Principles of multidisciplinary approach in the management of neuromuscular disorders

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Department of Neurology

Rare diseases center: Center of neuromuscular disorders Lithuanian University of Health Sciences, Faculty of Medicine Kaunas, Lithuania

Issam Kanso

6th year medical student

Principles of multidisciplinary approach in the management of

neuromuscular disorders

Supervisor: Prof. Milda Endzinienė 20-05-2020

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Chapter 1: Summary:

Standards of care for hereditary muscular disorders (HMD) involve a multidisciplinary team approach for optimal clinical outcomes. The standardized care has improved life expectancy of HMD patients and especially Duchenne muscular dystrophy (DMD) by more than 10 years, which underscores the importance of a regular, multidisciplinary approach to improve patient-related outcomes.

Identifying HMD is challenging as there is significant overlap of symptoms and signs between HMD and other neuromuscular disorders (NMD). Narrowing the differential diagnosis is extremely aided by pattern recognition approach of the myopathy. The 10 muscle pattern approach guides subsequent laboratory testing, histological studies and genetic testing needed to confirm the diagnosis.

After accurate diagnosis, disease related complications can be predicted, and that shifted multiple subspecialties within the framework of multidisciplinary management to more anticipatory diagnostic and therapeutic strategies, to achieve prevention, early identification, and treatment of potentially modifiable disease complications. Complications are widespread across many specialties such as gastroenterology and nutrition, rehabilitation, and neuromuscular, cardiovascular, respiratory, orthopedic, and surgical aspects, however the majority of NMD patients die from cardiorespiratory complications and management of these risk organs prolongs greatly the survival of neuromuscular patients.

The cornerstones of respiratory care in neuromuscular disorders are airway clearance, infection control, prevention of reflux and aspiration, and assisted ventilation.

Cardiac impairment represents a major obstacle to further improvements in the management of NMDs, timing and modes of cardiovascular assessment and follow-up are determined after definitive diagnosis. Regular monitoring for biomarkers of cardiac involvement and early management have increased the life of NMD patients.

The purpose of this literature review is to provide a framework for recognizing the primary manifestations and possible complications and for planning optimum treatment across different specialties with a coordinated multidisciplinary team.

Other identified concerns in the field of multidisciplinary management of neuromuscular disorders include public awareness towards NMD, education of the therapeutic team, the absence of a standardized referral pathway, the presence of expertise centers, the presence of a unified database and the low numbers of patients that qualify for participation in clinical trials.

Certain European organizations are tackling these concerns by constantly updating standards of care facilitating planning for multicenter trials and promoting disease natural history studies through the

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Chapter 2: Acknowledgments:

I would like to offer my sincere admiration to Prof. Milda Endzinienė for her expert in the fields of neurology, muscle and neuromuscular junction disease and coordinating the center of rare diseases.

Chapter 3: Abbreviations:

ACEI - Angiotensin-converting enzyme inhibitors

ALT - Alanine aminotransferase ALS – Amyotrophic lateral sclerosis ARB - Angiotensin Receptor Blockers AST - Aspartate aminotransferase BMD - Becker muscular dystrophy BMD - bone mineral density BTHS - Barth syndrome CK - Creatine kinase CM - Congenital myopathy CPF - Cough peak flows DM - Myotonic dystrophy

DMD- Duchenne muscular dystrophy EDMD-Emery-Dreifuss muscular dystrophy EF – Ejection fraction EMG - Electromyography FA - Friedreich ataxia FVC – Vital capacity FSHD – Facioscalpulopohumeral muscular dystrophy HF - Heart failure

ICD - Implantable cardioverter defibrillator LDH - Lactate dehydrogenase

LEMS - Lamberton Eaton muscular LDMD - Limb-girdle muscular dystrophy

MENA - Middle East, north Africa MFM - Myofibrillar myopathy MG - Myasthenia gravis

MIP - Maximal inspiratory pressure

MLPA - Multiplex ligation-dependent probe amplification

MRC - Medical Research Council MRI – Magnetic resonance imaging MUAP - Motor unit action potential NIV - Noninvasive ventilation NMD – Neuromuscular disorder NSAA - The North Star Ambulatory Assessment

ROM - Registry of Outcome measures SDB - Sleep Disorder Breathing SNIP - Sniff nasal inspiratory pressure VFSS - Video fluoroscopic swallow stud

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Chapter 4: Introduction:

The term “neuromuscular disorders” covers a large variety of diseases with the common feature of predominant affection of the neuromuscular unit including motor neuron, peripheral nerve, neuromuscular junction, or muscle fiber. In children and adolescents, most conditions are due to hereditary causes. Hereditary diseases primarily affecting the muscles make a big heterogeneous group of disorders that differ by their genetic mutations, the distribution of the involved muscle groups and other organs, also by their age at onset, course and prognosis. However, this group of diseases share some common clinical symptoms and complications related to the consequences of muscle involvement. Due to this, most patients with hereditary muscle disorders (HMD) need specific care that is valid for this group as a whole. As long as no curative therapy has been found especially for the genetic diseases, treatment has to include supportive measures, such as physiotherapy, bracing, respiratory treatment, cardiac care, and assisted feeding techniques. Along with these measures, life expectancy, for example, in Duchenne muscular dystrophy has been prolonged by more than 10 years.

Since the identification of dystrophin mutations in Duchenne muscular dystrophy in 1985, a steadily increasing number of causative genes in different primary muscular diseases has been identified, and this led to improved diagnosis and pathophysiological understanding. As DMD is the most common and best studied disorder among the hereditary muscle diseases, international guidelines for comprehensive care of DMD have been published and updated, and may serve as a model for the care for patients with other HMD. The first point of medical contact for people with HMD is often their primary care provider or, in acute medical situations, the local emergency department. The rarity of the disease means that clinicians in these settings often have little experience with the complications of HMD, making it difficult for them to provide optimum management. Understanding the pathophysiology and the patient pathway of HMD dystrophy patients, helps primary providers to early referrals and emergency doctors to avoid therapeutic nihilism. For many HMD, respiratory muscle weakness is common and together with cardiac disease they represent major causes of morbidity and mortality.

This purpose of this review is to shed light on HMD by providing a model of care with Duchenne muscular dystrophy; showing current approach to aid in the differential diagnosis of HMD; providing an approach to respiratory management in neuromuscular disorders as well as cardiac management and finally state limitations faced by the neuromuscular diseases community and potential opportunities.

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The upcoming model of care is an example that emphasizes the value of multidisciplinary involvement to anticipate early changes in many systems and to manage important spectrum of complications that can be predicted in most HMD.

Chapter 5: Aim and objectives:

• Overview on the spectrum of HMD, their clinical symptoms and potential multiorganic complications

• Describe the diagnostic tools to identify and manage HMD

• Explain the patient pathway through the multidisciplinary management

• Approach to management of the especially vulnerable organ systems : Respiratory and Cardiac

Chapter 6: Research methodology and methods:

Words relating to neuromuscular disorders, management, multidisciplinary, cardiac, respiratory evaluation, Duchenne muscular disorder, hereditary muscular disorders, complications have been searched on PubMed and collected. The most recent articles have been picked for literature review and summarized to illustrate the multidisciplinary management of neuromuscular disorders.

Chapter 7: Literature review:

I. General description of hereditary muscular disorders (HMD):

The aim of our research is to focus on the risks and complications that may occur in many HMD, we provide here the definition of the most common HMD or their groups and their clinical presentations (also provided in Table 1).

