RAB18 deficiency

RAB18 deficiency encompasses a spectrum of disorders, including Warburg micro syndrome and Martsolf syndrome, which affect the eyes, brain, and reproductive system.

Overview

RAB18 deficiency causes two conditions—Warburg micro syndrome and Martsolf syndrome—that share a genetic cause and similar clinical features. Warburg micro syndrome is the more severe form, while Martsolf syndrome is generally milder.

Symptoms

Warburg Micro Syndrome

This condition involves severe developmental and physical impairments from birth:

• Eye abnormalities: Clouding of the lenses (cataracts), abnormally small eyes (microphthalmia), small corneas, and optic atrophy.
• Neurological features: Severe intellectual disability, delayed development, hypotonia, and progressive spastic quadriplegia.
• Seizures: Recurrent epilepsy.
• Reproductive issues:Hypogonadotropic hypogonadism, leading to underdeveloped reproductive organs.

Martsolf Syndrome

This form affects the same systems but with reduced severity:

• Milder vision impairment and optic atrophy.
• Mild to moderate intellectual disability.
• Delayed but eventually acquired motor and language skills.
• Spasticity that typically affects only the legs and feet.

Causes

RAB18 deficiency is caused by mutations in the RAB18, RAB3GAP1, RAB3GAP2, or TBC1D20 genes. These genes regulate the RAB18 protein, which is essential for:

• Moving substances between cell compartments.
• Storing and releasing fats (lipids) via lipid droplets.
• Autophagy, the process of clearing unneeded materials from cells.

Mutations that completely eliminate protein function typically result in the more severe Warburg micro syndrome, while those that only reduce function may lead to Martsolf syndrome.

Inheritance

This condition is inherited in an autosomal recessive pattern, meaning an affected individual must inherit two mutated copies of the gene—one from each parent.