CRND Clinical-Translational Seminar Series - Dr. Marc Patterson

March 2, 2012 - Marc Patterson, M.D. Chair - Division of Child and Adolescent Neurology, Professor of Neurology, Pediatrics and Medical Genetics, Director - Child Neurology Training Program Mayo Clinic. Dr. Patterson is board certified in psychiatry and neurology (with special qualification in child neurology and in neurodevelopmental disabilities). Dr. Patterson is on the Scientific Advisory Board for the National Niemann-Pick Disease Foundation.

When my frail bark starts from the shore,
 Far out across the unknown tide;
May some good angel guide me o'er,
In safety to the other side! 
David Fletcher Hunton
Grand Haven Daily Tribune,February 15,1902


At some point or another, most of us realize the frailness of the bark upon which we sail. For many, steeped in a cultural denial of death and blessed with good health, this realization comes late. But, in the realm of rare diseases, the awakening to pure vulnerability often comes at an early age and well before the 72 years Hunton had secured when he wrote this verse. When this awakening comes, it often appears as an “unknown tide” – in waves of unanswered questions and grief. Then, it is vital, not to sink into hopelessness or denial, but as another poet sets it, “to take arms against a sea of troubles.”1 In our species, we first take up arms against the dark and unanswered troubles by naming them and pushing away speechless sorrow. The great botanist and father of classification, Carolus Linnaeus, was called “God's registrar” and he wrote about the significance of classification, which always begins at the boundary of the unknown deep:

“The first step in wisdom is to know the things themselves; this notion consists in having a true idea of the objects; objects are distinguished and known by classifying them methodically and giving them appropriate names. Therefore, classification and name-giving will be the foundation of our science .” (Systema Naturae ,1735. Trans., M. S. J. Engel-Ledeboer and H. Engel (1964), 19.)

On March 2, 2012, Dr. Marc Patterson visited the students and faculty of the CRND and delivered a seminar, which would have pleased old Linaeus, “An introduction to neurometabolic disease.” Last year, Patterson taught an in-depth class on NP-C disease; this year, he placed NP-C in the broad framework of metabolic diseases of the nervous system, focusing on the common characteristics which substantiate the working classification:“inborn errors of metabolism (IEMs).” This delicate phrase names the general class of more than 5,000 distinguishable disorders, which are now visible and subject to relational analysis and systematic experimentation.

Dr. Patterson explained IEMs as "genetic disorders in which absence or malfunction of the gene product perturbs the internal milieu." He described a variety of gene products, all of which are subject to errors that potentially manifest in the appearance of disease: enzymes, structural proteins, transporters, channel constituents, receptors, and transcriptional and translational factors. Given the number of factors that can be deranged in the process of gene transcription and translation, Patterson explained how the percentages of people affected by some form of rare disease quickly mount up. In the United States about 1 in 10 people has been estimated to suffer with a rare disease. Still, there is a significant problem with the undercounting of rare diseases.

According to Patterson, underestimation of disease prevalence may occur because of overreliance on classic disease profiles. These can blind us to the atypical presentations resulting from mild, complex, and combined genetic errors. Additionally, where the observable expression of a disease is developmentally staged or results from multiple downstream effects over time, we miss in our estimation of disease prevalence. Patterson illustrated the problem with an Italian study of Fabry Disease. The study found an actual incidence of 1:3,100 versus a previous estimate of 1:50,000 in a region of Italy because it captured atypical, mild and late-onset cases, which were previously overlooked. Compared to the classic profile of Fabry, atypical cases in this region ran 11:1. Underscoring the complexity of genetic unfolding and the general inadequacy of the models, Patterson summarized, "Whatever we're thinking, however complicated you think a system is, it is really much more complicated."

