Advances in supportive care have altered
the natural history of SMA
Any review of therapy for SMA would be remiss
without a discussion of the important and evolving
role of multidisciplinary supportive care.
SMA leads to predominantly proximal muscle
atrophy and weakness, and the potential for medical
complications such as scoliosis, joint contractures
and ventilatory impairment [Wang et al.
2007]. This latter complication is primarily the
result of respiratory muscle weakness, which
prevents the normal expansion and clearance of
the lungs leading to a restrictive defect. In recent
years, advances in pulmonary care and the
increasing application of noninvasive ventilatory
support has dramatically improved the morbidity
and mortality associated with pulmonary decline,
particularly among children with severe (type 1
and 2) disease phenotypes [Oskoui et al. 2007;
Bach et al. 2001, 2000]. Improvements in physical
therapy management and advances in surgical
approaches to scoliosis, including the use of
vertical expandable prosthetic titanium rib and
related ‘growing rods’ approaches [Hell et al.
2005], have allowed a more effective and timely
management of secondary musculoskeletal complications.
The optimization of nutritional management
to avoid potential complications arising
from both malnutrition [Messina et al. 2008] and
obesity [Sproule et al. 2009] has also emerged as
an area of increased attention in recent years
[Wang et al. 2007].
In the context of such advances to supportive
care, a notable improvement in the natural history
of SMA has been observed over the last two
decades despite an absence of efficacious therapy;
this is particularly true for children with SMA
type 1. Byers and Banker described 25 such subjects
in 1961 with a mean age at death (n¼23) of
10 months (range 17 days to 52 months), and a
mean age of 17 months in those who survived
(n¼2), range 10 24 months [Byers and
Banker, 1961]. A similar report by Zerres and
Rudnik-Schoneborn published in 1995 found a
survival probability of 32% at 2 years, of 18% at 4
years, of 8% at 10 years, and of 0% at 20 years
among 197 children with SMA type 1 [Zerres
and Rudnik-Schoneborn, 1995]. A recent analysis
of 143 patients with SMA type 1, comparing
those born from 1980 to 1994 (n¼65) with those
born between 1995 and 2006 (n ¼ 78) showed a
70% reduction in risk of death in the latter group,
likely associated with improvements in clinical
management, particularly with regards to noninvasive
ventilatory management [Bach, 2007;
Bach and Bianchi, 2003; Bach et al. 2000], and
a trend toward more proactive care [Oskoui et al.
2007]. While recent efforts have been made to
standardize clinical care with the publication of
a consensus statement of care for patients with
SMA [Wang et al. 2007], variability of clinical
care between centers and the evolving natural
history of the disease can both represent challenges
for trial design, as we discuss below.
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