Myotonic dystrophy

 

Muscular Dystrophy?

     Muscular Dystrophy are muscle disorders which have 3 features in common. They are all:

-Hereditary

-Progressive

-Cause a characteristic selective pattern of muscle weakness

 

There are a number of different types of Muscular Dystrophy (MD). One of the types of MD that will be discussed is Myotonic Dystrophy. It is the most common adult form of MD.

 

Myotonic Dystrophy?

     Myotonic dystrophy is an inherited disorder in which the muscles contract but have decreasing power to relax. With this condition, the muscles also become weak and waste away. Myotonic dystrophy can cause mental deficiency, hair loss and cataracts. Onset of this rare disorder commonly occurs during young adulthood. However, it can occur at any age and is extremely variable in degree of severity. The myotonic dystrophy gene, found on chromosome 19, codes for a protein kinase that is found in skeletal muscle, where it likely plays a regulatory role. (unknown,2008,myotonic dystrophy)

 

     Myotonic Dystrophy is inherited in an autosomal dominant pattern (Fig1).When a mutant gene is inherited from one parent it will result in the condition meaning the chance of inheriting it from an affected parent is 50%. The child's gender does not change the chances of inheriting the condition. If the abnormal gene is not received by the child, they will not get or pass the disease to their children. 

(University Of Rochester Medical Center, 2009)

 

Fig1: Myotonic dystrophy is inherited in an autosomal dominant pattern 

 

 

Types of myotonic dystrophy:

 

There are two types of myotonic dystrophy. They are designated type1 and type2.

 

Type 1 (DM1):

     DMPK (Myotonic dystrophy protein Kinase) which codes for a myosin kinase expressed in skeletal muscle is the affected gene. The location of this gene is on the long arm of chromosome 19.

In this type, a triplet repeat of CTG in the DMPK gene is seen. The repeat number differs from person to person, but in a healthy person the average number of repeats is normally between 5 and 37. Sometimes during cell division when the repetitive sequences of DNA are replicated the cellular machinery slips and an extra copy of the triplet repeat adds to the sequence. When triplet repeats in the DMPK gene exceed the maximum average number (37) the sequence appears to become unstable and the likely chances of slippage becomes more common. It is known that a person with this type of myotonic dystrophy usually has over 50 and can have as many as 2000 repeats.

 

DM1 can be subdivided into 4 distinct Types:

Congenital: Appears at birth and is most severe (not likely with DM2)

Juvenile: Appears after birth and in teen years

Adult: Appears in the late 20's to early 40's

Late Onset: Appears later after 40's and generally mild

 

Type 2 (DM2):

     Type 2 condition is caused by a defect of the ZNF9 gene located on chromosome 3q21 and the repeat expansion appears to be much larger in this type than in type1 (usually 75 to over 11000 repeats). Unlike in type1, the repeated DNA expansion size does not make any difference in the disease severity. It is also different to type1 for the reason it is not trinucleotide repeat disorder because it involves the repeat of four nucleotides.  

 (Robert D.Wells & Ashizawa,T, 2006)

 

Fig 2: Myotonic Dystrophy results from the effects of an expansion of a repeat sequence (red arrows) of DNA. [Richards, R.I and Sutherland,G.R.(1997)] 

 

 

 

 

 

Fig3:The genetic changes in Myotonic Dystrophy

 

 

 

Table1: Genetic differences/similarities between DM1/DM2 (Fuchs, J, & Podda, M, 2004)

 

Genetic aspects	DM1	DM2
Transmission	Autosomal dominant*	Autosomal dominant*
Gene locus	19q13,3	3q21,3
Mutated gene	DMPK	ZNF9
Gene product	Protein Kinase	Zinc finger protein 9
Function	Signal propagation**	Signal propagation**
Number of expanded repeats	50-5000	75-11000
Localization of mutation	3'Untranslated region	Intron-1
Gene dosage	Hetero/Homozygous	Homozygous
Somatic cell heterogensity	+	++
Congenital cases	+	-
Intergenerational repeat-size variation	+	++
Anticipation	+	-
Reversions of offsprings	+	++
Increase of repeat size with age	+	+
Transcribed into RNA	+	+
Translated	-	-
Intranuclear RNA-foci	+	+
Premutation differences mother/offspring	+	Unknown
Premutation differences father/offspring	+	Unknown

           *Disease despite normal allele               **assumed

 

 

 Signs and Symptoms:

 

     People suffering from myotonic dystrophy have continues muscle wasting and weakness beginning in their 20's or 30's. Wasting and weakness usually occur in their neck, face, legs and hands. In addition they have stiffness of their muscles (myotonia), so when a muscle is used, it is relaxed at a slower rate afterwards.

Example: unable to release their grip on in a handshake or on a doorknob.

People who have myotonic dystrophy also experience clouding of the eye lens (cataracts), and abnormalities in the electrical control of their heartbeat (cardiac conduction defects). Men sufferers have changes in their hormones that can cause balding and sometimes infertility. If someone is born with signs and symptoms of they tend to have difficulty in breathing, weakness of all their muscles, and delays in development (including mental retardation). At times these medical conditions are very severe and may even cause death.

(National human Genome Research,2009)

 

      A strange feature of this condition is that the severity of its signs and symptoms usually increases with each successive generation. This is due to mistakes in the copying of the gene from one generation to the next resulting in the amplification of a genomic 'AGC/CTG triplet repeat', similar to that found in Huntington disease.

