An expert neurologist, Emma Ciafaloni, MD, provides an overview of the epidemiology of spinal muscular atrophy and discusses symptom burden, differential diagnosis, and prevalence.
Dennis Scanlon, PhD: Hello and welcome to this AJMC® program, “Reducing Disease Burden through Early Diagnosis and Treatment of Spinal Muscular Atrophy [SMA].” I am Dr Dennis Scanlon, distinguished professor of health policy and administration at the Pennsylvania State University. Joining me today in this virtual discussion are my colleagues, Dr Emma Ciafaloni, professor of neurology and pediatrics at the University of Rochester Medical Center; Dr Maria Lopes, chief medical officer at AMC Health; Dr Kevin Stephens, regional chief medical officer with UnitedHealthcare; and Dr Mary Schroth with Cure SMA.
Today, our panel of experts will provide an overview of the burden of disease and unmet needs in SMA for adults and pediatrics. We’ll also review available treatment options, including some new therapies, and we’ll discuss future directions in the treatment of SMA, including some of the challenges and considerations with respect to ethics and cost effectiveness. Thank you and let’s begin.
Welcome, everyone. I really appreciate you joining me today. As we often do when we start a panel like this, we want to ground ourselves in the background of the epidemiology and the burden of disease. Dr Ciafaloni, can you describe for our audience what SMA is, its burden, the prevalence, and various typologies?
Emma Ciafaloni, MD: Thank you, and thanks for inviting me. Spinal muscular atrophy is a genetic monogenic disease, and it’s inherited in an autosomal recessive manner. The disease is caused by a mutation in the SMN1, survival motor neuron 1, gene. SMN1 is the main gene producing the SMN, survival motor neuron, protein. Although the disease is caused by just 1 gene, the phenotype is actually multiform in the sense that the severity varies, and it is classified into types 1 to 4. The types are defined by the onset of symptoms. In type 1, the onset of symptoms occurs between 0 and 6 months of age. In type 2, the onset of symptoms occurs between 6 months and 18 months. In type 3, the onset occurs at 18 months and older. Type 4, which is extremely rare, is when the onset of the disease is in adulthood, after age 18.
It’s important to remember that, although the disease sits in the pathophysiologies in the SMN1 gene, there is a backup gene, the SMN2 gene, that is the best-known modulator of phenotype severity. This becomes very important when we talk about the mechanism of action of different drugs. The more copies of the SMN2 gene, the milder the phenotype. For example, babies with type 1 usually have 2 copies of the SMN2 gene, patients with type 2 usually have 3 copies, and so forth. It’s not 100% correlated, but it’s the best-known modifier of the phenotype.
It’s also important to remember the natural history of, for example, type 1, which is the most severe type. These babies are never able to sit or reach major milestones. They will never be able to breathe on their own, eat on their own, or speak. It’s very well described. As we go into the milder phenotypes, especially in types 3 and 4, the natural history is not as robust as in type 1. This is relevant when we look at the data in the clinical trials.
The other important thing for what we’re going to talk about today is that when we look at new cases, the incidence of SMA is about 1 in 10,000. Those numbers are not perfect; they’re quite old. This is a rare disease overall, so with the newborn screening, we’re going to learn a whole new epidemiology and incidence prevalence. It’s important to remember that most of the new cases are either type 1 or type 2, but due to the very severe morbidity and mortality in babies with type 1 and type 2, the prevalent cases that we follow in our clinic are actually mostly types 2 and 3. Surviving patients with SMA tend to be types 2 and 3. This is all about to change due to the new disease-modifying treatments. It’s a recessive disease, so about 1 in 50 people in the population are carriers for the SMA gene defect. That’s it in a nutshell. It’s important to remember that there are milestones related to the phenotype.
Dennis Scanlon, PhD: Could you talk a little bit about the process of diagnosis and some of the differential diagnoses as you get into types 2 through 4?
Emma Ciafaloni, MD: Absolutely. In the big picture, SMA is by definition a rare disease. The FDA defines a rare disease as anything that affects fewer than 200,000 people. In a way, it’s ultra-rare, because we’re talking about a prevalence overall of about 10,000 to 12,000 people in the United States. For a neurologist like me, this is one of the most dreadful diagnoses that we are trained to diagnose. When you walk in the room and see floppy baby syndrome, SMA is not a difficult diagnosis, unfortunately. It’s one of the most traumatic, in the sense that these are very bright babies, and yet you know that their natural history is very severe and the outcome very poor. Over the years, the diagnosis has mostly been based on symptoms. Babies with the most severe form usually have floppy baby syndrome and are unable to breathe or swallow. They may or may not make it out of the NICU [neonatal intensive care unit], or they might go home and bounce back into the hospital with respiratory infection. They’re unable to really breathe, they have belly breathing, they’re floppy, and they cannot hold their heads up.
Type 2 usually comes a little bit later. They might reach [some] milestones like being able to sit independently, but then they clearly demonstrate major developmental delay, are never able to really walk independently, and they lose some of their motor skills. Type 3 consists of younger kids who walk independently, reach their milestones, and can breathe on their own. But over time, they have trouble, especially with lower extremity weakness and trouble walking, jumping, and running. Eventually, although they reach the milestone of independent ambulation over years, they will frequently become wheelchair-bound over time, develop scoliosis, contracture, and respiratory problems. It is a clinical diagnosis based on symptoms.
There have been published data that tell us that even in the type 1, which are very severely affected babies, the diagnostic delay or diagnostic odyssey is very prominent, like in many other rare neurological diseases. Even in type 1, we have a 3.6-month average delay between the onset of symptoms and diagnosis. If you go to types 2 and 3, that becomes even greater. In type 3, it’s a delay of almost 4 years. With type 4, which is adult onset and very rare, there are probably many patients being misdiagnosed with perhaps limb-girdle muscular dystrophy, MS [multiple sclerosis], or other neurological disorders. The main differential diagnosis is with either muscular dystrophy or congenital myopathies. Generally speaking, the cardinal features are the lack of sensory symptoms, usually absent reflexes, and motor delay. This shouldn’t be a difficult diagnosis for a neurologist.
Transcript edited for clarity.