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Most of this material is reprinted from Quest, from the MDA (USA) webpage: http://www.mdausa.org/
This page presents background information on a number of topics related to NMI. The articles are longer than glossary entries, therefore, I have presented this information as a glossary appendix.
Created: December 10, 2001. Revised: May 15, 2002.
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QUEST Volume 7, Number 5, October 2000
Diagnosis of neuromuscular disease hinges on a doctor's ability to identify a specific defect of neuromuscular function. Sometimes, a doctor can infer this functional defect - and the disease associated with it - by giving a physical exam, doing a blood test or looking at the anatomy of nerves and muscles.
But other times, the doctor may have to directly evaluate the functions of nerves and muscles and the connections between them by using two complementary techniques - nerve conduction velocity testing (NCVs) and electromyography (EMGs).
Action Potentials:
Both NCV and EMG rely on the fact that the activity of nerves and muscles produces electrical signals called action potentials. A nerve is actually a bundle of axons, cables that conduct action potentials from one end of a nerve cell (or neuron) to the other.
In motor neurons (neurons that connect to muscle), these action potentials travel toward the muscle, where they cause release of a chemical called acetylcholine. Acetylcholine opens tiny pores in the muscle, and the flow of sodium and potassium ions through these pores creates action potentials in the muscle, leading to contraction.
In NCV and EMG, these tiny electrical events are amplified electronically, then visualized on a TV-like monitor called an oscilloscope and even heard using audio equipment.
NCV and Axons
NCV measures action potentials conducted by axons, so doctors use it for diagnosing diseases that primarily affect nerve function, such as different forms of Charcot-Marie-Tooth disease (CMT).
It's done by placing surface electrodes (similar to those used for electrocardiograms) on the skin at various points over a nerve. One electrode delivers a mild electrical shock to the nerve, stimulating it to generate an action potential. The other electrodes record the action potential as it's conducted through the nerve.
Doctors often use NCV to determine the speed of nerve conduction (hence, its name). Conduction speed is influenced by a coating around axons, called myelin. Myelin insulates each axon and normally forces action potentials to "jump" quickly from one end of the axon to the other. If the myelin breaks down (as in CMT1), the action potential travels more slowly.
NCV also can measure the strength of the action potential in the nerve, which is proportional to the number of axons that contribute to it. If axons degenerate (as in amyotrophic lateral sclerosis) or become clogged with debris (as in CMT2), the action potential becomes smaller.
EMG and Muscle
An electromyogram measures the action potentials produced by muscles, and is therefore useful for diagnosing diseases that primarily affect muscle function, including the muscular dystrophies. Also, some EMG data can reveal defects in nerve function.
In EMG, the doctor inserts a needlelike electrode into a muscle. The electrode records action potentials that occur when the muscle is at rest and during voluntary contractions directed by the doctor.
While a healthy muscle appears quiet at rest, spontaneous action potentials are seen in damaged muscles or muscles that have lost input from nerve cells (as in ALS or myasthenia gravis). During voluntary contraction, dystrophic (wasted) muscles show very small action potentials, and myotonic (stiff) muscles show prolonged trains of action potentials. Altered patterns of muscle action potentials can indicate defects in nerve function.
A Little Discomfort
Though NCVs and EMGs are valuable tools for doctors, they can be distressing for patients. Some people find the electric shocks of the NCV or the needle penetration of the EMG uncomfortable or even painful. Young children might struggle during the tests, making it difficult for doctors to carefully monitor nerve and muscle activity. To ease discomfort, topical anesthetic can be applied to the skin - but it won't prevent muscle pain during the EMG. Sometimes sedating medications are needed to keep a child calm.
Partly because of these factors, NCVs and EMGs are generally used when it's not possible to gather the right information from other diagnostic tests. Muscle biopsy (excising and examining muscle tissue; see Quest, vol. 7, no. 4) can reveal hallmark anatomical features of some neuromuscular diseases, making EMG and NCV unnecessary. Genetic tests are now available for diagnosing some diseases, and in those cases, EMG and NCV usually can be bypassed.
Nonetheless, NCV and EMG remain the gold standards for evaluating the function of nerve and muscle. So, when a doctor suspects that a patient has a neuromuscular disease that isn't clearly associated with anatomical or genetic defects (like some types of CMT, or myasthenia gravis), NCV and EMG are among the most valuable diagnostic tools. (From: http://www.mdausa.org/publications/Quest/q75ss.html). *
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Elevated enzymes are a frequently encountered problem in general medical practice, but their meaning often isn't so simple to discern. When they're found with a neuromuscular disease, the situation can get complicated.
What's an Enzyme?
There are thousands of enzymes in the cells in our bodies, where they act as catalysts for all the chemical reactions that take place in these cells. Without them, these reactions either wouldn't occur or would be too slow for the cells' needs.