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I.1 Limb-girdle muscular dystrophy:

Limb-girdle muscular dystrophy (LGMD) is defined as a genetically inherited condition primarily affecting skeletal muscle that leads to progressive, predominantly proximal muscle weakness in individuals who have achieved independent walking and who have elevated creatine kinase levels.

There exist several LGMD subtypes with Calpainopathies (LGMD2A) being the most common.

In the recessively inherited LGMD2A, onset of weakness begins between 5 and 20 years of age in 75% of cases. With autosomal dominant disease, onset occurs on average 2 decades later and the severity of weakness is milder. Otherwise, recessively and dominantly inherited calpainopathies display similar features. Strength in the lower extremities follows a relatively distinct pattern with knee flexors, hip extensors, and hip adductors weaker than their paired antagonist muscles across the joint, the knee extensors, hip flexors, and hip abductors, respectively.

Joint contractures are common and can affect the ankles, hips, knees, and elbows in more than half of patients with LGMD2A.

Weakness is predominantly symmetric, loss of independent ambulation often occurs 2 decades after disease onset, but symptomatic pulmonary and cardiac involvement is distinctly uncommon.

Limb-Girdle Muscular Dystrophy Type 2B (LGMD R2 Dysferlin-Related), the second most prevalent LGMD subtype. However, in Asia, LGMD2B may be the most common subtype. Age of onset is quite broad, from infancy through the eighth decade, but weakness begins between 15 and 30 years of age in most cases. At onset, leg muscles exhibit the greatest weakness, but this lower extremity weakness can be proximal, distal, or both. Hip extensors, hip adductors, knee extensors, and ankle plantar flexors are most affected, with relative preservation of hip abductors and hip flexors. Of note, if someone with LGMD cannot stand on his or her toes within the first few years of disease onset, strong consideration should be given to LGMD2B (and LGMD2L). Rarely, patients with LGMD2B have calf hypertrophy at onset, but calf atrophy and weakness are more common. Cardiac involvement is virtually nonexistent in LGMD2B and uncommon in LGMD2A. Infrequent clinically significant respiratory insufficiency is seen only late in disease or in cases with early onset and severe weakness.

Limb-Girdle Muscular Dystrophy Types 2C, 2D, 2E, and 2F (LGMD R3, R4, R5 and R6 Sarcoglycan– Related. Disease onset ranges from infancy through adulthood but occurs in the first decade in most cases. Milder cases with later onset have been reported.

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in early-onset, more severe cases. Loss of ambulation occurs in the second through fourth decades, with the majority of patients wheelchair dependent in their teenage years. Dilated cardiomyopathy afflicts a minority of patients, but respiratory insufficiency necessitating nocturnal noninvasive ventilation affects many patients later in the disease course. (1)

I.2 The dystrophinopathies: Duchenne and Becker muscular dystrophies:

The dystrophinopathies are a spectrum of progressive muscular dystrophies that are caused by the absence of or decrease in the function of dystrophin protein. Dystrophin protein is the gene product of the dystrophin DMD gene, located on the X chromosome. Boys affected by the milder and variable skeletal muscle phenotype are often referred to as having Becker muscular dystrophy. The complete absence of dystrophin results in Duchenne muscular dystrophy, whereas even the presence of a relatively small amount of dystrophin in the muscle results in Becker muscular dystrophy or the intermediate phenotype.

The clinical spectrum of dystrophinopathies includes the prototypical progressive skeletal muscle weakness, X-linked cardiomyopathy, muscle cramp, and myalgia.

Proximal upper extremity weakness usually begins in boys with Duchenne muscular dystrophy during their early teenage years.

However, Duchenne phenotype often presents during early childhood, within the first year of life with certain clinical presentation and often with calf hypertrophy at 3-4 years of age. The landscape of dystrophinopathy has changed considerably in the past 2 decades, with life expectancy extending to the late thirties and early forties, especially in the severe form of the disease, Duchenne muscular. Skeletal muscle weakness follows a prototypical pattern, and most boys with Duchenne muscular dystrophy lose ambulation by the age of 12 or 13 years.

Cardiopulmonary failure is one of the most important causes of morbidity and early death in dystrophinopathy. The spectrum of cardiac symptoms in dystrophinopathy includes sinus tachycardia, dilated cardiomyopathy, and, rarely, pericardial effusion and cardiac tamponade. Patients with Becker muscular dystrophy tend to have more severe cardiac involvement, including cardiomyopathy, compared with those with Duchenne muscular dystrophy.

Nocturnal hypoventilation is one of the earliest manifestations of pulmonary compromise. A decline in pulmonary function presents as a weak cough, atelectasis, and recurrent respiratory infections. In dystrophinopathy, the decline in vital capacity is approximately 8% every year. Loss of ambulation has a tremendous impact on pulmonary symptoms and their management.

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The spectrum of the clinical features seen in dystrophinopathy is directly related to the amount of dystrophin present in the skeletal muscle, and dystrophin is integral to the stability of the subsarcolemmal muscle membrane.

To illustrate, even the presence of some functional dystrophin protein decreases the severity of underlying muscle membrane damage and clinically results in a milder phenotype.

Cognitive delay often postpones the diagnosis, in part because the spectrum of cognitive involvement in the disease is not fully appreciated. Speech delay is one of the commonly reported developmental symptoms and is 10 times more common in boys with Duchenne muscular dystrophy than in the general population. Therefore, all boys presenting with cognitive symptoms warrant easy screening with a serum creatine kinase (CK) level.

The spectrum of intellectual disabilities in dystrophinopathy ranges from lower IQ to attentional difficulties and learning disorders. Autism spectrum disorder and obsessive compulsive disorder, are 4 times more likely in those with dystrophinopathy compared with the general population. (2)

I.3 Facioscapulohumeral muscular dystrophies:

Facioscapulohumeral muscular dystrophy (FSHD) is a common muscular dystrophy affecting both pediatric and adult patients. The two commonly recognized forms of the disease are FSHD type1 (FSHD1) and FSHD type 2 (FSHD2). FSHD1 encompasses 95% of the disease population and is inherited in an autosomal dominant fashion. FSHD2 comprises the remaining 5% and is a digenic disorder. FSHD involves weakness of facial muscles, muscles that fix the scapula, and muscles overlying the humerus (biceps and triceps). Weakness and wasting are frequently asymmetric. Facioscapulohumeral muscular dystrophy presents with asymmetric weakness of the orbicularis oculi, orbicularis oris, rhomboids, serratus anterior, biceps, triceps, paraspinals, rectus abdominis, and tibialis anterior. Eventually, other muscles of the arms and legs may become involved.

Patients present with wide open eyes and often have a history of sleeping with their eyes partially open. They have an inability to pucker and may never learn to whistle. They frequently have a transverse or asymmetric smile. Babies with early-onset FSHD have a reduced ability to suck and may not develop a social smile.

FSHD has a wide range of onset and severity, including rapidly progressive infantile or early onset, slowly progressive young-adult onset, and asymptomatic carriers of the alleles.

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Cardiomyopathy is not associated with FSHD. Various studies have suggested that conduction defects or arrhythmias are more prevalent in FSHD than the general population.

Associated symptoms up to one-third of patients with FSHD who are non-ambulatory have respiratory involvement. The greatest impairment is found in those who are wheelchair dependent and have kyphoscoliosis. Early manifestations include nocturnal hypoventilation. Respiratory insufficiency requiring ventilator support is rare.

FSHD1 is associated with a retinal vasculopathy. Hearing loss has been considered an associated symptom of FSHD. Musculoskeletal pain is a frequent manifestation of FSHD, most frequently in the shoulders and lower back [3].

