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MLS, previously known as “Muscular Latency Syndrome,” is a congenital, genetic, progressive neuromuscular disease. Although the mechanism of disease is well understood (dysfunction of acetylcholinesterase at the neuromuscular junction, see below), the genetics are not. MLS tends to affect males more than females, so it's likely sex-linked, but scientists haven't yet identified the exact genes involved, and suspect it is probably due to multiple genetic factors.
Symptoms & Signs
The disease usually presents in early childhood, although due to its rarity, it is often misdiagnosed, or goes undiagnosed until later childhood, as early symptoms can often be mistaken for "growing pains." Children experience muscle pain and cramping, usually beginning in the lower limbs and working upward over time. Pain is often accompanied by muscle weakness, and ultimately paralysis. Although early in the course of the disease reflexes may be intact, over time reflexes diminish and ultimately disappear in the affected areas.
Most children need some kind of orthotic or other walking aid early in life, with the majority using wheelchairs by their late teens to mid-twenties.
In stage I of the disease, only the skeletal muscles are affected, usually beginning with the feet, progressing upward to the ankles, calves, thighs, hips, and then arms in a distal fashion. Progression is not perfectly symmetrical. Patients experience paroxysms, often precipitated or exacerbated by emotional or physiological stress, in which they experience asynchronous, asymmetrical fasciculations (muscle spasms), often accompanied by myotonia (delayed relaxation of the muscle due to overstimulation). Occasionally, spasms can be severe (and violent) enough as to be considered tetantic. Especially in the early stages of the disease, attacks are often followed by extended periods of extreme muscle weakness and hypotonia. Repeated overstimulation of the neuromuscular junction results in decreased sensitivity to acetylcholine, ultimately leading to paralysis of the affected muscles.
In stage II of the disease, smooth muscle and cardiac muscle (as well as the diaphragm) are affected, resulting in cardiac (bradycardia), circulatory (hypotension), and respiratory dysfunction (bronchoconstriction and increase mucosal secretions), in addition to GI disturbances and incontinence. As in stage I, the disease is progressive, with some patients losing function more quickly than others. Once a patient enters stage II, lifespan is usually no more than five years, with most dying of respiratory or cardiac failure.
Mechanism of Disease
The symptoms of MLS are caused by a defect in acetycholinesterase, the enzyme responsible for breaking down acetylcholine, the primary neurotransmitter involved in muscle contraction.
In normal muscle contraction, a nerve impulse results in the release of acetylcholine, which stimulates the muscle to contract. Acetylcholinesterase is then released to rapidly (and efficiently) metabolize acetylcholine in order to terminate the contraction.
However, due to the dysfunction of acetylcholinenesterase in the neuromuscular junction of MLS patients, acetylcholine is not broken down efficiently, causing it to build up and resulting in overstimulation of the muscle.
Although acetylcholine is found in the central nervous system, it is unaffected in MLS, as the defect is only in the neuromusclar junctions and acetylcholine does not pass the blood-brain barrier. This distinguishes MLS from other acetylcholinesterase-deficiency syndromes or neurotoxin poisoning such as organophosphate poisoning.
How the disease progresses from stage I to stage II is not fully understood, but it is theorized that it may have to do with a decrease in quality of acetylcholinesterase over time, perhaps due to secondary factors affecting acetylcholinesterase production.
In some very rare cases, patients actually produce and release more acetylcholine than normal, exacerbating symptoms, and leading to seepage of acetylcholine into the blood stream. In these patients, excess acetylcholine can reach areas of the body normally unaffected by the disease (at the current stage), such as the blood vessels, heart, diaphragm, and GI. These patients thus don’t present as pure stage-I or stage-II patients, but rather as a hybrid of the two during severe exacerbations. Although with current enzyme treatments this form of the disease is more easily managed, it is considered a more severe presentation than traditional dual-stage MLS.
Before the realization that acetylcholinesterase deficiency was the mechanism of disease, diagnosis of MLS was tricky, with many patients being misdiagnosed as having cerebral palsy or simply muscular dystrophy of unknown etiology. Diagnosis was often one of elimination, after other disorders had been ruled out.
Today, a simple blood test for acetycholine (along with history) is often enough to make a diagnosis of MLS.
Until 2006, treatment was largely devoted to maximizing function and minimizing pain through physical therapy and various muscle relaxants. Today, however, patients have access to enzyme-replacement therapy, which has revolutionized treatment of the disease.
Much like insulin for diabetics, MLS patients can dose themselves with replacement acetycholinesterase, decreasing blood and local acetylcholine levels, and minimizing symptoms. Early studies indicate that children who are diagnosed early and who begin rigorous treatment with enzyme replacement can minimize symptoms enough as to lead nearly normal lives. So far, early evidence indicates that enzyme replacement can vastly extend the lifespans of those with the disease, since stage II onset is greatly delayed and even possibly diverted in some patients.
However, access to enzyme therapy is limited due to the inherent instability of the enzyme and difficulty in producing it en masse, meaning many MLS patients must suffer without it until advances can be developed in its production, distribution, and cost.
Many patients, especially those suffering from the rarer variant in which excess acetylcholine is produced, can benefit from a low-choline diet, which minimizes the body’s ability to synthesize acetylcholine. However, acetylcholine is essential for proper nerve function (and choline is an essential nutrient), and thus cannot be completely eliminated from the diet. Likewise, due to the effects severe shifts of acetylcholine can cause, dosage of enzyme therapy must be carefully monitored and adjusted to prevent untoward side effects.
Dr. Ira Schwartz
Considered one of the foremost experts on MLS in the world, he founded a research and treatment clinic in New York City in 1980, devoted to researching new treatments for the disease as well as training nurses and therapists to ameliorate the lives of those afflicted by the disease. Largely due to a significant influx of private funding in 2005, Dr. Schwartz was able to develop an enzyme-replacement therapy, the first true treatment for MLS. He currently has expanded his clinic to both increase the amount of research as well as number of patients under his care, and is currently working on an improved enzyme treatment. In addition, his researchers are currently exploring the possible genetic origins of the disease in the hopes of one day finding a cure.