Familial periodic paralysis

Mr. Chang can't move his legs, and if something isn't done, his lungs will go next

CAN'T MOVE," SAID RITA, THE new intern, after examining her latest patient. "Twenty-three-year-old Chinese male. Says his brother has the same problem sometimes." Her face scrunched up. She was stumped.

"He's had it before?" I asked.

"Apparently."

"Did you ever hear of familial periodic paralysis?"

"No." She frowned.

"Neither had I until my first case seven years ago. Pretty odd, but very real."

There are thousands of Mendelian diseases, so called because they are passed from parent to child in much the same way Gregor Mendel's pea plants inherited traits such as color, height, and wrinkly pods. The periodic paralyses, a group of genetic diseases, are autosomal dominant, so a child with one affected parent has a 50-50 chance of acquiring the disease. Although the conditions are not common--they occur in roughly one in 100,000 people--certain ethnic groups have a higher frequency of the mutations that cause them. The hunt for the genes responsible has made for some fascinating molecular sleuthing over the past decade.

Rita and I strolled over to her patient, Mr. Chang. On the way, Karen, our translator, joined us.

"What's the matter?" I asked.

"He can't move his legs," Karen said.

"Since when?"

"This morning. Says he ate too many pancakes."

"How many times has he stopped moving before?"

"Three or four. Where he comes from in China, he says, everybody has it."

Mr. Chang, slim and unperturbed, answered our questions with his arms crossed behind his head, beach-chair style. That's always the weirdest part of this condition--how well the patients look. But just as he said, Mr. Chang couldn't lift his legs. His reflexes--ankle and knee jerks--had disappeared as well. But

his toes betrayed a faint wiggle. The rest of his exam was completely normal.

Something was going wrong in Mr. Chang's ion channels. Millions of them, staggeringly intricate in design and function, dot certain cell membranes, and Mr. Chang's muscle cells weren't about to move unless his nerves prompted their ion channels to spring open like molecular sluice gates. For the channels to work, the cells must reach a certain internal electrical charge. Only then will they let sodium and calcium rush in and potassium rush out. This flow of ions kick-starts the contractile proteins actin and myosin.

Each type of ion channel allows only one particular ion, whether potassium, sodium, or calcium, to pass through. And each type of channel opens at a different voltage. Yet the channels must act in flawless harmony each time you so much as blink an eye.

The key to restoring Mr. Chang's mobility was to create conditions in the blood that would help the cells reach the electrical charge they needed to fire. Getting his potassium to a normal level would do the trick. But we had to act fast. Although the paralysis is usually partial and transient, I had seen how quickly it could turn complete. Once I was on duty with an attending physician who recognized the syndrome but then got busy and didn't get around to checking the patient's potassium levels. After a few hours, the nurse rushed over, shouting that the patient wasn't breathing. Two anesthesiologists came charging down to intubate him. The respirator assisted his failing diaphragm while we pumped potassium down a nasogastric tube. He recovered, but it was a close call.

"Check his K," I told Rita. "There are two versions of periodic paralysis, one associated with low potassium, the other high. If you give potassium to a high, you can really paralyze him."

"So we wait for the lab results," Rita said, smiling. "You bet."

"What makes the potassium go up or down?" she asked.

"Nobody knows. High-carbohydrate meals do stimulate insulin secretion, which can push potassium into cells. But most of us don't end up paralyzed after a binge at International House of Pancakes," I explained.

Mr. Chang's potassium came back a startlingly low 1.5.

Normal is 3.5 to 5 milliequivalents per liter. We gave him some potassium to drink and sat back to watch.

These strange paralytic conditions have been described for nearly a century. Patients can often learn to prevent attacks by avoiding strenuous exercise, which can cause swings in potassium levels, and eating foods that are either high or low in potassium.

Thanks to the new tools of molecular biology, researchers have begun to tease out the genetic origins of diseases like the periodic paralyses. A landmark 1990 study of a large family with a tendency toward hyperkalemic (high-potassium) periodic paralysis helped identify the mutation responsible. Researchers decided to take a look at the gene that encodes the sodium channel in muscle. By comparing the gene in family members with and without the condition, they found the key difference. The mutant gene causes one wrong amino acid to be inserted in the proteins that form the channel, and that misfit amino acid causes the channel to malfunction.

A few years later, a similar slight change in the gene encoding the calcium channel in muscle was linked to hypokalemic (low-potassium) paralysis. But no one yet knows how it malfunctions, nor how a defective calcium channel could cause low levels of potassium in the blood. And other questions about the disorder remain. Why are men affected three times more often than women? Why do some people with the gene never show symptoms? And why do some patients have only a few episodes, while others suffer ever more frequent attacks, leading to permanent muscle damage?

Despite what we know about the genetics of the periodic paralyses, the origins of the disease are far from fully understood. For instance, just when the molecular details of hypokalemic paralysis appeared locked up, researchers discovered a family with normal calcium channels who still had symptoms of the disease. The family's problem was caused by a different mutation. Yet even when the disease is caused by the same mutation, it can provoke dramatically different degrees of illness. It turns out that predicting the effect of a defective gene is often a murky business, complicated by interactions with other genes and the environment.

Two hours after his first dose of potassium, Mr. Chang lifted his legs. We gave him another slug, and soon he was strolling about the emergency room, none the worse for his episode of paralysis.

A day later, Rita got ready to discharge Mr. Chang.

"See if he would like to try acetazolamide, " I told her. "It's a diuretic that seems to help by preventing potassium shifts. And one more thing."

"What?" she asked.

"Tell him to lay off the pancakes."

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COPYRIGHT 2000 Gale Group