I.4 Myotonic muscular dystrophy:

The myotonic muscular dystrophies are autosomal dominant disorders characterized by a clinical triad of progressive weakness, myotonia, and early-onset cataracts.

DM1 causes distal weakness in the long finger flexors, facial muscles, and ankle dorsiflexors. The myotonia (delayed muscle relaxation) is easier to evoke both clinically and electro-diagnostically in DM1 than in DM2. Individuals with DM2 are more likely to have proximal weakness and prominent muscle pain. Despite these differences, both disorders can cause multisystem manifestations in the brain, heart, gastrointestinal system, skin, and endocrine and respiratory systems.

Prior registry data suggest that it takes approximately 7 years for a patient with DM1 and 14 years for a patient with DM2 to receive the appropriate diagnosis.

If the symptoms of myotonic dystrophy type 1 begin at birth, it is called congenital myotonic dystrophy. The neonatal manifestations often include hypotonia, respiratory failure, feeding problems, and talipes equinovarus (clubfoot).

Childhood-onset myotonic dystrophy is defined as symptoms after the age of 1 and before the age of 10. These early childhood symptoms often include intellectual impairment and gastrointestinal symptoms. Cardiac manifestations of DM1 include cardiac conduction abnormalities, most often progressive atrioventricular block, and are the leading cause of death in the disease. Other cardiac arrhythmias include sinus node dysfunction, atrioventricular fibrillation, and atrial flutter.

The most impactful symptom in DM1 is fatigue, which may be driven by a combination of sleep apnea, respiratory failure, and excessive daytime sleepiness.

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Several studies have shown the median age of death to be in the early fifties in DM1. The primary causes of death include cardiac arrhythmias, respiratory failure, and cancer. Studies have not yet been conducted to determine whether patients with DM2 are at risk of a shortened life span.

Sensorineural hearing loss has been reported in DM1, although it is uncommon for patients to require hearing aids. The cognitive impairment in DM1 can vary widely. Patients may range from having no cognitive impairment to global intellectual impairment. Most commonly, executive function and visuospatial processing are impacted. In addition to the cognitive symptoms, patients may have an avoidant personality disorder and apathy, as well as a higher risk of depression.

The dysarthria and dysphagia are related to a combination of muscle weakness and myotonia. They may also have constipation, diarrhea, abdominal pain, or bloating. This symptom constellation is similar to irritable bowel syndrome, although it is more likely related to smooth muscle myotonia of the gastrointestinal system. A number of endocrine disturbances are seen in DM1. These include insulin resistance, hypogonadism, and thyroid disturbance. Patients with DM1 commonly have modestly elevated creatine kinase (less than 500 U/L), liver enzymes, and cholesterol levels [4].

I.5 Congenital muscular dystrophies and congenital myopathies:

Congenital muscular dystrophies and congenital myopathies are a heterogeneous group of disorders resulting in hypotonia, progressive muscle weakness, and dystrophic or myopathic features on muscle biopsy.

Weakness in patients with congenital myopathy and congenital muscular dystrophy is present from birth or becomes apparent in the first year of life.

In contrast to congenital muscular dystrophy, weakness in patients with congenital myopathies is less progressive, the CK is usually normal, and no central nervous system (CNS) involvement occurs.

With congenital myopathy, weakness can be profound in the newborn period but is usually stable overtime and can even show improvement. Weakness is typically generalized with a proximal predominance. Involvement of the face muscles, external ophthalmoparesis, and ptosis are common features.

Congenital muscular dystrophies are most often distinguished genetically by involvement of proteins important for stabilization of the cytoskeletal matrix to the sarcolemma membrane and the extracellular matrix and by dystrophic features on muscle biopsy.

Cardiac involvement is common in TTN- and MYH7-related congenital myopathies (core myopathies) and FKRP- and FKTN- related congenital muscular dystrophies (α-Dystroglycanopathies) but is uncommon

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in most other congenital muscular dystrophies and congenital myopathies. Additionally, respiratory and feeding difficulties are common in infants [5].

I.6 Mitochondrial and Metabolic myopathies:

Mitochondrial, lipid, and glycogen diseases are not uncommon causes of multisystem organ dysfunction, with the neurologic features, especially myopathy, occurring as a predominant feature.

Metabolic myopathies is a term applied to the individually rare genetic disorders involving energy metabolism that cause muscle disease. The process of energy metabolism involves the hundreds of metabolic reactions that convert the food we consume in the forms of carbohydrates, fats, and proteins into the molecules such as ATP that drive nearly all the energy-requiring biochemical reactions in the body. The metabolic processes that commonly result in muscle disease involve disorders of respiratory chain mitochondrial function, some of the steps of lipid metabolism, and disorders of glycogen storage or use. The use of the term mitochondrial diseases refers to the genetic disorders affecting respiratory chain function, mitochondrial DNA and mitochondrial DNA maintenance, and mitochondrial morphology. The other metabolic myopathies tend to be the result of disorders of glycolysis (the breakdown of glucose) or glycogenolysis (the formation and breakdown of glycogen), which are characterized as the glycogen storage diseases or the result of lipid dysmetabolism.

In general, most mitochondrial myopathic processes are symmetric and tend to initially affect the more proximal than distal skeletal muscles. Progressive external ophthalmoplegia is a very important sign when present but may be a feature in myotonic dystrophy, oculopharyngeal muscular dystrophy, and other disease processes.

Metabolic myopathies encompass a vast array of different genetic illnesses that present with myopathy, exercise intolerance, or rhabdomyolysis.

These disorders can start early in life or remain preclinical until later decades.

The sinoatrial and atrioventricular nodes are the most metabolically active tissues in the body, and the heart remains in constant motion from its embryonic state until death. Given this constant demand for energy, it remains a mystery why cardiac conduction defects and cardiomyopathy are not more frequent complications of mitochondrial dysfunction. As mitochondria are found in all human cells aside from the mature erythrocyte, patients who have primary mitochondrial diseases generally have multisystem involvement, although in some cases single organs can be affected. Mitochondrial diseases can present with or without muscle disease but when presenting with muscle disease can be considered a subset of the metabolic

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include migraine, dementia, seizures, ataxia, movement disorders, mood disturbances, strokes, and stroke like episodes. The onset of brain involvement may be abrupt and devastating. Patients may present with an encephalitic picture of alteration in mentation with or without seizures. Liver dysfunction can occur in mitochondrial diseases, but outside of infancy it is unusual for liver dysfunction to be the initial or isolated presentation. Clinical findings generally include elevation in liver enzyme levels, evidence of synthetic liver dysfunction, or fibrosis or cirrhosis as identified on imaging studies. Eye involvement is a common manifestation of mitochondrial disorders. Both retinitis pigmentosa and optic atrophy are features caused by many mitochondrial-targeted genes. Sensorineural hearing loss occurs in some patients with mitochondrial diseases. This often begins as a high-frequency hearing loss, and in some patients progresses to total deafness. Renal dysfunction in mitochondrial disease typically involves an inability to reabsorb electrolytes and amino acids and is more common in infants. And endocrine disorders are also a feature in mitochondrial disease of which Diabetes mellitus is the most common. Other endocrine disorders, including adrenal insufficiency, hypoparathyroidism, hypothyroidism, and hyperthyroidism, have been described in a number of disorders, but the absolute incidence is not known. (6)

Table 1 - The affected muscles, age at onset, risk of cardiac involvement, respiratory problems and others affected organs of common hereditary muscular disorders (HMD)

