Clinical characteristics: RAB18 deficiency is the molecular deficit underlying both Warburg micro syndrome (characterized by eye, nervous system, and endocrine abnormalities) and Martsolf syndrome (characterized by similar – but milder – findings). To date Warburg micro syndrome comprises >96% of reported individuals with genetically defined RAB18 deficiency. The hallmark ophthalmologic findings are bilateral congenital cataracts, usually accompanied by microphthalmia, microcornea (diameter <10), and small atonic pupils. Poor vision despite early cataract surgery likely results from progressive optic atrophy and cortical visual impairment. Individuals with Warburg micro syndrome have severe to profound intellectual disability (ID); those with Martsolf syndrome have mild to moderate ID. Some individuals with RAB18 deficiency also have epilepsy. In Warburg micro syndrome, a progressive ascending spastic paraplegia typically begins with spastic diplegia and contractures during the first year, followed by upper-limb involvement leading to spastic quadriplegia after about age five years, often eventually causing breathing difficulties. In Martsolf syndrome infantile hypotonia is followed primarily by slowly progressive lower-limb spasticity. Hypogonadism – when present – manifests in both syndromes, in males as micropenis and/or cryptorchidism and in females as hypoplastic labia minora, clitoral hypoplasia, and small introitus.
Diagnosis/testing: The diagnosis of RAB18 deficiency is established in a proband who either has suggestive clinical and neuroimaging findings and biallelic pathogenic variant(s) in RAB3GAP1, RAB3GAP2, RAB18, or TBC1D20 identified by molecular genetic testing or meets the clinical diagnostic criteria when molecular genetic testing has not been performed or has not revealed pathogenic variants in one of the four known genes.
Management: Treatment of manifestations: Treatment is symptomatic and supportive, and is best approached through collaborative multidisciplinary medical specialists and other professionals. Cataracts are usually removed surgically. Management of developmental delay / intellectual disability and feeding difficulties are as per standard practice. Treatment of seizures is by a neurologist based on seizure type. Motor dysfunction due to progressive spasticity may benefit from physical therapy to maximize mobility and use of durable medical equipment. Undescended testes may require surgical correction; hormone supplementation for hypogonadism may occasionally be undertaken.
Surveillance: Routine follow up with an ophthalmologist, neurologist, developmental specialist, feeding team and nutritionist, and endocrinologist is recommended.
Genetic counseling: RAB18 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the RAB3GAP1, RAB3GAP2, RAB18, or TBC1D20 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
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