On
March 2, 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).
According to Patterson, critical factors
for diagnosing and treating IEMs currently embrace 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 sea - 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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