Many enzymes are normally present in the blood and can be measured there. When cells are damaged by disease or injury, large amounts of these leak out, causing blood tests to show that enzymes are elevated above normal. (You can roughly compare this situation to a car that's leaking oil. Leaks in many parts of the engine can have the same result: oil all over your driveway.)
Where Did It Come From?
Measuring enzymes is only a clue to a possible diagnosis or problem, not a diagnosis in itself. An elevated enzyme level on a screening test should prompt a physician to look further into which areas of the body may be leaking enzymes into the blood, just as a good mechanic looks for the source of a car's oil leak. (In either case, finding the source is only the first step. The next steps are finding out why the leak has occurred and attempting to fix it.)
Two enzymes often measured on routine tests are known as ALT (alanine transaminase) and AST (aspartate transaminase). ALT is found in the liver, heart, muscles and kidneys. AST is in the liver, heart, muscles, kidneys, brain, pancreas, spleen and lungs. ALT is also known as SGPT (serum glutamic-pyruvic transaminase), and AST is also called SGOT (serum glutamic-oxaloacetic transaminase).
In many neuromuscular disorders, muscle tissue is gradually damaged, either by an attack from the immune system (as in inflammatory myopathies), or by a genetic mutation inside the cells (as in the muscular dystrophies). When routine tests measuring ALT or AST are performed in people with neuromuscular disorders, these enzymes are often elevated in the blood, because the ALT and AST are leaking out of damaged muscles. But they can also leak out of other organs, particularly the liver.
Liver or Muscle?
If a neuromuscular disorder hasn't yet been diagnosed, a doctor may be misled into thinking that a damaged liver, not damaged muscles, is the source of the enzyme leak. In the general population, liver damage is more common than muscle damage, so this assumption isn't too surprising.
The careful physician will, however, investigate further. An enzyme called GGT or gamma-GT (gamma-glutamyltransferase, also gamma-glutamyltranspeptidase) is found in the liver but not in the muscles. If it's unclear whether the liver is damaged, a normal GGT level can help a doctor decide that it's not, while a high GGT level would sway him or her toward thinking it is. (That's far from the only test that can be done, but it's an easy and relatively inexpensive one.)
CK (creatine kinase), also called CPK (creatine phosphokinase), is only found in the heart, skeletal muscles and brain. The MM form of CK is the type found in skeletal muscles, and it can be specifically measured when a doctor suspects a muscle problem. A normal CK level with elevated ALT and AST enzymes would sway a doctor toward thinking there's a liver problem; a high CK with high ALT and AST levels suggests that something's going on in the muscle.
So, doing additional enzyme tests after a general screen can help a doctor decide whether the high ALT and AST are more likely the result of liver or muscle damage.
Of course, there could be a problem in both liver and muscle. (Your 1982 Volvo could be leaking oil from both the oil pan and a gasket.) Some metabolic muscle disorders, such as acid maltase deficiency and debrancher enzyme deficiency, affect both tissues. And two diseases can occur in the same person.
What Damages Liver?
A person at high risk for hepatitis or other liver damage, whether or not he or she has a neuromuscular disease, needs further attention focused on the liver, with the medical history and physical exam taken into account. Liver problems may occur in someone who's had blood transfusions before 1990 (before modern hepatitis virus testing), taken drugs (prescription, over-the-counter or recreational) that are known to damage the liver, recently eaten potentially contaminated shellfish, had a history of malignancy or recently been stabbed in the abdomen whether there's a neuromuscular disease or not.
The medications riluzole, used to treat amyotrophic lateral sclerosis, and methotrexate, used to treat inflammatory myopathies and myasthenia gravis, are among the many drugs that have liver-damaging potential.
Most of the time, elevated ALT and AST levels in people with degenerating muscles don't mean much, other than that these enzymes, along with CK, are leaking out of the muscles. (The high levels of enzymes do no harm in and of themselves.) But sometimes, depending on results of other tests and the person's history, they can mean there's trouble in the liver or even in another organ. That's where medical detective work is needed. (From: QUEST Volume 8, Number 2, April 2001. http://www.mdausa.org/publications/Quest/q82ss.cfm). *
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QUEST Volume 7, Number 6, December 2000
As scientists continue to link inheritable diseases to specific genes, genetic tests are becoming a standard tool in the diagnosis of neuromuscular diseases. Many are available on a fee-for-service basis from commercial or university labs, and others are available (sometimes free of charge) from research laboratories studying certain diseases.
Because genetic tests look for genetic errors that are known to cause certain inheritable diseases, they can help provide a definitive diagnosis. Perhaps more importantly, they can detect an inheritable disease in a family even in the absence of any symptoms or family history, so they can help in early care and planning for the disease.
But while genetic tests have the potential to do these things, sometimes they seem to provide no information or even conflicting information. For example, patients sometimes receive a nearly certain diagnosis based on the results of other tests, but then the genetic test gives a negative result. How sensitive are genetic tests, and what factors influence their results? Knowing the answers can help you avoid confusion and frustration.
