A number sign (#) is used with this entry because of evidence that intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH) is caused by a heterozygous or hemizygous mutation in the CASK gene (300172) on chromosome Xp11.

Missense variants in the CASK gene have been shown to cause a milder intellectual developmental disorder, sometimes including nystagmus, most often in males (see 300422).

Intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH) is an X-linked disorder affecting males and females. In females, it is characterized by severely impaired intellectual development and variable degrees of pontocerebellar hypoplasia. Affected females have poor psychomotor development, often without independent ambulation or speech, and axial hypotonia with or without hypertonia. Some may have sensorineural hearing loss, eye anomalies, or seizures. Dysmorphic features include overall poor growth, severe microcephaly (-3.5 to -10 SD), broad nasal bridge and tip, large ears, long philtrum, micrognathia, and hypertelorism (summary by Moog et al., 2011). Like females with MICPCH, affected males have microcephaly that is congenital or evolves rapidly during the first few months of life. MRI findings show significant or severe pontocerebellar hypoplasia. MICPCH in males may occur with or without severe epileptic encephalopathy in addition to severe to profound developmental delay. When seizures are present, they occur early and may be intractable. A few males have been noted to have MICPCH and severe developmental delay but without severe epilepsy (summary by Moog et al., 2015).

Najm et al. (2008) reported several patients with a phenotype of congenital and marked postnatal microcephaly, severe mental retardation, and disproportionate pontine and cerebellar hypoplasia. Four were female and 1 was male. The first girl was referred at 4 years of age because of congenital and marked postnatal microcephaly, severe mental retardation, and sensorineural hearing loss. Her brain MRI showed reduced number and complexity of gyri, thin brainstem, and severe cerebellar hypoplasia. The male was severely affected and died at 2 weeks of age. Najm et al. (2008) also described 2 other girls with severe mental retardation, microcephaly, and disproportionate pontine and cerebellar hypoplasia (MICPCH). One had broad nasal bridge, large ears, optic nerve hypoplasia, and scoliosis; the other had plagiocephaly and spasticity.

Froyen et al. (2007) described a female patient who presented at the age of 14 years with severe mental retardation with microcephaly, progressive scoliosis, spasticity in all limbs, and severe growth delay. She had a coloboma of the right retina and a cleft palate that had been repaired in the neonatal period. Tonic-clonic convulsions were well controlled by valproate therapy.

Moog et al. (2011) described 25 girls, including 4 reported by Najm et al. (2008) and 1 reported by Froyen et al. (2007), with MICPCH resulting from heterozygous loss of CASK function. All were ascertained due to severe mental retardation and microcephaly (range, -3.5 to -10 SD). Psychomotor development was severely delayed, and most did not acquire independent ambulation or speech. Most had poor overall growth and axial hypotonia, and about half developed peripheral hypertonia sometimes evolving to spasticity. Eight had seizures, and 8 had sensorineural hearing loss. Dysmorphic facial features were variable, with the most common features being broad nasal bridge and tip, large ears, long philtrum, micrognathia, and hypertelorism. Nineteen patients had various ophthalmologic abnormalities, including optic nerve hypoplasia, optic disc pallor, and strabismus. Brain imaging showed variable severities of proportionate pontocerebellar hypoplasia and a dilated fourth ventricle. Eight had simplified gyration of the cerebral cortex. The corpus callosum was normal in all cases.

Hayashi et al. (2012) reported 10 unrelated Japanese girls with MICPCH who ranged in age from 11 months to 14 years. All were ascertained based on clinical features, and molecular analysis confirmed the diagnosis. Five patients had obvious microcephaly at birth (less than -2.0 SD), and all developed severe microcephaly by the time of last examination (up to -6 SD). All showed markedly delayed psychomotor development: only 2 could walk and only 1 could speak a few words. Five had hypotonia. Brain MRI in all showed patients revealed hypoplasia of the cerebellum, mesencephalon, and pons.

Saitsu et al. (2012) reported 2 unrelated Japanese males ascertained for severe early-onset epileptic encephalopathy consistent with a diagnosis of Ohtahara syndrome who were found to carry hemizygous loss-of-function mutations in the CASK gene. Both presented in infancy with refractory seizures and prominent cerebellar hypoplasia. One patient had microcephaly (-2.7 SD) at birth, whereas the other developed postnatal microcephaly (-2.7 SD at 16 months). EEG showed suppression-burst patterns; 1 patient had hypsarrhythmia. Dysmorphic features were variable, but included micrognathia, high-arched palate, short neck, long overlapping fingers, and micropenis. Both patients had severely delayed psychomotor development: 1 was bedridden at age 4 years, and the other had spasticity and hypertonia at age 3 months. One patient had an intragenic deletion inherited from his unaffected mother who was somatic mosaic for the mutation, and the other patient carried a de novo mutation resulting in premature termination. No CASK protein was detected by immunoblotting in lymphoblastoid cells derived from the 2 patients.

