News from the AAN Annual Meeting
Mutation Identified as a Cause of Novel Congenital Myasthenic Syndrome
ARTICLE IN BRIEF
Researchers identified a mutation causing a novel form of congenital myasthenic syndrome associated with cortical hyperexcitability, cerebellar ataxia, and intellectual disability in an 11-year-old girl.
WASHINGTON—The Mayo Clinic neurologist who was credited with identifying congenital myasthenic syndrome (CMS) in 1979 has now identified a mutation causing a novel form of the disease associated with cortical hyperexcitability, cerebellar ataxia, and intellectual disability in an 11-year-old girl.
Andrew G. Engel, MD, FAAN, a professor of neurology who this year is celebrating his 50th anniversary at the Mayo Clinic in Rochester, MN, was senior author of a paper published in Neurology that was presented here at the AAN Annual Meeting by his colleague and corresponding author Xin-Ming Shen, PhD, an associate professor of neurology at Mayo.
They and two other colleagues from Mayo used several methods to identify and characterize the molecular basis of the child's disorder, including clinical observations, studies of neuromuscular transmission, exome sequencing, immunoblotting, and other techniques.
Through exome sequencing, the researchers identified a dominant de novo p.Ile67Asn mutation in SNAP25B, a protein essential for triggering fast vesicle exocytosis, the process by which neurotransmitters packaged within synaptic vesicles are released from the synapse of one neuron so they can be taken up by another. SNAP25B also plays a role in docking the synaptic vesicles at the active zones of the presynaptic membrane, from which they can be released. In the absence of SNAP25, vesicle docking at the presynaptic active zones persists, but the pool of vesicles primed for release is empty, and fast calcium-triggered exocytosis is abolished.
Studies showed that the mutant SNAP25B expressed alone or in combination with wild-type SNAP25B reduces depolarization-evoked exocytosis from bovine chromaffin cells to about 30 percent of that found after transfection with wild-type alone.
Dr. Engel and colleagues concluded that the Ile67Asn mutation is pathogenic because it inhibits synaptic vesicle exocytosis. They treated the patient with amifampridine (Firdapse), which enhances synaptic vesicle exocytosis by increasing the entry of calcium into the nerve terminal when it is depolarized by a nerve impulse. It improved her weakness, but not her ataxia, and caused no seizures.
A longtime researcher in neuromuscular disorders praised both the study and Dr. Engel's long history of contributions to the field.
“Andy's laboratory has led the way in the elucidation of these syndromes,” said James F. Howard, MD, FAAN, chief of the neuromuscular disorders section at the University of North Carolina at Chapel Hill. “He is without doubt the most meticulous researcher in identifying the physiological, clinical, biochemical, and genetic aspect of these disorders. Our knowledge base is clearly linked to what his laboratory has been able to discover.”
The mutation in the SNAP25B protein is of interest beyond its effects on congenital myasthenic syndrome, Dr. Howard said. “This is a highly conserved protein through multiple species, with multiple neurological functions,” he told Neurology Today. “It's a bridge that can give us insight into other neurological diseases.” As noted in the paper, he said, variations in SNAP25 have been previously implicated in the pathogenesis of schizophrenia and may be associated with attention deficit hyperactivity disorder.
In an interview following Dr. Shen's presentation at the meeting, he and Dr. Engel called on clinical neurologists to think twice when they see patients who present with any of the perplexing array of symptoms, including delayed motor development, abnormal fatigability on exertion, eyelid ptosis, limited facial expression, dysphagia, dysarthria, limb and core muscle weakness, gait irregularities, or even shortness of breath.
“They can mimic other diseases and are often misdiagnosed,” Dr. Engel said. “Some neurologists are likely to suspect that it's a myasthenic disorder but aren't sure which type. It's important to know that medication that helps one type of CMS can make another type worse, so it's best to get an exact diagnosis.”
So far, more than 20 genes have been identified that cause CMS, Dr. Engel said. “At our center, we have investigated about 600 patients over the years. Among those, we have identified a genetic basis only in two-thirds. The remaining undiagnosed cases likely are caused by other mutations that we have not identified. But there's hope for the future. With the advent of better techniques for detecting mutations, such as exome sequencing and perhaps even whole genome sequencing, I would anticipate that more and more patients will be diagnosed.”
Disputing the notion that he was the first scientist to identify CMS, in 1979, Dr. Engel said he never considered lending his own name to the syndrome.
“I don't like eponymic diseases,” he said. “And mine was not the first description, because in 1937 Rothbart described a familial occurrence of myasthenia.”