Background
PCH | Type 1 | Type 2 | Type 3 | Type 4 | Type 5 | Type 6 | Type 7 |
---|---|---|---|---|---|---|---|
Distinctive features | Anterior horn cell degeneration | Dyskinetic movements Seizures (frequent) | Seizures Short stature Optic atrophy | Severe prenatal form of PCH2 with: Polyhydramnios Contractures Myoclonus Apneic episodes Early postnatal death | Severe prenatal form of type 2 with: Fetal onset of seizure-like activity Early postnatal death | Severe neonatal encephalopathy with: Hypotonia, and inconstantly Intractable seizures Edema Increased lactate Mitochondrial respiratory chain defects | Hypotonia Apneic episodes Seizures Vanishing testis |
Inheritance | AR | AR | AR | AR | AR | AR | Unknown |
Genes or loci |
VRK1
|
TSEN54
| 7q11-21 |
TSEN54
|
TSEN54
|
RARS2
| unknown |
TSEN54
|
TSEN34
| ||||||
RARS2
|
TSEN2
| ||||||
References |
Methods
Patients
Molecular analysis
Array-CGH analysis
Results
CASK molecular analysis
Patient | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Sex/age at last examination (years) | F/7 | F/3 | F/14 | F/13 | F/3 | F/1 | F/1 | F/10 | F/14 | F/8 | F/3.5 | M/15 | M/1.3 |
Birth (weeks) | 39 | 40 | 40 | 40 | 40 | 39 | 41 | 40 | 41.5 | 40 | 39 | 41 | 40 |
Pregnancy | pre-eclampsia | N | N | IUGR | INT | N | N | N | microcephaly IUGR | N | N | N | N |
OFC/weight/length at birth (SD) | -2/-1/-1 | -3/-1/-1 | -1/-1/-1 | -1/-1/-1 | -2/-1/-1.5 | -1.5/-1/-1 | -2/0/-0.5 | -1/0/-0.5 | -3/-2/-3 | -1/-1/-1.5 | 0/0/0 | -3/-1.5/-2 | -2/0/-0.5 |
feeding difficulties | ++ | + | + | + | NA | + | - | - | + | + | + | + | ++ |
Severe developmental delay/intellectual disability | + | + | + | + | + | + | + | + | + | + | + | + | + |
Language | bable | bable | bable | bable | NA | TY | TY | 2 words | 5-6 words | 10 words | - | 12 words | - |
Ability to hold his head | + | + | + | + | + | + | + | + | + | + | NA | + | - |
Ability to sit (age in months) | 13 | - | 36 | 20 | 18 | - | - | 24 | 18 | 18 | 27 | 18 | - |
Ability to stand (age in years) | 3 | - | 5 (briefly) | 4 (briefly) | NA | TY | TY | - | - | 2 | NA | 1.5 | - |
Method of movement | walks on 4 legs wheelchair | rolling | wheelchair | wheelchair | walks with support wheelchair | TY | TY | wheelchair | wheelchair | walks, runs | wheelchair | walks | bedridden |
Hand control | + | - | + | + | + | + | NA | + | + | + | NA | + | - |
Spasticity | ++ | + | + | ++ | + | NA | + | ++ | ++ | - | NA | - | +++ |
Dystonia | - | + | + | + | + | NA | + | + | + | - | NA | + | +++ |
Choreoathethosis | - | - | - | - | - | - | - | - | - | - | NA | - | - |
Epilepsy | - | - | - | + | - | - | + | + | - | - | - | - | +++ |
Stereotypies | - | NA | + | + | NA | NA | - | - | + | + | + | + | - |
OFC/height (SD) | -6/-3 | -6/-3.5 | -6/-2 | -7,5/-4 | -5/NA | -3/1 | -4/-1 | -6.5/-4.5 | -6/-4 | -4/-3 | -5/0 | -3.5/-3.5 | -6/-2 |
ophthalmologic anomalies | strabismus | ret | OA | meg, OA SP ret low vision | ret | meg bil glau | - | myopia | SP ret low vision | - | strabismus | - | OA |
Abnormal ERG | - | + | NA | + | + | NA | NA | - | ++ | + | NA | NA | - |
Hearing | N | unil SN deaf | NA | N | unil SN deaf | NA | N | bil SN deaf | N | N | N | N | - |
Sleep disturbance | ++ | ++ | ++ | + | NA | NA | ++ | - | ++ | ++ | ++ | - | - |
Scoliosis | + | + | + | + | NA | NA | - | - | + | - | - | - | - |
Extremities | N | N | N | long fingers and toes | N | long fingers | N | N | clinodactyly, overlapping toes | hypoplastic nails | slender hands and feet | 2-3 syndactyly | long slender fingers with retractions |
Dysmorphism | NA | + | + | + | NA | + | + | + | + | + | NA | + | + |
