Pediatric Neuromuscular Disorders Encountered in the Adult Neurology Clinic

Although many pediatric neuromuscular disorders are symptomatic early in life, resulting in neonatal or infantile hypotonia and gross motor delay, some genetic neuromuscular disorders may not present until young adulthood.¹ In some cases, these disorders may be present throughout life, with subtle pediatric symptoms that are only understood as related to the disorder in retrospect. In other cases, the first symptoms emerge in the transition to adulthood. 

As in much of neurology, neuromuscular disorders are often grouped by localization (eg, anterior horn cell/motor neuron, peripheral nerve, neuromuscular junction, muscle). Symptom characteristics and neurologic examination results are often sufficient for diagnosis, but additional testing can also be helpful in identifying the specifc anatomic location of the disorder. These tests may include creatine kinase (CK) tests, nerve conduction studies (NCS)/electromyography (EMG), muscle MRI and ultrasound, and nerve and muscle biopsy. NCS/EMG tests, which are among the first-line tests for the adult neurologist, are most helpful for identifying motor neuron disease, neuropathy, and neuromuscular junction defects (Table 1). CK tests are most helpful in cases of suspected muscular dystrophy, in which CK levels are markedly elevated, although more modest elevations can be seen in neurogenic processes. Muscle imaging can assist with diagnosis in genetic muscle disorders and outcome measures in clinical trials. Muscle biopsies were historically essential for diagnosis of myopathies and muscular dystrophies, but now have largely fallen to second or third tier when genetic testing or other workup is unrevealing.

This article highlights some pediatric neuromuscular disorders that adult neurologists may encounter in clinical practice, discussed by anatomic location from proximal to distal. 

Spinal Muscular Atrophy
The care of individuals with spinal muscular atrophy (SMA) has evolved dramatically over the past decade with the development of new treatments. SMA is a genetic disorder caused by biallelic variants (typically deletions) in the SMN1 gene, which leads to progressive motor neuron loss over time. Newborn screening in all 50 states has allowed early treatment (within the first month of life) and prevention of disease progression.

The most common clinical phenotype is SMA type 1, which is defined by the inability to sit and symptom onset by age 6 months. Before treatment became available, these children progressively lost motor function, leading to death or ventilator dependence by age 2 years. However, with disease-modifying therapies, many children can remain ventilator-independent and achieve motor skills such as walking and running.²

SMA type 2 presents between age 6 and 18 months with progressive muscle weakness affecting the trunk and legs, often impeding independent walking. Life expectancy varies, but depending on the severity of symptoms, children with SMA type 2 may have a lifespan between 20 and 40 years. 

Approximately 15% to 30% of individuals with SMA develop symptoms between 18 months of age and adulthood, referred to as "SMA type 3."³ Late adult onset SMA is often referred to as "SMA type 4" and is even more rare. Weakness first develops in the proximal lower extremities; therefore, affected individuals are frequently initially suspected of having a muscle disorder. People with SMA type 3 report difficulty ascending stairs and getting up from the floor (often requiring a Gower maneuver), as well as increased fatigability. Examination of individuals with SMA type 3 reveals areflexia in the lower extremities, which would be unexpected in myopathy. Unlike with SMA type 1, individuals with SMA type 3 do not typically have tongue fasciculations early on.^3a

Electrodiagnostic studies demonstrate low motor responses with normal sensory responses on NCS and a pattern of both acute denervation and chronic reinnervation on needle EMG. Adult neurologists may interpret such EMG results as the result of motor neuron disease or amyotrophic lateral sclerosis (ALS).^3a As such, it is important to distinguish between the clinical presentaiton of SMA and ALS. SMA typically presents with symmetric, proximal lower-limb weakness, whereas ALS often shows initial asymmetric weakness. In addition, ALS by definition includes upper motor degeneration, leading to upper motor neuron signs on neurologic examination; SMA is strictly a lower motor neuron disorder. 

The diagnosis of SMA is confirmed by genetic testing for the SMN1 gene. Diagnostic testing also typically includes testing for the SMN2 gene. SMN2 is often referred to as the “backup” copy of SMN1. SMN2 makes a small amount of full-length spinal motor neuron (SMN) protein. Individuals have multiple copies of the SMN2 gene. In the context of SMN1 deletions, a higher number of SMN2 copies predicts a less severe and later-onset phenotype. Type 3 SMA is typically associated with ≥3 copies of SMN2. However, the genotype–phenotype correlation between SMN2 copy number and clinical phenotype is not exact.²

