Currently, there is a rapid, ongoing increase in our understanding of genetic neuromuscular disorders at the molecular level: many causative genes have been found, giving hope for targeted genetic treatments, already proven effective in some diseases. In immune-mediated neuromuscular disorders, pathogenetic mechanisms are better understood, and this enables the development of more precise immunotherapies. Increased knowledge has led to a refinement of classifications and has added numerous subtypes to the already hundreds of possible neuromuscular diagnoses. Patients can only benefit from future targeted therapies if an accurate diagnosis is made. Moreover, a diagnosis needs not only to be precise; the diagnostic trajectory needs to be swift, as current and future treatments will be aimed at the prevention or the restriction of irreversible damage.
The best way to diagnose a neuromuscular disease at this point is probably to recognize the phenotypical pattern, to know its differential diagnosis, and to proceed from there. The classic categorization of neuromuscular disorders in diseases of the anterior horn cell, peripheral nerves, neuromuscular junction, and skeletal muscle is not always sufficiently helpful as a starting point in the diagnostic process. For example, inclusion body myositis may mimic an anterior horn cell disease. Kennedy disease, an anterior horn cell disease, affects muscle too, and may present with a myopathy – suggesting CK elevation. In distal weakness, it might be cumbersome to differentiate between neurogenic and myopathic disease, and some drugs can cause both a neuropathy and a myopathy, or a combination of a myopathy and a neuromuscular junction disorder. Yet, from a practical point of view it is useful to keep to this anatomical–functional division: it provides a basic insight in functions, in understanding disease mechanisms, and in applying diagnostic and therapeutic tools. Therefore, we give a brief clinical characterization of the four categories of neuromuscular disorders. Details on physiology and pathophysiology are not discussed here.
Anterior Horn Cell Disorders
Anterior horn cell diseases, except for those caused by the polio virus and some other viruses, are progressive degenerative diseases of the motor neurons in the spinal cord and brainstem. These disorders may be hereditary, such as spinal muscular atrophy (SMA) types 1 to 3 in children and SMA 4 in adults, familial amyotrophic lateral sclerosis (ALS), Kennedy disease, and distal hereditary motor neuropathies (HMN; distal SMA). ALS, progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), and segmental SMA are commonly sporadic. The clinical hallmarks of anterior horn cell disease are the lower motor neuron signs of weakness, wasting (atrophy), fasciculations, and reduced or absent tendon reflexes. In ALS, the upper motor neuron is also involved and in PLS this is the sole manifestation, characterized by hypertonia (spasticity), pseudobulbar symptoms, hyperreflexia, and abnormal plantar response. ALS, PMA, and PLS are collectively classified as motor neuron diseases.
Clinical assessment, that is, history taking and neurological examination, and exclusion of mimics usually suffice to establish a diagnosis of ALS or postpolio syndrome (PPS). Electrodiagnostic assessment (nerve conduction studies and needle electromyography) is a crucial step in the diagnostic process of PMA, segmental SMA, and distal HMN. Hereditary diseases (SMA, Kennedy disease) require genetic testing as first-tier ancillary investigation.
Infectious diseases affecting the anterior horn cells such as poliomyelitis anterior acuta are diagnosed by virus isolation from stool or pharyngeal swabs and the polio-like disease caused by West Nile virus (WNV) by testing of serum or cerebrospinal fluid to detect WNV-specific IgM antibodies.
Therapy is mostly supportive in distal HMN and segmental SMA, including physiotherapy, orthotics, occupational therapy, and pain and fatigue management. In motor neuron diseases, multidisciplinary treatment is required (i.e., a rehabilitation physician for preservation of motor abilities, a gastroenterologist for instalment of a percutaneous endoscopic or radiologic gastrostomy, a pulmonologist for (noninvasive) ventilation, a palliative care specialist, and others).
