INTRODUCTION:

Muscular Dystrophies (MDs) are the group of genetic disorders that causes progressive muscle weakness and degeneration of skeletal muscles, restricts their movement and functions, and is irreversible. In 1830, Sir Charles Bell identified and reported an unknown disease which caused progressive weakness in boys¹. Later, Giovanni and Gaetano Conteobserved two brothers suffered with progressive muscle weakness and reported in two consecutive publications of 1834 and 1836². In 1852, Dr. Edward gave a description about four boys from same family suffering with MD³. In 1829 researchers found two boys having undescribed disorder, later they referred most noticeable the sign of MD^{4, 5}. Guillaume Benjamin Amand Duchenne, French neurologist, wrote the first case of MD and gave a comprehensive review of 13 MD patients^{5, 6}.

Based on his extensive work, one of the critical forms of MD is named after him as ‘Duchenne Muscular Dystrophy (DMD)^{1, 7, 8.}

MD is a group of heterogeneous disorders characterized by the progressive loss of muscle mass and consequent muscle strength⁷. The degree of muscle loss and severity varies from patient to patient and it depends on the genetic sequence affected. The diagnosis includes clinical, historical, and histopathological study of muscular fibers; however, this does not completely define MD. To know the subtypes (the missing genetic codons), a strong study of the genes is required⁹. There is a variation in symptoms of different types of MD, but overall muscle is affected and the weakness spreads from affecting the skeletal muscles to the cardiac, ophthalmic, and respiratory muscles. Other symptoms include the weakening of several vital organs in the body and that of the central nervous system. The patients with the same type of MD also show variation in the symptoms and the severity of the disorder depending on their age, nutrition intake, body weight, mental stability, and management. MD patients should take great care and proper measures to manage and stabilize their health. There should also be a periodical checking of cardiac and pulmonary functioning for each patient¹⁰.

CENSUS AND EPIDEMIOLOGY:

From past two decades, DMD affected 83 and 106 for Becker Muscular Dystrophy (BMD) out of every 1,000,000 people. Fukuyama muscular dystrophy is the most prevalent in Japan due to recessive mutations. According to forbes health survey in 2016, MD affects up to 1 in every 5,000 males and 1 in 8,000 females. But the drawback in India is that there is no proper reports and differentiation of MD. The United States has about 72% registries while India being the second most MD populated country, which has only 5% of registries¹¹. Inside, according to the existing reports in India, there are nearly 4,000 MD patients in Tamilnadu state, and 10,000 MD patients in Andhra Pradesh and Telangana states combined. Since there is no proper registration to report MD, it is difficult to find the predominance of MD in individual states. Overall, it is estimated that about 100,000 patients were suffering with MD in India, among which DMD was affected in 1 among 3,500 people¹². In 2017, BMD was about one-fifth less frequent than DMD^13,
14. Myotonic dystrophy prevails in the ratio of 1:9400, mostly in adults. Limb Girdle Muscular Dystrophies (LGMDs) have a greater prevalence ratio of about 1 in 14,500-30,000 people where Autosomal Recessive (AR) forms are more common¹⁵. According to the case studies published by NIMHANS, in 2017, about 350 cases were evaluated over a span of 2 years out of which 226 unrelated patients were confirmed to have MD with muscle biopsy. Patients of 199 out of the 226 classified into various AR subtypes which were based on immunohistochemistry (IHC) and western blotting studies.

At least 1 MD patient in every 2,000 children estimated by Muscular Dystrophy Association (MDA) of USA. National Institute of Neurological Disorders and Strokes suggest that DMD and BMD, alone affect approximately 1 in every 3,500-5,000 people in USA. While we consider other western population, LGMD2A (calpinopathy) is the most common type and LGMD2B was found to be around 33.3% prevalence¹⁶.

The incidence rate of DMD in the UK is between 10-28% per 100,000 male births. The overall estimation of people living with MD are in the ratio of 1:200^{14, 17}. The scenario of India is the exact opposite when compared of the United States, the United Kingdom, and other Western countries. There is no proper data of people who are diagnosed with MD. The national population survey that specified the population of PWDs doesn’t provide concrete data on MD¹¹. However, on a wagered scale, there is an estimate of 1 out of every 2,000 people having MD. In South India, according to surveillance of Amaravathi Muscular Dystrophy Association (AMDA) and Telangana Muscular Dystrophy Association (TMDA), there have been about 4,000 MD patients in Andhra Pradesh till 2006 who have been inappropriately diagnosed and unrecognized¹⁸. The same scenario exists in Telangana with about 3,500-4,000 MD patients. Both associations could gather reports of only 500-1,000 patients in each state and the rest of them are in remote areas without proper awareness. In North India, there nearly 3,000 dystrophy identified patients¹⁸.