Takanashi et al. (2012) reported 15 Japanese girls and 1 boy between 2 and 16 years of age with genetically confirmed MICPCH. All had severely delayed psychomotor development with absence of speech. About half of the patients had microcephaly at birth, and all showed progressive microcephaly after 4 months of age. Most also had overall poor growth with short stature. Other common features included hypotonia (11 patients), muscle weakness (10 patients), and spasticity or hyperreflexia (12 patients). Dysmorphic facial features included oval face, large eyes or irides, large ears, broad nasal bridge, broad nasal tip, small nose, epicanthal folds, small jaw, long philtrum, and high-arched palate. Two had sensory deafness, 3 had ophthalmologic abnormalities, 4 had hypohidrosis, and 2 had hyposensitivity to pain. Eight of the girls had seizures of various types, including generalized, complex partial, and frontal lobe seizures. Brain imaging showed atrophy of the cerebrum, cerebellum, pons, and corpus callosum. The boy had epileptic encephalopathy and was severely affected.

LaConte et al. (2019) reported a 9-year-old girl with MICPCH who had microcephaly, mild cerebellar hypoplasia, global developmental delay, and severe intellectual and motor disabilities. She was ataxic and had truncal weakness. She had retinal dystrophy, and an electroretinogram at 5 years of age showed severe loss of rods greater than cones. At 7 years of age, her retinal exam was stable but she had mild to moderate atrophy of the optic nerves.

Moog et al. (2015) described 8 unrelated male patients with mutation in the CASK gene (7 with MICPCH and 1 (patient 8) with microcephaly and developmental delay) and reviewed the clinical phenotype and natural history of these patients and 28 previously reported CASK mutation-positive males. Moog et al. (2015) distinguished 3 phenotypic groups that represented a clinical continuum. The most severe phenotypic group is MICPCH with severe epileptic encephalopathy. Developmental delay is severe to profound and microcephaly is congenital or rapidly progressive. MRIs demonstrate significant or severe pontocerebellar hypoplasia. Other brain malformations include cortical atrophy, simplified gyri, and progressive hypomyelination. Seizures manifest as Ohtahara syndrome, West syndrome, early myoclonic encephalopathy, or unspecified intractable seizures. The second phenotypic group is MICPCH with severe developmental disorder without severe epilepsy. The phenotype of males in this group is comparable to the MICPCH phenotype in females and includes severe developmental/intellectual disability, variable microcephaly, and pontocerebellar hypoplasia. The degree of pontocerebellar hypoplasia does not necessarily correlate with the degree of developmental delay. Seizures have not been reported in this group. The third phenotypic group is mild to severe intellectual disability with or without nystagmus (see 300422).

In their first patient, Najm et al. (2008) found paracentric inversion of 1 X chromosome, 46,X,inv(X)(p11.4p22.3), by chromosome analysis. They narrowed the Xp22.33 breakpoint to a 20-kb gene-poor region, and found that the Xp11.4 breakpoint interrupted the CASK gene (300172) and possibly the GPR34 (300241) and GPR82 (300748) genes. Najm et al. (2008) noted that in a girl whose phenotype partially overlapped that of their first patient, Froyen et al. (2007) had detected a 3.2-Mb deletion resulting in loss of 8 annotated genes, including EFHC2, NDP (300658), and CASK exons 1 and 2, but not GPR34 or GPR82, using X-chromosome array comparative genomic hybridization. Subsequently, Najm et al. (2008) found copy number losses in Xp11.4 in 2 other girls with mental retardation and microcephaly. In 1 of these patients an approximately 740-kb heterozygous deletion encompassed CASK, GPR34, and GPR82. In the other 2, separate deletions of CASK, one 5-prime and the other 3-prime, were present, suggesting a complex rearrangement such as an inversion-deletion. The distal deletion breakpoint of the former individual and the most telomeric breakpoint in the latter were located in the same region, suggesting that nonallelic recombination may be a common mutational mechanism.

Moog et al. (2015) recommended CASK testing in male patients with the combination of developmental/intellectual disability or epileptic encephalopathy, postnatal microcephaly (less than -3 S.D.), and pontocerebellar hypoplasia.

Najm et al. (2008) considered CASK an excellent candidate gene for the microcephaly-disproportionate pontine and cerebellar hypoplasia (MICPCH) phenotype since it functions during neuronal development and Cask mutant mice have small brains, abnormal cranial shape, and cleft palate. They analyzed CASK for intragenic mutations in 46 individuals (33 males and 13 females) with the MICPCH phenotype. In a female patient they found a nonsense mutation (300172.0001); in a male a synonymous mutation, presumed to affect splicing, was found (300172.0002). Najm et al. (2008) stated that their finding of heterozygous loss-of-function mutations in CASK in 4 girls and partly penetrant splice mutation in a severely affected boy suggests that the CASK-associated phenotype belongs to the group of X-linked disorders with reduced male viability or even in utero lethality. However, mild (hypomorphic) mutations, such as the synonymous mutation in CASK exon 9, may be compatible with live birth in affected males. Najm et al. (2008) investigated the X chromosome inactivation pattern in genomic DNA extracted from lymphocytes in their 4 female subjects with heterozygous CASK mutations and found random X inactivation.

