortical atrophy, progressive hypomyelination |
MICPCH Severe epilepsy
| |
Pat 5
| Dup ex 4–20 mos | w 36 +1 -1.8/0/0.3 | 7 m | −7.8 (9 m) | −2.1 (9 m) | −0.6 (9 m) | severe | hypertonia | spasms and myoclonic seizures, no hypsarrhythmia | – | hyperopia | ? | micropenis, cryptorchidism | sparse hair, broad nasal bridge, epicanthal folds, long philtrum, retromicrognathia, fleshy uplifted ear lobules | small brain, hypo CBL + pons |
MICPCH epilepsy
|
Pat 6
| Del ex 1 mos | −2.9/-1.1/-1.7 | 16 m | −6 (11 m) | −2 (11 m) | −1.6 (11 m) | severe | hypertonia of limbs | – | – | hyperopia, strabism | – | cryptorchidism | broad nasal bridge, epicanthal folds, long philtrum, prominent premaxilla, mild retrognathia, simple/thin auricle | hypo CBL + pons |
MICPCH
|
Pat 7
| Del ex 3–9 mos | w 37–0.93/-0.5/-0.87 | 29 m | −3.56 (29 m) -2.55 (5;3 y) | −3.5 (29 m) -2.42 (5;3 y) | −1.97 (29 m) -1.45 (5;3 y) | severe | tonus regulation disorder | – | mild ataxia | – | – | – | prominent nasal bridge, thin upper lip, pointing chin | mild hypo CBL + pons mildly simplified gyri |
MICPCH
|
Pat 8
| Dup ex 1–5 mat | −2 /0/-1.4 | 20 m | −5 | −2 | −2 | Mild to moderate DD | – | – | FTT | long flat philtrum | mildly smaller frontal lobes, small CC (frontal), CBL and otherwise normal |
MIC + DD
| |||
Pat 16b
| c.1061T > C p.L354Pc ex 12 | 5 y | profound, no development | West s., intractable seizures | large eyes, large ears, broad nasal bridge, broad nasal tip, epicanthal foldsd
| MICPCH |
MICPCH Severe epilepsy
| |||||||||
Pat 1e
| Del ex 2 matf
| −1.2/-2/-1.4 | 4 y | −2.7 (1.4 y) | profound | Ohtahara s. | Long slender fingers, micropenis, needed tracheostomy + PEG | micrognathia, short neck | severe hypo CBL, hypo ponsd
|
MICPCH Severe epilepsy
| ||||||
Pat 2e
| c.1A > G ex 1 dn | −2.7/-3.3/-2.8 | 4 y | severe | hypertonia of limbs | Ohtahara s. | PHPV | – | short upper arms, overlapping fingers, clinodactyly | micrognathia, high arched palate | severe CBL hypo, hypo ponsd
|
MICPCH Severe epilepsy
| ||||
Case reportg
| c.227_228del p.E76Vfs*6 ex 3 dn | 0/0.1/1.4 | 8 m | −5.4 | severe | hypotonia | early myoclonic encephalopathy (EME) | dystonia, chorea | optic atrophy | CP, tetralogy of Fallot, AMC, hydronephrosis, VUR, needed tracheostomy | micrognathia | severe hypo CBL + pons |
MICPCH Severe epilepsy
| |||
Pat 13h
| c.278 + 1G > A in 3 dn | −2/0/-0.5 | 16 m | −6 | −2 | profound | profound hypotonia | intractable seizures, spasms + tonic seizures, suppression-burst | spastic tetraparesis, dystonia | optic atrophy | long slender fingers with contractures, needed PEG | retrognathia, high arched palate, low-set ears with prominent lobules, down-slanted palpebral fissures, broad nasal bridge | very severe hypo CBL, hypo pons |
MICPCH Severe epilepsy
| ||
Pat 12h
| c.316C > T p.R106* ex 4 mos | −3/-1.5/-2 | 15 y | −3.5 | −3.5 | severe | – | dystonia, dyskinesia | – | – | well-arched eyebrows, broad nasal bridge, hypertelorism?, anteverted nares, full lipsd
| mild hypo CBL |
MICPCH
| |||
Pat 5i
