2.1.  Oculopharyngeal muscular dystrophy

At least 20 different mutations in the PABPN1 gene have been found to cause oculopharyngeal muscular dystrophy. This condition is characterized by muscle weakness that begins in adulthood and largely affects the eyelids, throat, shoulders, hips, and legs. The PABPN1 gene mutations that cause this condition usually affect one of the two copies of the gene in each cell and result in a PABPN1 protein with an abnormally long (expanded) polyalanine tract that has 11 to 18 copies of alanine.

The age of onset and severity of the condition can be partly explained by the mutation. Most affected individuals have polyalanine tracts that are 13 alanines long and tend to develop muscle weakness in their sixties. Individuals with PABPN1 proteins that contain polyalanine tracts containing 16 to 18 copies of alanine often begin to experience muscle weakness in their forties or fifties. Individuals who have a polyalanine tract mutation containing 11 alanines tend to develop signs and symptom of the condition in their seventies. Some individuals have mutations in both copies of the PABPN1 gene that lead to expanded polyalanine tracts. These individuals often develop muscle weakness in their thirties or forties and may have disturbances in nerve function (neuropathy) and neurological problems.

The extra alanines cause the PABPN1 protein to form nonfunctional clumps within muscle cells. These clumps (called intranuclear inclusions) accumulate and are thought to impair the normal functioning of muscle cells, eventually causing cell death. The loss of muscle cells over time most likely causes the muscle weakness seen in people with oculopharyngeal muscular dystrophy. In severe cases, it is likely that intranuclear inclusions affect nerve cells as well as muscle cells.