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Muscular Dystrophy

Duchenne Muscle Dystrophy

Introduction

Duchenne muscular dystrophy (DMD) is a severe X-linked recessive neuromuscular disorder caused by mutations in the dystrophin gene. Dystrophin is a critical protein that helps stabilize muscle fibers during contraction. The absence or deficiency of functional dystrophin leads to progressive muscle degeneration, weakness, and eventual loss of ambulation.

Epidemiology

DMD is the most common and severe form of muscular dystrophy. It occurs almost exclusively in males, as it is linked to mutations in the X chromosome. However, approximately 10% of female carriers can exhibit mild to moderate symptoms due to skewed X-inactivation. The condition is universal, affecting individuals across all ethnic and geographic populations. The disease is typically diagnosed between 3 and 5 when symptoms such as delayed motor milestones and difficulty climbing stairs or running become evident. Advances in genetic screening have enabled earlier detection in some cases.

DMD primarily affects boys, with an estimated incidence of 1 in 3,500 to 5,000 live male births globally.

Clinical Manifestations

The hallmark of DMD is progressive skeletal muscle weakness. Clinical features typically include delayed motor milestones, waddling gait, frequent falls, and difficulty climbing stairs or rising from the floor (Gowers' sign). Proximal muscle weakness begins in the lower limbs and progresses to the upper limbs. By 10 to 12, most patients lose the ability to ambulate. The calves and tongue enlargement are based on fat and connective tissue infiltration. The diaphragm and intercostal muscle weakness leads to respiratory insufficiency, particularly in the second decade of life. Dilated cardiomyopathy is a common complication and a significant cause of morbidity and mortality in DMD patients. Other complications include Scoliosis, joint contractures, cognitive impairment, and neuropsychiatric disorders (in some cases).

The diagnosis of DMD is based on clinical presentation, laboratory findings, and confirmatory genetic testing. Serum CK levels (and ASAT level) are markedly elevated (10-100 times the standard limit) and serve as an initial screening test. Identifying mutations in the dystrophin gene confirms the diagnosis. This is the gold standard diagnostic method. Occasionally performed if genetic testing is inconclusive. Immunohistochemistry or Western blot can demonstrate the absence or deficiency of dystrophin. It helps differentiate muscular from neurogenic causes of weakness but is rarely required.

Currently, there is no cure for Duchenne muscular dystrophy (DMD), but treatment focuses on slowing disease progression, managing symptoms, and improving quality of life. Corticosteroids like prednisone and deflazacort are the primary treatments, helping to prolong ambulation and reduce respiratory decline. Exon-skipping therapies, such as eteplirsen and golodirsen, target specific mutations to restore partially functional dystrophin production. Gene therapy is an emerging approach aiming to introduce functional copies of the dystrophin gene.

Cardiac care involves regular monitoring and the use of ACE inhibitors or beta-blockers to manage cardiomyopathy. In advanced stages, respiratory support like non-invasive ventilation (e.g., BiPAP) or tracheostomy is essential for nocturnal hypoventilation. Physical therapy plays a crucial role in preventing contractures and maintaining mobility. Multidisciplinary care is vital and involves neurologists, cardiologists, pulmonologists, and physical therapists.

DMD is a progressive disorder with significant morbidity and mortality. Without intervention, life expectancy is typically in the late teens to early twenties due to respiratory or cardiac complications. Advances in multidisciplinary care, including respiratory and cardiac management, have significantly improved survival, with many patients living into their 30s or 40s. Ongoing research in gene therapy and molecular treatments holds promise for altering the disease course, offering hope for improved outcomes in the future.

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Becker Muscular Dystrophy

Introduction

Becker muscular dystrophy (BMD) is a genetic disorder characterized by progressive muscle weakness and wasting, primarily affecting skeletal and cardiac muscles. It is a type of dystrophinopathy caused by mutations in the DMD gene located on the X chromosome, leading to partial deficiency or abnormal structure of dystrophin, a protein essential for muscle cell integrity. Unlike its more severe counterpart, Duchenne muscular dystrophy (DMD), BMD typically has a later onset and a slower progression, allowing affected individuals to maintain mobility into adulthood.

