Nomination Review and Prioritization Workgroup (NRPW) Template

							   NOMINATION REVIEW AND PRIORITIZATION WORKGROUP - REVIEW FORM                        Summary

   The information is derived primarily from the Nomination Form. Submitted supporting references and other
   publicly available data may also inform this review.

      NOMINATED CONDITION: Spinal Muscle Atrophy                       Date of review: 10/20/08

1) The nominated condition(s) is medically serious.
      Spinal muscular atrophy (SMA, also known as Werdnig-Hoffman disease in its more severe form) is a very
   frequent condition (1:1:10,000 births or less) caused by progressive degenerative motoneuron disease. It is
   manifested by weakness, respiratory and feeding difficulties before 1 year of age. Expected lifespan is <3 years.
   Onset could be as early as birth, usually within 2-3 months of life. Even the more moderately affect cases of
   SMA2 comprising 10-20% of patients, experience severe symptoms by 18 months of life.


2) Prospective pilot data (U.S. and/or international) from population-based assessment are available for this
    disorder.
   Population screening using a PCR Luminex array system is facilitated by the genotype homogeneity of SMA, as
   most patients carry homozygous deletions of SMN1 exon 7. Analytical and clinical validation has been pursued
   extensively (40,130 bloodspots) but in a single laboratory, the Molecular pathology laboratory at Ohio State
   University. It remains to be seen how effectively the method could be implemented in public health
   laboratories. The study demonstrated that screening for SMA can be technically accomplished on a large-scale
   basis.

3) The spectrum of this disorder is well described, to help predict the phenotypic range of those children who will
   be identified based on population-based screening.

   SMA1, SMA2, SMA3 phenotypes can be discerned by PCR-based sequence and copy number analysis of the
   SMAT and SCMAC gene. The different genotypes largely correlate, although not perfectly, with SMA1, 2, 3
   (Prior and Swoboda).

4) The characteristics of the screening test(s) are reasonable for the newborn screening system (among other
   aspects, a low rate of false negatives).

   The proposed method is one of the first examples of a primary screening test based on genotyping. Accordingly,
   sensitivity and specificity are expected to be high. The nomination form mentions a potentially imminent pilot
   study.

4) If the spectrum of disease is broad, those who are most likely to benefit from treatment are identifiable,
   especially if treatment is onerous or risky.

   It is feasible to predict by genotyping the patients most likely to benefit from treatment. The screening assay
   can be performed from a DBS by real-time PCR perhaps with first tier screening by Luminex. The false positive
   rate of population-based analysis is not reported, even in the Ohio pilot (Prior), although Prior reports 95%
   sensitivity and 99% specificity for the PCR Luminex assay. Also, the screening test can be adapted to avoid
   identifying carriers.

6) Defined treatment protocols, FDA approved drugs (if applicable) and treatment are all available.
Those that could benefit from treatment are easily identifiable. Nutritional support and respiratory care are the
only available options at this time. There are unproven drug treatments under evaluation. Notably, their
effectiveness in mice depends on timing of administration BEFORE onset of symptoms.

Overall recommendations to the Advisory Committee:

The nomination of SMA might be premature for evaluation at this time by the evidence review group as critical
elements are missing for both the test characteristics (reproducibility outside of an esotheric academic lab) and
treatment efficacy beyond the relatively limited benefits of palliative measures.

The internal nomination and prioritization workgroup recommends no evidence review at this time and further
recommends the Nominator to conduct prospective pilot studies in one or more traditional public health
laboratories in order to show reproducibility of the preliminary findings in Dr. Prior’s laboratory. The time
frame required to collect the analytical evidence mentioned above could also lead to a better assessment of the
efficacy of novel treatment modalities under investigation.