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Information provided by Nationwide Children's Hospital - Published: 2010-08-11
Study details new findings in mouse model of disease; highlights existing gene delivery approach that may
provide therapy.
Along with skeletal muscles, it may be important to monitor heart function in patients with spinal muscular atrophy
(SMA). These are the findings from a study conducted by Nationwide Children's Hospital and published online ahead
of print in Human Molecular Genetics. This is the first study to report cardiac dysfunction in mouse models of SMA.
SMA is a debilitating neurological disease that leads to wasting away of muscles throughout the body. Historically,
scientists and physicians believed that SMA only affected skeletal muscles; however, new data suggests that this
genetic disease may also impact the heart.
"A few studies regarding SMA patients have implicated the involvement of the cardiovascular and the autonomic
nervous system," said the study's co-author Brian Kaspar, PhD, principal investigator in the Center for Gene Therapy
at The Research Institute at Nationwide Children's Hospital. "However, there have been few to no highly powered
and controlled studies to determine how common these cardiovascular anomalies are in these patients."
The reports of altered blood flow and slowed heart rate in some SMA patients prompted Kaspar's team to examine
whether a cardiac deficit is present in a mouse model of severe SMA, developed by Arthur Burghes, PhD, professor
of Molecular and Cellular Biochemistry at The Ohio State University College of Medicine, which is routinely used for
drug and therapeutic-based screening.
They analyzed heart structure of the SMA mice compared with normal mice, and found that there were significant
structural changes occurring in the heart of the SMA mice, along with severely impaired left-ventricular function. SMA
mice also had significantly lower heart rates. After examining the underlying structure of the mouse heart cells they
found it similar to the cellular structure of a heart biopsy from patient with type 3 SMA.
Kaspar's team recently developed a gene therapy approach shown to successfully deliver the missing SMN protein to
SMA mice and improve neuromuscular function. Next, the team studied whether the discovered heart defects could
be corrected by this gene delivery treatment. Results showed that restoring SMN levels completely restored heart
rates and prevented the early development of dilated cardiomyopathy.
Pam Lucchesi, PhD, director of the Center for Cardiovascular and Pulmonary Research at The Research Institute at
Nationwide Children's Hospital and study co-author, says it is still not clear which mechanisms are fully responsible
for the heart deficits seen in the SMA mice, but data suggests that neuronal, autonomic and developmental
components all may play a role.
"Our gene delivery strategy has unique advantages in that it targets neurons within the central and peripheral nervous
system as well as the cardiac tissues," said Lucchesi, also a faculty member at The Ohio State University College of
Medicine.
More research is needed to determine whether the cardiac deficits are unique to the mouse or whether SMA patient
of various severities have or will develop similar issues. Still, Kaspar, also on the faculty at The Ohio State University
College of Medicine, says clinicians should be acutely aware of potential heart dysfunction in a subset of SMA
patients.
Original article
Autonomic dysfunction in cases of spinal muscular atrophy
type 1 with long survival
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Yasuo Hachiyaa,
,
, Hidee Araib, Masaharu Hayashic, Satoko Kumadad, Wakana Furushimae, Eiko
Ohtsukaf, Yasushi Itof, Akira Uchiyamaa and Kiyoko Kurataa
aDepartment
of Pediatrics, Tokyo Metropolitan Fuchu Medical Center for SMID, 2-9-2 Musashi-dai, Fuchu-shi, Tokyo
183-0042, Japan
bDepartment
of Pediatrics, National Hospital Organization, Chiba Medical Center, Chiba, Japan
cDepartment
of Clinical Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan
dDepartment
of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan
eDepartment
of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan
fDepartment
of Pediatrics, Tokyo Women's Medical College, Tokyo, Japan
Received 22 November 2004;
revised 3 February 2005;
accepted 21 February 2005.
Available online 3 May 2005.
Abstract
In Japan, quite a few patients with spinal muscular atrophy type 1 (SMA type 1) survive with mechanical ventilation.
Since a patient with SMA type 1 and continuous artificial ventilation exhibited excessive perspiration and
tachycardia, we examined the autonomic functions in three cases of SMA type 1, undergoing mechanical ventilation.
Two cases exhibited the common sympathetic-vagal imbalance on R–R interval analysis involving 24-h Holter ECG
recordings in addition to an abnormality in finger cold-induced vasodilatation. Furthermore, one case showed blood
pressure and heart rate fluctuation with the paroxysmal elevation, and a high plasma concentration of
norepinephrine during tachycardia. These findings suggest that autonomic dysfunction should be examined in SMA
type 1 patients with long survival, although the pathogenesis remains to be clarified.
Keywords: Autonomic dysfunction; Epinephrine; Heart rate; Long survival; MIBG; Respirator; R–R interval; Spinal
muscular atrophy type 1
Article Outline
1.
Introduction
2.