HMD Affected Muscles Age at

onset Cardiac involvement Respiratory involvement Other symptoms

Limb girdle muscle dystrophy

LGMD2A Proximal muscles

and symmetric (knee flexors, hip extensors, his adductors) 5 – 20 years of age Uncommon Uncommon - LGMD2B Proximal, distal or both (Leg muscles) Infancy to the 8th decade - Uncommon -

LGMD2C,2D,2E,2F Proximal Upper

skeletal muscles Infancy to adulthood Dilated cardiomyopathy Respiratory insufficiency late in the disease Ankle contractions Scoliosis Dystrinopathies: Progressive muscle weakness Skeletal muscles First year of life, X- linked cardiomyopathy Nocturnal hypoventilation Cognitive delays Duchenne

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Becker early childhood

Cardiomyopathy ++

<Vital capacity Speech delays

Congenital muscular dystrophy Progressive muscle weakness First year of life Alfa-dystroglycan Cardiomyopathy Respiratory problems Feeding problems

Congenital myopathy Less progressive

( Facial muscles) Core myopathies associated Cardiomyopathy Facioscapulohumeral dystrophy (FSHD) (FSHD1,FSHD2) Facial muscles, scapular and humeral muscles Pediatrics and adults Conduction defects and arrythmias Nocturnal hypoventilation Retinal vasculopathy and hearing loss Myotonic muscular dystrophy (DM1, DM2) Progressive skeletal muscle weakness At birth early childhood Cardiac induction abnormalities

Sleep apnea and respiratory failure Catarracts Brain: Cognitive impairement Gastro-intestinal: diarrhea Endocrine: Diabetes

Mitochondrial Proximal skeletal

muscle weakness External ophthalmoplegia Early in life and remain preclinical in later decades

Not frequent Hypoventilation Brain:

Migraine, dementia Liver dysfunction Eye: Retinitis optic atrophy Sensorineural hearing loss Renal dysfunction Endocrine: Diabetes

Metabolic myopathy Proximal skeletal

muscle weakness

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II. Diagnosing Hereditary muscular disorders:

II.1 Medical History and examination:

Identifying the symptoms, their temporal pattern, the distribution of weakness, triggering events, family history, and associated symptoms and signs may help clinicians narrow the broad differential diagnosis into 10 muscle patterns. This efficient method may yield a correct diagnosis in most cases (Table 2) [7]. The main symptom that all patients with myopathies present with is weakness. Positive symptoms in myopathic disorders include myotonia (inability to relax/ stiffness), myalgia (pain), contractures and muscle hypertrophy.

Once these symptoms are found, the temporal pattern is important, whether it is acute, subacute or chronic, constant or episodic, age at onset or lifelong (suggesting congenital disorders).

The distribution of the weakness or stiffness can be proximal arms/legs; distal arms/legs; neck; cranial nerves.

Triggering events is also essential to further narrow the differential diagnosis according to patterns of occurrence of stiffness or weakness such as during or immediately after exercise; after brief or prolonged exercise (as in metabolic myopathies); after exercise followed by rest or after a high-carbohydrate meal (as in periodic paralysis); relieved by exercise (eg, stiffness in myotonic dystrophy); use of drugs/exposure to toxins (eg, statins induced myopathy);

Family history of a myopathic disorder helps classify disorders as X-linked, autosomal dominant, autosomal recessive, or maternally transmitted (mitochondrial).

Associated systemic signs and symptoms can include rash, baldness, fever, dark/red urine, dysmorphic features, cardiac dysfunction, pulmonary dysfunction, arthritis and other connective tissue disease findings, cataracts, developmental delay/dementia, skeletal contractures, skeletal deformities, Paget disease, neuropathy, and gastrointestinal dysfunction [7].

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Patients with proximal muscle weakness report difficulty in climbing stairs and rising from a chair, commode, or floor.

Involvement of the cranial muscles causes ptosis, diplopia, dysarthria, and difficulty with chewing and swallowing.

The presence of fluctuations in strength is suggestive of a neuromuscular junction disorder.

Muscle bulk enlargement, whether due to hypertrophy or pseudohypertrophy of the muscles, is seen in certain muscular dystrophies. When assessing children, it is important to obtain a detailed history from the

Weakness

Pattern Proximal Distal Asymmetric Symmetric Episodic Trigger Diagnosis Muscle Pattern 1:

Limb-Girdle

+ + Most myopathies,

hereditary and acquired Muscle Pattern 2:

Distal

+ + Distal myopathies (also

neuropathies) Muscle Pattern 3:

Proximal arm and distal leg (also known as scapuloperoneal) + Arm + Leg + FSH (Facioscapulo-humeral muscular dystrophy) + (Others) FSH, Acid maltase deficiency, Muscle Pattern 4: Distal arm/ proximal leg + Leg + Arm + Myotonic dystrophy Muscle Pattern 5: Ptosis/ Opthalmoplegia + + + Myotonic dystrophy, mitochondrial myopathies Muscle Pattern 6: Neck Extensor

+ + Isolated neck extensor

myopathy Muscle Pattern 7: Bulbar (tongue, pharyngeal, diaphragm) + + Oculopharyngeal muscular dystrophy Muscle Pattern 8: Episodic weakness/pain/ rhabdomyolysis + trigger + + + + McArdle disease, carnitine palmitoyltransferase deficiency Muscle Pattern 9: Episodic weakness, delayed or unrelated to exercise + + + +/- Primary periodic paralysis, secondary periodic paralysis, channelopathies (sodium, calcium) Muscle Pattern 10: Stiffness/ inability to relax + +/- Myotonic dystrophies, proximal myotonic myopathy

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parents, including asking for details on developmental milestones, as a child being described as “clumsy” or not athletic may be an early clue [7].

After obtaining the history, a complete neurologic examination should be performed. Most myopathies affect the proximal muscles more than the distal muscles.

Patients with myotonic dystrophy have facial weakness, hatchet face, frontal balding, and temporal muscle atrophy and weakness.

The patient’s posture should be assessed while sitting, standing, and walking. Excessive lumbar lordosis, hyperextension of the knee, and ankle contractures may be seen in patients with proximal muscle weakness. Patients with proximal weakness may have a wide-based waddling gait, hyperlordosis, hyperextension of the knee or, in the setting of Achilles tendon contractures, toe walking. Weakness of the shoulder girdle can result in winging of the scapula. In addition, a “trapezius hump” is caused by rising up of the shoulder secondary to poor fixation and is seen in patients with facioscapulohumeral muscular dystrophy.

Muscles should be inspected for wasting or hypertrophy and assessed for muscle tone and tenderness. In most myopathies and neuromuscular junction disorders, muscle tone is usually normal or sometimes decreased.

Myotonia is typically seen in distal muscles, although it can affect proximal or distal muscles and it generally improves with repetition.

In myotonic disorders, direct percussion of the muscle may lead to pronounced contraction of the muscle with delayed relaxation (percussion myotonia).

Other abnormalities can be noted on percussion. A peculiar wave of muscle contraction emanating from the site of percussion or biceps muscle pinching is seen in so-called rippling muscle disease.

Occasionally, a “mounding” of the muscle is observed, rather than a contraction indentation; this phenomenon is called myoedema and can be observed in patients with hypothyroidism.

Manual muscle testing is extremely important; the Medical Research Council (MRC) scale is commonly used for uniformity. The grading is on a scale of 1 to 5.

Sensation to various modalities is usually normal.

Muscle weakness in infants is associated with an overall decrease in tone; therefore, the term floppy infant is used to describe them.