| c.915G > A p.(=) ex 9 dn | † at 2 w | microcephaly | ? | severe hypo CBL + pons, thin and unmyelinated CC |
MICPCH
| ||||||||||
Pat II 4j
| Fam V c.2183A > G p.Y728C ex 23 (2 ♂) | 14 y | −4.4k
| −2.9 | thin | severe | N, strabism, optic atrophy | synophris, high nasal bridge, upslanted palpebral fissures, short columellad
| hypo CBL, pachygyria |
MICPCH + N
| ||||||
Pat II 2j
| 19 y | −2.4k
| −1.7 | thin | moderate | N, astigmatism | similar to II 4 | ND |
MIC + Moderate ID + N
| |||||||
Pat IV 1j,l
| Fam 74 c.2129A > G p.D710G ex 22 (4 ♂) | 42 y | normal | normal | mild | hand tremor | N, strabism | no dysmorphism | ND |
Mild ID + N
| ||||||
Pat III 3j,l
| 98th cen | normal | obese | mild | tremor, unsteady gait | N, strabism | ND |
Mild ID + N
| ||||||||
Pat III 12j,l
| 98th cen | normal | obese | mild | N | normal |
Mild ID + N
| |||||||||
Pat III 6j,l
| 59 y | normal | normal | mild | no dysmorphism | ND |
Mild ID
| |||||||||
Pat IV 1j,l
| Fam 16 c.802T > C p.Y268H ex 8 (4 ♂, 1 without clinical description) | normal | normal | severe/profound | + | toe walker | no N | autistic | no dysmorphism | ND |
Severe ID
| |||||
Pat III 4j,l
| severe | + | no N | ND |
Severe ID
| |||||||||||
Pat II 3j,l
| severe | toe walker | no N | obsessive behaviour | ND |
Severe ID
| ||||||||||
three Patj,l
| Fam 123 c.2756T > C p.W919R ex 27 (3 ♂) | normal | tall | mild | +, in one of three patients at age 17 y | N | no dysmorphism | ND |
All 3: Mild ID + N
| |||||||
Pat III 1j,l
| Fam 245 (K8919) c.1186C > T p.P396S ex 13 (4 ♂, 2 without clinical description) | 58 y | 0 | short stature, 152 cm | profound | tremor, unsteady gait | flat mid face, open mouth, eversion of lower lip | ND |
Severe IDS
| |||||||
Pat III 4j,l
| 52 y | 0 | short stature, 147 cm | severe | strabism | flat nasal bridge, anteverted nares, wide mouth, broad palate, broad grooved tongue, short broad neck | ND |
Severe IDS
| ||||||||
Pat III 3j
| Fam 683 c.2521-2 A > T in 25 (4 ♂) | 46 y | +1.6 | −2.2 | mild | +, absences | – | N, high myopia | no dysmorphism | ND |
Mild ID + N
| |||||
Pat II 3j
| mild | + | N, strabism, myopia, astigmatism | ND |
Mild ID + N
| |||||||||||
Pat II 4j
| mild | – | N, high myopia, optic atrophy, retinal pigment anomalies | ND |
Mild ID + N
| |||||||||||
Pat II 5j
| mild | + | N | ND |
Mild ID + N
| |||||||||||
Pat III 26m
| c.83G > T p.R28L ex 2 (3 ♂) | 2 y | relative macrocephaly | 50-75th cen | 25-50th cen | marked | hypotonia | EEG mildly abnormal | – | + | hyperactivity, aggressive behaviour, constipation | prominent forehead, frontal upsweep, hypertelorism, depressed nasal bridge, long philtrum, micrognathiad
| normal (on CT) |
IDS
| ||
Pat II 11m
| 34 y | relative macrocephaly | profound | hypotonia in infancy | + | aggressive behaviour, constipation | prominent forehead, hypertelorism, broad long philtrumd
| ND |
IDS
| |||||||
Pat II 17m
| 16 y | short stature | +, unspecified | hypotonia in infancy | + | hyperactivity, constipation, cryptorchidism | prominent forehead, frontal upsweep, long philtrum, epicanthal foldsd
| ND |
IDS
|