Significant advances in basic and clinical research paved the way for approved therapies in SMA with a focus on strategies aiming at increased survival motor neuron (SMN) protein expression, either via antisense oligonucleotides, small molecules, or viral gene transfer. These strategies have led to dramatic improvement of survival and motor function.
Peripheral Neuropathies
Disorders of nerve roots, plexus, or peripheral nerves are the most frequent neuromuscular diseases. Conditions caused by compression of one nerve root or nerve are usually handled by the general practitioner or neurologist based in a community hospital. Polyneuropathies are readily distinguishable from disorders of the anterior horn cell, neuromuscular junction, and skeletal muscle by the presence of sensory disturbances, but these may be mild and pure motor neuropathies do exist. Neuropathies can also be purely sensory. Neuronopathies, localized in the dorsal root ganglion, are associated with specific conditions, such as cancer. Typical pain patterns can point to a localization in nerve roots, plexus, or peripheral nerves. Neuropathic pain can be severe and should be treated appropriately.
Polyneuropathies can have many causes. Distinction between subacute and chronic disease course, onset in childhood or adulthood, symmetric and asymmetric symptomatology, length-dependent and non-length-dependent, and axonal and demyelinating pathogenesis is a useful approach for making a differential diagnosis. Nerve conduction studies complemented by ultrasound examination can establish a demyelinating pathogenesis. These are often immune-mediated. Recognition of these disorders has become increasingly important because of the increasing treatment options. Most polyneuropathies are chronic, symmetric, distal, and axonal. The most frequent causes are metabolic. Diabetic polyneuropathy, monoradiculopathy, and plexopathy can occur without a known prior history of type 2 diabetes. Evidence-based guidelines are useful in the diagnostic work-up of polyneuropathies.
Hereditary polyneuropathies can be axonal or demyelinating, as established with nerve conduction studies. In particular, axonal hereditary polyneuropathies can sometimes have their onset in adulthood, and these patients need not have typical deformities such as hollow feet. This is also the case in young children in whom often a pes planus is seen. Weakness can also present more proximal with difficulty rising from the floor and running. Many genes have now been identified, and these disorders can be increasingly diagnosed at the gene level, which is important for genetic counselling. Gene therapies for hereditary polyneuropathies have not been developed yet. Treatment is mainly supportive, including physiotherapy, orthotics, occupational therapy, pain and fatigue management, and – when indicated – orthopaedic surgery.
Neuromuscular Junction Disorders
Myasthenia gravis (MG) is the most common autoimmune disease affecting the neuromuscular junction. If the disease manifests with the typically fluctuating, variable, and fatigable ptosis and diplopia, the diagnosis can be readily made, but ancillary investigations are always indicated. MG can be distinguished into an ocular and generalized phenotype. MG is caused by antibodies directed at the acetylcholine receptor (AChR) situated on the postsynaptic membrane, or, much more rarely, at muscle-specific kinase (MuSK), which is needed for maintenance and clustering of the AChR. In particular, in ocular myasthenia, and rarely in generalized myasthenia, antibodies are absent or not detectable with current methods (e.g., seronegative MG). The diagnosis then rests upon the clinical phenotype, response to symptomatic treatment, and typical electrophysiological findings. The thymus plays a role in the pathogenesis of AChR MG showing hyperplasia or thymoma. Therapeutic strategies range from cholinesterase inhibitors, immunosuppressive or immunomodulatory treatment to immunotherapies that more specifically address distinct targets of the main immunological players in MG pathogenesis. If bulbar or respiratory muscles are affected, an emergency condition may occur, warranting adequate treatment and close monitoring in an intensive care unit (ICU). A myasthenic crisis is life-threatening, but if recognized early it is generally well manageable, with a good prognosis.
Lambert Eaton myasthenic syndrome (LEMS) is caused by antibodies directed at the voltage-gated calcium2+ channel in the presynaptic nerve ending. The influx of calcium is needed for the release of acetylcholine in the synaptic cleft. The clinical features are different from MG (namely, proximal weakness, autonomic dysfunction, and areflexia), and fluctuating weakness is less obvious as compared with MG. Apart from antibody testing, the diagnosis can be made by specific electrophysiological abnormalities. LEMS is strongly associated with small cell lung cancer, which should be screened for.