Epidemiology

BMD is a rare disorder, with an estimated prevalence of 1 in 18,000 to 1 in 30,000 live male births. As an X-linked recessive condition, it predominantly affects males, while females are usually carriers and may present with mild symptoms, such as muscle cramps or cardiomyopathy. Geographic and ethnic variations in prevalence are not well-documented, but the condition is distributed worldwide.

Clinical manifestations

The clinical presentation of BMD is highly variable. Symptoms typically appear during late childhood or adolescence and progress slowly. Muscle Weakness, like DMD, includes Proximal muscle groups, particularly in the pelvis and thighs, which are affected first, resulting in difficulty climbing stairs, running, or rising from the floor. Enlarged calf and tongue muscles are common due to muscle fiber replacement with fat and connective tissue. Gait abnormalities present, such as wailing gait and frequent falls, are early signs.

Dilated cardiomyopathy and arrhythmias are significant complications, often presenting later in the disease course. Contractures and Scoliosis are less common in BMD than in DMD but may develop in advanced stages.

Diagnosis of BMD involves a combination of clinical evaluation, family history, and diagnostic tests such as serum creatine kinase (CK), Genetic testing, muscle biopsy, electromyography (EMG), and cardiac assessment.

Treatment While there is no cure for BMD, management aims to slow disease progression, improve quality of life, and address complications.

The prognosis for BMD varies widely. Many individuals remain ambulatory into their 30s or beyond, but the progressive nature of the disease can lead to significant disability. Cardiac complications are a leading cause of morbidity and mortality, underscoring the importance of regular cardiac monitoring and early intervention. With advancements in supportive care and emerging therapies, life expectancy and quality of life for individuals with BMD continue to improve.

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Facioscapulohumeral Muscular Dystrophy (FSHD)

Introduction

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder characterized by progressive skeletal muscle weakness. It primarily affects the muscles of the face (facial-), shoulder blades (scapula-), and upper arms (humeral), although other muscle groups can also be involved. FSHD is one of the most common forms of muscular dystrophy, with a highly variable presentation ranging from mild Weakness to severe disability. The condition is primarily inherited in an autosomal dominant manner, though de novo cases can also occur.

Epidemiology

FSHD is estimated to affect approximately 1 in 15,000 to 1 in 20,000 individuals worldwide, making it one of the most prevalent muscular dystrophies. There is no significant gender predilection, and symptoms typically manifest in adolescence or early adulthood, although onset can vary widely. Rarely do individuals present symptoms in early childhood or later in life.

Pathophysiology

The pathophysiology of FSHD is primarily linked to genetic and epigenetic changes on chromosome 4. Most cases (FSHD1) result from a contraction of the D4Z4 microsatellite repeat region on chromosome 4q35, reducing the number of repeats to 1-10 units (compared to 11-100 in unaffected individuals). This contraction leads to the aberrant expression of the DUX4 gene, which is usually epigenetically silenced in healthy muscle tissue. DUX4 encodes a transcription factor toxic to muscle cells when expressed, leading to inflammation, oxidative stress, and muscle degeneration.

A minority of cases (FSHD2) are associated with mutations in genes that affect chromatin structure, such as SMCHD1, which result in similar DUX4 activation.

Clinical manifestations

Facial Weakness, characterized by difficulty closing the eyes, an asymmetrical smile, and trouble whistling or drinking through a straw, is a common early sign. Shoulder and upper arm weakness often manifests as scapular winging, reduced strength, and difficulty raising the arms above the head. Progressive involvement of abdominal, hip, and leg muscles can impair mobility and cause walking difficulties. Muscle weakness frequently presents asymmetrically, distinguishing FSHD from other muscular dystrophies. Other symptoms, such as hearing loss, retinal vascular abnormalities, and chronic pain, are occasionally reported.

The diagnosis of FSHD is based on a combination of clinical evaluation, family history, and genetic testing.

There is currently no cure for FSHD, and management is primarily supportive.

