This is Louise Spear. I'm a pediatric physiatrist at the University of Florida at Jacksonville. I have no relevant financial relationships to disclose. My learning objectives for this presentation is to familiarize you with some of the known causes and symptoms of neuromuscular diseases, particularly for the most common ones, review prognosis and some hopeful changes in prognosis for these conditions. I also went back and looked at the American Board of PM&R content for Step 1 of their general examination to get an idea of what's on there. I tried to include everything that was on that list. We are talking about disorders of muscle function. Disorders of muscle function caused by the peripheral nervous system or the muscle itself. They're from disorders of the anterior horn cell, such as you see with spinal muscular atrophy, abnormalities of the myelinated axon, abnormalities of the muscles, such as muscular dystrophies and myopathies. As you can tell from that previous slide, pediatric neuromuscular disorders are quite a heterogeneous group. They are commonly genetic, which differentiates it from adult neuromuscular disorders. They are surprisingly prevalent. Individual disorders are very rare, but the combined prevalence of neuromuscular disorders is somewhere around 160 per 100,000 live births. That's a rough estimate. Certainly, there's a lot of variability in that and more disorders being recognized as time goes on. If you see pediatric patients, you may not see a child with one particular disorder listed here, but the odds somebody's going to come through your door with one of these disorders is actually surprisingly high. It's important you recognize that you have them, both because they benefit from coordinated care, but also because the prognosis is improving. This presentation is being recorded in 2020. My hope is as the years go by, this presentation will become less and less relevant because there are going to be more disease-modifying therapies and more advances. They also don't forget the basics, so strengthening, therapy, splinting has improved outcome even prior to the development of some of these disease-modifying therapies. Children come to the attention of the medical community and receive their diagnosis at different times depending on the severity of their condition and associated manifestation. There is newborn screening available now for spinal muscular atrophy. The reason that has become available and recommended nationally since 2018 is that there are now effective treatments for that condition. Most other disorders come to medical attention later. Sometimes there is evidence of weakness or low tone that is concerning on evaluation. Other children are identified through gross motor delays. Here's a list of American Academy of Pediatrics recommended red flags for when a child needs further evaluation because their gross motor delays are significant and their motor development is falling more than two standard deviations below the norm. If you are evaluating a child, either because you're the first one that has evaluated a child or because there are concerns, things that you would look for that would indicate that this is a neuromuscular disorder are a combination of birth history, family history. This is particularly important because these conditions are largely genetic, so you want to see not just is there a history of someone in the family that had a similar type of presentation, but also who that person was, how they fell in relationship with this child. If there are multiple cousins, are they all maternal cousins? Are they male or female cousins? That would make a difference from, say, a mitochondrial disorder, which is always transmitted along the female line, to an X-linked disorder with female carriers and males presenting. Really looking at that in depth is worthwhile. Looking at developmental history, so not just do they have one of the red flags listed, but are they losing skills? This is huge for any child that comes in. If you have a child that used to, at one point, meet a particular motor milestone, so they were sitting, they were walking, they're running, and they stopped doing that, that is a very significant finding. Children really don't give up their motor milestone, so they stay active. They do what they can do, even if they've been sick or through a stressful situation, they should not lose walking, running, sitting. Sometimes this can be a difficult thing to fully parse out, especially if there was some concerns about how a child was developing, but things got worse. Is this truly a loss of skills, or is it more that perhaps there was always a delay in acquiring skills and it's just achieving more attention? You're looking more into it, either through their primary care doctor getting concerned or a therapist concerned. One thing I find really helpful to differentiate that is to ask for videos or pictures of what a child looked like in an earlier time. This has gotten much easier now. Just about everybody is carrying around in their iPhones years backlog of photos and videos and just really take a look. If the concern is a loss or a change in walking, try to find a video where a child is walking or running at some point in the past that they were doing better and look what they're doing now. If they look fairly similar, it's less concerning. If they clearly were walking, running without holding on to anything with a good steady gait and now they are holding on to walls or having problems walking at all, that's really a big concern. Children that have developmental regression, something concerning is going on and really you want them assessed very rapidly, ideally on the phone to their primary care for referrals or on the phone if you have a close relationship with