Biomarkers of Spinal and Bulbar Muscle Atrophy

This report was published in Frontiers of Neurology three days ago. Excerpts are below and the entire report ban be read by following the link.

Biomarkers of Spinal and Bulbar Muscle Atrophy (SBMA): A Comprehensive Review

Biomarkers in SBMA

A biomarker is a parameter that can be measured accurately and reproducibly and used as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention (WHO definition, 1998). An ideal biomarker should have a predictive value and capture subtle changes over relatively short periods of time. Additional requirements to biomarkers include cost-effectiveness, non-invasiveness, and reproducibility. It is generally agreed that no single biomarker is suitable for diagnostic, prognostic and monitoring roles and a panel of several markers may be better suited as multirole indicators. SBMA is a rare and slowly progressing condition, therefore the development of sensitive outcome measures would enable smaller sample-size and shorter duration of pharmaceutical trials.

Biomarkers of Neurological Involvement in SBMA

In recent years, an unprecedented interest has developed in the standardized assessment of neuromuscular performance in SBMA, evaluation of novel therapeutic strategies and in the launch of national SBMA registries. Many of the commonly used instruments, such as the MRC score, respiratory function parameters, the modified Norris scale, ALSFRS-r, Quantitative Myasthenia Gravis Score etc. are non-specific to SBMA, yet remain widely utilized. As these tools have been developed for other conditions, new batteries of tests have been recently proposed to specifically appraise disability in SBMA.

Discussion and Future Perspectives

Interest in SBMA biomarkers has grown steadily in recent years, fuelled both by accruing knowledge about pathogenesis and novel therapeutic strategies. SBMA is now widely recognized as a multisystem syndrome. A multitude of studies focus on multi-organ involvement, and the systemic phenotype is now considered just as relevant as the neurological manifestations. It is increasingly recognized that non-neurological features of the disease have an equally important impact on the patients' quality of life. Until now, clinical trials on SBMA focused almost exclusively on the treatment of motor symptoms, but a shift to targeted molecular therapies and focus on systemic processes are likely to be witnessed in the near future. From a clinical trial perspective, ideal biomarkers should undergo robust validation, sensitivity and specificity profiling, and sampling and measurement harmonization across different centers. Crucially, candidate markers should be able to detect the subtle changes expected after the administration of a specific treatment. Given the particularly slow progression rates observed in SBMA, the definition of an effective outcome measures is challenging. The integration of neurological, metabolic, and endocrine indicators seems essential into composite biomarker panels in addition to functional scales. Serum creatinine levels appear to correlate strongly with motor impairment and HOMA-IR index with disease duration. The convincing validation of these parameters and their use as effective outcome measures in clinical trials will require robust multicenter study designs.

Symptoms of Kennedy's Disease (SBMA)

Any time I list the potential symptoms of Kennedy’s Disease, aka Spinal Bulbar Muscular Atrophy (SBMA), there is a tendency for someone to comment, “I have that. Do you think it’s Kennedy’s Disease?”

My answer is always the same. “I don’t know. You need to see your primary care doctor and discuss your symptoms with her/him.”

When my symptoms started, there was no DNA test for Kennedy’s Disease (SBMA). Most doctors and many neurologists did not know about SBMA. Neurologists put you through a series of tests, some not very pleasant, to help determine the cause of the symptoms. Most often, it was an educated guess based upon available evidence. In my case, I was diagnosed with ALS.

Several years later, another doctor diagnosed it as SBMA and sent me to see Dr. Fischbeck for a second opinion. I still remember walking into Dr. Fischbeck’s office that morning. He saw my gate, nodded his head, and said, “You have the walk.” He performed a DNA test and confirmed Kennedy’s Disease.

Today, because of the DNA test, a doctor can draw a little blood and send it off to a lab. Within a few weeks you will have an answer as to if you have Kennedy’s Disease. If not, you will still have to go through more testing, but at least SBMA is ruled out.

In regards to the list of symptoms below, those of us living with Kennedy’s Disease normally do not have all of them. We will have several and some might not appear until later in the progression. The most common early symptoms are severe cramping, hand tremors, unexplained fasciculations, and gynecomastia.

Please note there is a wealth of information available on the Kennedy’s Disease Association website (http://www.kennedysdisease.org/index.php/about-kennedys-disease/what-is-kennedys-disease).

SYMPTOMS (I apologize for the formatting problem below)

Neurological:
Bulbar Signs	The Bulbar muscles are those supplied by the motor nerves coming off the brain stem. They control breathing, swallowing, talking and other functions of the throat. Bulbar signs are problems with these functions.
Dysphagia	Trouble swallowing. (One of the Bulbar signs.)
Intention Tremor	Hand tremors when trying to do something.
Normal Babinski	Normal plantar response, ie., when the bottom of the foot is scraped, the toes bend down. An abnormal response would be an upward bending of the toes indicating a problem in the brain itself.
Lower Motor Neuropathy	The lower motor nerves are those that run from the spinal cord to the muscles that they stimulate to move. Loss of that nerve leads to weakness and wasting of the muscle.
Primary Sensory  Neuropathy	Numbness over certain areas. Loss of sensation.
Decreased or Absent Deep Tendon Reflexes	When a doctor taps the knee with his hammer there is no response.
Muscular:
Fasciculations	Twitching of small muscles without purposeful movement. These can be seen through the skin.
Cramps	Large muscle spasms.
Postural Tremor	Shaky muscles with certain positions.
Muscular Atrophy	Wasting and shrinkage of muscles that occurs when the lower motor nerve does not stimulate the muscle adequately.
Hypertrophied Calves	Calf muscles that become thicker because of cramps.
Thoracic:
Gynecomastia	Enlarged breasts.
Endrocrine
Androgen Deficiency	Loss of masculinizing effect (qualities that are perceived as masculine).
Estrogen Excess	More of an apparent estrogen effect because of the lost of masulinizing effect.
Genito-Urinary:
Impotence	Erectile dysfunction.
Reduced Fertility	Low sperm count.
Testicular Atrophy	Testicles become smaller and less functional.
Miscellaneous Characteristics:
Late Apparent Onset	Symptoms could become apparent in 20's or 30's, but might not appear until the 60's or 70's.
Slow Progression	Near-normal lifespan.
Asymmetry of Clinical Signs	Muscles of one side may be more affected than the same muscles on the other side.
Laboratory:
Elevated Serum Creatine Kinase	Elevation of CPK enzyme in the blood test.  Can be confused with the enzyme released during a heart attack.