As shown in Fig 3, the degree of severity increases in each generation. The grandmother (right) is just a little affected, but the mother (left) has a characteristic narrow face and somewhat limited facial expression. As obviously seen in the picture, the baby is more severely affected and has an open, triangular-shaped mouth.The baby has more than 1000 copies of the trinucleotide repeat, whereas the mother and grandmother each have approximately 100 repeats.

 

Fig 3: A three-generation family affected with myotonic dystrophy

 

 

 

Molecular genetic testing:

 

DM1: Different tests are used to determine the expansions. Small expansions are determined by the standard polymerase chain reaction whereas larger expansions are identified by Southern blotting by hybridization of restriction-digested genomic DNA.

Southern blotting: Digesting the Genomic DNA with EcoRI and then using the agarose gel electrophoresis to separate them depending on their size. DNA fragments are later transferred onto a membrane, and then randomly probed with 32p-labelled cDNA25. Next, the blots are washed and exposed at -80oC for approximately 6-9days.

(Fuchs, J, & Podda, M, 2004)

 

There are two main reasons that make DM2 hard to diagnose.

1)      Different body parts are affected, so patients usually visit different specialists to treat different symptoms and not often get a diagnosis of DM2.

2)      There has been no simple and reliable test for the disease. The mutation is so large and unstable not allowing standard methods of genetic testing to reliably detect the abnormality.

An effective method named dubbed the DM2 "repeat assay,” was recently designed to detect the DM2 mutation. This new test uses a two-step procedure that detects large mutations that may be missed with standard testing. Researchers basically put together a genomic test called Southern analysis with a modified version of the polymerase chain reaction (PCR) test. The combination of these two tests was proved to successfully detect the DM2 mutation in 99 percent of cases, compared to 80 percent by genomic Southern analysis alone. 

 (National Institute of Neurological Disorders and Stroke, 2003)

 

Pathophysiology:

     The affected gene structure suggests that it is a serine threonine protein kinase. When the defect is present, improper transportation of messenger RNA of the gene to the cytoplasm occurs. This protein kinase may have a role in the normal function of skeletal muscle sodium channels.

(Beth Hogans, MD)

 

Histology:

 

Histological features of muscle biopsies from both types of DM patients are very similar with a stereotypical presentation which allows DM to be diagnosed based on biopsy alone.

 

Characteristics found in both types of DM include:

-Atrophic fibers

-Extreme fiber size variation

-Severely atrophic fiber with pyknotic myonuclei

-Proliferation of centrally located nuclei

-Fibrosis

(Robert D.Wells & Ashizawa,T 2006)

 

 

 Is there any specific treatment?

 

     There is no particular treatment for the muscle weakness and wasting in myotonic dystrophy, although braces for the legs and ankles have been made to help support the muscles as weakness progresses.

 

In addition, there are medications available for myotonia relieve, pain and excessive sleepiness. Heart problems, cataracts, and other abnormalities associated with the disease can also be treated but not cured. (Muscular Dystrophy Association ,2000)

 

What research is being done?

          Research scientists have been focusing on cell membrane defects and on defective gene isolation and mapping. It is known that the defect for myotonic dystrophy is on the long arm of chromosome 19. Eventually, further knowledge of the defective gene will allow accurate testing for those members of a myotonic dystrophy who show no signs or symptoms of the disease. It will allow early antenatal diagnosis as well as the possibility for more effective targeted treatments for the future. (Muscular Dystrophy Association ,2000)

 

 

 References: 

 

-Beth Hogans, (1998), Myotonic Dystrophy, Available:http://www.med.yale.edu/neurol/programs/neuromuscular/myontonic_dystrophy.html. Last accessed 02/09/09

 

-Day JW, Ricker K, Jacobsen JF, Rasmussen LJ, Dick KA, Kress W, Schneider C, Koch MC, Beilman GJ, Harrison AR, Dalton JC, Ranum LPW. "Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum." Neurology, February 2003, pp. 657-664

 

-Fuchs, J, & Podda, M (2004), "The Encyclopedia of Medical Genomics and Proteomics" Marcel Dekker,Vol.1, New York, pp 886,888

 

-Robert D.Wells & Ashizawa,T (2006), "Genetic Instabilities and Neurological disorders" Second Edition, California, pp 122

 

-Unknown,(2009),Learning About Myotonic Dystrophy,National human Genome Research, Available: http://www.genome.gov/25521207,Last accessed 24/08/2009

 

-Unknown. (2000). Myotonic Dystrophy Association,Available: http://www.mydr.com.au/first-aid-self-care/myotonic-dystrophy. Last accessed 16/09/09 

 

-Unknown, (2008), Myotonic Dystrophy,Available: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=myotonic%20dystrophy&rid=gnd.section.164. Last accessed 1/10/09

 

-Unknown, (2009), Myotonic dystrophy, Available: http://ghr.nlm.nih.gov/condition=myotonicdystrophy. Last accessed 24/08/09

 

-Unknown, (2009), National Registry of Myotonic Dystrophy and FSHD,University Of Rochester Medical Center Available: http://www.urmc.rochester.edu/neurology/nih-registry/education/Genetics.cfm. Last accessed 22/08/09