The progression of FSHD is highly variable. Some individuals experience mild symptoms and retain normal mobility throughout life, while others may become wheelchair-dependent. Life expectancy is generally not reduced, as respiratory and cardiac involvement is rare compared to other muscular dystrophies. Advances in genetic research and emerging therapies promise to improve future outcomes.

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Limb-Girdle Muscular Dystrophies (LGMDs)

Introduction

Limb-Girdle Muscular Dystrophies (LGMDs) refer to a diverse group of genetic disorders characterized by progressive muscle weakness primarily affecting the shoulder (scapular) and hip (pelvic) girdle muscles. Unlike other muscular dystrophies, LGMDs can manifest at any age, from childhood to late adulthood, and present with varying degrees of severity. The disorders are named for the muscle groups they predominantly affect and are caused by mutations in numerous genes responsible for muscle structure and function. LGMDs are classified into two major categories based on their mode of inheritance: autosomal dominant (LGMD1) and autosomal recessive (LGMD2), with multiple subtypes within each category.

Epidemiology

The prevalence of LGMDs varies widely depending on geographic and ethnic factors but is generally estimated to affect 1 in 14,500 to 1 in 45,000 individuals worldwide. Autosomal recessive forms (LGMD2) are more common than autosomal dominant forms (LGMD1). The age of onset and rate of progression also vary significantly, with some subtypes presenting in early childhood and progressing rapidly, while others have an adult onset with slower progression.

Pathophysiology

The pathophysiology of LGMDs is linked to gene mutations encoding proteins essential for muscle integrity, repair, and function. These mutations disrupt the normal function of the dystrophin-glycoprotein complex, sarcomere organization, or other muscle cell components.

Clinical manifestations

The clinical presentation of LGMDs varies depending on the subtype. Proximal muscle weakness, which affects the shoulder and pelvic girdles, can make climbing stairs, rising from a chair, or lifting objects difficult. Common features include gait abnormalities, including a waddling gait and frequent falls. Weakness in the shoulder muscles often leads to scapular winging, causing the shoulder blades to protrude. Advanced cases may develop joint stiffness (contractures) and spinal curvature (scoliosis). Specific subtypes, such as LGMD1B and LGMD2I, may involve cardiac conduction abnormalities, cardiomyopathy, or respiratory insufficiency, with muscle weakness sometimes progressing asymmetrically.

The prognosis for individuals with LGMD depends on the specific subtype and severity of symptoms. While some forms progress slowly, allowing for near-normal life expectancy, others are more aggressive and lead to significant disability.

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Emery-Dreifuss Muscular Dystrophy (EDMD)

Introduction

Emery-Dreifuss Muscular Dystrophy (EDMD) is a rare form of muscular dystrophy characterized by a triad of clinical features: progressive muscle weakness, joint contractures, and cardiac involvement. The condition is named after Drs. Alan Emery and Fritz Dreifuss first described it. EDMD affects skeletal and cardiac muscles and can lead to significant morbidity due to its cardiac complications. Depending on the gene mutation involved, the disease is typically inherited in an X-linked, autosomal dominant, or autosomal recessive manner.

Epidemiology

EDMD is a rare disorder, with an estimated prevalence of less than 1 in 100,000 individuals. The most common form is X-linked EDMD, caused by mutations in the EMD gene encoding emerin. Autosomal dominant and recessive forms are linked to mutations in the LMNA gene, which encodes lamin A and C, and other less common genes.

Pathophysiology

The primary pathology in EDMD arises from defects in nuclear envelope proteins such as emerin or lamin A/C. These proteins are crucial for maintaining the structural integrity of the nuclear envelope and for proper gene expression. Mutations disrupt nuclear stability, leading to muscle cell damage and progressive weakness. Cardiac muscle cells are particularly vulnerable, resulting in conduction defects and arrhythmias.

Clinical manifestations

Muscle weakness in the upper arms and lower legs progresses slowly, primarily affecting proximal muscles. Early-onset joint contractures, particularly in the elbows, Achilles tendons, and neck, are hallmark features often preceding muscle weakness. Cardiac complications such as conduction defects, arrhythmias, and dilated cardiomyopathy can be life-threatening if left untreated. Muscle and cardiac involvement also frequently lead to reduced stamina and exercise intolerance.

