Update on Treatment of Common Inherited Neuromuscular Disorders
- Nancy L. Kuntz, MD
- Attending Physician, Neurology; Medical Director, Mazza Foundation Neuromuscular Program, Ann & Robert H. Lurie Children's Hospital of Chicago; Associate Professor of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine
- Disclosure: Dr. Kuntz has no industry relationships to disclose and does not refer to products that are still investigational or not labeled for the use in discussion.
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At the conclusion of this activity, participants will be able to:
- Explain the clinical advantage of early diagnosis in common pediatric neuromuscular disorders such as spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD)
- Describe the supportive and preventive care strategies that have improved quality of life and lifespan in SMA and DMD
- Identify potential future treatment strategies for children diagnosed with SMA and DMD
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It is an exciting time in history to be involved in caring for children with neuromuscular disorders. Two of the more common and clinically significant neuromuscular disorders in children — spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) — will be used to emphasize the recent changes in knowledge base and treatment.
Within the past several decades, identification of the responsible genes for SMA and DMD, as well as ongoing clinical translation of advances in basic science, has improved our understanding of these common neuromuscular problems in children. At present, consensus amongst expert clinicians has provided “standards of care” recommendations that can guide appropriate preventive and supportive care to optimize function and health for children with these disorders. Technological advances have improved quality of life by improving pulmonary status in children living at home, promoting improved bone health in children who are non-ambulatory (Figure 1) to minimize risk of painful, pathologic bone fractures and increasing independent communication and mobility (Figure 2).
Registries have been developed for both DMD and SMA to provide the advocacy and research communities with important information regarding prevalence, characteristics and location of individuals with these disorders. (See Table 1 for information on registries and family support websites).
The next decade is likely to see DMD and SMA added to newborn screening programs in the United States as cost-effective methods for screening have been developed and treatment strategies are being developed. Clinical treatment trials are in introductory phases at this time (http://www.clinicaltrials.gov/) and natural history studies and biomarker discovery studies are being completed.
Spinal muscular atrophy
SMA is an autosomal recessive disorder (carrier rate of 1:40) that causes morbidity and can lead to premature mortality from diffuse, respiratory and bulbar weakness. It is the third most common neuromuscular disorder and second most common cause of mortality from genetic disorders in children (most common fatal genetic disorder in infants). It has always been characterized as a “motor neuron disorder” due to prominently decreased numbers of anterior horn cells noted at autopsy. However, scientists have identified the causative gene on chromosome 5 and it has been demonstrated to support RNA splicing.
It has been intriguing to speculate why such a ubiquitous gene defect primarily causes muscle weakness without other prominent symptoms. Current theories suggest that the motor axon and the neuromuscular junction are disproportionately impacted by the RNA splicing defect due to the demanding physiologic requirements of axonal transport. However, the reason is not certain and the most severely affected infants (with the most significantly decreased survival motor neuron or SMN protein levels) have deficits in sensory and autonomic functioning as well as cardiovascular and other birth defects.
All patients with SMA completely lack function of the SMN1 gene. However, SMA patients have variable numbers of SMN2 copies that produce some weakly functioning SMN protein (see Figure 3).
SMA patients who present during infancy (Werdnig-Hoffman phenotype or SMA I) usually have only 2 copies of SMN2 while ambulant SMA patients (Kugelberg-Welander or SMA III) who present during childhood have 3-6 copies. Careful physiologic studies performed by Swoboda have demonstrated that there is a dramatic loss of motor units within the first 6 months of life in infants with SMA I and within the first 2 years of life in children with SMA II, both followed by a plateau in motor unit counts and a clinical slowing of progression (see Figure 4).
Proactive management of nutrition and respiratory function in infants with SMA has been shown to improve quality of life and survival. Furthermore, early diagnosis with optimal supportive care will support upcoming randomized clinical treatment trials by having all potential study subjects in the best possible state of health.
Duchenne muscular dystrophy
DMD, an X-linked genetic disorder, occurs in 1:3500 live male births and has a high incidence of spontaneous gene mutation (approximately 30%), which limits the ability to prevent this disease through informed family planning.[3,4] DMD is associated with significant morbidity and, even with optimal supportive care, boys frequently lose independent ambulation by teenage years and often require ventilatory support by late adolescence or young adult years. Even as median survival has responded to improvements in supportive care, boys and men with DMD have shortened life expectancy, though a median survival to 40 years of age has been documented and is a significant improvement over years past.