In addition to taking the history and performing the neurologic examination, it is important to identify other organ involvement. Most importantly, cardiac disease and respiratory involvement as these can be associated with a number of myopathies [7].

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II.2 Laboratory Testing:

In patients in whom the diagnosis is still unclear after the history and examination, further testing is required.

Creatine kinase (CK) is the most useful blood test for myopathy evaluation. Elevated CK may not be seen in all myopathies. The degree of muscle weakness in any given patient may not correlate with the serum CK level.

Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) can also be elevated in muscle disorders. AST, ALT, and LDH are expressed in muscle as well as the liver, and in the case of aldolase, it is elevated in hepatitis.

Many physicians initially suspect liver disease however, to distinguish elevation of these enzymes due to liver disease versus a myopathic process, a serum CK and γ-glutamyltransferase (GGT) should be obtained. CK is specific for muscle disease, whereas GGT is specific for liver disease.

Electrolytes are also routinely tested such as high or low potassium levels and calcium levels can cause generalized weakness. Thyroid function test should be obtained as high or low thyroid hormone levels can cause myopathy. Erythrocyte sedimentation rate and antinuclear antibody level should be obtained for patients suspected to have an inflammatory myopathy.

With increased awareness of molecular genetics and availability of DNA testing, many hereditary myopathies can now be diagnosed [7].

II.3 Electrodiagnostic Examination:

Electrodiagnostic studies are important to distinguish myopathies from neuromuscular junction disorders (i.e. botulism, LEMS, and MG). Using nerve conduction studies, repetitive stimulation in which decremental response in repetitive movements is characteristic for neuromuscular junction disorders i.e. botulism, LEMS and MG. Needle EMG is a useful test for diagnosing neuromuscular conditions. Needle EMG testing looks at the motor unit action potential (MUAP) duration, amplitude, morphology, and recruitment. Electrodiagnostic medicine consultants can usually determine the presence of myopathy on this testing [7].

II.4 Histologic evaluation:

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testing is negative or equivocal. Muscle biopsy is used to indicate the exact type of myopathy. Needle EMG or muscle MRI can be helpful in selecting the muscle to biopsy in patients with mild muscle weakness. In some cases, immunostains to specific muscle targets may be done. Examples include dystrophin staining for Duchenne muscular dystrophy and Becker muscular dystrophy, merosin staining for congenital muscular dystrophy, sarcoglycan stains for limb-girdle muscular dystrophies, emerin stain for Emery-Dreifuss muscular dystrophy; in other cases, protein analysis (Western blot), metabolic analysis, or even electron microscopy may be conducted.

Western blot is useful for specific protein abnormalities (eg, dystrophin), biochemical assays on the biopsy specimens are useful for various enzyme deficiencies (eg, glycogen and lipid storage diseases) and DNA analysis for genetic mutations (eg, mitochondrial myopathies).

II.5 Molecular Genetic Studies and genetic counseling:

Many inherited disorders and phenotypes are genetically heterogeneous (ie, pathogenic variants in more than one gene can cause the same phenotype). To identify mutations that are associated with hereditary muscle diseases, peripheral blood testing and saliva DNA analysis are used.

Examples of commonly available genetic studies for muscle and neuromuscular junction disorders are included in Table 3; as it is important to emphasize that the list of available gene tests is constantly evolving and being updated.

Improvements in massively parallel sequencing techniques have led to the widespread clinical use of multigene panels that allow testing of more than 150 genes. These panels include sequence analysis, deletion/duplication analysis, and other non- sequencing-based panels and have a yield of 46%.

In order to capture a broader spectrum of mutations and acquire accurate data and insight into unexpected DNA variation, an entire human genome can be sequenced within a day using the Next-generation sequencing. This is used to sequence many fragments of DNA at the same time, and special computer techniques are used to put together these DNA fragments by mapping the individual reads to the human reference genome.

Significant numbers of variants of uncertain significance are identified during the sequencing as this is the most common finding. The variants can be benign, having no impact on the health or function of an organism, or they can be pathogenic (ie, associated with the disease). These variants can be triaged through evaluating the frequency of a variant of unknown significance in the general population as well as muscle biopsy.

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Whole-exome sequencing is used to identify and analyze the sequence of all protein-coding nuclear genes in the genome. With whole-exome sequencing, diagnostic utility for neuromuscular disease is about 37%, which is lower than the 46% yield of multigene panels. And the reason is Whole-exome testing would miscopy number variation(as in two-thirds of Duchenne muscular dystrophy cases that harbor deletions), large truncations (as in FSHD), and repeat sequences (as in myotonic dystrophy), thereby detecting only 11% of the three most common muscular dystrophies.

Combined approaches in gene testing are reducing that gap in Duchenne muscular dystrophy [7].

Genetic counseling (GC) is of upmost importance for the prevention of genetic diseases, especially for the untreatable ones. The process of GC includes diagnosis confirmation, identification of at-risk members, prenatal and pre-implantation diagnosis, as well as family orientation on management of affected patients. Inheritance patterns, risk to offspring, and potential implications for other family members should be clearly explained. With this information, families can make informed decisions to help deal with risks and potentially lessen the impact of the disease. In some cases, the information can assist in making financial, lifestyle, family planning, and career choices [8,9].

III. Complications related to HMD:

III.1 Physical:

HMD’s are characterized by well-known patterns of muscle weakness, postural compensations, risk of progressive contracture and deformity, and functional losses, depending on the genetic and pathophysiological background. The inability to move a joint through its full range of motion, chronic static positioning, muscle imbalance about a joint, pain (in FSHD) [12], myotonia (Myotonic dystrophy)[13] and fibrotic changes in muscles cause decreased muscle extensibility and joint contractures (DMD, BMD, LGMD) [10,14].

III.2 Orthopedic and surgical:

Scoliosis (lateral curvature of the spine), with or without associated rigidity of the spine, is very common in HMD’s (CMD, CM) [15,16] and early detection and management are essential. Worsening deformity negatively affects pulmonary and cardiac function, is often cosmetically unacceptable, makes seating difficult owing to associated pelvic obliquity and truncal deformity, can worsen the ability to walk, and frequently becomes painful. Functional limitation and impaired quality of life resulting from, progressive

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joint contractures (myopathies), underlying weakness and loss of motor function, musculoskeletal pain, altered gait, decreased mobility, abnormal positioning and loss of activities of daily living. Orthopedic deformity can include congenital dislocation of the hips, congenital hip subluxation or dislocation, hip subluxation or dislocation in non-ambulatory children, hip disease in ambulatory children, knee flexion contractures, foot and ankle deformities.

III.3 Bone health and osteoporosis:

Boys with glucocorticoid-treated such as in DMD frequently develop osteoporosis, which manifests as low-trauma vertebral or long-bone fractures. This outcome is not surprising given the potent osteotoxicity of glucocorticoid therapy combined with progressive myopathy, both of which are key risk factors for reduced bone strength. Vertebral fractures are frequently asymptomatic when identified in children with glucocorticoid-treated illnesses through a monitoring programme that includes a lateral spine radiograph, so the true prevalence is probably higher than existing reports suggest. Left untreated, vertebral fractures can lead to chronic back pain and spine deformity, while leg fractures can cause premature, permanent loss of ambulation. Children with reduced mobility are at increased risk of osteopenia and pathological fracture. The fact that vertebral fractures at any time point in a patient’s clinical course are predictive of future spine fractures even when the initial vertebral fractures are mild or asymptomatic, a phenomenon known as the vertebral fracture cascade, underscores the need for early identification.