The prognosis of EDMD varies depending on the severity of cardiac involvement. While muscle weakness progresses slowly and does not typically affect life expectancy, untreated cardiac complications can be fatal. Early diagnosis, regular monitoring, and appropriate interventions significantly improve outcomes and quality of life.

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Congenital Muscular Dystrophy (CMD)

Introduction

Congenital Muscular Dystrophies (CMDs) are rare genetic disorders characterized by muscle weakness and hypotonia (low muscle tone) present at birth or within the first few months of life. These disorders result from gene mutations in muscle structure, function, or interactions with other tissues, such as the brain. CMDs are highly heterogeneous, with varying severity, progression, and involvement of other organ systems, particularly the central nervous system.

Epidemiology

The overall prevalence of CMDs is estimated to be 1 in 20,000 to 1 in 50,000 live births, although the prevalence varies by subtype and geographic region. CMDs affect males and females equally and are inherited primarily in an autosomal recessive manner. Some forms may be more prevalent in specific populations due to founder mutations or genetic bottlenecks.

Subtypes

Congenital muscle dystrophy subtypes include more than 30 disorders and some of them Fukuyama congenital muscle dystrophy (FCMD), merosin-deficient CMD, rigid spine syndrome, and Walker-Warburg syndrome. Each has distinct features, such as varying severity and additional complications like cognitive impairments or joint contractures. The diversity in subtypes is due to gene mutations that affect muscle function and development.

Pathophysiology

Clinical Manifestations

Early-onset hypotonia and weakness are often seen in infants, who may show "floppy baby syndrome," delayed motor milestones, and feeding difficulties. The "floppy baby syndrome," is not exclusive to congenital muscular dystrophies, as it may be present in a variety of severe pediatric muscle disorders.

Joint stiffness, especially in the elbows, hips, and knees, is common and leads to contractures. Progressive muscle weakness can affect the respiratory system, sometimes requiring ventilatory support. Skeletal deformities, such as scoliosis, can develop as the condition progresses. In some subtypes, like Fukuyama CMD and Walker-Warburg Syndrome, there are associated brain malformations, intellectual disability, and seizures. Although rare, cardiac involvement may occur in LMNA-related CMD or certain glycosylation disorders.

The prognosis for CMD varies widely based on the subtype, severity, and associated complications. While some forms are compatible with a near-normal lifespan and minimal disability, others may result in severe physical limitations, respiratory failure, or early mortality.

Fukuyama congenital muscular dystrophy (FCMD)

FCMDis a rare, inherited neuromuscular disorder that primarily affects muscle strength and function. It is part of congenital muscular dystrophies, typically present from birth and progress over time.

FCMD is particularly common in Japan, where it was first described in the Fukuyama region, which is how the condition got its name. However, it is rare in other parts of the world. Genetic basis CMD is caused by mutations in the Fukutin gene (FKTN) located on chromosome 9. The gene plays a critical role in synthesizing a protein that maintains the structure of muscle cells. The condition follows an autosomal recessive inheritance pattern, meaning an individual needs to inherit two copies of the mutated gene (one from each parent) to develop the disease.

Muscle weakness is the most prominent symptom of FCMD, usually beginning in early childhood and affecting movement muscles, leading to walking, sitting, or standing difficulties. Affected children may also experience delays in motor milestones like crawling or walking. Over time, progressive muscle wasting and weakness occur, especially in the hips, thighs, and shoulders. Joint contractures, where muscles around joints tighten, are common and can limit mobility. Many individuals with FCMD also have cognitive impairments or developmental delays. In some cases, cardiac issues such as cardiomyopathy can weaken the heart muscle and affect its ability to pump blood.

FCMD is usually diagnosed through genetic testing, which identifies mutations in the Fukutin gene. A muscle biopsy may reveal characteristic changes in muscle tissue, such as fiber degeneration and inflammation. Blood tests can show elevated creatine kinase levels, indicating muscle tissue damage.