Why is my CPK so high - Revisited

Over the years, the post with the greatest activity has been “Why is my CPK so high?” Readers have posted more comments and asked more questions on this subject than any other post. For this reason, I thought it might be appropriate to review creatine kinase (CPK) and provide links to other posts on the topic.

The Johns Hopkins Arthritis Center provides a good explanation of creatinine kinase (CPK).

CPK also called creatine kinase (CK) is an enzyme (chemical) found specifically in muscle cells. One form of CPK is found in heart muscle cells, another in the skeletal muscle cells. CPK is also found in brain cells. When these cells are damaged for any reason, the CPK is released into the blood and can be measured by a blood test. If the heart CPK (CPK-MB) is elevated it can mean that the heart is damaged which can occur in a heart attack or in conditions in which the heart muscle is inflamed such as viral myocarditis. Skeletal muscle can be damaged in trauma such as in severe injury to the muscles, or after intense exercise causing an increase in the skeletal muscle form of CPK (CPK-MM). Certain drugs such as cholesterol lowering drugs (statins) can damage muscle and elevate CPK. Other causes are alcohol, viruses, hereditary conditions. Finally CPK can be elevated in certain autoimmune diseases that cause inflammation in the muscle such as polymyositis or dermatomyositis.

In the post on “Why is my CPK so high,” Terry Blytheway does a good job of explaining CPK.

“Going back to basics, there are three types of creatine kinase or isoenzymes in the body: CK-BB is mainly produced by the brain and the smooth muscle; CK-MB is primarily produced by the heart muscle; and most of CK-MM is produced by the skeletal muscle.”

He goes on to explain what higher than normal CPK might indicate.

“…if the test reveals that the level of creatine kinase circulating in the blood is higher than it should be in normal conditions, then chances are that the human body in question has suffered damage either to the muscle or the brain. In fact, astronomical levels of creatine kinase are indicative of injuries, rhabdodomyolysis, myocardial infarction, myocarditis, myositis, malignant hypethermia, McLeod syndrome, neuroleptic malignant syndrome, and hypothyroidism. If most of this sounds like gibberish to you, just remember that a heart attack, a muscle disease or a stroke may result in abnormally raised creatine kinase levels in the blood. Statin medications used to decrease serum cholesterol levels may also be the culprit.”

If you are interested, below are links to other posts on CPK.

• “Kennedy's Disease and elevated CPK”
• “Why is my CPK so high?”
• “Kennedy’s Disease and elevated CPK”

Kennedy's Disease and elevated CPK

Serum creatine kinase, or CPK or CK, levels have been a warning sign of the possibility of many disorders including Kennedy's Disease, aka Spinal Bulbar Muscular Atrophy. Long before I knew I had Kennedy's Disease and before DNA testing was available, my doctor noticed the elevated CPK levels and wanted further testing done. Some of these tests were not a lot of fun. Fortunately, the DNA test is much easier, far less expensive, and more accurate.

As I mentioned in earlier articles, in the last few years my CPK (or CK) count has declined to the high end of the normal level. I can only guess why this has happened (less muscle mass = less wasting).

Yet, it is interesting that there is a strong correlation between elevated CPK and Kennedy;s Disease. While doing some research on the subject, I came across four recently updated articles on the link between Kennedy's Disease and CPK (CK).

1. The Better Health Channel updated their webpage on Kennedy's Disease, aka Spinal Bulbar Muscular Atrophy. The article is well written and easy to understand. It mentions elevated CPK as one of the symptoms, Click here to go to the link.

2. Disabled World also has information on elevated CPK and its potential link to Kennedy's Disease. The article is titled, Creatine Phosphokinase (CPK) Test: Facts & Information. Click here to go to the link.

3. Medscape's article on Kennedy's Disease has this to say about elevated CPK levels. "Problems may arise in resolving apparent positive results obtained before genetic testing is done. For instance, serum creatine kinase (CK) testing is not indicated, yet the CK level may be elevated substantially. One of the author's patients had been treated for inflammatory myopathy for years before the correct diagnosis was made. In another case, the patient was aggressively treated for myasthenia gravis (including thymectomy) before KD was diagnosed.^[63] Sorenson and Klein have also reported elevation in CK and transaminases levels in asymptomatic patients with KD^." Click here to go to the link.

4. Prezi has a short slideshow on Kennedy's Disease and also links elevated CPK levels as a possible symptom. Click here to go to the link.