neurology within your group that's assessing. Just get them in as soon as possible to be seen. In addition to the history, neurologic exam can be telling. Sometimes there are patterns of malformations like arthrogryposis that can occur if there is weakness of the muscles in the womb. If there is weakness on exam, weakness can be hard to tell in children because very young children, scared children don't consistently participate in the manual muscle testing. One thing you can do is try to look at some type of functional activity and see how well a child could do that. For instance, you could ask a child just to sit up. Do they have to roll onto their side and push with their arms to sit up or they just pop right on up? Ask a child who is laying supine to lift their head and look at their belly button. That's a good sign for proximal axial weakness. There's the famous Gower sign. You ask a child to sit on the floor and try to get up directly from the floor. Can a child just pop up or do they have to go through this episode of pushing through their legs and sort of climbing up their legs up to a standing position? Asking children to stand on one leg, jump, hop, getting the parents involved in making a game of it can be very helpful. Hypotonia, so muscles that are weak are often also low tone. When you're looking for low tone, you want to look at obviously feeling, putting muscles through their range when they're relaxed. Children are not always relaxing either. So sometimes just laying a child on their back and looking at their characteristic position can be very helpful. With an infant, when you lay them supine on the exam table or on their mother's lap, you want to look to see what does their body do. Even newborns will normally have a flex position of the hips, of the arms, of the knees. So a concern would be if you see something called frog leg positioning. I'm not sure who came up with this term, but the idea is that if a frog, like our little reptile pictured here, chose to lay on his back, his legs would kind of flop out to the sides with his knees bent as opposed to being in a flexed position. If you pull a child up to a sitting position, does their head kind of go backwards? Head lag is something that you do see, of course, in newborns. Their heads are floppy, but they shouldn't be severely floppy. So if you grab even an infant by their arms and kind of try to pull them slowly up off the exam table, does their head pretty much follow them with maybe a little bit of a lag or is their head way back all the way onto their occiput, onto their back with really no head control? Slip-through refers to if you try to lift a child underneath their armpits, do they tend to fall through? So if you hold even an infant under their axilla, their muscle tone should kind of hold them up fairly well and assist with you supporting them. If their arms just go up to their sides and they just seem to try to be slipping through your arm, that's a concern that they have low resting muscle tone. In terms of developing a definitive diagnosis, genetic evaluation is essential. Most of these conditions now have genetic molecular diagnoses and that's really the go-to. In older days, blood tests, muscle biopsy, EMG, MRI were essential. They still are used and I'll go through a little bit of the characteristic findings you can see on EMG, but you're certainly not going to see as many patients coming to specialized stains, muscle biopsy, EMG, as you did in the past. Now when thinking about diagnosis of a child with low muscle tone, one thing to keep in mind is that neuromuscular disorders are still fairly rare. So cerebral palsy has a prevalence of two to three per thousand, so much higher than the aggregate prevalence of neuromuscular disorders. Some children with cerebral palsy have hypotonic cerebral palsy, so they have low resting muscle tone. So it's a lot more likely for a patient with low muscle tone to have cerebral palsy or a brain or spinal cord disorder than it is likely that they have neuromuscular disorders. Low tone and weakness, the combination does strengthen things, but again, you have to keep a wide differential there. Spinal muscular atrophy is a neurodegenerative disease. It's largely autosomal recessive and it involves abnormality of the anterior horn cells. You get progressive loss of those anterior horn cells and loss of motor nuclei of the lower brainstem. These alpha motor neurons that are supported from these anterior horn cells are some of the longest in our body. They provide innervation to the muscle throughout our body. Therefore, when you get progressive loss of these anterior horn cells, you get progressive weakness and it's everywhere. It's symmetrical. Proximal muscles tend to be affected first and more significantly, lower extremities affected first. Diminished deep tendon reflexes, muscle atrophy, respiratory insufficiency, which is progressive and restrictive. That depends on the severity of the condition. Some do not have significant respiratory insufficiency and cognition is unaffected. This helps to be a little bit of a clue that this is more of a muscle disorder you're looking at. So the combination of muscle weakness, low tone, and preserved cognition is important. Infants cognitive testing can be very difficult, but children often have that sort of alert expression, visual tracking, responsiveness to their environment, and in the conditions that present later, you can compare motor milestone development or loss compared to how are they doing with their speech milestones, five motor milestones, social milestones, which are associated with cognitive abilities. Genetics of spinal muscular atrophy is fairly well worked out and it also seems to be a favorite on board review, so probably worth looking