The current standard is to identify and treat early indications of bone fragility (eg, vertebral fractures) in individuals with chronic illnesses who have little possibility of recovery. This secondary prevention approach has the goal of mitigating osteoporosis progression and promoting recovery among patients presenting with early, rather than late, indications of osteoporosis and in those with little potential for medication-unassisted recovery because of persistent risk factors [11,16].

III.4 Gastrointestinal and nutritional and Oral Care Guidelines:

Individuals with HMD (DMD, CMD, CM, DM) often have gastrointestinal or nutritional complications, including weight gain or loss, dietary or nutrient imbalance, fluid imbalance, low bone density, constipation, gastro-esophageal reflux, swallowing dysfunction, drooling, mandibular contracture and orofacial problems. Contributing factors include glucocorticoid treatment, decreased energy expenditure, and immobility. These nutritional imbalances can negatively affect the respiratory, skeletal muscle, and cardiac

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undernutrition or malnutrition as they approach adulthood. In early childhood, glucocorticoid therapy increases the risk of overweight or obesity because of increased appetite and caloric intake, and sodium and fluid retention. Loss of ambulation leads to decreased activity, which reduces caloric needs and increases the risk of overweight or obesity. Swallowing dysfunction (dysphagia) is common in DMD [10]. Infants and children with congenital myopathies often have feeding and swallowing impairments that can affect many aspects of their general health, including growth, pulmonary function, oral health, and energy and activity level. Feeding and swallowing impairments can be due to weak suck which can be due to orofacial and bulbar weakness that can result in failure to thrive. The older child may present with deceleration of linear growth including height and weight and recurrent respiratory infections [16]. Patients with congenital muscular dystrophy often have a growth curve below what is expected for age [15]. Constipation in common in HMD’s (DMD, CM, CMD, DM) Risk factors include decreased colonic transit time, immobility, abdominal muscle weakness, and dehydration [4,10,15,16]. DM1 patients are at risk for pseudo-obstruction and experience other problems that may cause actual obstruction of small or large intestine, including endometriosis, acute gallbladder inflammation, ruptured ovarian cysts, sigmoid volvulus [13].

Risk factors for gastro-esophageal reflux (DMD, CMD, CM, DM) include esophageal dysmotility, delayed gastric emptying time, glucocorticoid therapy, and scoliosis. As skeletal muscle weakness progresses in individuals with DMD, a delay in gastric emptying (gastroparesis) can occur, which can lead to postprandial abdominal pain, nausea, vomiting, early satiety, and loss of appetite [10]. Symptoms suggesting gastroesophageal reflux include chest or upper abdominal pain, vomiting, aspiration, and recurrent respiratory infections. Excessive oral secretions (drooling) and risk of aspiration. Oral communication can be affected by difficulty in articulation and limited facial expression. The difficulties with speech and articulation are due to weakness of oral motor muscles, weak voice or hypophonia, difficulties with breath control, hypernasality, and abnormal.

III.5 Cardiac involvement:

Cardiac involvement is a leading cause of disease-related morbidity and mortality among individuals with HMD (DMD, BMD, LGMD, CMD, FSHD, DM). Dystrophin deficiency in the heart manifests as a cardiomyopathy. As the disease progresses, the myocardium fails to meet physiological demands and clinical heart failure develops. The failing myocardium is also at risk of life-threatening rhythm abnormalities, ventricular arrhythmias, conductive defects, and supraventricular arrhythmias are frequent [11,15]. Sudden cardiac death has been reported. Historically, individuals with DMD have not been referred

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management has been challenging because the New York Heart Association classification of heart failure relies on reduced exercise tolerance, a feature that in HMD arises from skeletal muscle and cardiac disease combined. The signs and symptoms of heart failure in the non-ambulatory individual are frequently subtle and overlooked. With the onset of heart failure symptoms or when abnormalities are first seen on cardiac imaging—e.g., myocardial fibrosis, left ventricular enlargement, or left ventricular dysfunction—the frequency of assessment should increase at the discretion of the cardiologist. Progressive myocardial fibrosis leads to ventricular dysfunction. Symptomatic heart failure can be particularly difficult to diagnose in non-ambulatory patients [11]. Clinical manifestations of heart failure—fatigue, weight loss, vomiting, abdominal pain, sleep disturbance, inability to tolerate daily activities, lethargy, dyspnea, pallor, palpitations, syncope, and light- headedness —are often unrecognized until late in the disease because of musculoskeletal limitations [11,15]. People with HMD are at risk of rhythm abnormalities— including atrial fibrillation or flutter, ventricular tachycardia, and ventricular fibrillation.

III.6 Respiratory system:

Respiratory complications are a major cause of morbidity and mortality in people with HMD (DMD, BMD, LGMD, CMD, CM, FSHD and DM). Complications include respiratory muscle fatigue, mucus plugging, atelectasis, pneumonia, and respiratory failure. If left untreated, patients are at risk of severe dyspnea, lengthy hospital admissions due to atelectasis or pneumonia, and death due to respiratory arrest or respiratory-induced cardiac arrhythmias. Earlier loss of ambulation was associated with an earlier and lower peak FVC as well as a more rapid decline in FVC than was later loss of ambulation. As their vital capacity decreases, patients with HMD develop stiff, non-compliant chest walls and lung volume restriction [11]. Scoliosis and chest wall deformities can develop secondary to the weak chest muscles and weakened diaphragm, further limiting chest wall excursion and lung expansion [15]. As they progress through the non-ambulatory stage, individuals with HMD develop weak cough efforts, placing them at risk of atelectasis, pneumonia, ventilation–perfusion mismatch, and progression to respiratory failure, especially during respiratory tract infections. With declining pulmonary function, patients develop symptoms of hypoventilation such as dyspnea, fatigue, difficulty concentrating and nocturnal hypoventilation resulting in headache.

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The endocrine complications include impaired growth, delayed puberty, and adrenal insufficiency. Impaired linear growth is common in individuals with DMD and exacerbated by glucocorticoid treatment. Delayed puberty due to hypogonadism is a potential complication of glucocorticoid therapy and can be psychologically distressing, impairing quality of life. Adrenal insufficiency due to suppression of the hypothalamic-pituitary-adrenal (HPA) axis is a rare but life-threatening condition that can develop if glucocorticoids are stopped suddenly because of illness or discontinuation of therapy [10]. With DM, thyroid deficiency, insulin resistance, hyperlipidemia, or testosterone deficiency can occur and need to be monitored [13].

III.8 Other potential complications:

III.8.a Speech:

Children with congenital muscular dystrophy may present with articulatory speech sound errors and substitutions. The presence of a tracheostomy can also affect communication ability. Orofacial problems, including malocclusion, facial deformities as a result of noninvasive ventilation, high arch palate, and poor oral hygiene and dental care, are very common findings in children with congenital myopathy. The anterior open bite, malocclusion, and facial weakness lead to difficulties with lip closure for production of some sounds, and as a result compensatory articulatory patterns can develop. These children present with a further dysarthric pattern of speech production due to weak breath support for phonation that can affect pitch and loudness. Palatal incompetence can lead to nasal resonance of speech. The mouth is the entry to the gastrointestinal tract, and weakness of oral muscles, oral hygiene, dental disease, malocclusion, and reduced mouth opening can all have an effect on nutrition and speech. Weakness in the masticatory muscles can affect chewing ability. Oral bacteria from dental caries or other infections can contribute to development of pneumonia. Mouth breathing can lead to dry mouth and increased risk of oral infection. Malocclusion with crowding of teeth can make tooth cleaning difficult. Malocclusion can increase over time because of imbalance in oral muscles. Gingival hyperplasia can occur because of prolonged ‘‘nothing by mouth’’ status. Reduced ability to swallow and cough must be taken into account when seating the patient in the dental chair. Risks concerning cardiac involvement and reduced lung capacity will also influence treatment planning [15,16].