Genes and Mutations
It's important to remember that a gene is a set of instructions for making a protein. Those instructions are written in the chemical language of DNA (deoxyribonucleic acid), which is based on an alphabet of just four "letters," called nucleotides (C, T, G and A). Some nucleotides -- located in "regulatory" regions of a gene -- spell out commands for making the protein, but don't contribute directly to the protein. Others -- in the "expressed" regions, or exons, of a gene -- spell out the protein.
An error, or mutation, anywhere in a gene can alter the quantity or quality of protein produced, interfering with vital events within the body's cells. Some mutations are deletions or duplications, which remove or add long strings of nucleotides, causing a potentially harmful loss or gain of protein. Other mutations, called trinucleotide repeat expansions, are long strings of a repeated three-nucleotide phrase that can turn into a tangled mess. Others are point mutations, which change, add or remove individual nucleotides, sometimes leading to disastrously altered proteins.
Fishing for Mutations
Genetic testing is done by drawing a blood sample, and extracting DNA from white blood cells. Genetic tests can accurately identify disease-causing mutations, but their use and sensitivity are limited by our current knowledge about inheritable diseases. Because genetic tests are designed to look for mutations in specific genes, they aren't available for inheritable diseases where the defective gene is unknown.
For a couple of reasons, there's a good chance a genetic test will yield a false negative (failure to detect a disease-causing mutation). First, diseases like Charcot-Marie-Tooth disease (CMT) can arise from mutations in one of many different genes; some of these genes are unknown and therefore beyond the limits of detection. Second, commercially available genetic tests are designed to detect the most common mutations that cause a disease; therefore, these tests will miss rare disease-causing mutations.
For example, diseases like hypokalemic periodic paralysis are associated with common point mutations. Therefore, genetic tests for these diseases are usually designed to detect those point mutations, and can miss other types of mutations. Diseases like Duchenne or Becker muscular dystrophy (DMD/BMD), on the other hand, are typically caused by genetic deletions or duplications. Therefore, tests for diseases like DMD/BMD are good at finding deletions and duplications, but poor at finding point mutations.
There's also the possibility that a mutation revealed by a genetic test might not be recognized as a disease-causing mutation. For instance, some single nucleotide changes have clear functional consequences, but many are "silent" with no obvious effects on health. Even detection of a trinucleotide repeat expansion can be ambiguous, since relatively short expansions are sometimes harmless.
Another shortcoming of most genetic tests is that they look for mutations in the expressed regions of a gene, but ignore the regulatory regions. So, even though a mutation in a regulatory region can cause detrimental loss of a protein, such a mutation might not show up in many genetic tests.
Using genetic testing to detect carriers -- people who have a mutation, but don't develop the disease -- is especially tricky. Typically, such a person has inherited a mutant gene from one parent and a normal gene from another parent. However, a carrier might also harbor a mutation that's only found in germ cells (the sperm or eggs), and only in some of those. In this case, a genetic test (done on white blood cells) will miss the mutation.
These limitations can severely restrict the sensitivity of genetic testing. For example, it's estimated that genetic tests miss about 30 percent of the mutations in the dystrophin gene that cause DMD/BMD. (The situation is improving: Scientists have recently developed a fast, accurate method for detecting point mutations in DMD, but it's not yet commercially available.)
Interpreting the Result
This high risk of false negatives doesn't mean that genetic tests are useless. In someone who has a neuromuscular disease, a positive result can distinguish among different diseases with similar symptoms. In someone with a family history of a disease, a positive result can tell if that person will develop the disease or pass it on to children.
A negative result might be a true negative or might mean that the genetic test wasn't sensitive enough to find the disease-causing mutation. The results of other diagnostic tests such as a muscle biopsy can help distinguish these two possibilities.
In general, if you have a genetic test done, you should be wary of drawing any strong conclusions from a negative result. If you have questions about a genetic test result, a genetic counselor through your MDA clinic is a good source for answers.
For a complete guide to available genetic tests and testing centers, searchable by disease, check out the Web site www.genetests.org. (From: http://www.mdausa.org/publications/Quest/q76ss.html) *
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Based on: http://www.tmc.tulane.edu/departments/peds_respcare/genetic.htm
Causes of Genetic Health Problems:
1). Inherited genetic diseases: caused by abnormal groups of genes passed down from one generation to the next. Examples: CF, Phenylketonuria, and muscular dystrophy. Spontaneous Genetic mutations are caused by an error in DNA replication leading to a base substitution or an insertion or deletion of one or two base pairs from the DNA.
2). Somatic genetic disease: caused by the sudden appearance of an abnormal form of a gene in one part of the body. Example: Cancer.
3). Chromosomal Aberrations: abnormalities of chromosomal structure. Example: Down Syndrome.
Types of Defects:
1). Genetic: caused by an abnormal gene or groups of genes. There are 3 types:
-Single mutant genes of large effect. (Mendelian disorders)
-Multifactorial inheritance: the defect is influence by genetic and environmental factors.
