Oculopharyngeal muscular dystrophy

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Oculopharyngeal muscular dystrophy
Other namesMuscular dystrophy, oculopharyngeal [1]
Autosomal dominant - en.svg
Autosomal dominant in majority of cases (autosomal recessive minority)
Specialty Neurology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Dysphagia [2]
CausesMutations on the PABPN1 gene [3]
Diagnostic method Muscle biopsy [2]
TreatmentOrthopedic devices for management [1]

Oculopharyngeal muscular dystrophy (OPMD) is a rare form of muscular dystrophy with symptoms generally starting when an individual is 40 to 50 years old. It can be autosomal dominant neuromuscular disease or autosomal recessive. The most common inheritance of OPMD is autosomal dominant, which means only one copy of the mutated gene needs to be present in each cell. Children of an affected parent have a 50% chance of inheriting the mutant gene. [2]

Contents

Autosomal dominant inheritance is the most common form of inheritance. Less commonly, OPMD can be inherited in an autosomal recessive pattern, which means that two copies of the mutated gene need to be present in each cell, both parents need to be carriers of the mutated gene, and usually show no signs or symptoms. The PABPN1 mutation contains a GCG trinucleotide repeat [4] at the 5' end of the coding region, and expansion of this repeat which then leads to autosomal dominant oculopharyngeal muscular dystrophy (OPMD) disease. [5] [3]

Signs and symptoms

Extraocular muscles are shown in this image of the left eye (lateral view). Click on the structures for more information. Lateral orbit nerves.jpg Lateral rectusSuperior obliqueSuperior obliqueSuperior rectusSuperior rectusSuperior rectusInferior obliqueInferior rectusInferior rectusMedial rectusMedial rectusMedial rectusIrisAnterior chamberLateral rectusSuperior obliqueSuperior obliqueMedial rectusOrbitOrbitOrbit
Extraocular muscles are shown in this image of the left eye (lateral view). Click on the structures for more information.

In terms of the signs (and symptoms) of oculopharyngeal muscular dystrophy would be consistent with the following: [2] [6]

  • Aspiration pneumonia (complication)

Though the aforementioned signs/symptoms are the most common, there have been cases though rare, where the peripheral nervous system has had involvement with significant reduction of myelinated fibers [2]

In homozygous cases, this muscular dystrophy is severe and starts earlier in the affected individuals life. [6]

Genetics

PABN1 Protein PABPN1 PDB 3B4D.png
PABN1

The genetics of this type of muscular dystrophy revolve around the PABPN1 gene. This gene suffers mutations that cause the PABPN1 protein to have extra alanine (amino acids), this manifests itself physically in the symptoms of this MD. [3]

The expansion caused by the mutations on the PABPN1 gene ultimately interrupts the cellular mechanics of poly(A) RNA. In most cases oculopharyngeal muscular dystrophy is inherited via autosomal dominance. [7]

The alleles, which are a variant form of a gene [8] involved in this form of MD are: PABPN1, (GCG)n EXPANSION, (GCG)8-13, PABPN1, (GCG)n EXPANSION, (GCG)7 and PABPN1, GLY12ALA. [4]

Diagnosis

The diagnosis of oculopharyngeal muscular dystrophy can be done via two methods, a muscle biopsy or a blood draw with genetic testing for GCG trinucleotide expansions in the PABPN1 gene. The genetic blood testing is more common. Additionally, a distinction between OPMD and myasthenia gravis or mitochondrial myopathy must be made, in regards to the differential diagnosis of this condition. [2]

Treatment

Currently no cure or specific treatment exists to eliminate the symptoms or stop the disease progression. A consistent diet planned with the help of a dietitian along with exercises taught by a speech therapist can assist with mild symptoms of dysphagia. Surgical intervention can also help temporarily manage symptoms related to the ptosis and dysphagia. Cutting one of the throat muscles internally, an operation called cricopharyngeal myotomy, can be one way to ease symptoms in more severe cases. However, for a majority of people, the benefits from such treatments are only temporary. There is currently no treatment available to address the proximal limb weakness. Many of those affected with the proximal limb weakness will eventually require assistive devices such as canes, braces or a wheelchair. As with all surgical procedures, they come with many risk factors. [9] [10] As the dysphagia becomes more severe, patients become malnourished, lose significant weight, become dehydrated and suffer from repeated incidents of aspiration pneumonia. These last two are often the cause of death. [11]

Epidemiology

The disease is found across 5 continents (30 countries) and is frequently seen in French Canadians, with a prevalence 1:1000. OPMD affects males and females equally, and affected individuals have been found in Europe (France), Jewish Ashkenazi, and Spanish Americans. [12]

See also

Related Research Articles

Genetic disorder Health problem caused by one or more abnormalities in the genome

A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.

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Limb–girdle muscular dystrophy Medical condition

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Walker–Warburg syndrome Medical condition

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Congenital muscular dystrophy Medical condition

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Emery–Dreifuss muscular dystrophy Medical condition

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Fazio–Londe disease Medical condition

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Bethlem myopathy Medical condition

Bethlem myopathy is an autosomal dominant myopathy, classified as a congenital form of muscular dystrophy, that is caused by a mutation in one of the three genes coding for type VI collagen. These include COL6A1, COL6A2, and COL6A3. Gower's sign, tiptoe-walking and contractures of the joints are typical signs and symptoms of the disease. Bethlem myopathy could be diagnosed based on clinical examinations and laboratory tests may be recommended. Currently there is no cure for the disease and symptomatic treatment is used to relieve symptoms and improve quality of life. Bethlem myopathy affects about 1 in 200,000 people.