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III.8.b Hearing involvement:

Infantile-onset patients with FSHD are at risk to have the most profound hearing loss that if not detected can lead to delayed language development and even the false perception that the child is cognitively delayed [12].

III.8.c Ocular involvement:

Ophthalmoparesis with or without ptosis can occur in myopathies. Patients are at high risk of developing eye irritation and corneal abrasions because of incomplete lid closure in combination with ophthalmoplegia [16]. Retinal vasculopathy is relatively frequent in FSHD but rarely leads to a symptomatic exudative retinopathy (Coat’s syndrome) which can, in turn, result in significant visual loss [12]. Relevant eye manifestations of DM1 include cataracts (occurring in most patients), strabismus, and other ocular motility problems, myopia, and astigmatism in congenital and juvenile-onset patients [13].

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DMD - Duchenne muscular dystrophy, BMD - Becker muscular dystrophy, LGMD - limb-girdle muscular dystrophy, CMD - congenital muscular dystrophy, CM - congenital myopathy, FSHD - facioscapulohumeral dystrophy, DM - muscular dystrophy.

Complicatio ns: DMD/ BMD LGMD CMD CM FSHD DM Mitochond rial and metabolic Neuromusc ular + + + + + + + Physical + + + + + Gastro-intestinal and nutritional + + + + Endocrine + + + Respiratory + + + + + + + Cardiac + + + + + + Bone Health and osteoporosis + Orthopedic and surgical + + + + Brain involvement + + + + Ocular involvement + + + + Hearing loss +

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IV. Principles of comprehensive management in HMD:

So far, specific international comprehensive long-term care consensus guidelines have been published for DMD, congenital myopathies, congenital muscle dystrophies, myotonic dystrophy type 1, facioscapulohumeral muscular dystrophy [10-16]. Expert opinions and guidelines related to specific organ systems affected by a certain HMD are also multiple. In this review, we try to summarize the main principles of comprehensive multidisciplinary approach to different HMD, based on the available literature.

IV.1 Pharmacological interventions:

IV.1.a Glucocorticoids in DMD:

Glucocorticoids are the only medication currently available that slows the decline in muscle strength and function in DMD which in turn reduces the risk of scoliosis and stabilizes pulmonary function [17].

For the initiation of glucocorticoid therapy, no generally accepted guidelines exist in the literature about the best time to initiate glucocorticoid therapy in an ambulatory boy with DMD. Recognition of the three phases of motor function in DMD (making progress, plateau, and decline) helps the clinician to make this decision. Initiation of glucocorticoid treatment is not recommended for a child who is still gaining motor skills, especially when he is under 2 years of age. The typical boy with DMD continues to make progress in motor skills until approximately age 4–6 years, albeit at a slower rate than his peers. The plateau phase, which might last only a few months, can be identified when there is no longer progress in motor skills, but prior to decline, as determined by history and timed testing. Once the plateau phase has been clearly identified, usually at age 4–8 years, the clinician should propose initiation of glucocorticoids to wait until the decline phase.

In patients who have used glucocorticoids while ambulatory, many experts continue medication after loss of ambulation with the goal of preserving upper limb strength, reducing progression of scoliosis, and delaying decline in respiratory and cardiac function [17].

In terms of glucocorticoid regimens and dosing, daily use of a glucocorticoid is preferred to alternative regimes. Prednisone (prednisolone) and deflazacort are believed to work similarly and neither one has a clearly superior effect on altering the decline in motor, respiratory, or cardiac function in DMD. The recommended starting dose for prednisone in ambulatory boys is 0·75 mg/kg daily and for deflazacort is 0·9 mg/kg daily, given in the morning.

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Attentive management of steroid-related side-effects is crucial once a child has started chronic steroid therapy. If a daily-dosing schedule generates unmanageable and/or intolerable side-effects that are not ameliorated by a reduction in dose at least once, then it is appropriate to change to an alternative regimen. If, however, any glucocorticoid side-effects are unmanageable and/or not tolerable, then an increase in glucocorticoid dose for growth or declining function is inappropriate, and in fact, a decrease in dose is necessary. A reduction of approximately 25–33% is suggested, with a reassessment by phone or clinical visit in 1 month to determine whether side-effects have been controlled. However, should adjustments to the glucocorticoid dosing and/or schedule regimens prove ineffective in making any significant side-effects sufficiently manageable and tolerable, then it is necessary to discontinue glucocorticoid therapy, irrespective of the state of motor function [17].

IV.1.b Lipid myopathy therapeutics:

Treatment for the lipid myopathies depends on the specific enzyme defect; some disorders have no specific therapy and others have treatments, which often involve dietary manipulation or the use of cofactors or vitamins. In general, the therapy for these disorders is to avoid fasting; eat frequent, smaller meals rich in complex carbohydrates; and consume fluids and carbohydrates before and during physical activity. Levocarnitine supplementation should be used if there is a carnitine deficiency or if there is a mutation in SLC22A5, the gene encoding the carnitine transporter protein that is necessary for carnitine transport into the cell. Therapy for rhabdomyolysis requires frequent monitoring of renal function and electrolytes with intravenous hydration with isotonic saline and bicarbonate. The CK level is a guide for monitoring improvement. For patients likely to have episodes, education of both the patient and the family is as critical as the education of the emergency department staff to ensure the safety of these patients when they do present with episodes [6].

IV.1.c Glycogen storage therapeutics:

In general, dietary therapy is a mainstay of therapy. Patients with glycogen storage diseases should be managed in conjunction with a dietician, using disease-specific recommendations tailored to the patient’s ability to follow those plans. Avoidance of fasting is critical, and patients should avoid meals high in simple carbohydrates, although patients with McArdle disease may feel better after a meal rich in simple carbohydrates. The use of high-protein diets with complex carbohydrates is recommended. Lifestyle modifications also include avoidance of strenuous exercise, although patients may benefit in terms of

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exercise tolerance from moderate amounts of physical activity. Many patients with these disorders do not have baseline weakness, but for those with chronic muscle weakness, standard approaches to screening and treating the manifestations of muscle weakness, nutrition, and respiratory insufficiency should be taken. Pompe disease has a specific therapy referred to as enzyme replacement therapy, which involves IV infusion of alglucosidase alfa. Patients with Pompe disease should be monitored and treated for cardiomyopathy and cardiac conduction defects [6].

IV.2. Muscoskeletal management:

The goal of muscle extensibility and joint mobility management is to prevent or minimize contracture and deformity. Prevent an unnecessarily sedentary or immobile lifestyle and the associated problems of social isolation and overweight, also to maintain motor function and independence for as long as possible, maximize quality of life, maintain a straight spine, promote bone health and safety, relieve pain, improve seating and stabilization and to enhance pulmonary function.

Rehabilitation personnel include physicians, physical therapists, occupational therapists, speech-language pathologists, orthotists, and durable medical equipment providers. Musculoskeletal management requires a team approach, with input from neuromuscular specialists, physical therapists, occupational therapists, rehabilitation physicians, orthotists, and orthopaedic surgeons [10-16].

