In the virtual high-tech health care of the late 21st century, newbornswill be delivered shrink-wrapped.

Actually, in the here and now, an estimated one to two dozenAmerican infants are born each year enveloped in a tight, form-fitting, whole-body translucent membrane _ literally shrink-wrapped. (It falls off in a couple of weeks.) These "collodion babies,"as medical geneticists call them, have inherited a rare, autosomalrecessive skin disorder called lamellar ichthyosis.

"Ichthy" is Greek for fish, which describes the thick scales ofepidermis that cover the bodies, from scalp to sole, of the 1,000 to2,000 individuals in the U.S. with lamellar ichthyosis (LI). Thoseguesstimates of LI incidence and prevalence come from NicholasGattucci, executive director of the Foundation for Ichthyosis &Related Skin Types (FIRST), based in Raleigh, N.C.

Gattucci told BioWorld Today that in the by-gone days of travelingside-shows, hapless ichthyosis sufferers were displayed as the likes ofAlligator Man, Lizard Lady and Fish-Skin Boy. He added ruefullythat today the check-out-counter tabloids perpetuate this put-down ofthe rare genetic disorder.

LI is no respecter of gender, ethnicity or geography. Of itself, thedisorder is not life-threatening, merely life-blighting. Besides thegross disfigurement of large, off-color scales or plates of epidermiscovering every patch of body surface, its disruption of the skin'souter protective layer leaves the body naked to microbial, chemicaland mechanical assaults, as well as dehydration and body-heat build-up. Current treatment is purely palliative and topical; it ranges fromskin lubricants to retinoic acid.

Linkage analysis and gene mapping have, in recent years, trainedtheir sights on the genetic basis of congenital LI, which is only theseverest of 20 or more variants of ichthyoses. Today's Science carriesa paper titled "Mutations of keratinocyte transglutaminase in lamellarichthyosis."

Its principal author is molecular dermatologist Daniel Hohl, whodirects the Laboratory of Cutaneous Biology at the University ofLausanne, Switzerland.

"The skin of collodion babies cracks easily," Hohl told BioWorldToday, "and 25 years ago, their mortality was 70 to 80 percent.Nowadays, due to advances in the field of neonatal care, 90 to 95percent survive to fulfill a normal life span."

Normal statistically, that is, but not socially. FIRST's Gattuccideplores the social ostracism of ichthyotically disfigured children andinsurmountable employment obstacles confronting adults.

In normal skin, the outer layer, or stratum corneum epidermitis, driesup and sloughs off every 12 to 14 days. A complex interplay ofstructural genes in the skin's lower levels continually replaces thesedead keratin cells with fresh live ones to keep the skin barrier whole.

This process of keratinization involves among other enzymes,transglutaminase, which cross-links proteins in the upper layer of theepidermis to form a sturdy scaffold. In LI, this gene is mutated, andthe enzyme ineffective.

In three families with five ichthyotic individuals, Hohl found"drastically reduced keratinocyte transglutaminase K activity. In twoof the families, gene expression was diminished or abnormal, and noenzyme at all detected." As reported in Science, he identified threemutations of the gene in both affected individuals of the thirdkindred, and "clear-cut alterations of the gene" in the other twofamilies.

"Although the families were too small to prove linkage, we confirmedthat transglutaminase K was a strong candidate gene," Hohlconcluded.

Medical geneticist Sherri Bale, of the National Institute of Arthritisand Musculoskeletal and Skin Diseases (NIAMSD), has performedlinkage analysis of the ichthyosis genomic region. Her paper in theDecember American Journal of Human Genetics, "Linkage ofautosomal recessive lamellar ichthyosis," is based on her presentationto the American Society of Human Genetics meeting in Montreal lastOctober.

"LI showed complete linkage to several markers within a 9.3centimorgan region on chromosome 14q11," Bale reported.

From Enzyme To Gene, To Gene Therapy

When Hohl learned of Bale's paper, he told BioWorld Today,"Having read their abstract, and having ourselves progressed alreadyquite far, working behind the scenes for the past two years, wethought, `OK, so now let's rush and push out everything we have todate.' This is why, when they first rang the bell, we just got alarmedthat we should hurry with our results." Hence, Hohl's paper intoday's Science.

Bale, who is acting chief of genetic studies section in the NIAMSD'sLaboratory of Skin Biology, told BioWorld Today: "We'vesequenced transglutaminase in several families, and identified twomutations in the gene." She has a paper in the works reporting thesemutations in LI.

The next step, she said, "is, once you know the underlying defect,you can start to think of ways to fix it," presumably by gene therapy.

"The most interesting thing about that," she observed, "is how todeliver a normal gene, if that's what needs to be done." She added,"It's an enzyme abnormality, which is nice, because most of the genetherapy that's worked has been done with enzymes. What's not niceis the delivery problem, delivering the gene to the skin."

Hohl is more gung-ho: "You simply need to replace one copy of thebad gene with a good gene. You can leave the other bad one."

He already is doing this in vitro, Hohl said, "using different promoterconstructs and retroviral vectors to check how the activity of thetransglutaminase will recover. After this, we will try to do it in vivo."

He concluded: "It's very magic, and we haven't made any trials sofar, but we will certainly try it." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.