Scenario of Prevalence:

MDs are very rare and the severity varies from person to person, but most commonly all the affected persons are confined to bed within 10-15 y after the onset of the disease. Although MDs prevailed in the ancient times; they have been unrecognized and were mistaken as some conditions related to either nerve weakness or polio. However, with the increased awareness and consciousness towards health, there has been a distinction between those diseases the past 5-10 y.

In spite of this increased awareness, there are some areas that have a majority of uneducated patients that have no information on their MD condition. The most common type of MD is myotonic dystrophy that affects both men and women and decreased life expectancy¹⁹. It affects gastrointestinal tract, central nervous system, hormonal glands and ocular muscles²⁰. Patients with DMD need a wheelchair accommodation by the age of 12 and they face severe heart and breathing problems, cognitive impairment, and the deformation of the arms, legs and spine. DMD leads to death in the early teens or 20’s²¹.This contrasts with BMD²², where usually patients with BMD can usually walk into their 30’s and can live further into adulthood. LGMD patients also face walking difficulties within the first 20 y and their life expectancy is up to late adulthood²³. FSHD does not affect the patient’s ability to walk and it does not have a major effect on the patient’s life span²⁴. Oculopharyngeal MD causes muscle weakness in eye and throat²⁵. In the case of Emery-Dreyfuss and Distal MD, severity of muscle weakness is less when compared to other forms of MD²⁶.

Genomic Theory:

MD does not only affect the muscles but also the organs of the body (heart, kidneys, lungs). It results in the breakdown of skeletal muscles over time²⁷. Eventually, many people lose the ability to walk as every muscle in the body become restricted and gradually bedridden. The severity of progression varies from person to person but, 99% of the individuals become dependent on a helper for daily activities by the age of 35-40 y²⁸.

Types of muscular dystrophy:

There are nine categories of MD, with each type involving an eventual loss of strength, possible deformity and increasing disability. DMD and BMD are two well known MD. Becker (adolescence to early age), congenital (birth), duchene (2 to 6 y), distal (40 to 60 y), emery-dreifuss (childhood to early teens), facioscapulohumeral (childhood to early adults), limb-girdle (late childhood to middle age), myotonic (20 to 40 y), oculopharyngeal (40 to 70 y). Each category they are various sub-types, and all of them accounting for about 30-50 categories^20-28.

DMD:

DMD is the second most single gene disorder in Western countries, characterized by the absence of dystrophin protein. This is because of eventually mutations in coding, which led to aberrant intracellular signaling pathways yielding muscle weakness, friability, necrosis. The transcribing time is 16 h of this DMD gene. Dystrophin protein is located between sarcolemma and myofibril and it links up actin filaments to other support proteins (present in muscle fibers of sarcolemma). Dystrophin is also responsible for strengthening the muscle fiber and reducing the stiffness of muscle. DMD patients become dependent in their early childhood and gradually develop cardiac hypertrophy resulting in premature death in first three decades of their life. Coming to genomics, DMD is X-linked recessive hereditary diseases caused by mutations of dystrophin gene, which is most common. The gene span has a distance of 2.5 million base pairs situated at the Xp21 locus and it consists of 79 exons²⁸. The deletions are non-random and detected at specific areas of gene such as 1, 3, 4, 5, 8, 13 and 19 Exons at 5’proximal portion of the gene (about 20%) and the mid-distal region exons such as 42-45,47-48, and 50-53 (about 80%)^29-31. The deletion pattern (number of deletions) observed in some group of DMD. Molecular study suggests that low or no production of functional dystrophin was observed in DMD is the deletions which causes shifting of reading frame of dystrophin mRNA. Approximately 83% of the deletions were located on mid-distal hotspot (between 42-52 exons). Exon 49 and 50 are frequently deleted where as exon 3 was not deleted^32-34. The highest percentage of deletions was found in DMD/BMD patients of UK and USA. About 552 patients from UK and 550 from USA were examined and the deletion pattern observed is about 61% and 72% respectively.

India (68%) showed the highest deletion pattern next to USA. Patients in Turkey with DMD/BMD have intragenic deletions in about 60% population. The lowest deletion pattern was observed in patients of France (44%) in about 105 patients. While the deletion patterns are approximately 59%, 63%, 53%, 51%, 52% observed in DMD/BMD patients of Australia, Canada, China, Egypt, France and Japan.