Example: Diabetes, Hypertension
-Chromosomal disorders: abnormal chromosome or wrong number of chromosomes. Can result from a cellular "accident" or from a parent who carries a chromosomal aberration
2). Congenital Defects: " born with" unusual growth or development.
Single Gene Defects:
Biochemical Basis of Single gene Disorders:
1). Enzyme defects: Mutations result in the synthesis of a defective enzyme with reduced activity or reduced amount.
This can lead to 3 results:
a. Accumulation of the substrate: Example: A deficiency of phenylalanine Hydroxylase results in the accumulation of phenylalanine (PKU)
b. An enzyme defect can lead to a metabolic block and a decreased amount of end product. Example: A deficiency of melanin resulting from a lack of tyrosinase results in albinism.
c. Failure to inactivate a tissue damaging substrate. Example: Alpha1 - Antitrypsin deficiency
2. Defects in receptors and transport systems. Example: Hypercholesterolemia: a reduced function of LDL receptor leads to a inability to transport LDL into the cell. For CF patient there is a impaired CL - transport across sweat glands, lungs and pancreas.
3. Alterations of Proteins: Example: Sickle cell Anemia
4. Genetically determined: Adverse reactions to drugs: Example: A person that
has a deficiency of the enzyme G6P normally is not affected by this, but if you
give that person the anti malaria drug primaquine, a severe hemolytic anemia can
result.
Transmission patterns of Single Gene Defects (Mendelian disorders)
1). Autosomal recessive: Both parent have the recessive gene. One in 4 chance
of having disease, 2 in 4 chance of carrying the disease, 1 in 4 chance of being
normal. Example: diseases include Sickle cell anemia, CF, Familial hypercholesterolemia
2). Autosomal dominant: At least one parent is affected. Can affect both males
and females. Every child has a 1 out of 2 chance of having the disease. Can result
from a spontaneous mutation. Example: Marfan, achondroplasia, Huntington's disease,
spinal muscle atrophy.
3. X link recessive: Almost all X link disorders are recessive. Offspring of carrier mom: for daughters, 1 out of 2 are normal, 1 out of 2 are carriers. Males have 1 out of 2 chances to have the disease, 1 out of 2 of being normal. An affected male does not transmit the disease but all daughters are affected. Example: Muscular dystrophy, hemophilia, Diabetes Insipidus.
4. X link dominant: There are only a few of these. An affected female will transfer the disease to half her sons and half her daughters. An affected male will transfer the disease to all his daughters but none of his sons. Example: Hypospadius
Chromosomal Defects
Karotype: The study of chromosomes. Includes the staining of chromosomes in the metaphase period. Normal Karyotype: 46 XX or 46 XY
Table of Abnormal Karyotypes:
1. Trisomy: 47XX+ 21 Example: Down Syndrome (.15% of all live births), Trisomy results in a failure to separate during meiosis.(nondisjunction) A number of Trisomy's do permit a live birth but most die at an early age. Another example is Klinefelter syndrome: XXY these males are sterile, mentally retarded and have a lanky build ( 1 in 1000 births)
2. Monosomy: 45 XY ?6. Monosomy is the result of Anaphase lag where during either meiosis or mitosis, the chromosome lags behind and is left out of the cell nucleus. Example: Turners syndrome XO. Monosomy generally involves the loss of too much genetic information to permit live birth.
3. Mosaicism: When mitotic errors give rise to two populations of cells in the same individual. More common in the sex chromosomes. For example, one of the daughter cells receives 3 sex chromosomes while the other only receives one. 45X/47XX in the same patient.
4. Polyploid: 23X3 = 69, results when 2 sperm fertilize one egg. Common in still births or miscarriages.
5. Structure changes in the Chromosome: Results from breakage followed by loss or rearrangement of material. Can occur spontaneously or by exposure to environmental mutagens such as chemicals or radiation.
Structure changes include the following:
1. Deletion: refers to a loss of a portion of a chromosome. 46XY 16p (indicates loss of arm 16)
2. Translocation: A segment of one chromosome is transferred to another.
3. Ring chromosome: deletion occurs at both ends and the damaged ends fuse together.
4. Inversion: Involves 2 breaks within a single chromosome with re - incorporation of the inverted segment.
Congenital Malformations
Defined as abnormal development unrelated to genes or chromosomes.
Congenital malformations are divided into 2 categories: Single Primary and Multiple
Malformation Syndrome.
Single Primary defects vs. Multiple Malformation Syndromes
a). Single Primary defects involves only 1 structure. Some of the most common
are congenital hip dislocation, cleft lip and cardiac septal defects. Etiology
is unknown. Associated with multifactorial inheritance.
b). Multiple malformation syndromes: several observed defects have the same known etiology. Can be caused by chromosomal abnormalities, teratogens, single gene defects or fresh gene mutations. Except for Down syndrome occurs in 1 every 3000 live births.
Causes: 42% Unknown, 8% Teratogens, 3% Maternal conditions
Teratogen - an agent or factor that causes the production of physical defects in the developing embryo.
