Mental Retardation X-linked with Cerebellar Hypoplasia and Distinct Facial Appearance is an extremely rare syndrome of cerebellar dysgenesis characterized by intellectual disability, cerebellar anomalies, and distinct facial features. Affected male patients present with moderate to severe intellectual disability, major language and behavioral problems, and impairment in adaptive behavior. The distinct facial phenotype includes a long face, prominent forehead, deep-set eyes, prominent supraorbital ridges, marked infraorbital creases, strabismus, short or upturned philtrum, prognathism, and large ears. There is severe developmental delay and hypotonia, sometimes associated with early-onset complex partial or tonic-clonic seizures in nearly half of the patients. Patients may also show strabismus, dysmetria, and occasionally, ataxia. Brain findings include posterior vermis dysgenesis, vermian parasagittal cleft, cerebellar hypoplasia, cortical atrophy, and enlargement of the cerebral ventricles. Affected females have a milder version of the condition, with mild learning difficulties and congnitive impairment, strabismus, and subtle facial features. Some females may show a reduced cerebellar size.
The condition is diagnosed based on the clinical features. Other X-linked forms of mental retardation may also be associated with similar features. Therefore, a confirmatory diagnosis can only be made on the basis of molecular testing. The condition is managed using speech, occupational, and/or physical therapy. There is a potential for the use of gene therapy, especially targeted towards Rho Kinase inhibitors. However, these therapies are in very early stages of development.
MRX60 is an X-linked recessive condition, which explains why males are more severely affected than hemizygous females. Mutations in the Oligophrenin 1 (OPHN1) gene are implicated in the pathogenesis of this condition. This gene was identified from the characterization of a balanced X;12 translocation in an affected female. The OPHN1 protein is a Rho-GTPase-activating protein that stimulates GTP hydrolysis of members of the Rho family. These Rho proteins play an important role in signal transduction cascades, especially in spine morphogenesis and synapse development.
Al-Owain et al (2011) described a Saudi family in which four brothers and one sister were affected with XLMR associated with cerebellar hypoplasia, strabismus, and distinct facial features. The siblings were born to unrelated parents. The proband was a 19-year old boy who had generalized hypotonia and developmental delay since infancy. He had autistic features with minimal social interaction, and poor speech and eye contact. He had seizures which were under good control. Facial dysmorphic features included a long semi-triangular face, deep-set eyes, strabismus, broad high nasal root, peaked prominent nose, and a prominent chin. Two other affected younger brothers showed similar clinical features. The youngest brother, however, was affected much more severely, with severe global developmental delay, and severe intractable seizures. The EEG in his case showed multifocal epileptiform discharge suggestive of hypsarrhythmia. The two oldest brothers had a mildly ataxic gait. The only affected female had a much milder phenotype with mild cognitive delay, moderate speech impairment and ADHD, and seizure disorder with an episode of status epilepticus. While brain imaging in two of the three male patients showed severe cerebellar hypoplasia, ventriculomegaly and brain atrophy, on the other hand, the female patient had only mild cerebellar hypoplasia. The authors highlighted the presence of intrafamilial phenotypic variability in the expression of the disease.
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