There is no cure for FCMD, so treatment mainly focuses on managing symptoms and improving quality of life. Physical therapy is important for maintaining joint mobility and strength and preventing contractures. Cardiac care may be necessary for those with heart issues, requiring regular monitoring of heart function. In the later stages of the disease, respiratory support may be needed if breathing becomes compromised.

The severity of FCMD can vary widely between individuals. In some cases, affected individuals may have a relatively mild course; in others, the disease can progress rapidly. Life expectancy may be affected by complications such as respiratory failure, cardiac issues, or other organ-related problems. Early intervention with supportive therapies can help improve mobility and overall well-being.

Walker-Warburg syndrome (WWS)

WWS is a severe form of congenital muscular dystrophy that is often associated with significant neurological and structural abnormalities.

It is caused by mutations in genes responsible for the development and functioning of the muscles and nervous system, most commonly the POMT1 or POMT2 genes, which are involved in the glycosylation of proteins essential for muscle and brain function.

Muscle weakness is a hallmark of Walker-Warburg syndrome (WWS), with profound weakness that begins at birth and worsens over time. Affected individuals often struggle with basic movements, such as sitting or walking. Neurological abnormalities are common in WWS, including brain malformations like hydrocephalus, where fluid accumulates in the brain, and lissencephaly, which results in a smooth, less-developed brain surface. Microcephaly, an abnormally small head, is frequently observed in affected children. Vision problems are another characteristic feature, with retinal dysplasia or other eye abnormalities leading to significant vision impairment or complete blindness.

Most individuals with WWS experience severe developmental delays, including intellectual disabilities and a lack of motor skills. The condition can severely impact a child's ability to communicate or perform basic tasks. Due to the combination of these complications, WWS is generally a life-limiting condition, with many affected children not surviving beyond infancy or early childhood.

Walker-Warburg syndrome (WWS) is typically diagnosed through genetic testing, which identifies mutations in genes such as POMT1 or POMT2, which are responsible for protein glycosylation. Prenatal ultrasound may reveal signs of brain malformations, such as hydrocephalus or lissencephaly, raising suspicion of the disorder. A brain MRI can provide detailed images showing structural brain abnormalities, such as the smooth brain surface characteristic of lissencephaly.

Additionally, ophthalmologic examinations may detect retinal dysplasia or other eye abnormalities, further supporting the diagnosis.

There is currently no cure for Walker-Warburg syndrome (WWS), and treatment primarily focuses on managing symptoms and providing supportive care. Physical therapy can help maintain muscle strength and flexibility, although the progression of muscle weakness is often rapid. Surgical interventions may be needed to manage hydrocephalus, such as the placement of a shunt to drain excess fluid from the brain. Respiratory support, feeding assistance, and other therapies may be necessary to address complications and improve the quality of life, but the overall prognosis remains poor.

WWS is a life-limiting condition, with many children not surviving beyond infancy or early childhood due to complications such as respiratory failure or infections.

Merosin-deficient congenital muscular dystrophy (MDC1A)

MDC1A is a rare genetic disorder caused by mutations in the LAMA2 gene. These mutations lead to a deficiency in the merosin protein, which is essential for maintaining muscle structure and function. This condition results in severe muscle weakness, motor delays, and progressive muscle wasting, often presenting at birth or in early infancy.

Merosin-deficient congenital muscular dystrophy (MDC1A) is caused by mutations in the LAMA2 gene located on chromosome 6, which encodes the merosin protein. Merosin is a key component of the extracellular matrix in muscle cells and helps maintain the structure and function of muscle fibers. The absence or reduction of merosin disrupts the stability of muscle tissue, leading to muscle weakness and degeneration. MDC1A follows an autosomal recessive inheritance pattern, meaning that affected individuals inherit two copies of the mutated gene, one from each parent.

Merosin-deficient congenital muscular dystrophy (MDC1A) is characterized by severe muscle weakness that typically presents at birth or in early infancy. This weakness primarily affects the muscles used for movement, leading to difficulties with motor milestones like sitting, standing, or walking.

