The Journal of the Arkansas Medical Society Med Journal Feb 2020_Final | Page 16

by Kapil Arya MBBS, MD 1 ; Amit Agarwal, MD 2 ;
Vikki Stefans, MD 3 ; Aravindhan Veerapandiyan, MD 1
Scientific Article
1
Pediatric Neurology; Arkansas Children's Hospital, University of Arkansas for Medical Sciences, Little Rock, Ark.
Pediatric Pulmonology; Arkansas Children's Hospital, University of Arkansas for Medical Sciences, Little Rock, Ark.
3
Physical Medicine and Rehabilitation; Arkansas Children's Hospital, University of Arkansas for Medical Sciences, Little Rock, Ark.
2
Spinal Muscular Atrophy: the Changing Landscape of
Diagnosis and Management in Arkansas and Beyond
Abstract
S
pinal muscular atrophy (SMA) is a
neurodegenerative, autosomal reces-
sive disorder usually due to biallelic
deletions or, in rare cases, inactivating
mutations of exon 7 of the SMN1 gene. Clinical
classification is based on the highest motor mile-
stone achieved. Intrathecal nusinersen treatment,
the first disease modifying therapy approved by
the U.S. Food and Drug Administration, produces
improvements in motor function for patients with
SMA. Also, single-dose SMN gene replacement
therapy shows very promising results and awaits
FDA approval. Research indicates that early treat-
ment leads to the greatest benefit, emphasizing
the need for newborn screening for SMA.
preserved reflexes that gradually diminish over
time, can typically stand and walk, and have a
wide spectrum of motor functional impairment.
Type IV is the mildest form of SMA. It is adult
onset with very slow progression. There is also
a form of later adult onset autosomal dominant
disease due to mutation of a different gene that is
outside the scope of this discussion. Cognition is
preserved in all types. Prognosis is varied based
on the clinical severity across the four types and
within each type. 2 Failure to achieve motor de-
velopmental milestones or, in less severely af-
fected patients, a gradual loss of acquired motor
milestones, is due to hypotonia plus weakness.
Weakness is typically more profound in the low-
er than the upper extremities, where antigravity
function may be preserved. Fine motor effects
and tremor, if present, are relatively mild.
Introduction
Spinal muscular atrophy (SMA) is an autosomal,
recessive severe motor neuron disease and the
leading genetic cause of infant mortality, affect-
ing approximately 1 in 10,000 babies. About
1 in every 50 Americans is a genetic carrier for
SMA. 1 Patients are roughly categorized into one
of four types of SMA clinically, based on age of
symptom onset and the highest physical mile-
stone achieved. Type I SMA has symptom onset
before the age of six months, and patients gener-
ally do not attain the ability to sit independently.
Typical clinical manifestations include neonatal
hypotonia, proximal weakness, tongue fascicu-
lations, and areflexia progressing to respiratory
and bulbar weakness. There may be reduced
fetal movement in utero. Children with type II
SMA may have slightly later onset of symptoms,
often between six and 18 months of age; they
achieve independent sitting, but are typically un-
able to walk. Children with type III SMA become
symptomatic after 18 months of age, may have
164 • The Journal of the Arkansas Medical Society
Genetics
SMA is caused by homozygous deletion or mu-
tation of survival motor neuron 1 (SMN1) gene
at chromosome 5q. Genetic diagnosis is made
by deletion/duplication analysis and/or gene se-
quencing from blood samples. SMN1 produces
survival motor neuron (SMN) protein, which is
present in the cell body, axons, and dendrites
of motor neurons. Absent or insufficient levels
of SMN protein leads to the selective death of
spinal motor neurons, possibly mediated by dys-
function of small ribonuclear proteins that affect
splicing of other essential genes. A second and
almost identical gene, survival motor neuron 2
(SMN2), is present in most human genomes and
makes low levels of SMN protein. During SMN2
splicing, a small segment of required RNA, exon
7, is excluded from the final mRNA transcript;
this results in the production of mostly truncated
and rapidly degraded SMN protein, with only 10-
15% functional SMN protein. Thus, the greater
the number of SMN2 copies, the milder the SMA
phenotype. Most children with type I SMA have
only one or two SMN2 copies, most with type II
have three copies, and with type III or IV there are
three to four copies or more. Some infants with
one copy are very severely affected and unable to
breathe independently at birth. It is thought that
with no copies, the condition is lethal in utero,
accounting for the discrepancy between carrier
rate and birth rate. SMN2 production does not
directly make up for the loss of SMN protein
production from SMN1, but the SMN protein
production is increased proportional to the SMN2
copy number. Therefore, the number of SMN2
copies is inversely related to symptom severi-
ty and clinical subtype. However, considerable
variation in clinical phenotypes can occur both
between patients with the same number of SMN2
copies. Research on discordant families has led
to the identification of several genetic modifiers
of SMA, including plastin-3 and neurocalcin del-
ta. It is likely, therefore, that further genetic and
other disease-modifying factors are still to be dis-
covered. 1,2,3
Management
Historically, the management of SMA focused on
symptomatic and supportive treatment, with an
emphasis on supporting ventilation. There is pro-
gressive respiratory failure. Ineffective cough is a
result of respiratory muscle weakness and con-
tributes to repeated respiratory infections. The
goal of pulmonary management is to normalize
gas exchange by decreasing atelectasis; this is
achieved by airway secretion mobilization and
clearance, assisted coughing, and respiratory
support via invasive or non-invasive ventilation.
Supplemental oxygen is not the first line of treat-
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