Spinal Muscular Atrophy (SMA) Biomarkers Study in the Immediate Postnatal Period of Development

Aim 1. To establish the validity of putative physiological SMA biomarkers in the immediate
postnatal period. A longitudinal, natural history examination of physiological markers of
muscle innervation will be performed in healthy and SMA infants. The first week of life is
the ideal first time point, with visits occurring at scheduled visits up to the age two.
Compound motor action potential (CMAP) amplitude and electrical impedance myography (EIM)
will be examined and will be correlated with motor function. Each of these is associated with
muscle innervation and provides information on the number and function of lower motor neurons
in the spinal cord, the cellular target of SMA therapeutic interventions. This trial will
establish the natural history of these putative SMA biomarkers as the disease evolves in
affected infants. Moreover, our approach will allow for measurements in pre-symptomatic and
early symptomatic subjects and determine their predictive value.

Aim 2. To establish the validity of putative molecular SMA biomarkers in the immediate
postnatal period. Survival Motor Neuron (SMN2) copy number is a valid, predictive molecular
SMA biomarker; however, it is fixed, and therefore not useful as a biomarker of clinical
progression or response to therapy. SMN messenger Ribonucleic acid (mRNA) ( and protein
expression is variable in different cell types and, in mice, naturally decreases with age
postnatally. In this study, SMN expression levels will be measured longitudinally in SMA
patients and controls. Additional putative molecular SMA markers that have been identified to
correlate with motor function will be determined in an effort to distinguish between
predictive markers that change prior to development of weakness and those that change as a
consequence of weakness.

Inclusion Criteria:

All infants will be between 0-6 months of age at the time of enrollment. Parents or
guardians of the enrolled infants must sign an informed consent form prior to any study
procedure being performed.

The infants with SMA must have already had a positive DNA test outside of the study to
qualify for enrollment. An infant with SMA can have any number of SMN2 gene copies.
Knowledge of the number of SMN2 gene copies prior to enrollment is not required.

Healthy control infants who meet the following criteria will be enrolled:

- Birth between 36 and 42 weeks inclusive of gestation

- Siblings of children with SMA must have had prior SMA genetic testing completed
con-firming the infant is a healthy control

- Principal investigator feels the family/infant is able and willing to comply with
study procedures

- Parent or guardian able to give informed consent

SMA infants who meet the following criteria will be enrolled:

- Birth between 36 and 42 weeks inclusive of gestation

- Positive SMN1 gene mutation/deletion

- Principal investigator feels the family/infant is able and willing to comply with
study procedures

- Parent or guardian able to give informed consent

Exclusion Criteria:

- Use of any putative therapy intended to increase the amount of SMN protein in cells

- Enrollment in an SMA therapeutic trial at the time of enrollment in the SMA biomarker
study

- Have a systemic illness requiring ongoing treatment, such as pneumonia

- Clinically significant abnormal findings (as determined by the investigator) on the
physical examination or medical history (including history of tracheostomy tubes and
ventilator-dependency)

- Dependency upon non-invasive ventilatory support (ie: BiPAP) for more than 12
hours/day