Moebius syndrome occurs randomly in the general population and patients generally have no family history of the disease. Mutations of chromosome 13 have been associated with Moebius syndrome, as well as mutations in the genes PLXND1 and REV3L.
Rare familial patterns of inherited Moebius syndrome have been observed. The prevalence of Moebius syndrome is about one in 250,000 live births, but familial cases make up only 2% of all documented cases. In such cases, the disease is inherited as an autosomal dominant trait. This means a single copy of an abnormal gene can cause the disease to develop, and can be passed on to offspring.
Genes and Environment
In general, genetic and environmental factors are thought to contribute to a developmental defect of the hindbrain that causes Moebius syndrome. There are a number of theories about the possible causes of the syndrome.
Vascular disturbances during fetal development are thought to increase the risk for Moebius syndrome. A temporary loss of blood supply to the brain in the first trimester could decrease oxygen to the brain, affecting the growth of the cranial nerves.
Illness and trauma to the mother are also thought to be potential contributors to Moebius syndrome. Such events could trigger a disruption of blood supply to vital areas. Testing procedures such as chorionic villus sampling, or illnesses like hyperthermia, could also create conditions predisposing to the development of the syndrome.
Toxins, medications, or recreational drug abuse by the mother during pregnancy are considered to be possible causes of Moebius syndrome.
These environmental influences may in many cases combine with genetic factors to lead to the manifestation of the disease in the child.
Mutations
Whether triggered by reduced blood flow, toxins, or another cause, it is believed that an initial insult leads to a series of damaging events in the brainstem. It is not clear what role genetic mutations may play in this cascade of developmental injury. The genes that have been associated with Moebius syndrome, PLXND1 and REV3L, are found in unrelated pathways. PLXND1 is involved in neural migration during hindbrain development. REV3L, on the other hand, is part of the pathway of DNA translesion synthesis, which is an important component in the machinery for replicating damaged DNA.
Patterns of Impairment
The failure of infants to smile and their inability to suck is caused by the paralysis of cranial nerve VII. There are three patterns of ocular motility changes in Moebius syndrome:
- Pattern A-Inability to move eyes side to side but with no strabismus, found in 41% of cases.
- Pattern B-Convergent strabismus and crossing of the eyes, found in 50% of cases.
- Pattern C-Divergent strabismus, spasms of the neck muscles (torticollis), and vertical eye misalignment, found in 9% of patients. Includes involvement of cranial nerves III and IV.
If other cranial nerves are also maldeveloped, various characteristic syndromes may develop. For instance, the involvement of cranial nerve XII can lead to lingual palsy and hypoplasia. If the disease affects cranial nerve V it can lead to symptoms in and around the mouth. And damage to cranial nerve IX leads to immobility of the palate and pharynges. If the cochlear branch of cranial nerve VII is affected, it can cause language delay.
References
- https://rarediseases.org/rare-diseases/moebius-syndrome/
- https://ijponline.biomedcentral.com/articles/10.1186/s13052-016-0256-5
- http://insidetheclinic.com/moebius-syndrome/
Further Reading