Three main agents include:
1. Drugs, Example: Thalidomide: causes phocomelia, anomalies of ears, teeth Warfarin: causes hypoplasia of nose, shortened digits Tetracyclines: causes enamel dysplasia
2. Maternal condition, example: Diabetes: causes CHD Alcoholism: growth retardation, mental deficiency
3. Intrauterine Infections, Example: Rubella, CMV, Toxoplasmosis Uterine factors: Severe oligohydramnios.
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QUEST Volume 8, Number 1, February 2001.
Very early in the development of a an embryo, cells that are the ancestors of the child's future sperm or egg cells separate from the rest of the developing embryo. Since sperm and egg cells are known as germ cells (from the Latin word germen, for "bud" or "embryo"), this batch of cells that's set aside is called the germ line.
As the embryo develops into a fetus, and continuing after the child's birth, the germ line cells divide and multiply. For boys, sperm cells don't complete their development until the child becomes an adolescent. A girl's egg cells complete part of their development during fetal life and part at puberty.
At any stage - from embryonic life through puberty or even later - mutations (changes) in the genes in the germ cells can occur. If mutations occur early, they affect many "offspring" (new sperm or egg cells) of the early germ cells. If they occur late, they affect very few, or maybe even just one, cell.
When germ line mutations occur, they rarely affect other cells in the body, because the germ line was segregated from the other body cells (somatic cells) early in embryonic life. When mutations occur after the germ line has separated, there's a good chance they'll affect many sperm or egg cells but not any other cells, such as blood or skin cells, which are used in genetic testing.
The condition of having some germ cells affected and some not is called germ line or germinal mosaicism, derived from the idea of a mosaic pattern. (Picture, for example, a mosaic of blue and white tiles to represent affected and unaffected cells.) Another term is gonadal mosaicism, since the ovaries and testes, where eggs and sperm reside, are called gonads.
If a child is conceived with one of the germ cells carrying a mutation, the child can inherit a disease-causing gene flaw, even though blood DNA tests in the parents won't show any flaw.
Predictions and Odds
A person may have a genetically flawed child and still test negative on DNA tests based on analysis of blood cells. Such a person may be a germ line mosaic. The birth of the flawed child may be a one-time event, however, it may not have been.
The future daughters of this person also run a greater than average risk of being carriers of a mutation, since their possible germ line mosaicism could transmit a mutation fairly often.
It isn't possible to get an accurate test of whether a man or woman is a germ line carrier for a particular disease because there's no way to test a representative sample of someone's sperm or egg cells. Even if a sample of germ cells shows no mutations, other germ cells that were not tested still may have the mutation. Nor can tests show what percentage of a person's germ cells has a flaw.
Once a flawed gene has been introduced into the family from the germ lines, it becomes part of the inheritor's blood DNA and germ line DNA (as well as part of all other cells) and can be passed on to future generations.
DMD and Other Diseases
Men, as well as women, can be germ line mosaics, and Duchenne dystrophy isn't the only disease in which germ line mosaicism is a factor. However, this phenomenon has been particularly well studied in women who've had more than one child with DMD despite showing no dystrophin mutations in their blood cell DNA tests.
In one small study, six out of 41 mothers of boys with DMD whose blood cells showed no dystrophin mutation went on to have second sons with DMD, presumably because of germ line mosaicism. (Based upon: http://www.mdausa.org/publications/Quest/q81ss.cfm). *
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A muscle biopsy is a surgical procedure in which one or more small pieces of muscle tissue are removed for further microscopic or biochemical examination. The procedure, often used in the diagnosis of a neuromuscular disorder, is considered "minor" surgery and is usually performed under local anesthetic.
A doctor is likely to call for a muscle biopsy after looking at preliminary blood tests, performing an electromyogram (EMG) and physical examination, and determining that the patient's symptoms indicate an underlying neuromuscular disorder. The muscle biopsy can help distinguish between muscular and neurological problems and can help pinpoint the exact neuromuscular disorder present. Not everyone suspected of having a neuromuscular disease requires a muscle biopsy. In some cases, diagnosis can be made by symptoms and a DNA test based on a blood sample.
Open or Needle Biopsy
There are two types of muscle biopsy. The open biopsy involves the removal of one or more small pieces of muscle tissue with sharp scissors.
The neuromuscular specialist selects a muscle, usually the biceps, triceps, deltoid or quadriceps muscle, that should yield the most information about the disease. Usually moderately affected muscles are chosen; the weakest muscles may already be too degraded for analysis. The procedure involves a 2-to-3-inch incision, which is then closed with stitches and may feel sore for a few days.
In a needle biopsy, used since the 1960s, a pea-sized muscle sample is collected with a large bore needle. Although this is less invasive than the open biopsy, the doctor loses the ability to examine the muscle visually first, and the specimen collected is smaller.