Dr. Patterson's review of IEMs outlined known genetic mechanisms, molecular mechanisms, and the correlations between genotypes and phenotypes. He illustrated particular disorders and described symptomatic manifestation for the audience. The genetic mechanisms underlying IEMs include loss-of-function mutations, gain-of-function mutations, regulatory mutations, multiple downstream effects, and mutations based in epigenetic influences and Mosiacism. Examples of small molecule diseases take in amino acidopathies, organic acidopathies, urea cycle defects, fatty acid oxidation defects, disorders of oxidative phosphorylation, porphyrias, and neurotransmitter disorders. These conditions are associated with phenotypic presentations, including severe life threatening neonatal catastrophes, milder episodic dysfunction and cerebral organic acidemias. Examples of large molecule diseases comprise sphingolipidoses, mucopolysaccharidoses, neuronal ceroid lipofuscinosis, and glycoproteinases. These conditions share phenotypic traits such as progressive neurodegeneration, organomegaly, dysostosis, coarsening of the features, ocular changes, and cutaneous lesions. Many of the small and large molecule diseases share a common problem of deficiencies in enzymes, cofactors (these activate enzymes) or enzyme transporters. Complex IEMs include congenital disorders of glycosylation (CDG), childhood ataxia with central hypomyelination (CACH - vanishing white matter disease) and Cockayne's syndrome. These complex disorders are characterized by combined symptoms of large and small molecule diseases (i.e., features of slow deterioration with episodic decompensation).

Patterson outlined the critical factors for diagnosing and treating IEMs: history, examination, presentation, and investigation. Elements to be considered in the patient's history include membership in an at-risk population, consanguinity, multiple miscarriages, and certain problems during gestation. Neonatal issues may also give an early indication to genetic disorders (eg., jaundice, organomegaly, acute encephalopathy). Beyond infancy, other signs may aid diagnosis: dietary preferences and aversions, unusual odors, episodic decompensation, mimicking static encephalopathy and problems with developmental progress (eg., too slow or significant regressions). Patterson predicted that in the future, genetic testing will play an increasing role, although he noted social concerns and the importance of understanding that an identified genetic issue might not actually manifest phenotypically until late in life.

During this highly technical presentation, Dr. Patterson made a special point of conveying to students his testimony on the art of medicine. Given the daunting scope of IEMs and the very real suffering signified by each of them, it was helpful to hear Dr. Patterson's philosophy on treatment. He is after all, a practitioner. He faces the daily challenge of nurturing the inner resilience of his patients and their families as the waves of unanswered questions beat against them.

I want to emphasize one thing to you. There are no untreatable disorders. We can treat everybody. We can help everybody – however rare their disease. Whether or not there is 'a curative' ...there is almost no curative therapy for anything - or [often no] disease modifying therapy. Just by giving people good general medical care, you make a huge difference. You've got to educate them about the disease. You've got to educate their networks about the disease. And, learn from them – it's a two-way process. You've got to support their nutrition, make sure they're fit, make sure they've got all the support that society can get. And, that can be a nightmare – navigating your way through the different systems that exist. Does it make a difference? Yes! Cystic Fibrosis. You've all heard of it. One of the most common recessive, lethal diseases in the Caucasian population. When I was a medical student starting in the '70s, hardly anybody survived their teen-age years. Now, the median survival is up into the 40s and its getting up towards 50! Is there a curative therapy? Well, there was just a paper published about a disease modifying therapy. But [until now] there's been nothing! So, what changed? People developed specialized clinics. They started to get aggressive about treating these children. They developed protocols. They updated them. They tracked progress. And, they made a huge difference in the survival from this disease. So, that's a great model for all rare disease. You can make a huge difference. You shouldn't be a nihilist. You can help all of these people make a big, big difference. That is probably the most important message of this talk.

Thus, the brilliant lodestar of the healer appears above the dark waters - attend its light and chart a course across the sea of uncertainty that is rare disease medicine.


tagline: Patterson, Marc C. Classification: Angel of Mayo.



1 William Shakespeare, Hamlet, 3.1






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