Treatment and Management of Spinal Muscular Atrophy and Congenital Myopathies

Introduction

Although spinal muscular atrophy (SMA) and the congenital myopathies (CMs) have different etiologic features, they have similar clinical characteristics, and the decision to address them together is consistent with the similarities in the supportive management of these two groups. Advances in gene-based therapies over the last few years have significantly altered the therapeutic management and natural course of these disorders, in particular SMA. We will discuss the distinctions in medical management, as well as future directions for therapies.

Common clinical features include early onset, proximal, symmetrical weakness, hypotonia, and, in most, preserved mentation.

Some of the severe, neonatal forms of CM resemble SMA type 1. Without therapeutic interventions, respiratory support is frequently necessary for both groups and there is high rate of morbidity and mortality related to restrictive lung disease (RLD). Prior to the development of gene-based therapies for SMA, the prognosis of severe forms of CM was more favorable than that for SMA type 1. However, with treatment, the natural history of all types of SMA is changing and course of disease is more stable or less severe. There is much more to learn about the long-term outcomes of patients with SMA who have been treated with novel gene therapies.

Diagnosis and Evaluation

SMA is an autosomal recessive neuromuscular disorder of infancy, childhood, and young adulthood. Its incidence is estimated to be 1 in 11,000 live births. SMA was first described at the end of the nineteenth century ( ; ), and its causative gene, SMN1 , was discovered in 1995 ( ). Homozygous deletion or other mutations of the SMN1 gene located on chromosome 5q cause degeneration of anterior horn motor neurons. 5q SMA represents 95% of all SMAs. The rest represent a heterogeneous group of disorders sharing the same involvement of anterior horn motor neurons, such as SMA with distal involvement, Kennedy disease, SMA with respiratory distress (SMARD), Hirayama disease, and juvenile amyotrophic lateral sclerosis. Clinical entities with established genetic linkage are included in Table 13.1 . SMA is characterized by progressive, predominantly proximal symmetrical muscle weakness with normal sensation, depressed or absent reflexes, and preserved cognition. Prior to gene-based therapies, an acute phase of rapid decline in muscle strength was noted, followed by a phase of relative stabilization, which extended over long periods of time.

Since the initial classification in 1961 ( ), multiple classification systems have been described. Prior to the emergence of gene therapies, the most accepted classification included types 1 to 4, and these were described based on onset of symptoms and highest motor function achieved ( ). This phenotypical classification may no longer apply since gene-based therapies have an effect on phenotype, prognosis, and survival. It is perhaps more useful to describe SMA type based on the ability to sit or walk, for example, “nonsitters,” “sitters,” and “walkers.” Another possible option is a classification based on the number of copies of the SMN2 genes. Without any treatment, type 1 patients have symptom onset in the first 6 months, are unable to sit independently, have early feeding and breathing difficulties, and die by age 2 years. Pectus excavatum or carinatum, bell-shaped chest, and paradoxical breathing are common ( Figs. 13.1 and 13.2 ). Type 2 SMA is characterized by onset between 6 and 18 months; patients sit unsupported and survive into young adulthood or later. They have proximal symmetrical muscle weakness of the lower extremities more than upper. They often present with failure to achieve the ability to walk. Type 3 patients have onset after 18 months of age, walk independently at some time, and can have normal life expectancy. Some lose ambulation by midadolescence and some develop RLD. This clinical heterogeneity was in great part explained with the discovery of the SMN2 gene, whose transcription produces a small amount of full length (fl-) SMN protein. In general, the more copies of SMN2 gene, the less severe and the later the onset of the disease ( ).

SMA diagnosis used to rely on electrodiagnostic studies (denervation with normal motor and sensory nerve conductions) and muscle biopsy (grouped atrophy). Currently, targeted mutation analysis is used to detect deletion of exons 7 and 8 of the SMN1 gene and to determine the number of copies of the SMN2 gene. A homozygous SMN1 deletion is diagnostic. This is the initial test in an infant or child with a typical presentation and should be performed as soon as a diagnosis is suspected. SMA was added to the Federal Recommended Uniform Screening Panel for newborn screening in 2018. Currently, several states have adopted and implemented newborn screening for SMA ( ). Establishing a diagnosis early is of vital importance as the treatment outcomes are better the earlier an individual is treated. Serum creatine kinase (CK) can be normal or mildly elevated in SMA. If targeted mutation analysis detects one copy of the SMN1 gene in an otherwise typical patient, gene sequencing is necessary as a small proportion of SMA patients (2%–5%) may have an intragenic mutation of SMN1 . Occasional patients with double heterozygote SMN1 point mutations are seen. SMN1 gene sequencing should be considered in typical patients with two SMN1 copies and negative SMARD genetic testing. If SMA genetic testing is negative, then 5q SMA is not confirmed and further genetic testing, electrodiagnostic studies, or muscle and nerve biopsies should be pursued.

