A disease almost no one has heard of....yet

A short, clear introduction to the cause, history, clinical picture and inheritance of MCOPS12 — linked back to the original literature.

Syndromic microphthalmia 12 (MCOPS12) is an ultra-rare neurodevelopmental disorder caused by mutations in the retinoic acid receptor beta (RARB) gene (Srour et al. 2016).

HISTORY & PREVALENCE

It was first described in the medical literature in 2013 (Srour et al. 2013). The most recent systematic review, published in 2023, compiled clinical data from 52 individuals worldwide, making MCOPS12 one of the rarest disorders known (Caron et al. 2023). Because many children with this condition may be undiagnosed or misdiagnosed as having cerebral palsy or an unspecified neurodevelopmental disorder, the true number of people living with MCOPS12 is likely higher.

CLINICAL PICTURE

Most children with MCOPS12 show a combination of developmental eye anomalies (such as microphthalmia, meaning one or both eyes are smaller than normal), low muscle tone (hypotonia), and progressive movement disorders (dystonia and/or spasticity) that appear in the first years of life (Trieschmann et al. 2023). Some also have a global developmental delay, swallowing difficulties, and peripheral defects such as diaphragmatic anomalies or congenital heart defects. The range of symptoms is wide and varies strongly in severity, and not every child has every feature.

INHERITANCE

MCOPS12 is usually an autosomal dominant condition, meaning that a change in just one of the two copies of the RARB gene is enough to cause the disorder. In most families the gene change happens spontaneously in the affected child and is not present in the parents — this is called a de novo variant. In a small number of families the variant is inherited. A very rare recessive form, in which both copies of RARB are affected, has also been reported (Srour et al. 2013).

Facts about MCOPS12

An ultra-rare neurodevelopmental disorder caused by mutations in the RARB gene.

Also referred to as RARB-related disorder.

Usually an autosomal dominant condition, meaning that a mutation in just one of the two copies of the RARB gene is enough to cause the disorder.

Most frequent RARBvariant: p.Arg387Cys (p.R387C) - found in ~30% of diagnosed individuals

RARB iss as a transcription factor activated by retinoic acid, a metabolite of vitamin A, and plays a crucial role in the development of the eyes, diaphragm, heart, and brain.