BMD:

Becker Dystrophy causes progressive weakness and wasting of cardiac muscles. It also results in the other symptoms that are similar to DMD. But the severity and progressive rate is different than those of DMD. The occurrence of BMD is estimated to 1 in every 30,000 male births. Prevalence rate is about 1 in every 11,000 births. The genetical aspects of DMD and BMD are similar. Dystrophin is non-functional in DMD where as dystrophin is partially functional in BMD. The dystrophin protein on the X chromosome is made from a particular gene that is partially functional in BMD. BMD is inherited from the X-linked recessive pattern. In this, a female carrier who has one mutated copy of the gene has a 50% risk of passing on the mutated gene to the child. Male and female children each have a 50% risk to be a carrier. Females are less prone to inheritance and occurrence when compared to males²³.

LGMD:

LGMDs are non-syndromic and have clinical involvement limited to skeletal muscles. LGMD’s symptoms are seen mostly in patients of middle and adult ages. Prevalence range is about 1 in every 14,000 people^24,
35. Because of heterogeneity and lack of proper diagnostic specificity, reporting of LGMD is poor. The dystrophy has a wide range of pathogenic variants that classify them in various numbers. There are about 50 loci that cause LGMD (Table 1 and Table 2).

Table 1 Symptoms, age of onset, defective gene, and its locus of various dominant LGMD types³⁶

LGMD type	Gene	Locus	Onset Age	Symptoms
LGMD1A Myotilinopathy	MYOT	5q31.2	18-40 y	Proximal weakness
LGMD1B	LMNA	1q22	Birth to adulthood;1/2with childhood onset	Proximal lower limb weakness
LGMD1C Caveolinopathy	CAV3	3p25.3	5 y	Rippling muscle disease, mild-moderate proximal weakness, cramping
LGMD1D	DES	2q35	Less than 25 y	Weakness in proximal muscle and defect in cardiac conduction
LGMD1E	DNAJB6	7q36.3	18-40 y	Progressing to the unaffected regions, Proximal or distal weakness in lower limbs
LGMD1F	Unknown	7q321.1-q32.2	1-58 y	Weakness in proximal lower limb
LGMD1G	Unknown	4q21	30-47 y	Weakness in proximal lower limb
LGMD1H	Unknown	3p25.1-p23	16-50 y	Weakness in proximal lower limb

Table 2 Symptoms, the onset age, age of wheelchair bound, defective gene, and the locus of various recessive LGMD types.^37,
38

LGMD type	Gene	Locus	Onset Age	Wheelchair Bound Age	Symptoms
LGMD2D Alpha sarcoglycanopathy	SGCA³⁹	17q21.33	3-15 y	15 y	Difficulty in walk, frequent exercise cramps
LGMD2E Beta -sarcoglycanopathy	SGCB³⁹	4q12	3-15 y	15 y	Difficulty in walk, run; cramps, exercise
LGMD2C Gamma -sarcoglycanopathy	SGCG	13q12.12	3-15 y	15 y	Difficulty in walk, run; cramps, exercise
LGMD2F Delta-sarcoglycanopathy	SGCD³⁹	5q33.3	3-15 y	15 y	Difficulty in walk, run; cramps, exercise
LGMD2A Calpinopathy	CAPN3	15q15.1	2-40 y	11-20 y after onset	Difficulty in walk; toe walk, stiff back
LGMD2B Dysferlinopathy	DYSF	2p13.2	17-23 y	5-7 y after onset	Difficulty in walk, run; Inability to tiptoe
LGMD2G⁴⁰	TCAP	17q12	9-15 y	18 y after onset	Difficulty in walk, run; foot drop
LGMD2H^{41, 42}	TRIM32	9q33.1	1-9 y	Late in life	Waddling gait, facial weakness, difficulty in stairs
LGMD2I³⁸	FKRP^{43, 44}	19q13.32	1.5-27 y	23-26 y after onset	Difficulty in run, walk
LGMD2J⁴⁴	TTN	2q31.2	5-25 y	20 y after onset	Difficulty in walk, run; cramps, exercise
LGMD2K^{38, 45}	POMTI	9q34.13	1-3 y	May be 7-17 y/still ambulatory	Difficulty in climbing stairs and running; cognitive delay with limited language development, fatigability
LGMD2L⁴⁶	ANO5	11p14.3	Late teens 50s	Not reported	Difficulties standing on toes, Proximal lower and upper limb weakness
LGMD2M^{38, 47}	FKTN	9q31.2	4months-4 y	Not reported	Severe muscle weakness, difficulties in climbing stairs
LGMD2N^{38, 45, 48}	POMT2	14q24.3	18months; asymptomatic at 5 y	20 y	Walking and running slowly
LGMD2O^{38, 45}	POMGNTI	1p34.1	12 y	19 y	Sever myopia, difficulties in climbing stairs, raising up
LGMD2Q⁴⁹	PLEC	8q24.3	2-3 y	24 y	Difficulties in climbing stairs, delayed motor milestone, keeping up with peers

