Neuromuscular Disorders, SMA, Myastenic Syndrome Flashcards
What are neuromuscular disorders?
Neuromuscular disorders are a group of medical conditions that affect the function of muscles and the nerves that control them. These disorders interfere with the transmission of signals between the nervous system and muscles, leading to weakness, muscle wasting, sensory deficits, and sometimes paralysis. The primary defect in neuromuscular disorders lies in the PNS, although some also involve the CNS.
- Neuropathies : Damage to the peripheral nerves, which can be caused by conditions like Guillain-Barré syndrome, Charcot-Marie-Tooth disease, or diabetic neuropathy. These can result in pain, sensory loss, and motor deficits.
- Motor Neuron Diseases : Affect motor neurons in the spinal cord or brain, such as amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy (SMA), leading to progressive muscle weakness and atrophy.
- Neuromuscular Junction Disorders : Conditions like myasthenia gravis or Lambert-Eaton syndrome, where communication between nerves and muscles is impaired.
- Myopathies : Diseases of the muscle itself, such as muscular dystrophies (e.g., Duchenne and Becker) or inflammatory myopathies like polymyositis.
- Peripheral Nerve Disorders : Involving damage to nerve fibers or Schwann cells that affect conduction velocity and nerve function.
- Channelopathies : Genetic conditions affecting ion channels in muscles or nerves, such as periodic paralysis or myotonia.
Diagnostic flowchart in neuromuscular disorders? General symptoms and signs?
The first thing to do is to identify if the problem is in the CNS or PNS and localize it anatomically.
We must collect case history, familiar history, symptoms, medical examination, muscle tone, muscle strength, deep tendon reflexes and sensory evaluation.
General signs may include : skin rash, ptosis, opthalmoplegia, syncope, scoliosis, fatigue, gait abnormalities, muscle tone changes, abnormal muscle movements (fasciculations, myokemia, tremors), pain and cramps, numbness etc.
What is Gower’s sign? How do we measure the weakness of a muscle?
The sign describes a patient that has to use their hands and arms to “walk” up their own body from a squatting position due to lack of hip and thigh muscle strength.
It is quite typical of muscle dystrophy but not only.
Dynamometer is a specialized tool used to measure the weakness of the muscle. If the muscle fully contracts its a 5 if it is not even able to activate it is 0.
Bone deformities in neuromuscular disorders?
They are mostly found in more chronic situations.
They include scoliosis, pes cavus, hammertoe, clawhand.
Muscle biopsy?
It is common to perform biopsy of both muscle and nerve. It isn’t very invasive and is done with local anesthesia. A cylindrical muscle biopsy is taken then sliced and frozen to preserve the structures.
It then can be stained differently to visualize different things.
What is spinal muscular atrophy?
Spinal Muscular Atrophy refers to a group of genetic disorders characterized by the degeneration of anterior horn cells in the spinal cord, leading to muscle atrophy and weakness. It is an autosomal recessive disorder caused by mutations in the SMN1 gene, affecting motor neurons—specialized neurons found in the central nervous system (CNS) that project their axons to the peripheral nervous system (PNS) to innervate muscles.
Incidence: 1 in 6,000–10,000 live and is the second most common autosomal recessive condition in infancy, following cystic fibrosis.
SMA Pathophysiology?
Spinal muscular atrophy (SMA) is a genetic disorder caused by mutations in the SMN1 gene on chromosome 5, which is essential for motor neuron survival. The absence of functional SMN1 protein leads to motor neuron degeneration, resulting in muscle weakness and atrophy. SMA is inherited in an autosomal recessive manner, meaning both parents must carry the mutation for their child to have the disease, with a 25% chance of inheritance in each pregnancy.
Adjacent to SMN1 is the SMN2 gene, which is nearly identical but less effective due to a single nucleotide difference that excludes exon 7 during mRNA splicing. Consequently, SMN2 produces only small amounts of functional SMN protein, insufficient to compensate for the loss of SMN1. Most SMA cases involve homozygous mutations in SMN1, particularly affecting exon 7 or exons 7–8.
