Walker-Warburg syndrome (WWS) is a rare multisystem disorder characterized by muscle, brain and eye abnormalities, often leading to death in the first weeks of life. However, the specific symptoms and severity of WWS can vary greatly from case to case. The most consistent features are (1) a smooth appearance of the surface of the brain due to lack of normal folding pattern (lissencephaly or agyria), often with malformations of other brain structures including the cerebellum and brain stem, (2) various developmental abnormalities of the eye and (3) progressive degeneration and weakness of the voluntary muscles which is called congenital muscular dystrophy. WWS demonstrates autosomal recessive inheritance, with a recurrence risk of 1 in 4 or 25% for a couple who has previously had a child diagnosed with this genetic condition.

WWS is a severe form of the broader spectrum of conditions referred to as CMD (congenital muscular dystrophy), which is a group of disorders characterized by weakness and atrophy of various voluntary muscles of the body. Approximately 30 different disorders make up the muscular dystrophies. These disorders affect different muscles, may or may not have other body systems involved, and have different ages of onset, severity and inheritance patterns. The disorder was first reported in the medical literature in 1942.

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).

Warburg Micro syndrome is caused by alterations (changes) in one of at least four different genes. The four genes known to be associated with this disorder are RAB18, RAB3GAP1, RAB3GAP2, and TBC1D20. In some people, no alternation in any of these genes has been found. This suggests that additional genes may cause this disorder. A SNP chromosomal microarray should also be done because some submicroscopic chromosomal deletions have similar symptoms, particularly deletion 1q43-44 and deletion 1p36.

Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation occurs in a gene, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain and the eyes.

The genetic alterations that cause Warburg Micro syndrome are inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

All individuals carry 7-8 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

The treatment of Warburg Micro syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, eye specialists (ophthalmologists), clinical geneticists, speech pathologists, physical therapists, psychologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended for affected individuals and their families.

Treatment options that may be used to treat individuals with Warburg Micro syndrome can be complex and varied. The specific treatment plan will need to be highly individualized. Decisions concerning the use of specific treatments should be made by physicians and other members of the health care team in careful consultation with an affected child’s parents or with an adult patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.

Warburg Micro syndrome is an extremely rare disorder. As with many rare disorders, the exact incidence or prevalence of this disorder is unknown. The disorder probably goes misdiagnosed or undiagnosed making it difficult to determine the true frequency in the general population. Fewer than 100 people with this disorder have been described in the medical literature.

Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.

Additional treatment is symptomatic and supportive. Surgery may be performed to remove cataracts. However, vision remains poor despite successful cataract removal. Surgery may also be used to treat contractures. Medications that treat seizures (anticonvulsants) can be tried, but seizures may persist.