Analyzing the Sample
When the muscle samples are sent to a laboratory for analysis, the technicians cut them into many thin sections for examination. Using different tests on different sections, they look at the tissue's overall appearance, chemical activities in the tissue, and the presence or absence of critical proteins. The information these tests provide helps determine exactly what disease and what form of it the person has.
Histology tests (histo means tissue) employ chemical stains to see the muscle's overall appearance and the structure of the muscle cells. This analysis can yield information about muscle degeneration and regeneration, fiber type abnormalities, mitochondrial abnormalities, scar tissue, inflammation and other clues to specific disorders.
Histochemistry uses stains to detect chemical activities in the cells, including the actions of specific enzymes and metabolic processes. A lab that performs only histology may miss important metabolic abnormalities.
Immunohistochemistry uses antibodies to detect the presence or absence of proteins. This analysis can show whether the cells are missing dystrophin (indicating Duchenne or Becker MD), sarcoglycans (limb-girdle MD), merosin (congenital MD) or other proteins whose absence causes specific muscular dystrophies. Specific antibodies can also be used to identify the nature of inflammatory cells found in the muscle.
The lab may also use electron microscopy to get very high magnification views of the cellular structure, which can confirm structural abnormalities, like the presence of nemaline rods.
Finally, a DNA analysis can be performed on a muscle sample to detect a genetic mutation. Although a blood sample is usually adequate for a DNA test, a muscle sample may be needed to test for mitochondrial DNA mutations.
Multiple Biopsies
Yadollah Harati, a neurologist and director of the Muscle and Nerve Pathology Laboratory at Baylor College of Medicine in Houston, usually takes as many as five separate muscle samples from different regions of the muscle incision. Several are analyzed and at least one is frozen for future use. Harati believes no biopsy should be done unless the amount of tissue removed is adequate for a complete study.
Having at least three muscle samples gives the lab an adequate amount of tissue to work with. In some disorders, particularly "patchy" disorders like the inflammatory myopathies, signs of the disease may not be present in all regions of the muscles, so more samples give a better chance of accuracy.
It's important that the tissue samples be frozen promptly and properly after the biopsy and be stored carefully. If they're not handled and stored correctly, the results may be inaccurate.
Your doctor may occasionally recommend a new biopsy even though you've had one in the past, especially if you've been given a tentative diagnosis or now suspect your diagnosis was incorrect. With many new muscle-protein antibodies now available for testing biopsy samples, as well as new understanding of mitochondrial disorders and new DNA tests, a new biopsy may be desirable.
According to Harati, tissue that was frozen promptly after removal and maintained carefully is useful for many years. In autoimmune diseases, tissue changes over time in your body may necessitate a new biopsy for the most accurate diagnosis.
Getting Results
The analysis of a muscle biopsy sample is a very tedious and labor-intensive process in which many sections of the muscle must be cut, many different types of procedures performed, and the results carefully analyzed. Harati's lab usually performs a few basic histology tests immediately after the biopsy and then, based on these results, determines what further tests should be made.
His lab typically makes an initial report on the day of the biopsy and a full report in two to three weeks. (From: http://www.mdausa.org/publications/Quest/q74ss.html). *
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QUEST Volume 8, Number 4, August 2001.
Simply Stated . . .Neuromuscular Terminology
Medical terminology can be a confusing morass of words that sound similar but have different meanings - or words that sound different but mean the same thing.
One way to simplify "Medspeak" is to break it into its basic components. In neuromuscular diseases, those components are often Greek root words.
Here is a quick glossary to help you understand how the names of various neuromuscular diseases arose, and the differences among them.
Myopathy: From the Greek words myo, meaning muscle, and pathos, disease or suffering
Definition: any disease or abnormal condition of voluntary muscle
Neuropathy: From the Greek words neuron, meaning nerve or sinew, and pathos, disease or suffering
Definition: any disease of the nervous system. Amyotrophic lateral sclerosis and spinal muscular atrophy, in which loss of nerve cells prevents muscles from working, are neuropathies, as are diseases in which nerve fibers malfunction, such as Charcot-Marie-Tooth and Dejerine-Sottas disease.
Dystrophy: From the Greek words dys, meaning abnormal or faulty, and trophe, nourishment
Definition: a disorder caused by defective "nutrition" or metabolism
Muscular dystrophy: This term is actually a misnomer based on the wrong assumption made many years ago that muscle was being damaged by a lack of nutrients. In modern usage, it refers to a group of genetic myopathies in which a muscle protein is absent, deficient or abnormal.
The disorders classified as "muscular dystrophies" are myopathies in which a genetic defect results in structural damage to the muscle. Other myopathies involve damage to the muscle's contraction apparatus or energy production system.
Atrophy: From the Greek words a, meaning not, and trophe, nourishment
Definition: a decrease in the size of an organ or tissue (wasting). Common causes of diseases involving muscle atrophy are a lack of nutrients or blood supply or loss of signals from nerve cells.
Spinal muscular atrophy: The muscle wasting or atrophy in this genetic disorder results from loss of signals from nerve cells in the spinal cord.
