In 1963, an endocrinologist at Vanderbilt University Medical Center,in Nashville, Tenn., examined a teen-age girl from Alabama. Thedoctor, Grant Liddle, diagnosed severe hypertension and lowpotassium levels. He later reported in medical literature that severalof this young patient's juvenile siblings also suffered from the samesymptoms of high blood pressure.
Liddle suggested that their trouble might be an inability to handlesalt in their diet.
Meanwhile, the family disappeared off Vanderbilt's radar screen. Itnext surfaced 28 years later, in Montgomery, Ala. There, at theUniversity of Alabama, that teen-ager, now a woman in her 40s,received a kidney transplant for end-stage renal failure. The organgraft normalized her blood pressure. The woman's extendedfamily, by 1991, had expanded to include 18 members with early-onset, severe hypertension.
This rare form of high blood pressure is now known _ though stilllittle-known _ as Liddle's syndrome. The term hasn't yet made itsway into the medical dictionaries.
Under-Appreciated, Investigated, Diagnosed
"If you look in any textbook prior to about 1990," said medicalgeneticist Richard Lifton, of the Howard Hughes Medical ResearchInstitute at Yale University, "you won't find much discussion ofgenetic forms of hypertension." He told BioWorld Today, "This areawas really under-appreciated and under-investigated until the genetictools for doing such studies came along.
"In fact," Lifton added, "that was a major motivating reason why Igot into this field; it was obvious that genetic linkage studies weregoing to shed new light on the pathophysiology and treatment ofsome very interesting diseases that nobody had picked up on."
One such disorder was Liddle's syndrome.
At the University of Alabama, the chief of nephrology, DavidWarnock, had re-evaluated the 18 members of that family with thesyndrome. He sent their blood samples to Lifton at Yale for studiesto reveal the genetic connection to their high blood pressure.
Meanwhile, last spring, Swiss researchers at the University ofLausanne cloned in rats the rodent genes responsible for regulatingsodium reabsorption in the kidneys. Surmising that mutation in thecorresponding human genes might result in Liddle's syndrome,Lifton and his co-workers found, in every member of Warnock'sAlabama kindred, a mutated gene on chromosome 16 that controlspart of the epithelial sodium channel.
Today's issue of the journal Cell carries their report, with Lifton assenior author, titled: "Liddle's Syndrome: Heritable humanhypertension caused by mutations in the b subunit of the epithelialsodium channel." It concluded that the abnormal gene causes thekidney to retain, rather than excrete, excessive amounts of salt andwater, which leads to the syndrome's high blood pressure inchildhood.
High blood pressure usually affects the middle-aged and elderly.Some 50 million Americans suffer from hypertension, and 200,000 ayear die from stroke, heart attack and kidney failure.
While its cause remains largely unknown, physicians advise theirpatients with blood pressure above the norm to reduce salt in thediet, and take diuretic pills that promote urinary excretion.
In Japan, baseball is the national sport, and food pickled in salt brinea national dietary staple. Japan leads the world in deaths from stroke.Every year, when the country's two major universities field theirbaseball teams, if there's a home run at the bottom of the ninth, adozen or so fans leave the stands on stretchers, felled by apoplexy.
What connects their lethal surge of excitement to cerebral stroke is ahormone called aldosterone. Produced in the adrenal gland, it causesthe tubules in the kidneys to reabsorb sodium, in exchange forpotassium.
Liddle's syndrome frustrates this constantly regulated process. Itsmutated gene keeps the sodium channel jammed in the "open"position, so salt water flows through unchecked, and builds upcontinuously in the renal tubules.
Direct sequence analysis of this variant found a single basesubstitution, C to T, that introduced a stop codon. This deleted thelast 75 amino acids from the channel's encoded protein. As Cellnotes, "That this striking variant is completely linked to the traitlocus and is not found in unaffected subjects strongly argues that thisis the functional mutation causing Liddle's syndrome."
Predicted: A Founder Family Six Generations Back
Besides tracking down the faulty gene in that Alabama founderfamily, the Cell paper describes four other Liddle kindreds sincediscovered, one each from California, Mississippi, New York andWisconsin. "When we analyzed closely linked genetic markers,"Lifton said, "they also had exactly the same set on the diseasechromosome 16, which proves that all four have, in fact, inheritedthe same mutation from a common ancestor." He added, "It musthave passed the gene on over at least six generations. This was notappreciated until we had the molecular evidence."
Prior to the Cell report, he observed, "Liddle syndrome was a verydifficult disease to diagnose. We think it's important for physiciansto recognize that now a very simple, rapid genetic test is available:"It would involve," he explained, "obtaining a small blood samplefrom any patient in whom the diagnosis is in question, and lookingfor the mutation in a very small segment of DNA."
With a confirmed diagnosis, Lifton added, "we can block the activityof the specific overactive sodium channel, and thereby correct thehypertension. An existing but little-used anti-hypertensive drug,amiloride, Lifton said, "should be efficacious in these patients; it'sone example of where we may be able to tailor treatment to theunderlying gene defect." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.