Materials and methods
2.1. Subjects
2.2. Measurement of blood pressure, heart rate, and plasma catecholamine for 24 h
2.3. Head-up tilting
2.4. Finger cold-induced vasodilatation
2.5. Cardiac MIBG SPECT
3.
Results
3.1. Measurement of blood pressure, heart rate, and plasma catecholamine for 24 h
3.2. Head-up tilting
3.3. Finger cold-induced vasodilatation
3.4. Cardiac MIBG SPECT
4.
Discussion
References
Fig. 1. The results of measurement of blood pressure (closed rhomboids), heart rate (open circles), and plasma
catecholamine for 24 h in case 1. Remarkable fluctuation of blood pressure and heart rate was observed.
Abbreviations: bpm, beats per minute; HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure.
View Within Article
Fig. 2. Head-up tilting in case 1. Case 1 exhibited no abnormal response of either blood pressure (closed rhomboids)
or heart rate (open circles) during head-up tilting, although the concentrations of plasma norepinephrine and
epinephrine continued to be high. Abbreviations: bpm, beats per minute; HR, heart rate; SBP, systolic blood
pressure; DBP, diastolic blood pressure; E, epinephrine; NE, norepinephrine.
View Within Article
Table 1. Summary of clinical features
View Within Article Table 2. Summary of the results of plasma catecholamine analysis and power-spectral analysis
in three SMA 1 patients
In case 1, the plasma concentration of norepinephrine was increased at the time of paroxysmal tachycardia and
remained high even after the fit had finished. The LF/HF ratio was increased in all cases. LF/HF was calculated
using the data obtained on 24 h-Holter ECG. Abbreviations: ND, not determined; LF, low-frequency components;
HF, high-frequency components.
View Within Article
Corresponding author. Tel.:+81 42 323 5115; fax: +81 42 322 6207.
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Copyright © 2005 Elsevier B.V. All rights reserved.
Brain and Development
Volume 27, Issue 8, December 2005, Pages 574578
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Researchers Confirm Prenatal Heart Defects in Spinal Muscular
Atrophy Cases
ScienceDaily (Oct. 10, 2010) — University of Missouri researchers believe
they have found a critical piece of the puzzle for the treatment of Spinal
Muscular Atrophy (SMA) -- the leading genetic cause of infantile death in the
world. Nearly one in 6,000 births has SMA, and it is estimated that nearly one
in 30 to 40 people have the trait that leads to SMA.
See Also:
Health & Medicine
Heart Disease
Birth Defects
Diseases and Conditions
Human Biology
Chronic Illness
Nervous System
Reference
Spinal muscular atrophy
Sensory neuron
Motor neuron
Echocardiography
In a new study in Human Molecular Genetics, Christian Lorson, professor in the
Department of Veterinary Pathobiology and the Department of Molecular Microbiology
and Immunology, has found prenatal cardiac defects in mice with SMA. Lorson believes
this discovery has implications for eventual treatment as clinicians can no longer
concentrate exclusively on the nervous system when treating SMA.
Lorson's research team, headed by Monir Shababi, research scientist, examined two
animal models of SMA and discovered that cardiac defects are found throughout SMA
development and include neonatal fibrosis in the heart, ventricle malformation, thinning
of the cardiac wall and slower heart rates.
"It is likely that in severe cases of SMA, the disease is not limited to motor neurons;
rather, it becomes a multisystem disease, and the cardiac contribution is just one of the
systems," said Lorson, who works in the MU Bond Life Sciences Center. "These results
are consistent with clinical reports of severe SMA cases that describe a number of
cardiac defects. To fully address this disease, any new therapies or drugs must be
effective in every tissue, not just motor neurons. The more we understand the disease,
the better off we will be in terms of developing therapeutics or better supportive care.
What this conservatively means for humans is that therapies have to go beyond the
nervous system in the most severe and most profound cases."
Spinal muscular atrophy is caused by loss of a gene known as SMN1. Humans have an
additional gene called SMN2 which only makes a small amount of the normal SMN
protein -- the protein required to prevent SMA. SMN1 and SMN2 are greater than 99
percent identical, but a small difference between the two causes the dramatic difference
in the amount of functional protein produced by SMN2.
Typically, the disease moves from the outlying limbs into the trunk of the body. Most
deaths are caused by respiratory failure in the lungs. Researchers have been targeting
SMN2 -- what Lorson calls the "partially functioning backup copy" -- because any
increase in SMN2 means better results.
"SMN2 is like a light that's been dimmed, and we're trying anything to get it brighter.
Even turning it up a little bit would likely help dramatically," Lorson said.
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Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by
University of Missouri-Columbia
"Increasing reports of autonomic dysfunction together with our current findings warrant increased attention to the
cardiac status of SMA patients, and potentially highlights the need to investigate cardiac interventions alongside
neuromuscular treatments," said Kaspar.
This research was funded in part by a 2009 American Recovery & Reinvestment Act grant from the National Institutes
of Health.
Read more: http://www.disabled-world.com/disability/types/mobility/sma-heart.php#ixzz1NtvKC2PV