Diagnosis of DMD occurs at a mean age of 5 years. This late identification of disease likely occurs because of the high fraction of de novo mutations, in which case families are unprepared for delays in a boy’s motor development. Late identification of DMD is unfortunate because the peak of inflammatory and necrotic pathologic change occurs within the first few years of life before clinical symptoms are obvious to the family. Figure 5 displays muscle biopsies from 2 boys with DMD. The histologic section on the top is from a 2-year-old boy with DMD. While there is a mild increase in variability of fiber diameter and a cellular infiltrate, there is little evidence of frank necrosis of muscle fiber or fatty/fibrous replacement. The panel on the bottom shows a histologic section from a 6-year-old boy with DMD demonstrating that necrotic change with fat and fibrous replacement of much of the muscle has occurred by the time the diagnosis is usually made.
Newborn screening pilots have demonstrated effective identification of infants with DMD.[4,8] However, ethical standards for newborn screening require that treatment be available for any condition that is to be presymptomatically identified. Infants and toddlers with DMD usually demonstrate mild delays in acquisition of motor milestones. However, they clearly gain muscle strength and motor skills over a number of years before they plateau and then lose motor skills. This natural history makes it complex to select outcome measures for DMD clinical treatment trials beginning in early infancy.
The Centers for Disease Control and Prevention (CDC) has examined the issue of diagnosing DMD and has encouraged 2 changes in general pediatric health surveillance, summarizing this guidance with slogans: “Watch them walk” and “If delay, think CK.” Dystrophin, the deficient protein in DMD, also occurs in heart muscle and brain. Heart involvement is usually symptomatic later than skeletal muscle and cardiomyopathy is an important contributor to morbidity. Females who are carriers of dystrophin mutations can develop symptomatic cardiomyopathy, usually during adult life. There is an increased incidence of autism spectrum disorder and the median IQ is slightly lower in dystrophinopathies than age-matched peers. Verbal and language skills appear to be more affected than performance issues. Therefore, if young boys have mild motor delays, language or cognitive delays or autistic features, a cost-effective diagnostic screen would be to obtain a serum CK, which is always significantly elevated during preschool years.
As attention has been directed over the past decade toward nutrition, bone health and prevention of orthopedic and respiratory problems, there has been a clear improvement in function, quality of life and survival for children with neuromuscular disorders. For example, SMA patients were historically subdivided by age at onset and survival with the most severe form (Type I) defined as infants with clinical onset by 6 months of age and death by 2 years of age. With the recognition of a plateau in clinical progression and with proactive respiratory and nutritional supports, survival and quality of life for non-ambulatory SMA patients has increased. Natural history studies have noted that individuals with milder forms of SMA who are able to sit independently (but who do not progress to independent ambulation) maintain their sitting to a median age of 14 years. SMA patients who can walk independently, but whose weakness is marked enough that they are diagnosed prior to 2 years of age, have walked independently to a median age of 12 years. Other ambulant SMA patients, diagnosed after 2 years of age, walked to a median age of 44 years. Consensus standards of care for infants and children with SMA were developed and published in 2007 and have created a useful benchmark for all care. Table 2 outlines considerations in providing comprehensive care to infants and children with SMA.
Table 2: Consensus Standards for Treatment of Children with Spinal Muscular Atrophy
o Impaired cough
o Hypoventilation during sleep
o Chest wall deformities
o Recurrent infection
|GI and Nutritional Care:
o Feeding and swallowing problems
o GI dysmotility
o Nutrition and growth
|Orthopedic Care and Rehabilitation:
o Scoliosis and posture management
o Contracture and pain management
o Orthotics and adaptive equipment
o Developmental therapies
Textbooks had classically defined Duchenne muscular dystrophy as a disorder that caused loss of ambulation by 12 years of age with death by 20 years of age. More recent experience demonstrates that, with current levels of supportive care, many boys with DMD walk independently until their late teens with a median survival of 40 years of age for boys and men treated with non-invasive ventilatory support, steroid therapy and management of scoliosis. Standards of supportive care have been published both to improve outcomes as well as to promote equivalent types of care in preparation for introducing new treatments via clinical trials. Table 3 details the multiple areas of focus for clinicians providing care to boys with Duchenne muscular dystrophy.
Table 3: Consensus Standards of Care for Boys with Duchenne Muscular Dystrophy
· Neuromuscular and skeletal assessments
· Use of glucocorticoids
· Psychosocial management
· Management of muscle extensibility and joint contractures
· Physical therapy interventions
· Surgical interventions for low limb contracture
· Exercise recommendations
· Skeletal management
· Assistive/adaptive devices
· Respiratory management
· Cardiac management
· Nutritional, swallowing, GI and speech and language issues
· Pain management
· Surgical considerations
Development of multidisciplinary clinics staffed by professionals from a number of different disciplines – neuromuscular specialists, pulmonologists, orthopedic surgeons, cardiologists, physiatrists, metabolic bone health specialists, physical therapists, occupational therapists, orthotists, nutritionists, nurse educators, genetic counselors and social workers – have improved the ability of centers and families to provide the comprehensive care that has improved the health and quality of life of infants, children and adolescents with complex neuromuscular conditions. (Read about the multidisciplinary Muscular Dystrophy Association (MDA) Clinic at Lurie Children’s or call 312.227.4473.)