Facioscapulohumeral muscular dystrophy (FSHD):

FSHD symptoms are significantly different and are present mostly before 20 y of age. Facial muscle weakness and foot dorsiflexors are two prominent symptoms. Individuals may not show significant facial weakness, so they might resemble having LGMD. There is a progressive facial weakness. Their walking pattern deteriorates and require wheelchair apparently 95% of affected individuals have a deletion of integral copies of 3.3 kb DNA (D4Z4)²⁶.

Emery-dreyfuss muscular dystrophy (EDMD):

Symptoms of EDMD include slow progressive muscle weakness, cardiac palpitations, congestive heart failure and joint contractures. Coming to genetics, due to the pathogenic variation in Emerin Gene Encoder (EMD), the X-linked form is the reason for EDMD. The pathogenic variants in the gene encoding lamin A/C, LMNA causes dominant/recessive forms²⁶.

Congenital muscular dystrophy (CMD):

CMD is an autosomal recessive dystrophy with low muscle tone and contractures. It represents a group of disorders that are present from birth. Almost 50% of CMD is caused by merosin deficiency.

Clinical Symptoms:

In DMD, infants may show calf muscle enlargement, wagered walking, frequent falls, difficulty in getting up from the floor, and/ or toe walking. In the worst cases, children may face difficulty in raising arms, waddled gait, and abnormal posture. Mostly, DMD children are bound to wheelchairs by the time they are 12 y and require support in almost every part of daily life. The dreadful stage of DMD patient begin between 9-15 y when there is a loss of muscle layer of heart and a weakening of lung muscles that result in difficulty breathing, nightmares, and heart weakness. Mostly, DMD patients pass away due to sudden heart attacks and respiratory problems between 9-16 y of age. The symptoms of DMD and BMD differ in that the progression rate is slower in BMD. BMD patients experience less severity when compared to DMD patients. The symptoms vary depending on the genotype of the patient. Weaknesses involve mainly proximal and distal parts of the body and are not syndromic.

In LGMDs, the progression of muscle weakness is started from limb muscles and then moves on to the shoulder muscles. The patient may have a waddling gait, difficulty in climbing stairs, standing up, combing hair, and holding the arms stretched out. As the onset age of the disease progresses, the patients face difficulty in using their fingers and holding objects in their hands. They also face declines in respiratory function, restriction to wheelchairs, and continuous assistance for daily life activities. For instance, they would not be able to eat food with their own hands.

FSHD occurs before 18-20 y of age and the symptoms are often facial muscle weaknesses that are slowly progressive. EDMD is characterized by weakness in the scapular, pelvic, and cardiac muscles. It also leads to palpitations. The CMD can be characterized by floppy appearance with muscle contractures and weak muscles from the time of birth.

Clinical Diagnoses:

Diagnosis first involves the physical examination of the body, medical history, symptoms and family history. The various tests involved in ascending order are:

● Elevated levels of serum creatinine concentration in blood are the primary evidence (MD suspected).

● Electromyography and nerve conduction tests study the strength and function of nerves and muscles.

● Histopathological tests (ex. muscle biopsy) typically show the degeneration of muscle fibers followed by immunoblotting to determine the involvement of specific proteins.

● Muscle biopsy increases muscle deterioration and inflammation. Hence, muscle MRI is preferred.

● Molecular genetic study analysis confirms the type of phenotype/genotype involved. Genetic confirmation study involves gene analysis (DNA analysis to check mutation presence), gene sequencing, and gene confirmation.

● Type of LGMD is difficult to identify and next generation sequencing studies is required.

● Prenatal helps confirm MD in the pregnancy stage and carrier identification studies can identify if a non-symptomatic carrier has the chance of inheriting MD to next generation.

Scenario of Diagnosis in India:

In spite of the above-mentioned cases, the diagnosis, categorization, and research are in a bad condition in India, and in extending a helping hand to MD patients. It is the responsibility of a physician to help in the complete diagnosis of a diseased patient. But, according to studies held by AMDA, about 70-80% of the MD diagnosed patients are not recommended for the genetic diagnosis. According to the reports, there about 10,000 MD affected persons from most of the highly populated states of India. But, AMDA (which is focusing on the complete diagnosis of each and every patient throughout the country) identifies that, of the 1,000-2,000 patient registries have preliminary tests done, 50-60% have not undergone genetic sequencing. The North India associations who have got 1,000 registries out of which only 900 i.e. not even 1/4^th members have their complete diagnosis¹⁰. The physicians are neglecting the diagnosis because there is no cure for MD. But, when the physician knows that this disease is at genetic level, it is mandatory for the intervention of the data as it leads to research growth in MD and is a key factor to finding a complete cure.