CMs are a genetically and pathologically heterogeneous group of muscle disorders that share a similar clinical picture dominated by neonatal or infantile weakness and hypotonia and characteristic morphologic changes on muscle biopsy ( Table 13.2 ). The incidence of CM is suspected to be at least 1–25,000 with core myopathies, and specifically RYR1 mutations being the most common ( ; ). Facial weakness, bulbar weakness, and ptosis are common. Ophthalmoparesis is not typical but has been described with some mutations (DMM2, MTM1, and autosomal recessive [AR] RYR1 mutations). Other common characteristics include decreased or absent reflexes, respiratory insufficiency, early feeding problems, small muscle bulk, craniofacial deformities, and spine and limb deformities. Cardiomyopathy and malignant hyperthermia are associated with some forms of CM. Sensation and cognition are typically preserved. The spectrum of severity of CM extends from fatal neonatal forms to minimally symptomatic adult forms. In severe forms of CM, symptoms can start prenatally with reduced fetal movements and polyhydramnios, leading to craniofacial dysmorphisms, arthrogryposis, or pulmonary hypoplasia ( ; ). Most CMs have a nonprogressive course, although some forms may show progressive weakness.

As with SMA, the diagnosis of CM used to rely on clinical exam, history, electrodiagnostic studies, and muscle biopsy. The emergence of next-generation sequencing has led to faster and less invasive diagnosis when a myopathy is clinically suspected. Many novel genes have been discovered using this technology, and to date, there are at least 32 genes that are associated with a definitive clinical and histopathologic diagnosis of CM ( ).

Genetic testing yields a diagnosis in approximately 60%–80% of the clinical cases. Comprehensive neuromuscular gene panels are currently the most effective for genetic diagnosis. However, whole exome sequencing is more widely used ( ). Creatine kinase (CK) levels, electrodiagnostic studies, and muscle biopsy still play a role in diagnosing atypical cases, when variants of unclear clinical significance are found and need pathologic correlation, or when a genetic cause is not identified. CK levels are usually normal or slightly elevated (less than 5 times the upper limit of normal); higher levels should raise suspicion for an alternative diagnosis such as muscular dystrophy. Nerve conduction studies show usually normal sensory responses, and motor studies may show normal or low amplitude units. Electromyography shows myopathic changes. Muscle ultrasound and muscle magnetic resonance imaging can be used as a screening tool and to help differentiate between CM types. Ultrasound may be particularly useful in younger patients as it does not require sedation. The detection of pathological changes can be helpful in guiding muscle biopsy, and the description of the muscle involvement pattern might help in the differential diagnosis ( ; ).

A genetic diagnosis has important benefits beyond the diagnostic value. It allows for counseling for carrier status and family planning, prognosis, and risk for other organ involvement; with current gene-based therapy advances, it may help identify treatments for specific gene mutations in the future.

Traditionally, CMs have been classified by characteristic morphologic changes on muscle biopsy ( Table 13.2 ). The most common and better described are central core disease, nemaline myopathy (NM), centronuclear myopathy (CNM), and congenital fiber-type disproportion (CFTD). The increased identification of genetic mutations causing CM has demonstrated an overlap between the different genetic changes and traditional histologic subtypes on muscle biopsy. In other words, multiple gene mutations can cause the same histologic changes, and some gene mutations can cause more than one pathologic change. Furthermore, some genetic changes are not associated with any of the classical pathologic changes. It is also now recognized that cases arising from mutations in genes traditionally associated with CM can also lead to a congenital muscular dystrophy phenotype ( ; ; ; ). In the last several years, the use of muscle biopsies has declined, decreasing the association of pathological features with specific gene mutations, and it has therefore become more common to refer to CM by its causative gene, rather than the traditional pathological changes, e.g., ACTA1 -disease, RYR1 -related diseases, and titinopathies.

