Causes of oculopharyngeal muscular dystrophy
Reviewed by Oculopharyngeal muscular dystrophy (OPMD) is an inherited muscle disease (myopathy) that progresses slowly, causing weakness in the upper eyelids and throat.
OPMD is caused by changes in a gene. Genes provide instructions for different processes in the body. The gene change behind OPMD guides protein production in ways that affect muscle development.
The symptoms of OPMD usually appear between the ages of 40 and 60 years and may include drooping eyelids (ptosis), swallowing difficulties (dysphagia), and weakness in the arms and legs. Treatment depends on the signs and symptoms present in each person.
What causes oculopharyngeal muscular dystrophy?
OPMD occurs due to mutations in the PABPN1 gene, which contains the instructions for making the polyadenylate binding protein (PABPN1).
The gene is located on chromosome 14. Two copies of this chromosome are present in every cell of the body, one inherited from each parent.
Inheritance pattern for OPMD
- There are two known types of OPMD, autosomal dominant and autosomal recessive. Their distinction lies in how the disease is inherited.
- Autosomal dominant OPMD: This occurs when there is a mutation in only one of the genes on chromosome 14, inherited from one parent. Children of a parent with the autosomal dominant form of the disease have a 50% chance of inheriting the gene and developing OPMD. Autosomal dominant OPMD is the most common form of this disease.
- Autosomal recessive OPMD: The recessive form of OPMD occurs when there are mutations in both copies of the gene, with one inherited from each parent. Parents of a child with autosomal recessive OPMD each carry one copy of the mutated gene, but typically do not show any signs or symptoms. The probability of passing both mutations on to the child is 25%.
What does the PABPN1 gene normally do?
The main PABPN1 gene function is to produce the PABPN1 protein.
A healthy PABPN1 protein plays an important role in processing molecules called messenger RNAs (mRNAs), which are copies of a gene that can be read by a cell’s protein-making machinery.
This protein protects high-quality mRNA from degradation, allowing it to move within the cell. It may also support mRNA production and promote the breakdown of poor-quality mRNA.
In a normal PABPN1 protein, alanine — an amino acid that functions as the building block of the protein — is repeated 10 times in a row. This is known as a polyalanine tract.
How does the gene change damage muscle cells?
At least 20 different mutations in PABPN1 have been identified as causing OPMD. These mutations usually result in a PABPN1 protein with a longer stretch of alanine.
Abnormal PABPN1 protein
OPMD mutations lead to extra alanines in the polyalanine chain — a process known as PABPN1 repeat expansion.
In autosomal recessive forms of OPMD, the PABPN1 protein typically contains 11 consecutive alanines. Some PABPN1 proteins associated with autosomal dominant OPMD contain 16 to 18 consecutive alanines.
Protein buildup inside muscle cell nuclei
These extra alanines cause the PABPN1 protein to form toxic clumps, known as protein aggregates, within the nuclei, or control centers, of muscle cells.
Scientists believe that these protein aggregates hamper the cells’ ability to work as intended and, eventually, kill them.
Progressive muscle cell dysfunction and loss
Protein changes cause the symptoms of OPMD through muscle cell damage and dysfunction in several ways.
The clumps formed by polyalanine expansion trap other vital RNA-processing proteins, muscle-maintenance proteins, and cellular cleanup machinery.
PABPN1 normally tells the cell how to properly complete the production of genetic instructions (mRNA) and export them from the nucleus. Essentially, the clumps sequester vital genetic modifiers and mRNA, locking them away so they cannot be read.
Failure to process the correct RNA results in misshapen muscle cells that shrink, wrap, and detach from one another. Muscle stem cells then lose their ability to fuse and repair wear and tear.
As muscle fibers break down, the body tries to repair the tissue with unhelpful fat and scar tissue.
Why OPMD affects swallowing and the eyelids
OPMD causes drooping eyelids, swallowing problems, and choking problems because the eyelid and throat muscles develop differently before birth. They have distinct types of muscle fibers and rely on specialized nearby stem cells to work, unlike larger arm or leg muscles.
These muscle fibers make people with OPMD far less able to handle the RNA-processing problems and cellular stress that result from faulty PABPN1’s polyalanine clumps.
While the eyelid and throat muscles are the main areas the OPMD affects, it also commonly affects the tongue, legs, and arms. Limb weakness can progress over time and affect mobility, potentially requiring the use of a wheelchair or other mobility aid later in life.
Why can OPMD severity vary between people?
OPMD can be relatively mild and slow to progress, but for around 5%-10% of people, it is more severe. The severity depends on the extent of the gene changes and number of mutated PABPN1 gene copies inherited.
Longer polyalanine chains are associated with an earlier age of onset.
Symptoms are also more likely to be severe if a person inherits a faulty copy of PABPN1 from each parent (autosomal recessive OPMD), rather than just one (autosomal dominant OPMD).
How is the genetic cause of OPMD confirmed?
Genetic testing for OPMD is the primary means of diagnosis. A primary care physician may refer an individual to a specialist in neuromuscular diseases, a neurologist, or a genetic counselor if symptoms or family history are concerning.
OPMD results from a single gene defect and is the only known disorder caused by PABPN1 gene mutations. For this reason, a medical assessment and blood test are enough to identify the changed gene and diagnose OPMD.
Doctors previously requested a muscle biopsy to confirm the diagnosis, but this is no longer necessary, as the genetic test is simple and accurate.
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