Scientist Says Clinical Trials Should Test Findings
have found evidence suggesting that the severity of
spinal muscular atrophy (SMA) may be ameliorated by
The findings by researchers at the University of Pennsylvania
School of Medicine, which are to be published Thursday
in the journal Molecular Cell, suggest that folic acid
and Vitamins B12 may limit the severity of symptoms
that afflict SMA patients.
"We are not suggesting that this is a cure. But
it may help," said Gideon Dreyfuss, PhD, Isaac
Norris Professor of Biochemistry and a Howard Hughes
Medical Institute Investigator at Penn, and principal
author of the study.
SMA afflicts one of every 6,000-to-10,000 people and
is the leading genetic killer of children under the
age of two. But its symptoms-muscle weakness and wasting-differ
in severity from person to person across a range of
debilitation that scientists still cannot explain fully.
Most SMA patients die in their infancy, but some SMA
patients do not become wheel-chair bound before the
age of 20, and still others can live relatively normally
until late in life. Until now, this variability has
been attributed to "genetic modifiers" but
the present study raises the possibility that it is
influenced, perhaps to a significant extent, by nutritional
Individuals afflicted with SMA have a genetic deficiency
in a protein called SMN (survival of motor neurons),
which is a "housekeeping" protein required
by all cells -- especially motor neurons, the nerve
cells that control the activity of muscles. When the
levels of the SMN protein are too low, motor neurons
are the first cells to degenerate, in turn leaving the
major muscle groups without the stimulation they need
to be viable.
To perform its function, SMN interacts with numerous
proteins in the cell, helping them create some of the
critical molecular machines that make messenger RNA
and myriad proteins. In their research, Dreyfuss and
his Penn colleagues, Westley J.Friesen, PhD, Severine
Massenet, PhD, Sergey Paushkin, PhD, and Anastasia Wyce,
PhD, have been studying what makes SMN interact with
its partners in the cell.
The scientists made the surprising observation that
SMN will bind efficiently -- and carry out its functions
-- if the proteins to which it needs to bind are first
"tagged" by specific enzymes. The tags are
made up of methyl groups that are attached through the
amino acid arginine to specific sites on SMN's protein
targets (the process is 'methylation'), where they sit
like "bumps" or "buttons" on the
In addition to unraveling the function of the methylation
of arginines in proteins -- a common modification process
that was first reported more than 30 years ago whose
function remained unknown until now -- the findings
may have important implications for neurodegenerative
The methyl group tags are supplied by a "methyl
donor" called SAM (for S-adensylmethionine), and
SAM receives this methyl group from folic acid (also
known as folate) through a pathway that requires vitamin
This, the Penn researchers believe, raises the possibility
that deficiency in folate (many vegetables, grains and
fruits are especially rich in folate) or the B vitamins
could be particularly detrimental to SMA patients --
because it could result in under-methylated proteins,
which are exactly the kind of proteins SMN needs to
find to function properly.
Since SMA patients are already compromised in their
levels of SMN, they might be expected to be more severely
afflicted by such nutritional deficiencies.
"We would like to say, very cautiously, that our
work raises the possibility that folic acid, and vitamin
B12 may be helpful in lessening, even if only slightly,
the severity of the disease for some SMA patients-or
at least ensure that their condition is not worse than
their genetics dictate," Dreyfuss said.
He cautioned against putting forth folic acid and the
B vitamins as a "cure" for the disease, noting
that his team's findings are based on laboratory biochemical
studies which point the way to animal and/or human studies
that need to be done before any clinical or therapeutic
implications are drawn. "Certainly, we hope clinical
studies will be initiated to see whether folate and
the B vitamins make a difference for SMA patients that
extends beyond laboratory research," he said.
The research was funded by a grant from the National
Institutes of Health and by the Howard Hughes Medical
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.
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