at. There is a survival motor neuron gene, SMN1 gene, on chromosome 5, and it is responsible for the production of survival motor neuron protein, which as the name implies, helps the motor neuron survive. It's essential for anterior horn cell survival. All children with spinal muscular atrophy lack a functioning SMN1 gene. That's what defines the condition. The children are missing this essential gene for the survival of the anterior horn cells. Children that lose the SMN1 gene, they rely on their SMN2 gene for production of this essential protein. Unfortunately, the SMN2 gene is not very effective at doing this. It also is affected by normal human variability, how many copies of the SMN2 gene you have. Children can have as low as one copy of this gene to as high as four copies of this gene. The SMN2 gene produces a truncated survival motor neuron protein, which doesn't fold well. It doesn't work, but 10 to 15% of the messenger RNA from this SMN2 gene produces a functional survival motor neuron protein. That's why the number of SMN2 genes is so essential. If you have a gene that only leads the production of 10% of the normal amount of the survival motor neuron protein, if you have four genes producing 10%, then you're going to have 40%. You may have a very mild course. If you have only one gene, then you're only going to get the 10%. It also varies how well the survival motor neuron is able to produce this SMN2 protein. There's that 10 to 15% number. If you have a SMN2 gene that really is functioning well, you might have only two copies, but you might have a relatively milder course. If you have an SMN2 gene that produces very little functional protein, you're going to have a lot more severe course. So SMA is divided into types, the type 0 through 4, and starting off with type 0, which is prenatal onset. These children with SMA, because of the condition, they're lacking a functional SMN1 gene. All of them are, and they have only one copy of this SMN2 gene. What that means is they have very little survival motor neuron protein. You notice there are changes even in pregnancy. You have decreased intrauterine movement, particularly later in pregnancy, shortening of the joints, arthrogryposis. You get joint contractures with skin changes across the joints because you're not showing in utero movements of those joints. You have intrauterine growth retardation. Newborns show very severe weakness. They basically do not meet any motor milestones. They don't develop the ability to roll and lift their head in prone. There's just a whole list there of basically what you'd expect if you're missing most of your motor neurons, including facial weakness and difficulties in terms of respiratory function, heart defects, and death is from respiratory failure, unfortunately, in this condition, typically by six months of age, although hopefully with prenatal testing and treatment, that will be better. SMA type 1. Children have one to three copies of the SMN2 gene. Some kids have very hardworking SMN2 gene single copies. They are able to look fairly typically developing, at least until birth. They're not weak prenatally. This is also known as infantile onset, infantile spinal muscular atrophy, Werdnig-Hoffmann. It goes by a few different names. Weakness occurs anywhere from birth to six months of age. Children never sit, so type 1 is one to three copies, never sat. Word to Kauffman. On exam, you see severe weakness, weak cry, poor suck. You do get progressive respiratory failure. Paradoxical breathing just refers to the fact that the intercostal muscles are more affected than the diaphragm muscles. You have the diaphragm working, trying to bring air in, but the chest is basically just collapsing. As the diaphragm tries to bring air in, the chest collapses and you have this appearance of the abdomen sticking out and the chest going in. You get, because of the intercostal weakness, that bell-shaped chest is collapsing. Unfortunately, these children also have a severe loss of functioning. Historically, these children have passed prior to two years of age from respiratory failure. With good respiratory support, newer treatments, life expectancy is increasing. SMA type 2 intermediate form, Dubowitz disease, just as it says, it's intermediate. Not as mild as the very later onset, but not as severe as infants. Three copies of SMN 2. What determines this disorder functionally is that children do achieve sitting, but not standing or walking. SMA type 3 is also known as juvenile form, Kugelberg Weylander disease. That onset is toddlerhood into adulthood. This is children that do walk. Type 0, no motor milestones. Type 1 may acquire some motor milestones, but not sitting. Type 2 is sitting, but not standing. Type 3 is walking independently, but difficulty with stares and falls and with progressive loss of those motor neurons. Eventually, a lot of these children will lose their ambulation, but it's important that they ambulate at some time in the past. This is that developmental regression. Children tend to have a normal lifespan and they have three to four copies of the SMN 2. SMN type 4 is also known as adult onset. That's relatively rare and there's a lot of other things that cause loss of walking and weakness later in life, so I'm not sure this would be kind of thrown in there, but it is possible to not have this disorder present until adulthood. The development of disease modifying therapy for children with spinal muscular atrophy has been a very significant improvement in patient's course and even survival. Nucinursin helps with the splicing of the SMN 2 gene products to produce a more normal survival motor neuron protein. You get better protein, better survival of the motor neurons. There also is now a gene replacement for the mutated