With over 100 published families, researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, corpus callosum hypoplasia, intellectual disability, and hypogonadism. RAB3GAP1 encodes the catalytic subunit of a GTPase activator protein and guanine exchange factor for Rab3 and Rab18 respectively. Rab proteins are involved in membrane trafficking in the endoplasmic reticulum, axonal transport, autophagy and synaptic transmission. The Rab3 protein family is also involved in regulated exocytosis of neurotransmitters and hormones, and Rab18 functions in organelle tethering and autophagy. Rab18 is a critical regulator of neuronal migration and morphogenesis, and Rab18 is a physiological substrate of TBC1D20. It is important to note that affected individuals may not have all of the symptoms discussed below. Every child is unique. Parents should talk to their children’s physicians and medical team about their specific case, associated symptoms and overall prognosis.
Children with Warburg Micro syndrome have problems with vision and their eyes. This includes abnormally small eyes (microphthalmia) and abnormally small corneas. The corneas are the clear (transparent) outer layer of the eyes. Some infants have clouding of the lenses of the eyes at birth (congenital cataracts). Cataracts usually affect both eyes. Degeneration of the optic nerve can also occur (optic atrophy). The optic nerve is the main nerve of the eyes that carries impulses from the eyes to the brain to form images. An affected individual’s vision is usually very poor due to optic atrophy and damage to the part of the brain that controls vision (cortical visual impairment). Some children may develop glaucoma, a condition characterized by increased pressure within the eyes.
Affected children may also have atonic pupils. Atonic pupils are abnormally large, irregularly-shaped pupils that react poorly to light. Normally, the pupil gets smaller (constricts) in the presence of light or when focusing on nearby objects. The pupil normally opens wider (dilates) in dim light or darkness, when focusing on far away objects, or when a person is excited.
Affected children have Intellectual disability that is often severe. They may fail to reach developmental milestones on time (developmental delays). Some children will be unable to sit independently, walk or talk. Some children will eventually display autistic features. Although less common, Seizures can also occur. There are several abnormalities of brain development associated with Warburg Micro syndrome. These include underdevelopment of the ‘bridge’ that connects the right and left halves (cerebral hemispheres) of the brain (hypoplasia of the corpus callosum), shrinkage of the brain (cortical atrophy), progressive shrinkage of the area of brain that controls coordination and balance (cerebellar atrophy), and polymicrogyria, a condition in which there are too many folds in the brain, and the folds are abnormally small. Some infants may experience a delay in the formation of the myelin sheath (delayed myelination). The myelin sheath covers and protects nerve fibers, acts as an insulator, and increases the speed of transmission of nerve signals. These brain findings may differ from one child to another.
Affected infants exhibit Growth failure and may have diminished muscle tone (hypotonia) so that they appear floppy. As they get older, they may have increased muscle tone and stiffness (spasticity), particularly in the legs. Spasticity can lead to the development of contractures, in which a joint become fixed in a bent or straightened position. Contractures can partially or completely restrict the movement of the affected joint. Eventually the arms become involved. Progressive Muscle Weakness will develop and affected individuals may not be able to move their arms and legs (quadriplegia).
Most children will exhibit underdevelopment and reduced activity of the testes or ovaries (hypothalamic hypogonadism). Affected boys may have a small penis, underdeveloped scrotums, and their testes may fail to descend into the scrotum (cryptorchidism). Affected girls may have underdevelopment of the clitoris and labia minora, and an abnormally small opening that leads to the vagina (small introitus). In girls, hypogonadism can be mild and may go unnoticed.
Some infants and children with Warburg Micro syndrome may have Distinctive facial features including a narrow mouth, a wide bridge of the nose, and deep-set eyes.
Additional symptoms have been reported including abnormal front-to-back and/or sideways curving of the spine (kyphoscoliosis) and excessive hair growth (hypertrichosis).