Multidisciplinary rehabilitation assessment of motor functioning includes measures of passive ranges of motion, muscle extensibility, posture and alignment, strength, function, quality of life, and participation in all normal activities of everyday life. Specialized functional assessment includes analysis of patterns of movement and standardized assessments specific to DMD and other neuromuscular disorders. The North Star Ambulatory Assessment (NSAA) and timed function tests are foundational clinical assessments of function during the ambulatory period and should be done every 6 months. The NSAA and timed function tests have high validity and reliability, as well as correlation between tests across time, minimum clinically important differences, and predictive capabilities regarding functional motor changes that are important in monitoring clinical progression and assessing new and emerging therapies. Assessment by rehabilitation specialists is recommended at least every 4–6 months throughout life, with more frequent assessment triggered by a clinical concern, a change in status, or specific needs [18]. It is recommended at least yearly in DM1 or DM2 [13] and in congenital muscular dystrophy early evaluation is a minimal recommendation [15]. Measures for rehabilitative assessment can include goniometry, spinal assessment, observation, physical examination, radiograph, functional scales, dual energy radiographic absorptiometry, manual

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IV.2.a Management of muscle extensibility and joint contractures:

Early conservative/ nonoperative intervention aimed at prevention is preferred as a first approach. From the day of symptom onset, preventive therapy is an essential part of daily management. Contractures, once developed, are not easily improved in many forms of congenital muscular dystrophy [15,16].

Regular stretching should include the joints of the limbs, iliotibial bands, neck, spine, and jaw, using active and passive techniques during the day and passive positioning at night [15,16]. Effective stretching of the musculotendinous unit requires a combination of interventions, including active stretching, active-assisted stretching, passive stretching, and prolonged elongation using positioning, splinting, orthoses, and standing devices (as standing and walking become more difficult).

Prevention of contractures also relies on resting orthoses, joint positioning, and standing programmes. Resting ankle–foot orthoses (AFOs) used at night can help to prevent or minimize progressive equinus contractures and are appropriate throughout life, can be of value in the late ambulatory and early non-ambulatory stages. Active, active-assisted, and/or passive stretching to prevent or minimize contractures should be done a minimum of 4–6 days per week for any specific joint or muscle group [19].

Maintaining good posture and spinal alignment should be accomplished through training correct seating, standing, and bracing [15]. Environmental modifications for home, school, and work include ramps, rails, shower chairs, stair glides, and lifts (or hoists). Assistive devices that increase independence include mobile arm supports, bath aids, reachers, and canine assistants[13,15,16].

IV.2.b Assistive devices for musculoskeletal management:

A passive standing device for patients with either no or mild hip, knee, or ankle contractures is necessary late ambulatory and early non-ambulatory stages [19]. Standing is strongly recommended even for extremely weak children [16]. Equipment recommended for assistance in standing, ambulation, and/or other forms of mobility included canes, walking frames, standing frames, swivel walkers, knee–ankle–foot orthoses, ankle–foot orthoses, reciprocating gait orthoses, scooters, and wheelchairs [15]. Particular, patients with DM1 often require ankle-foot orthoses relatively early in the disease course given the prominent dorsiflexion weakness [13]. Promotion of independent mobility is essential to patients with congenital myopathies and is often accomplished using assisted ambulation or manual or power wheelchairs [16].

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In DMD, during the early ambulatory stage, a lightweight manual mobility device is appropriate. In the late ambulatory stage, an ultra-lightweight manual wheelchair with solid seat and back, seating to support spinal symmetry and neutral lower extremity alignment, and swing-away footrests is necessary. In the early non-ambulatory stage, a manual wheelchair with custom seating and recline features might serve as a necessary back-up to a powered wheelchair [19].

IV.2.c Surgical intervention:

For contractures in the lower-limb: In DMD, if lower-limb contractures are present despite range-of-motion exercises and splinting, there are certain scenarios in which surgery can be considered. In the early ambulatory phase: Procedures for early contractures including heel-cord (tendo-Achillis) lengthenings for equinus contractures, hamstring tendon lengthenings for knee-flexion contractures, anterior hip-muscle releases for hip-flexion contractures, and even excision of the iliotibial band for hip-abduction contractures have been performed in patients as young as 4–7 years. However, this approach, is not widely practiced today but does still have some proponents [19]. In LGMD, release of functionally limiting contractures (especially of the Achilles tendons) may be necessary especially in LGMD1B, LGMD2A, in childhood onset sarcoglycanopathy or LGMD2I [14]. In the middle ambulatory phase: Approaches to lower-extremity surgery to maintain walking include bilateral multi-level (hip–knee–ankle or knee–ankle) procedures, bilateral single-level (ankle) procedures, and, rarely, unilateral single-level (ankle) procedures for asymmetric involvement. The surgeries involve tendon lengthening, tendon transfer, tenotomy (cutting the tendon), along with release of fibrotic joint contractures (ankle) or removal of tight fibrous bands (iliotibial band at lateral thigh from hip to knee). Hamstring lengthening behind the knee is generally needed if there is a knee-flexion contracture of more than 15°. In the late ambulatory phase: Surgery in the late ambulatory phase has generally been ineffective. In the late non-ambulatory phase: severe equinus foot deformities of more than 30° can be corrected with heel-cord lengthening or tenotomy and varus deformities (if present) with tibialis posterior tendon transfer, lengthening, or tenotomy [19].

Surgical scapular fixation is effective in improving shoulder function in FSHD, the fixation of the scapula with screws, wires or plates with bone grafting (arthrodesis), is the preferred surgical procedure [12]. IV.2.d Spinal management:

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if scoliosis is observed [19]. Scoliosis in LGMD occurs mainly after wheelchair dependence and attention should be paid to seating [11]. In the non-ambulatory phase, clinical assessment for scoliosis is essential at each visit [19]. A spinal examination by clinical observation should be done at every visit with the patient in sitting or standing positions [16]. Spinal radiography is indicated as a baseline assessment for all patients around the time that wheelchair dependency begins with a sitting anteroposterior full-spine radiograph and lateral projection film. An anteroposterior spinal radiograph is warranted annually for curves of less than 15–20° and every 6 months for curves of more than 20° [19]. In non-ambulatory children, sitting baseline radiographs in anterior–posterior and lateral projections are taken at the first sign of clinical scoliosis and every 6 months if the curve is worsening [16]. Treatment: Spinal fusion is done to straighten the spine, prevent further worsening of deformity, eliminate pain due to vertebral fracture with osteoporosis, and slow the rate of respiratory decline [19]. In congenital myopathy progressive curves beyond 50o prompt consideration of spinal surgery. Growing rods are indicated in some children less than 10 years of age to allow for correction of deformity and internal stabilization while growth of the spine continues. Many surgeons still prefer to use spinal orthoses to stabilize scoliotic curves even greater than 50o in the first decade of life and then perform definitive spinal fusion early in the second decade when most or all of spinal growth is completed [16].

IV.2.e Fracture management:

Internal fixation is warranted for severe lower-limb fractures in ambulatory patients. In the non-ambulatory patient, the requirement for internal fixation is less acute. Splinting or casting of a fracture is necessary for the non-ambulatory patient, and is appropriate in an ambulatory patient if it is the fastest and safest way to promote healing and does not compromise ambulation during healing [19].

IV.2.f Bone-health management:

Muscle interaction with bone by mobility, physical activity, and even by standing maximizes normal bone development. Vitamin D should be supplemented at 400 IU daily in all children, and serum 25-hydroxyvitamin D levels should be measured annually to ensure normal blood levels. Calcium intake should be maintained at the recommended daily intake through diet or supplementation. Pubertal assessment (Tanner staging) should be undertaken from age 11 years to monitor the pubertal progression [16]. Recommended bone health assessments include serum calcium, phosphare, alkaline phosphatase, 25 OH