Central core myopathies are histologically characterized by foci lacking oxidative enzymes in myofibers. These are usually seen in type 1 muscle fibers by light microscopy. They are further divided into central core and multiminicore myopathies. Most core myopathies are associated with autosomal dominant or AR gene mutations in the ryanodine receptor (RYR1) gene ( ; ). Phenotypes are variable ranging from mild to severe, and severity of phenotype can vary within members of the same family. AR mutations are clinically more severe. Most individuals with RYR1 mutations have mild to moderate weakness with a static or slowly progressive course. Patients with this mutation may also be at risk for malignant hyperthermia. There are severe neonatal core myopathies that can present with marked joint laxity, severe weakness, muscle atrophy, respiratory insufficiency, and failure to thrive. There are some reports of cases that present with fetal akinesia and congenital arthrogryposis ( ). Multiminicore myopathies also have variable phenotypes with onset typically in childhood or adolescence. The most common type presents with axial weakness, scoliosis, respiratory involvement, and torticollis. The degree of weakness does not typically correlate with the severity of respiratory insufficiency ( ; ).

Nemaline myopathies are histologically characterized by electron-dense nemaline bodies or rods within myofibers. Variants include cap myopathy, zebra body myopathy, and core rod myopathy ( ). Clinical phenotypes are highly variable. Most NMs present with axial and limb-girdle weakness progressing to distal muscles. Congenital forms present with facial, respiratory, axial, and proximal muscle weakness. Some present with arthrogryposis and dilated cardiomyopathy. Many patients succumb because of respiratory failure or aspiration pneumonia in the first year of life. There are some forms of NM that present with hypertonia and muscle stiffness. There are several genes associated with NM. Mutations of the Nebulin (NEB) are the most common form of recessive “typical” nemaline rod myopathy. Other genes like α-Actin (ACTA1) represent 20% of rod myopathies, usually inherited in an AR fashion, but dominant and sporadic forms have been identified ( ).

Centronuclear myopathies are histologically characterized by centrally located nuclei that resemble fetal myotubules. Myotubular myopathy refers to the X-linked form and is caused by mutations in the myotubularin ( MTM ) gene. It mostly affects boys and can present in utero with polyhydramnios and decreased fetal movements ( ). Boys are born with hypotonia, arthrogryposis, pronounced facial weakness, ophthalmoplegia, respiratory insufficiency, and axial muscle weakness. It has high mortality and morbidity rates from pulmonary complications in the first year of life ( ). Autosomal CNM myopathies have a greater genetic heterogenicity and variable phenotypes. De novo mutations have been described and have an earlier onset and more severe phenotype. Most present in childhood or adulthood with slow progression of weakness, fatigue, and exercise intolerance. Some cases of asymmetric weakness have been described. Mutations in SPEG can also cause cardiomyopathy. Individuals with some subtypes of CNM may have neuromuscular junction (NMJ) features and respond to anticholinesterase therapy ( ).

CFTD:fiber type disproportion can be seen with several types of myopathies, central nervous system disorders, and metabolic disorders. However, the difference in caliber is typically smaller than with CFTD, which is defined by type 1 fibers being consistently smaller in diameter than type 2 fibers by more than 35% to 40% in the absence of other histopathologic abnormalities. Most CFTD myopathies are static or slowly progressive. They present with variable degrees of hypotonia, respiratory insufficiency, facial diplegia, dysphagia, and ophthalmoparesis ( ).

Other histologic features have been described, including hyaline body or myosin storage, neck lace fiber, radial sarcoplasmic strands, actin aggregates, cylindrical spirals, and lobulated myofibers.

Treatment and Management

Until 2016, no treatment was available for SMA, and management consisted of supportive measures: providing adequate nutrition and respiratory support, and preventing complications of weakness. There are now three novel gene therapies for SMA, and more therapies are being studied for treatment of SMA and some types of CM. In addition to treatment with these novel therapies, symptomatic management remains a vital part of caring for patients with both SMA and CM. The goal is to manage the complications of weakness and hypotonia while maintaining quality of life ( ; ; ). Management is multidisciplinary and should take place in specialized neuromuscular clinics under direct supervision of a pediatric subspecialist (usually a pediatric neurologist) with expertise in SMA and CM. Specialties involved should include orthopedics, pulmonology, and gastroenterology as well as physical, occupational, and speech therapists. Patient and parent education is paramount and should start at the time of diagnosis. Parents should be exposed to all available options of treatment and palliation and supported to make the best decisions in their particular circumstance. They should have a clinic contact number and clear guidelines for when to seek medical attention and fast access into the specialty hospital. Families should also talk to a specialist prior to major procedures that may require anesthesia, as some CMs are associated with malignant hyperthermia and/or are more sensitive to sedatives.