Identifying and confirming the diagnosis of later-onset SMA is important because disease-modifying therapies for SMA can change the trajectory of the disease and are most effective when started early, even in adults (Figure 1).⁴ Three treatments for SMA are approved for use in the United States: onasemnogene abeparvovec (Zolgensma; Novartis Gene Therapies, Bannockburn, IL), nusinersen (Spinraza; Biogen, Cambridge, MA), and risdiplam (Evrysdi; Genentech, South San Francisco, CA). Onasemnogene abeparvovec is only approved for children age >2 years; nusinersen and risdiplam are available across the lifespan. Both nusinersen and risdiplam are SMN2 gene modifiers that increase the amount of full-length SMN. Risdiplam is a daily oral treatment that is absorbed systemically, and nusinersen is delivered as an intrathecal injection every 4 months. Data on the efficacy of these 2 treatments in adults with SMA are more limited but support the use of nusinersen and risdiplam in all adults with SMA of any type to stabilize motor function and/or slow disease progression.⁵ Additional therapies, mostly to be used in combination with existing treatments, are in various phases of development.⁶

Figure 1. The general trajectory of motor function over time in spinal muscular atrophy (SMA) types 1 through 3 (A) and the impact of treatment (B) (green line), which largely depends on timing of treatment initiation and thus how many motor neurons remain at the time of treatment.
Reprinted with permission from Sumner CJ, Crawford TO. Two breakthrough gene-targeted treatments for spinal muscular atrophy: challenges remain. J Clin Invest. 2018;128(8):3219-3227. doi:10.1172/JCI121658. 

Charcot-Marie-Tooth Disease
Charcot-Marie-Tooth disease (CMT) encompasses many subtypes of genetic sensorimotor neuropathies that share some typical clinical features of distal predominant weakness, atrophy, numbness, and reduced reflexes. Depending on the subtype, the age at onset and clinical symptoms can vary. CMT1A is by far the most common subtype, and symptoms often begin in adolescence. However, for many subtypes of CMT, neurologic care is not sought until early adulthood, often by way of orthopedics or podiatry.^6a

People with CMT may report frequent ankle sprains as a child, clumsiness, inability to keep up with their peers in athletic pursuits, and an evolving foot morphology of high arches and hammertoes (Figure 2). Individuals do not often volunteer this information, which they may not link to their current symptoms, so specifically asking about childhood and teenage development and exercise can be useful. When an adult presents for first evaluation of neuropathy, key symptoms and signs that may allow for differentiation from more common acquired or idiopathic neuropathies include motor predominance with distal hand or foot weakness and atrophy, lack of positive sensory symptoms, diffuse areflexia, and the characteristic foot deformities (ie, high arches, hammertoes).^6a

Figure 2. Classic foot morphology in Charcot-Marie-Tooth disease. Note the high arches and hammertoes with distal lower-extremity atrophy. This morphology can be seen in any chronic neuropathy. 

NCS/EMG studies are typically the first diagnostic tool (Table 1) to confirm the presence of neuropathy and identify whether its pathophysiology is axonal or demyelinating. If there is a high suspicion and a family history, physicians could consider genetic testing first. Treatment is largely supportive, although clinical trials are ongoing using many different therapeutic approaches.⁷

Myotonic Dystrophy
Myotonic dystrophy (DM) is most commonly an adult-onset multisystemic disorder with a unique constellation of neuromuscular manifestations including ptosis, facial weakness, distal limb weakness, and myotonia (ie, impaired muscle relaxation after contraction). In the classic adult-onset form, physical manifestations, including the typical facial features and ptosis, can be identified in photographs going back to childhood.^8,9

DM type 1 results from a repeat expansion disorder in the DMPK gene leading to impaired gene splicing. DM type 1 exhibits genetic anticipation (ie, occurrence of increasing disease severity and increasing age of onset in successive generations) and therefore can manifest throughout the lifespan. Individuals with >1000 repeats can present with a severe congenital form, typically presenting with profound hypotonia, weakness, and respiratory failure in the neonatal period. Childhood-onset phenotypes are associated with a more prominent neurodevelopmental syndrome with less prominent myotonia; therefore, these individuals are often evaluated by a general neurologist. DM type 2 results from a heterozygous pathogenic repeat expansion in the CNBP gene, does not have a childhood onset form, and often presents with more proximal weakness. CK levels are mildly to moderately elevated and EMG reveals electrophysiologic myotonia. Genetic testing must be performed either on a genome platform or targeted for the repeats because short-read exome sequencing and neuromuscular panels will not detect the repeat expansion. There are no available disease-modifying therapies for DM, although many are being evaluated in early-stage clinical trials (primarily RNA-directed therapies).¹⁰ Screening for multisystemic manifestations in individuals with DM is crucial, particularly given the risk of cardiac arrhythmia in this population (Figure 3).^9a

