Paula and Bobby
Parents of Lillie
Mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH)
What is Mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH)?
This rare disease is a genetic condition affecting brain development. Intellectual disability is the main symptom of the syndrome.
Males have more severe symptoms, due to the nature of inheritance of the syndrome, but are less likely to survive to birth.
This syndrome is also known as:
CAGH39 CAMGUK Camguk, Drosophila, Homolog Of; Cmg CMG FGS4 LIN2 Mental Retardation, X-linked, Syndromic, Najm Type; Mrxsna MICPCH Micpch Syndrome MRXSNA Najm (2008) - microcephaly, brainstem, cerebellar hypoplasia (CASK) TNRC8 Vertebrate Lin2 Homolog; Lin2
What gene changes cause Mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH)?
A mutation in the CASK gene causes the syndrome. The syndrome is inherited in a X-linked pattern.
Syndromes inherited in an X-linked recessive pattern generally only affect males. Males only have one X chromosome, and so one copy of a gene mutation on it causes the syndrome. Females, with two X chromosomes, only one of which will be mutated, are not likely to be affected.
With syndromes inherited in an X-linked dominant pattern, a mutation in just one of the copies of the gene, causes the syndrome. This can be in one of the female X chromosomes, and in the one X chromosomes males have. Males tend to have more severe symptoms than females.
What are the main symptoms of Mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH)?
Severe intellectual disability is a main symptom of the syndrome. Other symptoms relating to mental development can include issues sleeping and repetitive behaviors, including self-biting and hand flapping. Most affected individuals do not learn to walk or speak.
A very small head is a common symptom of the syndrome. As is underdevelopment of the cerebellum and the pons parts of the brain.
Hearing loss and eye abnormalities are also common symptoms of the syndrome. These eye abnormalities might include crossed eyes, and underdeveloped optic nerves (these nerves carry information from the eyes to the brain).
Unique facial features include a short nose, arched eyebrows, a long philtrum, an upper jaw that protrudes a short chin and large ears.
How does someone get tested for Mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH)?
The initial testing for Mental retardation and microcephaly with pontine and cerebellar hypoplasia syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH)
Najm et al., (2008) reported a female with a 46X, inv (X)(p11.4p22.3 who was severely retarded, microcephalic and had hypoplasia of the cerebellum and brainstem (especially the pons). Mutations in CASK were found. This is a multi-domain scaffolding protein that interacts with transcription factor TBR1 and regulates genes involved in cortical development.
Moog et. al. (2011) described eleven females with CASK alterations. Clinical characteristics included intellectual disability, severe postnatal microcephaly, growth retardation, axial hypotonia, hypertonia of extremities and eye anomalies (mainly optic nerve hypoplasia). Dysmorphic features were prominent and broad nasal bridge and tip, small or short nose, long philtrum, small chin, and large ears.
Burglen et al., (2012) reported 13 females with PCH on imaging and with clinical features not compatible with PCH1 and PCH2. Cask gene screening found mutations in almost all. There was in addition, two males who were mosaic. Clinically, the females had severe intellectual disability, progressive microcephaly, dystonia and scoliosis. A female with late-onset seizures was reported by Nakajiri et al., (2015). She was severely delayed and had optic atrophy.
A patient with a CASK mutation had PCH3 and a Fallot tetralogy (Nakamura et al., (2014).
Moog et al., (2015) reviewed eight males with CASK mutations. They propose three phenotypes: 1) Sporadic males with microcephaly, pontine, cerebellar hypoplasia and severe epileptic encephalopathy; 2) Microcephaly, pontine, cerebellar hypoplasia, severe intellectual disability without severe epilepsy; 3) Mild to severe intellectual disability with or without nystagmus. The authors suggested that CASK mutations should be looked for in males with developmental delay/intellectual disability, or epileptic encephalopathy plus postnatal microcephaly and pontocerebellar hypoplasia.
A cohort of 41 patients with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH) was analysed by Hayashi et. al. (2017). Causative or candidate genomic aberrations were found in 37 patients. CASK alterations were found in 32 patients.
LaConte et. al., (2018) described three female patients with heterozygous missense mutations in the CASK gene. All patients had intellectual disability, microcephaly and hindbrain hypoplasia.
Cristofoli et. al. (2018) described four females with hemizygous mutation in the CASK gene. Clinical characteristics included congenital microcephaly, and moderate to profound intellectual disability. Additional features were dystonia, hypotonia, nystagmus and strabismus.
* This information is courtesy of the L M D.
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