Muscle biopsy vs Gene sequencing

Muscle biopsy is almost 3-4 decades old pathological test procedure where a small piece of muscle surgically taken from the thigh of a patient is subjected to a "histopathological" procedure by mixing with solvents separate for each type of 6-8 (can be corrected by the expert) muscle dystrophy types ONLY. With the advent of genetic sequencing, doctors have identified around 20-types of mutations which could be responsible for various phenotype manifestation on the patient. As the science progresses, more and more mutations are cropping up which could manifest into different types of physical conditions. Now with the availability of next generation sequencing both the time taken and cost of sequencing has fallen 10-15 times as it used to be 6-7 years ago.

I may never be able to say: "whether biopsy is superior or sequencing" it is an expert's call.

I can certainly say (still may be at flaw).... biopsy has its limitations of NOT able to rule out all the newly found mutations. It is also not a sensitive tool of diagnosis. Genetic sequencing also has its own share of issues. There are cases where a negative mutation doesnt rule out the patient suffering from some kind of mutation or the other. There are also cases where patients are found to have more than one mutation in different genes.

These days the sequencing agencies are offering an option called "gene panel" sequencing; meaning, they would check for a list of genes mutation at an affordable cost. Strange but true; a known patient does suffer from MD ailments; but her gene panel tests came negative. So where does the problem lie.

Bottom line:
One must undergo a gene sequencing test; this is the ONLY way he/she can hope to look for modern treatment options like "exon skipping" in the case of DMD. So... please go for it.... you may certainly avoid muscle biopsy....

[EXPERTS... PLEASE FORGIVE ME (a fighting father) FOR ALL THIS KNOWLEDGE I HAVE ACCUMULATED OVER A PERIOD OF 9-YEARS, AFTER I KILLED THE SPACE SCIENTIST IN ME]

LGMD, The First Step in understanding

Limb Girdle Muscle Dystrophies, LGMD, is a class of muscle weakening diseases fall under a deadly rare disease category called Muscle Dystrophy (MD). While the most dreaded disease among this category is Duchenne Muscle Dystrophy (DMD; which picks 9 to 10 out of 10 on the worst scale; not able to survive by mid 20s), the LGMD can be called as medium mild type (5 to 7 out of 10; wheel chaired in 8-15 years of diagnosis). The very first symptom of these diseases is weakness in limbs i.e., hands and legs, apart from many other difficulties one individual faces. There are at lest 23- plus types of LGMDs depending upon the underlying gene mutation. The purpose of this article is to introduce LGMD in a layman's language; of course it is written by a non-specialist. As my daughter has fallen pray to the similar type of disease (LGMD-2A) in 2008; I have now left my active research in Space Sciences; in the capacity of core science team member of Indian Lunar Mission, our instrument CHACE went on to discover water on the moon.

Courtesy : MDA

The present discussion would cover:
LGMD - types
LGMD - How to diagnose
LGMD - How to manage
LGMD- What is the future ???
Post 90's scenario has brought a great deal of change in the way one assesses a given disease. With the spurt in genetic research leading to the unraveling of human genome; the cause of every disease is now assigned to a flaw in the genetic structure as compared to a normal gene pattern, called gene mutation. While the LGMD as such divided into two primary classes whether one inherits the same from their ancestors labelled as autosomal dominant while in the other class there could be a new form of mutation appearing on its own called as autosomal recessive. While autosomal dominant are labelled as LGMD-1A, 1B, 1C....  the autosomal recessive are LGMD-2A, 2B...... The modern diagnosing tools have now been fairly successful in categorizing the disease on the basis of underlying genetic mutation. For example LGMD-2A is an autosomal recessive due to mutation in the Calpain gene, called Calpainopathy; while LGMD-2B is a recessive mutation due to Dyeferlene gene and is called Dysferlenopathy. Each type of LGMD has its own way of manifestation on an individual. Not a great deal of work has been done in understanding and looking for treatment options; though with the advent of genetic tagging to each type of disease, now a systematic way of understanding these disease has been made possible. A few group of doctors (mainly Europe and USA) across the globe have indeed made appreciable efforts in characterizing these diseases by studying the rarely available group of patients across the country. Awareness among the society too has been quite rapid in the past decade or so even in the third world countries, thanks to the media and internet.