Myasthenia: From myo, meaning muscle; a, without; and sthenos, strength Definition: muscle weakness or lack of strength. Today, "myasthenia" refers specifically to muscle weakness resulting from faulty communication between nerve and muscle at the place where nerve and muscle meet (the neuromuscular junction).
Myotonia (adjective myotonic): From myo, meaning muscle, and tonos, tone
Definition: inability to relax muscles after contraction
Myotonic dystrophy: This genetic disorder involves (but isn't limited to) both myotonia and structural damage to muscles (dystrophy).
Myositis: From the Greek word myo, meaning muscle, and the Greek suffix itis, meaning inflammation of
Definition: an inflammation of the muscle, which can result from infection, injury, or attack by the immune system on muscle tissue.
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QUEST Volume 7, Number 2, April 2000
Every day we're bombarded with information about foods that contain "antioxidants" and supplements that block "free radicals." But where do free radicals come from and why should we block them? Is there a connection between free radicals and neuromuscular disease?
Oxygen: The Double-Edged Sword
The oxygen we breathe is needed by our cells to create energy. In fact, the very work "oxygen" has come to mean something that is vital for existence. But this life-giving gas also has a dark side.
Although most of the oxygen used by our bodies to create energy is incorporated into harmless water molecules, up to 2 percent may be spun off into our cells as highly charged, destructive molecules called free radicals, or reactive oxygen species.
These charged molecules are inherently unstable and constantly strive to achieve balance by stealing electrons from neighboring molecules. In turn, molecules that have had their electrons stolen become destabilized and continue the cycle of vengeance by stealing electrons from their neighbors.
This process, known as oxidation, is the same type of chemical reaction that causes iron to rust, and it can wreak havoc on cell membranes, proteins and genetic material. Although all this may sound ominous, under normal circumstances, our cells have built-in mechanisms for neutralizing free radicals.
But when these systems get disrupted or overwhelmed, a cell may suffer from oxidative stress, and the resulting damage may kill the cell or render it cancerous.
The Disease Connection
Signs of oxidative stress have been linked to a number of diseases (either as a cause or a symptom), including cancer, cataracts, Alzheimer's disease and heart diseases. Some researchers even think that aging is due to the effects of slowly accumulated genetic damage caused by free radicals.
In addition, there's evidence that oxidative stress plays a prominent role in three types of neuromuscular disorders: amyotrophic lateral sclerosis (ALS), mitochondrial/metabolic disease and Friedreich's ataxia. In each case, researchers suspect that aberrant cellular chemistry causes the muscle or nerve cells to produce excess free radicals, or to lose the ability to neutralize free radicals. It's not clear in any case, however, whether oxidative stress is the main cause of symptoms or merely a symptom itself.
In other types of neuromuscular disorders, there's less evidence that oxidative stress is a problem, although some researchers have speculated that it might play a role in Duchenne and Becker muscular dystrophies.
Preventing Oxidative Stress
Our cells have many strategies for neutralizing free radicals. These tend to fall into one of two categories: special proteins made by the body called enzymes (with names like superoxide dismutase and catalase) that help incorporate free radicals into inert molecules; or small nonprotein molecules that are able to accept extra electrons without becoming destabilized themselves (this category includes vitamin E and coenzyme Q10). Both types of substances are known as antioxidants.
Although enzymes can be powerful antioxidants, researchers studying oxidative-stress-linked diseases are still searching for ways to deliver these specialized proteins to cells. Strategies include persuading cells to make more enzymes, or modifying the enzymes so that they can be taken up by cells after injection into the bloodstream.
Antioxidants of the small, nonprotein type are sold over the counter in the form of vitamins and supplements and some are found in foods. Although there's evidence that some of these may help prevent diseases like cancer, it's less clear whether this type of antioxidant can actually stop or reverse a disease process that has already begun.
Recently, coQ10 has been shown effective in slowing the course of ALS in mice with the disease. (Human trials are currently under way at Columbia University in New York.) Very preliminary studies indicate that idebenone (a form of coQ10) seems to improve heart conditions in people with Friedreich's ataxia.
Despite many studies, there's no overwhelming evidence that antioxidants are effective in mitochondrial or metabolic disorders, but they're usually prescribed on the theory that they "can't hurt."
If you have a different type of neuromuscular disease or if you don't have a neuromuscular
disease, the choice as to whether to take over-the-counter antioxidants is up
to you. Most aren't harmful if taken in reasonable amounts but you should first
discuss the idea with your doctor. Some people believe they're worth taking for
potential anticancer or anti-aging benefits, but these benefits are still in question.
