It's the most frequent childhood neurodegenerative disorderworldwide.
So said molecular biologist James Gusella, describing an inheritedsyndrome known as Batten disease (BD). Gusella _ best known fordiscovering the Huntington's disease gene three years ago (seeBioWorld Today, March 25, 1993, p. 4) _ is a leading member ofthe International Batten Disease Consortium. This joint task forceunites the efforts of 27 researchers in five countries to unmask theguilty secrets of BD.
Last September, Gusella's associate, Terry Lerner, at the MolecularNeurogenetics Unit of Massachusetts General Hospital, in Boston,cracked BD's key cryptogram. That is, she led co-workers in theConsortium to isolate the gene on human chromosome 16's shortarm, which causes the disease when mutated.
The intact gene has an open reading frame of 1,314 base pairsencoding a 438-amino-acid protein of unknown function _ and nohomology to any other known gene. Its mutation takes the form of a1.2 kilobase deletion, which occurs in 81 percent of BD cases.
In the U.S., Gusella told BioWorld Today, Batten disease affects onein every 25,000 newborns, which works out at more than 10,000cases among this country's 250 million-plus population.
Finland, a Montana-size country in Northern Europe, is home tosome five million people, of whom about 500 _ one in 20,000 births_ have Batten disease.
"The Batten gene is enriched in our population," explained Finnishclinical and molecular geneticist Irma Jrvel, Finland's consortiummember.
"It's a little less common in other countries," Jrvel told BioWorld."Still, with three cases in 50,000 newborns here, it's much morecommon than, for example, Friedreich's ataxia, with a 1:25,000frequency, whose gene was recently cloned." (See BioWorld Today,March 3, 1996, p. 2.)
"Batten disease usually starts," she related, "when a child goes toschool at six or seven years old. That's when parents and teachersnotice that he or she cannot see very well. It's the first sign of thedisease."
(A British ophthalmologist named Frederick Batten described BD,about a century ago.)
Death Comes Early
Jrvel , who is at the University of Helsinki's Children's Hospital,continued: "At 11 years of age comes epilepsy. Its seizures can becontrolled by drugs, but they don't cure the disease. Then, slowly,mental and motor deterioration follow. By magnetic resonanceimaging, one can see brain atrophy at about age 15.
"The patients lose their skills of walking. Before the age of 20, someare bed ridden. And the mean age of death is 25."
Jrvel is senior author of a paper in this week's The Lancet, datedApril 13, 1996, that reports the first instance of prenatal diagnosis forBD by direct gene-sequence analysis.
The patient, who already had a son with BD, came to the Helsinkihospital in her 12th week of pregnancy. Electron microscopy ofplacental membranes retrieved by chorionic villi sampling revealedlipopigments suggestive of BD. PCR then amplified and visualizedthe gene sequences in the fetal sample as well as in the affectedsibling.
Accordingly, the pregnancy was terminated last September, andtesting of the fetal cells confirmed the diagnosis of Batten disease.
In the real world, though, Jrvel pointed out, "It's very rare to getthis disease. A family becomes pregnant and have one Batten child.They ask what are the chances of a second one. As BD is anautosomal, recessively inherited disease, the answer is 25 percentrisk. But by the time you diagnose BD in a child of six, the youngersiblings have already been born."
She added, "The greater need is prenatal diagnosis for the infantile,rather than the juvenile-onset, form of the disease. This infantileBD," she observed, "is the earliest and most severe version of thedisease, and we study it very much here in Finland."
She and her co-workers now are developing a mini-sequencing test todetect the BS gene deletion.
Gusella observed that that first prenatal diagnosis, reported in thecurrent Lancet, "was a natural consequence of finding the gene.Knowing the gene, makes it possible to do prenatal diagnosis basedon that mutation, and cover about 75 percent of the carrier parents."He also noted that "the infantile form is peculiar to Finland."
Batten disease, the Massachusetts researcher pointed out, is knownmedically as juvenile neuronal ceroid fuscinosis, because of the waxypigment it builds up in neurons of the brain and many other bodilytissues.
"The neurons in the retina," Gusella said, are one of the primarytargets for the pigment. So the children start from being absolutelynormal, then begin to lose their sight, and gradually go through adegenerative process that lasts for years until they've lost most oftheir brain."
Much of the BD consortium's funding worldwide comes from theU.S. National Institute of Neurological Disorders and Stroke.Neurogeneticist Judith Small administers the institute's grantprogram, which last year had a budget of $2.5 million, she said.
Small suggests that building on the BD gene discovery, a useful nextstep will be to create knockout mice for studying possibletherapeutics and gene therapy. n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.