Mutation | Xp11.4 deletion 0.3 Mb | Xp11.3-p11.4 deletion 3 Mb | Xp11.4 deletion 0.5 Mb | c.1968 G > A (p.Trp656*) | c.2040-2A > G | c.2080 C > T (p.Gln694*) | c.2074 C > T (p.Gln692*) | c.2302 + 5 G > A | c.2039 + 1 G > T | c.1970 G > A (p.Trp657*) | c.1501dupA (p.Met501fs) | c.[ =/316 C > T] (p.Arg106*) mosaic | c.278 + 1 G > A |
Exon/intron | exons 1-8 | exons 1-27 | exon 1 | exon 21 | intron 21 | exon 22 | exon 22 | intron 24 | intron 21 | exon 21 | exon 15 | exon 4 | intron 3 |
X-inactivation | NA | random | random | random | random | random | random | random | random | random | NA | na | na |
Parents |
de novo
| NA |
de novo
|
de novo
|
de novo
|
de novo
|
de novo
|
de novo
|
de novo
|
de novo
|
de novo
|
de novo
|
de novo
|
Array results
X-inactivation study
Clinical phenotype of the 13 patients with CASK anomalies
Phenotype of the 11 female patients
Phenotype of the two male patients
MRI features
Discussion
Conclusion
Acknowledgements
Competing interests
Authors' contributions
Type of mutation | Exon | Mutation | Protein change predicted | Family | Sex | Phenotype | Reference |
---|---|---|---|---|---|---|---|
Nonsense | 2 | c.79 C > T | p.Arg27* |
nd
| F | MICPCH | [28] |
4 | c.316 C > T | p.Arg106* |
de novo/de novo
| F/M | MICPCH | [28], This study | |
5 | c.379 C > T | p.Glu127* | nd | F | MICPCH | [29] | |
17 | c.1639 C > T | p.Gln547* | nd | F | MICPCH | [29] | |
21 | c.1915 C > T | p.Arg639* |
de novo
| F | MICPCH | [26] | |
21
|
c.1968 G > A
|
p.Trp656*
|
de novo
|
F
| MICPCH | [27], This study | |
21
|
c.1970 G > A
|
p.Trp657*
|
de novo
|
F
| MICPCH | [27], This study | |
22 | c.2074 C > T | p.Gln692* | nd/de novo | F | MICPCH | [29], This study | |
22
|
c.2080 C > T
|
p.Gln694*
|
de novo
|
F
| MICPCH |
This study
| |
27
| c.2632 C > T | p.Gln878* |
de novo
| F | MICPCH | [28] | |
Frameshift |
2
| c.68delT | p.Phe23fs |
de novo
| F | MICPCH | [29] |
3
| c.243_244delTA | p.Tyr81* | nd | F | MICPCH | [28] | |
15
|
c.1501dupA
|
p.Met501fs
|
de novo
|
F
| MICPCH |
This study
| |
16 | c.1578delG | p.Arg526fs |
de novo
| F | MICPCH | [27] | |
Splice defect | I2 | c.173-2A > C |
Skipping of exon 3 leading to premature stop codon
|
de novo
| F | MICPCH | [29] |
I3
|
c.278 + 1 G > A
|
Exon skipping ?
a
|
de novo
|
M
| MICPCH |
This study
| |
I4 | c.357-1 G > A |
Skipping of exon 5 or skipping of exon 5
and insertion of partial intron 5
|
de novo
| F | MICPCH | [28] | |
I5 | c.430-2A > T |
Exon skipping ?
a
| nd | F | MICPCH | [29] | |
I8 | c.831 + 2 T > G |
Exon skipping ?
a
|
de novo
| F | MICPCH | [29] | |
9 | c.915 G > A |
Skipping of exon 9 leading to an in-frame deletion
of 28 amino-acids
| Mother normal | M | MICPCH | [26] | |
I17 | c.1668 + 1 G > A |
Exon skipping ?
a
|
de novo
| F | MICPCH | [29] | |
I21
|
c.2039 + 1 G > T
|
Exon skipping ?
a
|
de novo
| F | MICPCH |
This study
| |
I21
| c.2040-1 G > C |
Skipping of partial or entire exon 22
| de novo | F | MICPCH | [28] | |
I21
|
c.2040-2A > G
|
Exon skipping ?
a
|
de novo
| F | MICPCH |
This study
| |
22 | c.2129A > G | p.710_718del
splicing defect leading to an in-frame deletion of 9 amino acids
| familial | M | ID-nystagmus | ||
I24
|
c.2302 + 5 G > A
|
Skipping of exon 24 leading to an in-frame deletion of 28 amino acids and insertion of a Asp residue
|
de novo
| F | MICPCH |
This study
| |
I25 | c.2521-2A > T |
Splicing defect leading to 2 in-frame deletions (3 amino acids; 28 amino acids)
| familial | M | ID-nystagmus | [35] | |
Missense | 2 | c.83 G > T | p.Arg28Leu | Familial | M/F | FG syndrome | [34] |
8 | c.802 T > C | p.Tyr268His | Familial | M | ID-nystagmus | ||
13 | c.1186 C > T | p.Pro396Ser | Familial | M/F | ID | ||
23 | c.2168A > G* | p.Tyr723Cysb | Familial | M/F | ID-nystagmus | [35] | |
27 | c.2740 T > C** | p.Trp914Argc | Familial | M | ID |