survival motor neuron 1 gene delivered through a viral vector. Both of these treatments require considerable commitment. Nucinursin has to be repeated every four months. Genome placement is one time only, but it is extremely expensive. They're both extremely expensive. It's also important to know that this treatment needs to be started as soon as possible, both because of the difficulties of the treatment, the expense of the treatment, starting it early. If you suspect a child of SMA, you want them evaluated. You want them with a provider who can assist with getting these medications as soon as possible. The therapies and the production of the survival motor neuron protein is only helpful for maintaining the motor neurons. When motor neurons are lost, they're lost. So if you have a child that's lost a significant number of motor neurons and then you provide them with this treatment, they may not see the same kind of progress, the same kind of improvements that they would see if you started the therapy earlier. I threw in a question here about spinal muscular atrophy. I'll let you read through the choices on your own and just look. It's basically talking about some of the gene differences that we talked about and the clinical course of this condition. The answer, in terms of which one is true, is that the number of copies of the survival motor neuron 2 gene is associated with age of onset and severity of the illness. On to the muscular dystrophies. These are a group of related inherited diseases. They are generally progressive, sometimes slowly so, sometimes rapidly and severely progressive. They cause muscle weakness, loss of muscle mass. They can affect different areas of the body, the limb muscles, axial muscles, facial muscles, and some forms can affect respiratory muscles and cardiac smooth muscle, leading to severe disability and shortened life expectancy. The muscular dystrophies are divided into different categories depending on age of onset. Since this is a pediatric review, we will concentrate on the pediatric conditions, particularly the most common childhood onset muscular dystrophy, Duchenne muscular dystrophy. Just to mention a word in passing about Becker muscular dystrophy because sometimes it does come up. Becker muscular dystrophy is much rarer than Duchenne's, but very similar to Duchenne's. It is X-linked because of the dystrophin gene is on the X chromosome and caused by a mutation on the dystrophin gene. However, in Becker muscular dystrophy, there is abnormal production of dystrophin, not absence. Therefore, Becker muscular dystrophy symptoms are milder and occur later in life when compared to Duchenne muscular dystrophy. Duchenne muscular dystrophy is the most common form of muscular dystrophy. It is an X-linked recessive condition, so boys are affected, female carriers. There are sometimes mildly affected females, but generally this is a disease of boys. The dystrophin gene is the largest gene yet identified in humans. Its function is to shield the muscle sarcolemma from degradation, so loss or non-functioning genes are associated with progressive loss of the muscle sarcolemma. Prenatal testing for Duchenne's muscular dystrophy is possible, but generally done if mom is a known carrier. However, one-third of cases of Duchenne's muscular dystrophy are due to new mutations. Symptoms of Duchenne's muscular dystrophy are usually noticeable by four years of age. A common first indication of Duchenne's muscular dystrophy is a distinctive waddling gait related to proximal muscle weakness and poor hip stability in stance. On exam, symptomatic children may show a gower sign. This is something we discussed earlier and I have just included a little illustration there. Basically, a child trying to stand up from the floor can't just pop up, so they go through this process of using their whole body there and then pushing off through their knees to come into stance. You can also see toe walking related to ankle plantar flexor weakness. So basically, children are tilting themselves forward onto their toes to help with propelling themselves forward because they have difficulty completing a toe off. Calves may demonstrate marked pseudo hypertrophy caused by infiltration of fat among atrophic muscles. So the calves appear very large, but the ankle plantar flexors are weak. Children typically lose their ability to ambulate by 8 to 12 years, but this may be extended by 2 to 3 years with treatment. Unfortunately, Duchenne's is associated with a shortened life expectancy. Tragically, for most children, life expectancy is the late 20s, but some individuals do live longer. Duchenne is characterized by a very high CPK on blood testing, often above 6,000. Traditionally, myonecrosis, an absence of dystrophin on muscle biopsy coupled with EMG findings typical of myopathy, were used in the diagnosis of Duchenne's muscular dystrophy. However, the accuracy of genetic testing is almost entirely limited in the need for this, and biopsy should only be considered after extensive genetic evaluation. So genetic testing will detect a gene duplication or deletion in 70 to 80 percent of cases, but even in those 20 to 30 percent of individuals that don't have a detectable duplication of deletion, now genetic testing is improved to the point you can detect single mutations by scanning and sequence analysis. So most genetic causes of the Duchenne's can be found with this alone. Standard medication treatment for Duchenne's muscular dystrophy is glucocorticoids. Glucocorticoids should be started before significant decline in ambulation, ideally less than four years of age. When started early, they can extend ambulation, decrease the risk of scoliosis, and improve strength. Effects of glucocorticoids on cardiomyopathy and life expectancy