COMMON SOURCES OF ANTIOXIDANTS
Vitamins E, C, A*, and riboflavin and niacin* (forms of vitamin B)
Supplements: Coenzyme Q10, idebenone (a form of coQ10), selenium* (a mineral)
Foods: Phytochemicals (leafy green vegetables), lycopene (cooked tomatoes), polyphenols (green tea), vitamin C (citrus fruits), and beta carotene* (carrots)
*Can be toxic in large quantities (From: http://www.mdausa.org/publications/Quest/q72ss.htm )
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QUEST Volume 7, Number 3, June 2000
Neuromuscular diseases can cause a variety of symptoms other than muscle weakness. Some people may feel their muscles are stiff or don't respond quickly; others might complain of cramps or twitches; while still others get tired quickly during exercise.
Not all of these symptoms are painful, but some can be inconvenient or annoying. Learning the medical names and natures of these symptoms can lead to better discourse between you and your doctor, and sometimes better management of symptoms.
Cramps
A true cramp is a specific condition in which muscles undergo painful involuntary contractions (muscle shortening). The classic muscle cramp is neural in origin, meaning the contractions are caused by abnormal nerve activity rather than abnormal muscle activity. This type of contraction problem usually has a sudden onset and may be ended by stretching the muscle passively.
True cramps can occur in anyone, particularly after exercise or at night. Neuromuscular diseases in which classic cramps are common are amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA).
A second kind of cramp, which doesn't involve abnormal nerve activity, occurs when a muscle is temporarily locked in a contracted state. This is technically called a contracture, but isn't to be confused with the more common use of "contracture" to indicate fixed joints.
This sensation can be painful and is often described as a cramp. People with paramyotonia congenita, some forms of myotonia, rippling muscle syndrome or metabolic myopathies due to glycolytic defects (McArdle's disease, Cori's or Forbes' disease, Tarui's disease, phosphoglycerate kinase deficiency and lactate dehydrogenase deficiency) may experience muscle pain during exercise due to nonneural muscle cramps.
Fasciculation
"Fasciculation" is basically a fancy term for a twitch. Like classic cramps, fasciculations are caused by abnormal nerve activity, but they tend to involve only a small portion of the affected muscle and aren't generally painful.
While one is occurring, you may observe a small muscle "jump" under the skin. Fasciculations are common in ALS, spinal bulbar muscular atrophy, X-linked SMA and SMA type 1 (in the tongue and mouth).
Neurologist Valerie Cwik of the University of Arizona Health Sciences Center in Tucson says that everyone gets fasciculations now and then, particularly around the eye, in the small muscle of the back of the hand between the thumb and index finger, and in the feet.
Fasciculations are made worse by stress, lack of sleep and caffeine. They may also be seen in people with overactive thyroids, and there's a syndrome of benign (harmless) cramps and fasciculations. While some people with cramps and fasciculations develop ALS, in others the problem remains restricted to these symptoms.
Myotonia
Myotonia occurs when contracted muscles relax too slowly due to electrical problems in the muscle or nerve cells. A person with myotonia may have difficulty releasing his grip after holding an object - the sensation is sometimes described as stiffness. Myotonia can be sensitive to exercise, temperature or diet, and occurs in paramyotonia congenita, myotonia congenita, hyperkalemic periodic paralysis and myotonic dystrophy.
Myalgia
Myalgia, or muscle pain, can be caused by mechanical stress without muscle injury (as in classic or nonneural muscle cramps), or by injury. Muscle injury can occur in anyone who "overdoes it" during exercise, including those with types of muscular dystrophy that render muscle cells more fragile.
Muscle injury can also occur in response to problems with the immune system, as in polymyositis and dermatomyositis, or in response to a lack of energy and buildup of toxic metabolites, as in carnitine palmityl transferase deficiency.
Fatigue
Fatigue can mean a subjective feeling of tiredness or an objective measurement of a decline in muscle force with use, but is always distinguished from weakness. Fatigue is associated with myasthenia gravis, ALS, SMA, myotonic disorders, metabolic disorders (McArdle's and Tarui's diseases) and mitochondrial disease. It can be a feature of many of the muscular dystrophies as muscles weaken and greater energy is expended to move them.
Hypertonia
Hypertonia means "an abnormal increase of muscle tone," or increase of the normal degree of tension in the muscle at rest. Hypertonia often occurs in some cases of muscle disease when some muscles are able to overcompensate for other weakened muscles.
Hypotonia
Hypotonia means "lack of muscle tone," or absence of the normal degree of tension in the muscle at rest. The condition is seen most often in infants and children with neuromuscular problems, who may appear "floppy" because of the lack of muscle tone.
Hypotonia can occur in many muscle disorders, including acid maltase deficiency, mitochondrial disorders, congenital myopathies (central core disease, nemaline myopathy and myotubular myopathy), congenital myotonic dystrophy, congenital muscular dystrophies, neonatal and infantile myasthenia gravis, SMA type 1 and "benign" congenital hypotonia.
These muscle symptoms have many different primary causes. Although not all can be treated, some respond to gentle stretching, heat or cold, while others may respond to drug treatments.
Your MDA clinic director will help you identify and possibly treat these symptoms.
(From: http://www.mdausa.org/publications/Quest/q73ss.html)
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