It is important that children with SMA and DMD receive comprehensive supportive care both to improve their individual health and well-being and also to provide a cohort of patients at a similar baseline level of intervention who will be available for participation in upcoming clinical treatment trials.
Clinical treatment trials
The NIH sponsored website (http://www.clinicaltrials.gov/) lists completed, active and recruiting trials relating to different diseases. The SMA listing indicates 16 completed trials relating to treatment, primarily evaluating repurposed drugs which had shown promise in basic science screens of SMA cell lines and in animal models: valproic acid, hydroxyurea, sodium phenylbutyrate, riluzole and salbutamol. While individual patients sometimes appear to have benefitted from treatment with these agents, controlled trials have not demonstrated clear benefit from any of these agents. At present, there are several trials relating to improving definition of the natural history and establishing imaging and serologic biomarkers of disease progression. One of these multicenter trials sponsored by the NeuroNeXT network is currently enrolling infants with SMA 6 months of age and under for participation. There are ongoing safety trials evaluating intrathecal administration of antisense oligonucleotides (ASO) in small numbers of older children with SMA. This gene therapy hopes to improve SMN protein levels by having the ASO bind to the SMN2 gene and improve RNA splicing. Another upcoming treatment trial for SMA involves systemic administration of a quinazolone compound that was identified in high throughput drug screens funded by Families of SMA as an agent that increased SMN protein production in SMA cell lines. Subsequent research has optimized the compound for maximum efficacy and minimum side effects in animal models of SMA. A major pharmaceutical company has recently contracted with Families of SMA to implement future clinical drug trials of quinazolone compounds in SMA patients . The timing of the gene therapy and quinazolone clinical treatment trials are currently undetermined. Participation in the International SMA Registry and MDA clinics is the most certain manner to remain informed and optimize potential future participation.In addition to natural history and biomarker discovery trials, clinicaltrials.gov lists 32 completed clinical treatment trials for DMD and 20 that are actively recruiting, including some directed toward prevention of cardiomyopathy. About 15% of dystrophin mutations are nonsense mutations (stop codon) that truncate the protein, producing a non-functional form of dystrophin. Pharmaceutical companies have performed several treatment trials with ataluren, a compound which promotes reading-through the stop codon. Phase II trials have been promising enough that a Phase III trial is currently ongoing for boys with this type of mutation. While oral corticosteroid regimens have been used for several decades, different formulations of corticosteroid and different dosing regimens are used in various parts of the world. An international, multi-center trial comparing daily prednisone, daily deflazacort (a fluorinated corticosteroid formulation currently not FDA approved in the US) and intermittent prednisone is ongoing. Phase II/III trials of EGC (a green tea extract) are ongoing. There are Phase I/II trials ongoing with gene therapy for DMD. AAV vector- delivered microdystrophin gene has been injected directly into muscles with demonstration of subsequent local dystrophin expression. Future efficacy of this approach for treatment of DMD will depend on whether local administration can lead to more widespread expression of the dystrophin and whether systemic administration of the viral vector will be proven safe and effective. Additionally, exon-skipping using IV or subcutaneous administration of various forms of antisense oligonucleotides has demonstrated induction of dystrophin expression. With these protocols, the treatment creates additional deletion of the dystrophin gene designed to bring the gene back into reading frame and producing some, shorter length dystrophin protein (a Becker-like phenotype) rather than having no dystrophin protein produced (a Duchenne phenotype). Larger trials of gene therapy are anticipated. Finally, compounds to promote production of utrophin (a structural protein similar to dystrophin that is present during fetal life but which doesn’t persist into postnatal life under typical circumstances) are likely to be involved in clinical trials within the next few years.
The hope for improved quality of life and curative treatments held by families whose children have SMA and DMD is closer to being achieved. Basic science has identified the genes involved and begun to unravel the pathophysiology of tissue injury and destruction in these disorders. Consensus standards of care (to optimize health and function) have been implemented and are available to children in comprehensive multidisciplinary clinics. Technological advances are supporting improved communication and mobility in infants, children and adolescents with neuromuscular disorders. Early safety and dose-finding trials have been conducted for some supportive treatments and gene therapy in SMA and DMD. Additional trials using refined and more targeted therapies are being planned. Concurrently, natural history and biomarker discovery trials are being planned and performed to support the clinical treatment trials. Inclusion of SMA and DMD in newborn screening programs will be important as early initiation of treatment will clearly mitigate some of the tissue injury from these inherited neuromuscular disorders. It is a very rewarding time to care for children with neuromuscular problems.
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