The lack of SMN protein disrupts motor neuron function and survival, leading to progressive muscle atrophy. Treatments often focus on increasing SMN2 protein production or addressing the genetic defects in SMN1.
SMN function?
The SMN1 protei is ubiquitously expressed and it is involved in the splicing process of mRNA. SMN1 is localized either in the nucleus or in the cytoplasm.
SMN1 is involved in transcription termination, RNA trafficking, translation regulation and other functions.
In neurons the SMN protein serves crucial functions that might explain why motor neurons are particularly vulnerable. They are responsible from axonal transport, neural outgrowth and guiding the axons in the cell bodies.
Muscular function of SMN?
Full SMN1 knockout in mice is lethal. SMN1 knocked out only in muscle tissue causes myopathy. Mice with SMN1 knockout exhibit phenotypic characteristic like the ones see in human SMA such as motor neuron degeneration, muscle weakness, impaired motor function.
Types of SMA? Functional classification?
SMA is categorized into several types based on the severity of symptoms, age of onset, and motor function capabilities. All types are caused by identical mutations in the SMN1 gene, but the severity depends on the number of SMN2 gene copies, which partially compensate for the lack of SMN1 protein.
Type 1 are called non sitters and are the most severe from of the disease, type 2 and some type 3 are called sitters and some type 3 and type 4 are walkers.
Nonsitters never acquire the ability to sit, sitters develop the capacity but later in life, walkers gain the ability to walk although the ability may still be compromised.
Various types of SMA and their associated genetic profiles?
• SMA type 0 : No copies of either SMN1 or SMN2. Babies with this form typically die shortly after birth.
• SMA type 1 : No copies of SMN1 and 1-2 copies of SMN2. With only 10-15% of the required protein produced, this form is severe and often fatal.
• SMA type 2 : No copies of SMN1 and 3 copies of SMN2. Although severe, this form tends to be less
severe than type 1.
• SMA type 3 : No copies of SMN1 and 3-4 copies of SMN2.
• SMA type 4 : No copies of SMN1 and 4-5 copies of SMN2. This form is generally very mild in comparison to other types of SMA.
Type 1 SMA?
Epidemiology —> SMA type 1 is the most severe and common form of SMA, accounting for approximately 45% of all cases. The condition typically manifests between birth and 6 months of age, with most cases presenting before 3 months. Without treatment, affected infants rarely survive beyond 18 months due to respiratory failure.
Clinical presentation —> Infants present with diffuse hypotonia, giving them a floppy appearance, and adopt a characteristic “frog legs” posture. Proximal muscles are more affected than distal, with lower limbs more severely impacted than upper limbs. Deep tendon reflexes are absent or reduced, but facial and ocular muscles are spared, allowing for smiling. Hallmark features include weak crying, inability to sit, poor feeding, and respiratory difficulties, often leading to a bell-shaped chest. Death typically occurs due to respiratory failure, with 50% of infants dying by 7 months and 95% by 17 months.
DDX —> CMT, congenital muscular dystrophies, myasthenia gravis, and glycogen storage disorders. These conditions share overlapping features of hypotonia and muscle weakness but have distinct diagnostic criteria.
Histopathology —> Histological examination reveals significant motor neuron loss and muscle atrophy. Surviving motor neurons attempt to reinnervate more muscle fibers, leading to increased workload, which further contributes to progressive muscle weakness.
SMA type 2?
Epidemiology —> SMA type 2 accounts for approximately 20% of all SMA cases. It typically presents between 6 and 18 months of age. Patients achieve the ability to sit independently but are unable to stand or walk unaided.
Clinical presentation —> patients exhibit motor disabilities such as not being able to stand or walk, muscle weakness, tongue fasciculations, muscle cramps, increased susceptibility to scoliosis.
SMA type 3?
Epidemiology —> SMA type 3, also called Kugelberg-Welander disease, represents approximately 30% of SMA cases. Onset varies widely, occurring between 18 months and adulthood. Disease severity correlates with the number of SMN2 copies.