The most tricky part one goes through in this ordeal is: after a simple CPK test decides whether an individual is NORMAL (within 100 count) or NOT (few 100s to 1000s); to find which is THE type of LGMD. Having got the high CPK count; it is a steep uphill task for the family to go even an inch further. The decades old pathological tests viz., CPK test, EMG test followed by an ultimate painful muscle biopsy are un-successful in nature and more often they are found to be in-efficient in pinning down the type of disease. I went through the agony of all these tests for my daughter. Even as a trained researcher, having spend months together in reading on the internet and of course meeting a large number of neuromascular experts in Indian cities my quest for finding the type LGMD was very very frustrating. The internet helped me a lot; my relentless efforts in reaching to experts has landed me at the door steps of Prof. Andrew Engel, Mayo Hospitals, Rochester, USA; who published his first research paper on muscle dystrophy some 3-decades ago. He had helped me in re-assessing the muscle biopsy samples and gave the same report as I had got within India; Yes MD may exists but the type is not known. I owe Prof Engel for his humane touch in entertaining me to re-assess my daughters samples from thousands of miles away. This point is only to illustrate the limitation of past pathological tests. Having failed in getting a genetic assessment done in my country, India; I tried globally in Europe, USA and found the genetic assessment from a group led by Dr. Sabrina Gallati, University of Berne, Switzerland (diagnostic details). The result came positive for one known and another unknown mutation in a Calpain gene; though this was the last nail in a coffin of my hopes; I was content with my pursuits that finally I have resolved the issue. As mentioned in this link; what one need to do is to approach the Genetic Assessment center anywhere in the world and by sending the blood samples at normal room temperature would suffice the requirements of gene test for a given mutation. Since the disease is rare; there are very few experts in each country and hence it is only with the help of these experts one needs to opt for a given mutation test. The good news on this mutation test is; the charge of ruling out each (suspected) genetic mutation has come down quite drastically from few 1000s of dollars to 100s; also many diagnostic options are now getting available within India.


January: 2014
Thanks to Dr. Ashwin Dalal of CDFD , India; he has helped me in tracking every laboratory in the world which takes up the gene sequencing of various muscular dystrophy; this information is distributed by none other than the most trusted research entity in USA, the NIH, the site is: Genetic Testing Registry. For example, in my case of LGMD-2A, the site gave me 27-centers across the globe which are taking up the gene sequencing for CALPAINOPATHY.

How to manage LGMD is as complex and as much in dark shades as it was to diagnose the type of the disease.  Since the modern science says there is no treatment solution for the LGMD, having been living in a country like India; where there are many alternative medicine options are available, it took enormous efforts on my part to resist the same as a father. What should one do next? One should first get the physical assessment done including the vital organs viz., heart, lungs. THE ONLY WAY TO PROCEED FURTHER IS TO FOLLOW A SPECIFIED PHYSICAL EXERCISE PROGRAM AND TO KEEP THE TONE OF THE MUSCLES IN GOOD SHAPE. This requires assessment and proper guidance form a well informed  Neuromascular / Orthopedic experts. Any over doing would lead to catastrophic effects as the weakening of muscles would lead to a permanent damage; at the same it is absolutely essential to tone up the muscle strength on every single day.

The future...
On an optimistic note, the future is turning out to be very very bright. My doll was struck in late 2008; I have read and been following every whisper on Muscle Dystrophy (via Google alerts) since then. What I have learned in the past 3-months is much much exciting than what all has been happening (at the snail speed) in the past 3-decades from the agonising wait and the stories of many individuals loosing their lives to the dreaded DMD. WHY???

There are two drug companies: Sarepta, GSK (Prosena); both are in a race to find the FIRST time ever solution to the treatment ( link ) of DMD, Duchenne-disease. They have shown very positive and encouraging results in the Clinical trials II-B that the patients treated with their respective medicine are responding very positively and not only showing the arrest of progressive muscle wasting but also a dramatic improvement in the muscle strength on 6-minutes walk test (6-MWT).  In scientific jargon the trick followed by these companies is called EXON skipping drug. If this scheme succeeds, the treatment options for other dystrophies namely LGMD which are the most prevalent among all muscle dystrophies would be round the corner. There are clinical trials initiated for LGMD both in USA and Europe based on gene replacement; which is a good news.

It is absolutely on the personal view point that: if the DMD drugs can be made available (with FDA approval) by the THIRD quarter of 2014; we can certainly hope to have LGMD based drugs being made available within 1-2 years time.

June-2014: 
It is a great setback to all those kids ( DMD) who had kindled great hopes around these drug developments; unfortunately both the drugs ran into some rough weather where their final results (trial-III) could NOT bring convincing results and hence had to face the wrath of being sent back (by FDA) to more authentic re-assessment and a conclusive proof that they do help the patient recover from the disease. However, another drug from PTC therapeutics, USA got a nod from European Medicine agency to develop their drug called ATALUREN; details of this is put up on my post here : " DMD Treatment "


Important link for Calpainopathy patients: LGMD-2A
Coalition to Cure Calpain, 3:  link
Here is the place where the co-founders of the organisation themselves are suffering due to Calpainopathy and they are taking every possible step which will inch towards the cure of this disease.