Over time, muscle wasting and progressive weakness occur, especially in the proximal muscles of the limbs. Many individuals with MDC1A also develop joint contractures, where the muscles around the joints tighten, limiting movement. Cognitive impairments may be present, though they are typically milder compared to other forms of congenital muscular dystrophy. Additionally, individuals with MDC1A may experience respiratory issues, which can become more severe as the disease progresses.

Merosin-deficient congenital muscular dystrophy (MDC1A) is diagnosed through genetic testing, identifying mutations in the LAMA2 gene responsible for the condition. Muscle biopsy may also be performed, revealing the absence of merosin protein in muscle tissue, a hallmark of MDC1A. Additionally, electromyography (EMG) and muscle MRI can help assess muscle function and detect abnormalities associated with the disease.

There is no cure for Merosin-deficient congenital muscular dystrophy (MDC1A), and treatment mainly focuses on managing symptoms and improving quality of life. Physical therapy is essential to maintain muscle strength and prevent joint contractures, which can improve mobility and function. Respiratory support may be necessary as the disease progresses and breathing muscles weaken.

Additionally, cardiac care may be required for individuals who develop heart-related issues, and other supportive treatments, such as nutritional support and assistive devices, can help manage complications.

The prognosis of Merosin-deficient congenital muscular dystrophy (MDC1A) varies, but it generally involves progressive muscle weakness and disability that worsens over time. Most individuals experience significant motor delays and may lose the ability to walk, with some requiring wheelchair assistance by early childhood. Respiratory and cardiac complications can limit life expectancy, and while early interventions can improve quality of life, MDC1A is a life-limiting condition in many cases.

Rigid Spine Syndrome (RSS)

Rigid Spine Syndrome (RSS) is a rare neuromuscular disorder characterized by progressive stiffness and reduced spine flexibility. It often results from underlying congenital muscular dystrophies or other genetic disorders affecting the muscles and connective tissues that support the vertebral column. The hallmark feature is limited spinal mobility, particularly in the neck and back, which becomes more pronounced over time.

RSS is often associated with gene mutations that affect muscle and connective tissue structure and function. For example, mutations in the SEPN1 gene, which encodes the selenoprotein N, are commonly linked to RSS. SEPN1-related myopathies impair the ability of muscle cells to maintain structural integrity, leading to muscle stiffness, particularly in the axial muscles that support the spine. The condition is typically inherited in an autosomal recessive pattern, requiring two copies of the mutated gene (one from each parent) to manifest symptoms.

Spinal stiffness, noticeable in early childhood or adolescence, is the most prominent feature of the condition, significantly reducing flexibility. Postural abnormalities, such as scoliosis or hyperlordosis, often develop progressively over time. The stiffness in the thoracic spine can impair chest expansion, leading to restrictive lung disease and breathing difficulties. Generalized muscle weakness may also occur, particularly in the axial and proximal muscles. Additionally, joint contractures, especially in the hips and knees, can further limit mobility and exacerbate physical challenges.

Clinical assessment involves evaluating spinal mobility, postural abnormalities, and family history of genetic disorders. Genetic testing can identify mutations in the SEPN1 gene or related genes, while imaging studies like X-rays or MRI help assess spinal rigidity and structural changes. A muscle biopsy may sometimes reveal characteristic abnormalities, such as fiber degeneration.

There is currently no cure for rigid spine syndrome, so treatment focuses on managing symptoms and improving the quality of life. Physical therapy is essential for maintaining spinal mobility, preventing contractures, and strengthening the supporting muscles. Respiratory support, such as non-invasive ventilation, may be required for individuals with respiratory insufficiency. Orthopedic interventions, including bracing or surgery, can help address severe scoliosis or other postural abnormalities. Additionally, supportive care involves using assistive devices for mobility and managing complications associated with the condition.

The severity and progression of rigid spine syndrome vary depending on the underlying genetic condition. While some individuals retain mobility and respiratory function into adulthood, others may experience significant disability due to spinal rigidity, scoliosis, or respiratory complications. Early intervention with physical therapy and supportive care can improve quality of life and delay disease progression.