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05/15/2013 08:15 am ET | Updated Jul 15, 2013

The Curious Tale of a Narcolepsy Case Evolving to Dementia and Premature Death

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Dr. Atle Melberg and Dr. Emmanuel Mignot in Sweden

Coming back from Scandinavia last week, I had the pleasure of meeting for the first time Atle Melberg, a 59-year-old physician working in Uppsala, close to Stockholm, Sweden. Dr. Melberg, who I had only known through email for the last 10 years, is certainly a character; meeting him was one of the highlights of my trip! Born in Norway, he had several careers in multiple countries, including being a member of the swimming team at the University of Wisconsin, Madison, where he received a B.S. degree majoring in biochemistry. He only started in medicine at age 31, after medical studies at the Royal College of Surgeons in Ireland, Dublin. Setting up in Uppsala in 1990, he found his calling in neurology, training there and applying a discipline similar to his regular swimming routine to his profession as a neurologist. Speaking to his trainees, he is somewhat of a legend as an astute and dedicated clinician of few words but many deeds. As I learned later, neurologists are too few and overworked in Sweden, something that leaves Dr. Melberg totally unfazed.

Upon his arrival in Sweden, his department head suggested to Dr. Melberg that he not only complete his neurology training but also make a research contribution, a custom that has largely disappeared from medical education today. Among the neurological disorders that peaked his interest were mitochondrial disorders, strange diseases where the mitochondria -- the "energy factory" of the cell -- is defective. This is often the result of genetic defects that transmit through the mother's line. (Mitochondria have their own special genomes and come from the egg, not the sperm.) As mitochondria are present in all cells of the body, mitochondrial disorders have very complex manifestations that can affect diverse organs such as the heart, the endocrine system (causing, for example, diabetes), and, for reasons not always well understood, some but not other aspects of brain function. These brain conditions typically lead to balance problems (ataxia due to cerebellum issues), deafness (due to the inability of the inner ear to react to sounds), or blindness (due to degeneration of the optic nerve). Many different genetic defects are now known to cause mitochondrial diseases, and these have particular manifestations and associated genetic tests. During his training, Dr. Melberg made a special effort in collecting and learning about patients with these diseases in Sweden, often traveling long distances to see specific patients and trying therapies.

One day late in 1990, a patient presented that did not exactly fit the picture of known mitochondrial diseases, piquing his interest. The patient, a 44-year-old man, reported having had increased problems with sleepiness in the last 20 years, falling asleep at his job and being increasingly tired. He also was finding his dreams to be increasingly more vivid and disturbing, sometimes so real that he was not sure these were dreams anymore. He would also occasionally find himself waking up paralyzed when coming out of a dream, or feel weak in his body during the daytime when confronted with specific emotions. Although this had occurred for many years, he had not bothered discussing this with a doctor until things started to change.

He was now much more troubled by the fact that he now also had hearing loss. He had increasing trouble with his balance. He also began experiencing a general decline of his mental function. Imaging and clinical studies ensued, confirming that the patient had narcolepsy. He was noted to extremely rapidly enter Rapid Eye Movement (REM) sleep upon falling asleep. This diagnosis explained his sleepiness, dreaming, and paralysis symptoms. (During REM sleep, the sleeper is paralyzed and actively dreams, but usually this occurs in the middle of sleep leaving the sleeper unaware in the morning.)

More worryingly, however, the patient also had clear signs of brain atrophy (shrinkage) on imaging studies, notably in the cerebellum. Further, the loss of hearing and sight was due to a degeneration of the nerves associated with these functions, as found in many mitochondrial diseases. This suggested that this patient had an uncommon combination of two ills not previously connected: the sleep disorder narcolepsy and a neuronal degeneration issue of unknown cause affecting the cerebellum and hearing.

Consistent with the idea that this new syndrome could have been a mitochondrial genetic problem, Dr. Melberg, through a careful family history, discovered that the mother of the patient had passed away following a similar successive set of symptoms: narcolepsy, followed by deafness, cerebellar ataxia, and finally dementia. This new condition was baptized with the unwieldy name "Autosomal Dominant Cerebellar Ataxia, Deafness and Narcolepsy" or ADCA-DN. Curiously, however, investigations at the time were unable to establish a mitochondrial cause, and the family was too small to allow thorough genetic studies at the time, leading to a report published in neurology of this new syndrome.

The patients with ADCA-DN evolved into dementia and passed away before age 60. In time, some of their children started showing signs of the disease as well. Looking at the brain of these patients, pathologists were also unable to find why or how the brain and cerebellum were shrinking, as no abnormal deposits such as those found in many other neurodegenerative brain problems such as Alzheimer's dementia or Parkinson's disease were found.

The publication of Dr. Melberg had not escaped the notice of our team in California working on narcolepsy. Although this was clearly more than just narcolepsy, it was possible that the constellation of symptoms was due to a small genetic alteration that included both a narcolepsy-causing gene and a mitochondrial gene located close by on the same chromosome. We contacted Dr. Melberg for further genetic analysis. We were initially unable to find anything with the techniques available at the time, and the syndrome was set aside until two years ago when new investigations were initiated.

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/.

Source:

Melberg A, Hetta J, Dahl N, Nennesmo I, Bengtsson M, Wibom R, Grant C, Gustavson KH, Lundberg PO. Autosomal dominant cerebellar ataxia deafness and narcolepsy.
J Neurol Sci. 1995 Dec;134(1-2):119-29.

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