Figure 3. Myotonic dystrophy (DM) is a multisystem disease. Certain manifestations are most severe in congenital DM type 1 (cDM1), such as respiratory failure requiring ventilatory support, substantial intellectual disability with global developmental delay, and diffuse weakness and hypotonia from birth, with complications of scoliosis and contractures. Often, clinical myotonia, the hallmark of the disorder, is minimal in cDM1. Whereas adult-onset DM type 1 can include any combination of the symptoms or manifestations, core features typically include clinical myotonia, distal weakness, cardiac arrythmias, ocular disease, and typical facial features (eg, ptosis, balding). Screening and management recommendations can be found in the clinical care guidelines published by the Myotonic Dystrophy Foundation (https://www.myotonic.org/sites/default/files/pages/files/MDF_Consensus-basedCareRecsChildrenDM1_1_21.pdf). 

Muscular Dystrophies and Myopathies
Dystrophinopathies are disorders related to absence or dysfunction of the dystrophin protein, which is encoded by the DMD gene. Duchenne muscular dystrophy (DMD) is the most common and well-known phenotype. Children with DMD typically present in early childhood with proximal weakness, toe walking, falling, and fatigue. Other phenotypes related to abnormalities in the DMD gene that are most likely to be encountered in the adult neurology clinic include Becker muscular dystrophy (BMD), the pseudometabolic phenotype, and manifesting female carriers.¹¹

In BMD, children or young adults often present with exercise-induced myalgias and may have mild weakness, muscle pseudohypertrophy, or elevated CK levels. The degree of weakness is variable, with some individuals losing ambulation in early adulthood and others maintaining the ability to walk late into life. Some men with BMD never develop weakness but have exercise-induced myalgias, elevated CK levels, and recurrent rhabdomyolysis—sometimes referred to as the pseudometabolic phenotype. Some men have asymptomatic hyperCKemia. Some female carriers can have muscle symptoms, myalgias, exercise intolerance, elevated CK levels, or weakness. All individuals with dystrophinopathies are at risk for cardiomyopathy and need to be screened even if skeletal muscle symptoms are mild. Many treatments are approved for DMD, but no treatments currently exist for the other forms of dystrophinopathy (Table 2).¹²

Limb-girdle muscular dystrophies (LGMDs) are a group of disorders with multiple genetic causes characterized by childhood or early-adult onset of proximal weakness with markedly elevated CK levels.¹³ Inheritance of LGMDs can be dominant or recessive. Examination will reveal proximal lower-extremity more than upper-extremity weakness, often with calf pseudohypertrophy. Depending on the LGMD subtype, respiratory or cardiac manifestations may be present or require monitoring. Inflammatory myopathies can have overlapping features, but typically have a more rapid onset. The use of multigene panels can help clinicians distinguish among the different LGMD genetic subtypes.¹⁴

Congenital myopathies are a genetic form of nondystrophic muscle disorders that do not lead to progressive muscle breakdown and weakness over time but are typically associated with a more stable or mildly progressive weakness (facial, axial, or proximal) from a young age. Most congenial myopathies are apparent soon after birth or in the first years of life, owing to hypotonia, gross motor delay, and bulbar and respiratory dysfunction. Some milder forms, with RYR1-related myopathy being the most common, may not get diagnosed in childhood even if symptoms were present earlier.¹⁵ While the majority of congenital myopathies have a proximal pattern of weakness, some distal predominant myopathies do exist.¹⁶ Examples include dysferlinopathies and Udd distal myopathy-tibial muscular dystrophy associated with TTN variants. Although these myopathies often mimic CMT and neuropathy due to the distal weakness and atrophy, sensation should be normal. NCS/EMG tests can assist with the clinical dignosis of these conditions. CK levels in individuals with myopathies are typically normal. Muscle imaging is increasingly being used for diagnosis, with some myopathies having characteristic patterns of muscle changes.¹⁷ Genetic testing (usually multigene panel or exome tests) is often the first-line diagnostic test, and is followed by muscle biopsy if the diagnosis remains unclear. 

Conclusion
Genetic pediatric neuromuscular disorders are frequently encountered in adult neurology clinics for several reasons: the expanding phenotype of many genetic neuromuscular disorders, now including adult-onset forms; recognition of neuromuscular symptoms in female carriers of pediatric X-linked disorders, such as DMD; and the increasing lifespan of children with previously life-limiting neuromuscular disorders, such as SMA. These forces require adult neurologists and neuromuscular providers to be familiar with a group of disorders previously considered outside their scope of practice.