Magnetic resonance imaging (MRI) demonstrating ADCA-DN in severely affected (A), mildly affected (B), and normal (C) brains.
Previously, I introduced you to a rare familial disorder baptized Autosomal Dominant Cerebellar Ataxia, Deafness and Narcolepsy or ADCA-DN, first described in a small Swedish family by the Scandinavian Neurologist Dr. Atle Melberg in 1995. This terrible disease — characterized by narcolepsy evolving into neuropsychiatric problems and dementia — stayed in my mind until 2010, when Dr. Guiseppe Plazzi called me to ask my opinion regarding a specific case. Dr. Plazzi directs the sleep program at Bologna University, the oldest medical university of the world, and a rival to Stanford for its pioneering work in sleep medicine and narcolepsy. This particular day, Dr. Plazzi was very much worried about a patient he just saw, who had narcolepsy and had just developed cerebellar ataxia. Upon mentioning this case, I asked if the patient was also deaf and, as he was, it was fairly certain that it was the same disorder. Most interestingly in this case, however, while the patient was in his 40s, both parents were in their 70s and doing well, suggesting that it could not be a familial form like in the Swedish family.
The occurrence of such a “sporadic case” with the same syndrome can mean two possible things. First, it is possible that the same disorder has several causes, some related to genetics and others not, explaining the two possible variants. Second, the “sporadic” instance can be the result of a new or “de novo” mutation that appeared in the same gene in the father or mother germ line of the patient. In this instance, we are witnessing the appearance of a new genetic mutation that will thereafter be transmitted to future generations. Although it was impossible at the time to distinguish between these possibilities, two additional factors made us decide to pursue and seek the cause of the syndrome through genetic analysis.
First, at about the same time, I was also made aware of a second family that had the same syndrome in Minnesota. After talking to the daughter of one of the affected people, I became convinced that the same problem was also striking another family, this time in the United States. Second, a new technique called “exome sequencing” had just been invented by genetic researchers and seemed ideal to use in this case. The technique, now almost routine in genetic research, is the result of many years of rapid improvements in DNA sequencing technology.
The concept of exome sequencing rests on the idea that for many genetic disorders that have very dramatic manifestation (such as ADCA-DN), the causative mutations are DNA changes that often occur inside “exons.” Exons make up about 1 percent of the human DNA nucleotide sequence. Nucleotides are the units that constitute the DNA sequence and come in four different flavors: A, T, C, and G. These genetic units serve as guides to create proteins, which have various functions within the body. In effect, exome sequencing is a high-yield strategy for finding disease mutations without having to sequence and analyze all the DNA, which has about 3 billion nucleotides. In addition, as a lot is known on how DNA changes affect protein structure, it is fairly easy to distinguish if a change in the genetic code is pathogenic or not in a gene. This is especially true when we can analyze several independent patients with the same disease. For example, when a particular DNA sequence is absolutely indispensable to function, it is always the same in all normal individuals and even in species other than humans.
With this in mind, we collected blood samples and consent from these families and sent the DNA samples to the University of Munich for exome sequencing analysis. A few months later, the results came back and revealed that the U.S. and Swedish families, as well as the Italian patient, all had strange DNA changes in the same exact gene. These changes or mutations were likely to make the protein malfunction, as these were in a part of the protein that was conserved and identical even in the honey bee, a species separated from us by several hundred million years of evolution.
Even more interesting, the mutation found was in a very old and indispensable gene that has attracted the attention of researchers for many decades called DNA methylase 1, or DNMT1. Looking at the scientific literature, we also found that a few months prior to our finding, another group of researchers discovered that mutations in the same gene, but at a different location within the gene, produced a different disease called Hereditary Sensory and Autonomic Neuropathy Type II (HSAN2, another difficult name). This rare condition primarily affects the sensory nerve cells. In this disease, patients lose the ability to feel pain or sense hot and cold. They often damage their feet and hands without realizing it, often leading to the need to amputate these extremities. In the individual with the DNMT1 mutations causing HSAN2, however, subjects also eventually became deaf and demented, suggesting that even though the first manifestations were distinct (narcolepsy in ADCA-DN and loss of sensation in HSAN2), the final evolution of the disease was similar, with the entre brain affected.
Since then, seven more families and sporadic ADCA-DN cases due to DNMT1 mutations (a condition we would prefer to call Melberg syndrome for simplicity’s sake) have been described. In all probability, thousands of patients likely have this terrible disease without even knowing about it. Even more sadly for us, we discovered many family members in our identified families who are still young have the mutation, and thus will eventually develop the disease when reaching their 40s. Feeling a responsibility toward these families, we have started work to find a treatment before it is too late, a race against the clock for these family members. We feel this is possible, as after all these patients are normal until they reach 40, so that if we could simply slow down the process a little bit by acting on DNMT1, maybe the disease would never manifest. This is not only worthwhile for these patients, but it may also have application in other dementias.
Winkelmann J, Lin L, Schormair B, Kornum BR, Faraco J, Plazzi G, Melberg A, Cornelio F, Urban AE, Pizza F, Poli F, Grubert F, Wieland T, Graf E, Hallmayer J, Strom TM, Mignot E. Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Hum Mol Genet. 2012 May 15;21(10):2205-10.
Dr. Mignot is the director of the Stanford Center for Sleep Sciences and Medicine. This center is the birthplace of sleep medicine and includes research, clinical, and educational programs that have advanced the field and improved patient care for decades. To learn more, visit us at: http://sleep.stanford.edu/.
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