In 20 girls with MICPCH, Moog et al. (2011) identified different loss-of-function mutations or deletions/duplications in the CASK gene (see, e.g., 300172.0010-300172.0012). High-resolution molecular karyotyping of 8 girls found that 6 had intragenic deletions and 2 had intragenic duplications. The smallest deletion was a de novo 60-kb deletion; 1 patient had a 4.24-Mb deletion encompassing the entire gene. Sequence analysis in 12 patients identified 10 heterozygous mutations in 9 patients. The remaining 3 patients were found to have deletions involving CASK using FISH or RT-PCR. All mutations in patients with parental information were shown to occur de novo. All mutations were predicted or demonstrated to result in a null allele. Moog et al. (2011) emphasized that the brain malformation phenotype in females caused by loss-of-function mutations in CASK is different from the milder phenotype caused by hypomorphic mutations in CASK in males, which results in variable intellectual disability with or without nystagmus.

By targeted analysis of the CASK gene in 10 unrelated Japanese girls with clinical features suggestive of MICPCH, Hayashi et al. (2012) found genomic aberrations of the CASK gene resulting in a null mutation in all. Three had nonsense mutations, 1 had a 1-bp deletion, 2 had splice site mutations, 2 had heterozygous deletions encompassing the CASK gene, and 2 had intragenic duplications affecting the CASK gene. All patients for whom parental DNA was available were found to carry de novo mutations. There were no molecular hotspots, and the phenotypes were similar regardless of the mutation. The findings extended the variety of genetic alterations causing CASK null mutations, including copy number variations.

In 8 male patients (7 with MICPCH with or without severe epilepsy and 1 with microcephaly with developmental delay), Moog et al. (2015) identified CASK alterations by Sanger sequencing, copy number analysis (MLPA and/or FISH), and array CGH. Sequence analysis revealed 3 pathogenic mutations: a nonsense mutation (R27X; 300172.0016) in patient 4, a 5-bp deletion (300172.0017) in patient 1, and a transition affecting the start codon (300172.0018) in patient 3. All of these patients exhibited MICPCH with the severe epileptic encephalopathy phenotype. In the 2 patients with MICPCH without epilepsy, MLPA identified mosaic deletions of the CASK gene, including a mosaic deletion of exon 1 (300172.0019) in patient 6. Moog et al. (2015) proposed that CASK mutation-positive males could be distinguished into 3 phenotypic groups that represent a clinical continuum, with inactivating CASK germline mutations associated with the most severe phenotype (MICPCH with severe epileptic encephalopathy); CASK mutations in the mosaic state or partly penetrant CASK mutations associated with an attenuated phenotype (MICPCH); and CASK missense and splice site mutations that leave the CASK protein intact but likely alter function or reduce the amount of normal protein, associated with intellectual disability with or without nystagmus (see 300422).

In a 9-year-old girl with MICPCH, LaConte et al. (2019) identified a heterozygous missense mutation in the CASK gene (L209P; 602414.0013). Overexpression of the L209P mutation in HEK293 cells resulted in abnormal cytoplasmic aggregates. Pull-down assays with mutant L209P CASK demonstrated normal interaction with neurexin (see NRXN1, 600565) and VELI (see LIN7A, 603380) but disrupted interaction with MINT1 (APBA1; 602414). Accordingly, MINT1 interacts with CASK's CaMK binding domain, where the mutation is located. LaConte et al. (2019) concluded that the L209P mutation likely disrupts the regulatory scaffolding function of CASK, which links neurexin to molecules such as MINT1. Clinical features in the patient included microcephaly, cerebellar hypoplasia, and bilateral retinal dystrophy. It had initially been reported that mutations in the C terminus of CASK were responsible for nystagmus, but this patient also had nystagmus and the L209P mutation is in the N terminus.

In female heterozygote CASK knockout mice (Cask +/-), Guo et al. (2023) found that the overall size of cerebellum was reduced compared to wildtype due to the death of cerebellar granule (CG) cells. Analysis of homozygous Cask knockout CG cells showed that cell death was apoptotic and was independent of Bdnf (113505) secretion mediated by neurexins (600565). Rescue analysis in cultured CG cells showed that the CaMK, PDZ, and SH3 domains of Cask were required for the survival of CG cells. Accordingly, in human patients manifesting neurologic symptoms, the authors identified CASK missense mutations in the CaMK, PDZ, or SH3 domains that affected the survival of CG cells. Three of the mutations, R106P, R255C, and Y268H (300749.0004), were located in the CaMK domain and resided on the binding interface between the CASK-CaMK domain and liprin-alpha-2 (603143), disrupting its structure. This result suggested that interaction with liprin-alpha-2 through the CaMK domain was involved in the molecular mechanism by which CASK maintained CG cell survival.