Clinical presentation —> SMA type 3 is marked by progressive proximal muscle weakness, particularly in the limb girdle, leading to difficulties with activities like running and climbing stairs. Some patients can walk independently, but many require assistance, with ambulation often lost by age 14. Other features include scoliosis, reduced deep tendon reflexes, tremors, fasciculations, and sleep-related respiratory issues requiring ventilatory support.
Therapies for SMA?
SMN2 modulation —> SMN2 modulation targets the SMN2 gene, a backup for the defective SMN1 gene. Therapies like Nusinersen and Risdiplam promote the inclusion of exon 7 in SMN2 transcripts, increasing the production of functional SMN protein. These therapies have proven effective in improving motor function and slowing disease progression across SMA types. Early administration maximizes benefits by protecting motor neurons before significant damage occurs.
• Nusinersen: Administered intrathecally due to its inability to cross the blood-brain barrier. It requires an initial loading phase followed by maintenance doses every four months. It has shown remarkable results in infants, enabling developmental milestones and reducing ventilation dependency.
• Risdiplam: An oral medication that crosses the blood-brain barrier, offering systemic benefits. While convenient, it requires daily administration, and costs may align with Nusinersen over time. Both drugs significantly benefit SMA types 1, 2, and 3, though early diagnosis and intervention are crucial.
Gene therapy —> Gene therapy offers a transformative approach by addressing the underlying genetic defect. The small size of the SMN1 gene makes it ideal for delivery using viral vectors like adeno-associated viruses (AAVs).
• Onasemnogene abeparvovec (Zolgensma): A one-time gene therapy using an AAV9 vector to deliver a functional SMN1 gene directly into motor neurons. It crosses the blood-brain barrier effectively, replenishing SMN protein. Corticosteroids are used to manage potential immune responses and liver toxicity. While highly effective, Zolgensma is costly (around $1 million per injection) and may not fully prevent complications like scoliosis.
What is Multifocal Motor Neuropathy?
It is a form of immune neuropathy predominantly affecting motor functions. Characterized by multifocal involvement, it presents as a polyneuropathy. Manifestations primarily in the upper limbs.
Male prevalence, onset adult age, mild progression, often asymmetric, absent sensory deficits, fatigue, muscle atrophy.
Pathogenesis : presence of antibodies targeting antigen1 leading to an immune reaction specifically at the nodes of ranvier in motor nerves.
Most common blocks include ulnar 80%, median 70% and radial 40%. Shows 50% redcution of proximal vs distal CMAP amplitude.
Diagnosis : EMG shows proximal to distal CMAP reduction, serum autoantibodies, anti GM1 (30-50%) and CSF protein mildly elevated (33%).
ALS vs MMN?
Distinguishing MMN from ALS can be challenging due to their similar presentations. However, MMN patients typically exhibit motor defects, often asymmetrically, with atrophy starting in the hands and progressing to the feet.
Unlike ALS, MMN patients do not develop respiratory insufficiency, and their condition is characterized by an immune reaction. Historically, MMN cases, particularly those with symmetric manifestations, were frequently misdiagnosed as ALS. However, MMN patients differ from ALS patients in their disease progression and the absence of respiratory involvement.
Treatment of MMN?
Treatment of multifocal motor neuropathy primarily relies on high doses of immunoglobulin therapy, as other drugs have shown limited effectiveness. Immunoglobulin therapy can effectively reverse nerve dysfunction, particularly during the acute phase of manifestation. It can rescue nerve function, typically within a few weeks of initiation.
What is anti MAG neuropathy?
Anti-MAG neuropathy is a type of sensory neuropathy associated with monoclonal gammopathy, most commonly involving IgM antibodies that target myelin-associated glycoprotein (MAG), a protein crucial for maintaining the integrity of myelin. Histologically, MAG is localized in uncompacted myelin areas such as paranodes, Schmidt-Lanterman incisures, and the periaxonal cytoplasmic collar. It plays a role in cell adhesion and ensures the proper separation between the axonal and Schwann cell membranes.