Congenital myasthenic syndromes (CMS) are extremely rare and heterogeneous genetic diseases with variable phenotypes. Most CMS are treatable. Some agents that benefit one type of CMS can be ineffective or harmful in another type, and therefore an accurate molecular diagnosis prior to symptomatic treatment is paramount.
The neuromuscular junction may be targeted by various drugs and toxins. Botulinum toxin (as drug or foodborne) and snake venoms such as β-bungarotoxin (cobra, mamba) block the ACh release at the presynaptic nerve terminal, which is resistant to anti-venoms. Organophosphates, present in pesticides such as parathion and used as poison (e.g., Novichok), inhibit acetylcholinesterase, which causes an excess of acetylcholine and may result in a possibly fatal cholinergic crisis including paralysis. Curare, snake venoms such as α-bungarotoxin, and muscle-relaxant drugs such as pancuronium competitively block the AChR prohibiting depolarization. Suxamethonium chloride (succinylcholine) is a muscle relaxant that binds to the AChR, causing depolarization, but not allowing for repolarization and subsequent depolarization, because it is broken down slowly. Tetrodotoxin, found in the liver of puffer fish, blocks the voltage-gated Na+ channel. Diaphragm paralysis can follow very quickly.
Myopathies
Myopathies – diseases of the skeletal muscles – can be acquired or hereditary. The distinction, important because of the differences in diagnostic work-up and treatment options, rests initially upon careful history taking focused on age of onset and rate of progression. Acquired myopathies are commonly immune-mediated, and weakness progresses in weeks or a few months. A more protracted course can, however, occur, and these immune-mediated myopathies may lack inflammatory changes in a muscle biopsy, which may add to the difficulties in differentiating this group of diseases from a muscular dystrophy. An increasing number of autoantibodies is linked to the pathogenesis, and some forms are associated with cancer, which requires screening.
Hereditary myopathies are caused by DNA variants causing dysfunction or absence of proteins involved in, for example, the extracellular matrix, sarcolemmal structure and function, the nuclear envelope, metabolic pathways and mitochondria, the contractile apparatus, and ion channels. In particular, if the sarcolemma is affected, there is leakage of intracellular substances such as CK. A serum CK elevation of more than 10 times the upper limit of normal is commonly consistent with a myopathy. In many myopathies, however, CK activity is only mildly increased and may even be normal.
Many hereditary myopathies have specific complaints or abnormalities on clinical examination, needle electromyography (EMG), or muscle biopsy. Muscle biopsies should best be performed in a neuromuscular centre, in order to allow for appropriate processing. The final diagnosis, however, is made by genetic investigation, and EMG and muscle biopsy are often not indicated in the diagnostic work-up. The possibilities to diagnose a myopathy at the genetic level are expanding very rapidly, albeit a fair proportion is still awaiting a definite molecular diagnosis. Neuromuscular multidisciplinary teams therefore should include, among others, clinical and molecular geneticists, who can help interpret the results of genetic analyses and offer genetic counselling to patients and their families.
Causal treatment of hereditary myopathies is currently mostly restricted to enzyme replacement therapy, which is effective in Pompe disease, in which gene transfer therapy is now also in development. Rehabilitation treatment includes optimizing physical functioning and engagement in social life. In many progressive myopathies, there is an imminent danger of insufficient swallowing and respiratory function. Cardiac involvement can occur in various myopathies, leading to cardiomyopathy, dysrhythmias, or conduction abnormalities with the risk of sudden death. These complications require close monitoring to ensure timely interventions such as percutaneous endoscopic gastrostomy, noninvasive ventilation at home, or prevention or treatment of cardiac failure or instalment of devices (pacemakers, defibrillators).