are less certain, but there is some thoughts that it can lead to improvements in these areas also. There are a variety of emerging therapies for Duchenne's muscular dystrophy. Some are limited to only certain types of mutations. So the exon skipping treatments are limited to patients that have skipping mutations or nonsense mutation. Basically they affect the dystrophin pre-messenger RNA and actually encourages the body to produce a more functional dystrophin from the abnormal gene. There are investigational therapies and certainly the hope is at some point we'll see a more curative gene therapy for this condition. Congenital myopathies are usually apparent in infancy, but some do not become apparent until early childhood. They're characterized by marked hypotonia and often either non-progressive or slowly progressive proximal weakness. Myotonic dystrophy is the most common form of muscular dystrophy in adulthood. However, a variant of type 1 myotonic dystrophy called congenital myotonic dystrophy is apparent at birth, is associated with physical and intellectual disability, and can be life-threatening. Mitochondrial myopathies were first characterized in the 1980s. An understanding of mitochondria's role in diseases of the muscle and central nervous system is rapidly evolving. Patients frequently present with multi-system dysfunction involving the brain, heart, and other areas. However, as muscle tissue is very metabolically active, it may be the first affected. There is currently no disease-modifying therapy, but gene treatments are under investigation. Diagnosis is complex and good family history can be helpful. Molecular genetic studies increase accuracy, but muscle biopsy is often needed. In terms of the inflammatory myopathies, juvenile dermatomyositis is the most common inflammatory myopathy of childhood. It has a variable presentation with fatigue, irritability, muscle weakness, and a characteristic rash. The rash involves erythematous lesions on the sun-exposed extensor surfaces. You can also see papules on joints, heliotrope rash of the eyelids, periorbital edema, and erythematous malar rash. Peripheral neuropathies in children have significantly different etiologies than adults. Most are related to autosomal recessive conditions. These autosomal recessive conditions are usually characterized by gradual and symmetrical onset. You can see slowly worsening weakness, sensory loss, ataxia, pain, and paresthesias. EMG testing can be helpful in differentiating type of childhood neuropathy. You can evaluate for sensory versus motor involvement. Demyelinating neuropathies are characterized by slow nerve conduction velocities, temporal dispersion on C-map, conduction block, prolongation of distal latencies. EMG may also show reduced recruitment pattern. Axonal neuropathies are characterized by reduced amplitude C-map with relatively preserved nerve conduction velocities and reinnervation patterns on E-map. Acquired peripheral neuropathies in children, the most common is Guillain-Barre. Guillain-Barre is actually a group of heterogeneous conditions. The most common is acute inflammatory demyelinating peripheral neuropathy, but there can be variants that involve axonal injury, and there are also variants that involve cranial nerve autonomic dysfunction. Generally, you see this condition two to four weeks after respiratory or GI infection. You see leg weakness ascending with arm weakness, and children should be monitored closely for respiratory failure. Recovery is generally excellent in children with Guillain-Barre. Some 80 to 90% of children have no limitations in mobility by six months post-Guillain-Barre. However, children should still be monitored. 65% will have some ongoing sequelae. Most commonly, paraseasures or pain, but some children may have an unsteady gait if they don't have visual input or fatigue quickly. Children are susceptible to the same acquired peripheral neuropathies we see in adults, but they are less common in children. Hereditary neuropathies. Charcot-Marie-Tooth or hereditary sensory motor neuropathy is divided into different types. There is type 1 to 7 and an X-linked form. There are gene defects associated with Charcot-Marie-Tooth have been identified. The most common type of Charcot-Marie-Tooth is type 1 and 2, which is autosomal dominant, so family history is extremely important. Children experience lower extremity weakness. There is characteristic muscle atrophy, typically more distal than proximal, tripping and falling, loss of distal sensation. Later on, children may experience arm weakness. Foot deformity, particularly pes cavus foot, is common and you have absence of reflexes. On EMG, you see characteristic demyelination changes with slowing of nerve conduction velocities. Treatment of Charcot-Marie-Tooth is largely symptomatic, however, you need to be very careful to limit exposure to neurotoxic agents, particularly if children need chemotherapy. Considerations should be given to trying to limit agents associated with peripheral neuropathy, particularly vincristine. Our he-monk doctors are now in the habit of checking for family history of neuropathy prior to administering this medication because it can cause such severe weakness. As with our other conditions, orthotics, rehabilitation, strengthening can be helpful and there are some investigational gene therapies. There are a handful of other hereditary neuropathies of childhood, but there are generally rare. I appreciate your attention and thank you listening through this presentation. If you have interest in further reading, I have included a bibliography. Thank you.

neuromuscular diseases

pediatric physiatrist

spinal muscular atrophy

Duchenne muscular dystrophy

early recognition

genetic evaluation

treatment options