This condition typically affects individuals over 50 years old and presents with sensory disturbances, gait ataxia, and deficits in deep sensation. Symptoms are bilateral and often include pain in about 28% of cases. Weakness is generally absent in the early stages but may develop later, primarily in the small muscles of the distal limbs, such as the hands and feet. Tremors, particularly intentional tremors, are observed in around 30% of patients, most noticeably in the arms. Deep tendon reflexes are reduced, and the disease progresses slowly over time.
Diagnosis is based on high levels of IgM anti MAG antibodies, nerve biopsy may be performed revealing myelin wide spacing, onion bulbs etc, EMG shows a demyelinating neuropathy
Treatment : there are no therapies that provide complete resolution. Drugs like rituximab, cyclophosphamide and plasma exchange have been used.
What is paraneoplastic sensory neuropathy?
Paraneoplastic Sensory Neuronopathy is a neuropathy associated with cancer, either due to the tumor itself or as a result of anticancer treatments. It arises from mechanisms such as nerve infiltration or compression by tumors, as well as the release of toxins or inflammatory substances by cancer cells. Cancer therapies like chemotherapy or radiation can also damage healthy nerves, contributing to neuropathy.
It is the most common paraneoplastic neuropathy and can precede cancer diagnosis by month or years.
Clinical onset include paresthesia, dysesthesia and negative summits like sensory loss and reduce tactile sensitivity.
Epidemiologically it is more common in women with a mean age of onset in the 60s and strong association with smoking. It is most frequently associated with small cell lung cancer. It is also associated tot neurological syndrome like epilepsy, vestibular disorders, limbic encephalitis.
PSN diagnosis and treatment?
Diagnosis include testing for anti Hu antigen (highly associated to SCLC), clinical presentation, EMG shows sensory neuropathy, identification of underlying malignancy and CSF can show high protein and high cell count.
Therapy included removal of the neoplasm which leads to better prognosis. Can use corticosteroids, IVIG, plasmapheresis, immunosuppressants.
What is Charcot Marie tooth?
CMT is a chronic neuropathy that predominantly affects the distal portions of the body. It manifests with motor and sensory deficits, distal muscular atrophy, sensory ataxia, pain, and bone deformities (pes cavus and hammertoe), which are most common in the lower limbs but may also appear in the upper limbs. Onset typically occurs in early adulthood or infancy.
There are two main types of CMT : demyelinating (CMT1, CMT4) and axonal (CMT2). Demyelinating CMT is characterized by motor nerve conduction velocities below 38 m/s in the upper limbs, while axonal CMT shows velocities greater than 38 m/s. Intermediate forms present velocities ranging between 25 and 45 m/s.
Pathophysiology of CMT?
The pathophysiology of CMT disease is rooted in genetic mutations that affect nerve function, particularly through disruptions in myelin production or axonal integrity. The initial discovery of the PMP22 gene in 1992, which plays a crucial role in myelin formation, was a significant milestone in understanding the disease. To date, around 130 genes have been implicated in CMT, with ongoing research aimed at identifying additional relevant genes.
In clinical diagnostics, duplication of PMP22 accounts for about 70% of demyelinating CMT cases and 50% of all CMT cases.
Diagnostic flow chart for CMT?
- Clinical presentation, evaluation of symptoms —> distal muscle weakness or atrophy, sensory deficits and bone deformities.
- Electrophysiological studies —> demyelinating CMT if motor nerves conduction velocity is less than 38 m/s and atonal CMT if more than 38 m/s, intermediated between 25 and 45 m/s.
- Genetic testing —> start with PMP22 gene and check for duplication. Then check for MFN2 or GJB1(CMTX, X linked) to associate axonal forms and SH3TC2 from demyelinating forms.
- Atypical presentations like pyramidal signs, test for 4cNT2A especially in axonal forms and vocal cord paralysis.
- Further investigation with NGS and exome sequencing.
- Nerve biopsy rarely used, only in cases with unclear genetic results and atypical presentations.