Care and Management:

Management of MDs involves exercise and physiotherapy that can stabilize the progression of the disease to a certain extent. Respiratory management and cardiac care are a must for DMD patients. A well-balanced diet with more protein-fiber content is helpful in balancing the optimal weight as excessive weight gain is a severe problem. MDs should not be restricted to the bed; any passive exercises or mental activity should be done to maintain their strength of positivity and also to discourage the weakening of muscles. The aid of power wheelchairs, twitches, and other mobility aids can make it easier for MD patients to move. Utmost care should be taken and respiratory infections should not be compromised. Some surgical corrections can be made in case of contractures, scoliosis etc.

Treatment:

MD can’t be cured and can be managed by different ways. Foremost gene therapy and stem-cell therapy provided emerging platform for the treatment of MD by stopping the progression of diseases associated with MD. Deformities of the joints and spine were managed by well designed clinical care and it helps for maintaining the mobility. Different therapies like occupational, respiratory, physical, speech and assistive technologies like wheelchairs, canes and walker supporting for better management of MD. Chemotherapy approaches based on symptoms proved better. Researchers suggesting integrative therapies which focuses on diet (anti-inflammatory diet, avoids stimulants), supplementations (antioxidants, multivitamins-mineral, fish oil, vitamin D, calcium, magnesium, coenzyme Q) and mind-body connection can be relieve the symptoms. Natural products also used frequently by our ancestors for treatment of MD which helps to strengthen and invigorate the healing systems. Melatonin is a natural hormone plays vital roles in multiple homeostatic processes. Chinese herbal medicines (Chinese herbal extracts) becoming popular among DMD patients to slow down the disease progression. It has glucocorticoids activity to treat DMD. Green tea extract had anti-inflammatory and antioxidant activity due to presence of high levels of polyphenols used by DMD patients. Taurine, soybeans, curcumin, resveratrol had antioxidant and anti-inflammatory activity to treat disease. This improves the fore limb muscle strength, reduce stretch induced damage, improved isometric force (taurine), improved EDL muscle function, biceps muscle strength (soybeans), improved contractile properties, grip strength and hang time, reduced necrosis (curcumin), increased fatigue resistance in soleus, decreased fibrosis, reduced bodyweight, decreased immune cell infiltration in gastrocnemius (resveratrol). Beet root juice, vitamin D and L-arginine increasing nitric oxide availability ultimately helps to treat MD.The neutraceuticals never cure the MD, it counter-acting the damaging effects of chronic inflammation or oxidative stress and improves the quality life. A traditional Japanese herbal medicine (Go-sha-jinki-gan) clinically proved increases the muscle weight in MD mice.

CONCLUSIONS:

MD is a rare genetic disease need unique care for the management of symptoms. Treatment and management of MD without any side effects is still a challenge for the medical system. There are different categories of MD, DMD and BMD are two well known MD. Severity of MD will vary from person to person and commonly all MD patients are confined to bed within 10-15 y after the onset of the disease. Inability to walk, difficulty climbing steps, and the loss of muscle strength are the common symptoms. Most of the dystrophies are present from birth, but the symptoms develop either in childhood, adolescence, or late adolescence. Elevated levels of serum creatinine concentration in blood, electromyography and nerve conduction tests, histopathological tests, muscle biopsy, MRI, molecular genetic study, prenatal and carrier identification diagnosis are the diagnosis toll used for the identification of MD. Study concludes in India, 70-80% of the MD diagnosed patients are not recommended for the genetic diagnosis. Well planned life style includes exercise, physiotherapy, well-balanced diet, yoga, pranayama, panchakarma treatment, respiratory management, cardiac care, gene therapy and stem-cell therapy can improve the strength, mobility, flexibility. Need based treatment and care help for the better management of MD. Hence, there is a requirement of patient education, awareness campaign, workforce and services will helps to manage the MD. Thus, a better understanding of the MD and novel approaches in formulation technology and therapy could guide the formulation scientists and clinicians towards the successful management of the disease.

CONFLICTS OF INTEREST:

The authors declare no conflict of interest in this article.

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Received on 04.07.2020 Modified on 15.10.2021

Research J. Pharm. and Tech 2022; 15(11):4901-4907.

DOI: 10.52711/0974-360X.2022.00823