William B. Rizzo, MD
University of Nebraska Medical Center

Recent advances in “Next-Generation” DNA sequencing technologies promise to revolutionize the ability to diagnose patients with genetic diseases and discover new forms of ichthyosis not previously recognized. These new methods, including “whole exome sequencing”, allow researchers to detect alterations or mutations in the functional parts of all of the genes. A recent example of the power of these DNA sequencing methods is the identification of a new form of ichthyosis caused by mutations in the gene called ELOVL4 that codes for an enzyme with the same name.

The story behind the discovery of ELOVL4 deficiency actually goes back to a few years ago when researchers generated a strain of mice with the equivalent ELOVL4 gene “knocked out,” or inactivated. The reason for making the mutant mice was to investigate a rare form of human childhood-onset blindness with macular dystrophy that is caused by ELOVL4 mutations. Surprisingly, rather than being blind, the ELOVL4 knockout mice had severe ichthyosis at birth and died several hours later from dehydration. ELOVL4 is an enzyme that is present in the skin, eye and brain, and is needed to make very long-chain fatty acids, a group of lipids that are important for the epidermal water barrier. The deficiency of cutaneous very long-chain fatty acids, and consequent abnormal water barrier in the knockout mice, accounts for the ichthyosis. Although the ELOVL4 enzyme is present in the brain, the newborn mice never had any neurologic symptoms before they died.

Now fast-forward to about 1 year ago. Dr. Fowzan Alkuraya, a geneticist in Saudi Ariabia, saw a 6-year-old boy with congenital ichthyosis, mental retardation, severe seizures, and spasticity. He thought the boy might have Sjögren-Larsson syndrome (SLS), which is also associated with ichthyosis and neurologic symptoms, so he sent us the boy’s cultured skin fibroblasts for testing. Our tests ruled out SLS and we considered that he might have another similar "pseudo-SLS" disease. Because his parents were genetically-related as cousins, which greatly facilitates genetic studies, Alkuraya investigated the boy using whole exome DNA sequencing and found that he carried a mutation in the ELOVL4 gene that is destructive to the enzyme. But mutations in this particular gene were only known to cause macular dystrophy in humans - not the ichthyosis and neurologic symptoms seen in the Saudi boy. We reasoned that if the ELOVL4 mutations actually caused his symptoms, additional patients should exist elsewhere. We and Alkuraya therefore decided to look for ELOVL4 mutations among other pseudo-SLS patients who lacked a diagnosis. After screening the gene in 15 such patients, a boy in India was found to carry a different destructive ELOVL4 mutation. This child had some of the same skin and neurologic symptoms as the Saudi boy; unfortunately he died at 2 years of age from the severe neurologic disease.

For now, we know very little about ELOVL4 deficiency. Why do some mutations cause ichthyosis with severe neurologic disease, whereas other mutations only cause childhood blindness? Neither boy had macular dystrophy, but they may have been too young to show it. However, this genetic defect raises the potential for treating the ichthyosis with topical application of very long-chain fatty acids (and related lipids) and lends an urgency to identifying additional ELOVL4-deficient patients.

The discovery of ELOVL4 deficiency as a new form of ichthyosis is a testament to the power of next generation DNA sequencing and the collaborative efforts of researchers worldwide (who, in the case of ELOVL4 deficiency by the way, have yet to meet each other!). Even more remarkable is that the discovery involved a single affected patient - not a family with many affected members, as previously required for gene identification. Like ELOVL4 deficiency, we can expect that additional new forms of ichthyosis will be revealed in the near future as next generation DNA sequencing is applied to more and more patients. These DNA advances will undoubtedly lead to more specific and effective therapies for many patients with ichthyosis, which should be a cause for hope and anticipation.