Poly(A)-binding protein RNA binding protein

Poly(A)-binding protein is a RNA-binding protein which triggers the binding of eukaryotic initiation factor 4 complex (eIF4G) directly to the poly(A) tail of mRNA which is 200-250 nucleotides long. The poly(A) tail is located on the 3' end of mRNA and was discovered by Mary Edmonds, who also characterized the poly-A polymerase enzyme that generates the poly(a) tail. The binding protein is also involved in mRNA precursors by helping polyadenylate polymerase add the poly(A) nucleotide tail to the pre-mRNA before translation. The nuclear isoform selectively binds to around 50 nucleotides and stimulates the activity of polyadenylate polymerase by increasing its affinity towards RNA. Poly(A)-binding protein is also present during stages of mRNA metabolism including nonsense-mediated decay and nucleocytoplasmic trafficking. The poly(A)-binding protein may also protect the tail from degradation and regulate mRNA production. Without these two proteins in-tandem, then the poly(A) tail would not be added and the RNA would degrade quickly.

PABPN1

Polyadenylate-binding protein 2 (PABP-2) also known as polyadenylate-binding nuclear protein 1 (PABPN1) is a protein that in humans is encoded by the PABPN1 gene. PABN1 is a member of a larger family of poly(A)-binding proteins in the human genome.

X-linked spinal muscular atrophy type 2 Medical condition

X-linked spinal muscular atrophy type 2, also known as arthrogryposis multiplex congenita X-linked type 1 (AMCX1), is a rare neurological disorder involving death of motor neurons in the anterior horn of spinal cord resulting in generalised muscle wasting (atrophy). The disease is caused by a mutation in UBA1 gene and is passed in an X-linked recessive manner by carrier mothers to affected sons.

Ullrich congenital muscular dystrophy Medical condition

Ullrich congenital muscular dystrophy is a form of congenital muscular dystrophy. It is associated with variants of type VI collagen, it is commonly associated with muscle weakness and respiratory problems, though cardiac issues are not associated with this type of CMD. It is named after Otto Ullrich, who is also known for the Ullrich-Turner syndrome.

Muscle–eye–brain disease Medical condition

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Calpainopathy Medical condition

Calpainopathy is the most common type of autosomal recessive limb-girdle muscular dystrophy (LGMD). It preferentially affects the muscles of the hip girdle and shoulder girdle.

References

  1. 1 2 "Oculopharyngeal muscular dystrophy | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 3 January 2018.
  2. 1 2 3 4 5 6 Trollet, Capucine; Gidaro, Teresa; Klein, Pierre; Périé, Sophie; Butler-Browne, Gillian; Lacau St Guily, Jean (1993-01-01). Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora J.H.; Bird, Thomas D.; Fong, Chin-To; Mefford, Heather C. (eds.). Oculopharyngeal Muscular Dystrophy. Seattle (WA): University of Washington, Seattle. PMID   20301305.update 2014
  3. 1 2 3 Reference, Genetics Home. "oculopharyngeal muscular dystrophy". Genetics Home Reference. Retrieved 2016-05-28.
  4. 1 2 "OMIM Entry - * 602279 - POLYADENYLATE-BINDING PROTEIN, NUCLEAR, 1; PABPN1". www.omim.org. Retrieved 2016-05-29.
  5. https://www.ncbi.nlm.nih.gov/gene/8106 "PABPN1 poly(A) binding protein, nuclear 1 [ Homo sapiens (human) ]"]11 OCT 2014.
  6. 1 2 "Oculopharyngeal muscular dystrophy" (PDF). Retrieved 28 May 2016.
  7. "OMIM Entry - # 164300 - OCULOPHARYNGEAL MUSCULAR DYSTROPHY; OPMD". www.omim.org. Retrieved 2016-05-29.
  8. Reference, Genetics Home. "What is a gene?". Genetics Home Reference. Retrieved 2016-05-29.
  9. Davies, Janet E.; Berger, Zdenek; Rubinsztein, David C. (January 2006). "Oculopharyngeal muscular dystrophy: Potential therapies for an aggregate-associated disorder". The International Journal of Biochemistry & Cell Biology. 38 (9): 1457–1462. doi:10.1016/j.biocel.2006.01.016. PMID   16530457.
  10. Abu-Baker, Aida; Rouleau, Guy A. (February 2007). "Oculopharyngeal muscular dystrophy: Recent advances in the understanding of the molecular pathogenic mechanisms and treatment strategies" (PDF). Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1772 (2): 173–185. doi:10.1016/j.bbadis.2006.10.003. PMID   17110089.
  11. Malerba, A.; Klein, P.; Bachtarzi, H.; Jarmin, S. A.; Cordova, G.; Ferry, A.; Strings, V.; Espinoza, M. Polay; Mamchaoui, K.; Blumen, S. C.; St Guily, J. Lacau; Mouly, V.; Graham, M.; Butler-Browne, G.; Suhy, D. A.; Trollet, C.; Dickson, G. (31 March 2017). "PABPN1 gene therapy for oculopharyngeal muscular dystrophy". Nature Communications. 8: 14848. Bibcode:2017NatCo...814848M. doi:10.1038/ncomms14848. PMC   5380963 . PMID   28361972.
  12. "Oculopharyngeal muscular dystrophy | Disease | Your Questions Answered | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2016-05-29.

Further reading