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Developmental biology - Genes|
Spinal Muscular Atrophy Amongst The 'Plain People'
A child with SMA has inherited two mutated copies of the SMN1 gene, one from each of his or her parents. Each parent of a child with SMA - an autosomal recessive inherited disorder - carries their own single copy of the mutated SMN1 gene. DNA microsatellites, which are the repeat sections of DNA, plus 2.6 million-marker single nucleotide polymorphisms (SNPs) were examined to determine similarities in SMA patients symptoms and outcomes.
• Two Mennonite haplotypes: M1a = 1 copy SMN2: M2 = 2 copies SMN2
• A single Amish SMA haplotype: A1 = 1 copy SMN2
• M1a/M1a, M1a/M2, and M2/M2: are the prominent SMA genotypes
There are important differences in timing and severity of motor nerve degeneration based on the number of copies of SMN2 and SMA haplotype genes received from a parent.
The difference in clinical severity and survival time between individuals with A1/A1 compared to M1/M1 haplotypes - even though both have the same number of SMN2 gene copies, was a surprise. Researchers plan to use their data to compare A1 and M1a copies of the SMN2 gene at higher resolution in order to account for these differences.
We correlate chromosome 5 haplotypes and SMN2 copy number with disease expression in 42 Mennonite and 14 Amish patients with spinal muscular atrophy (SMA). A single haplotype (A1) with 1 copy of SMN2 segregated among all Amish patients. SMN1 deletions segregated on four different Mennonite haplotypes that carried 1 (M1a, M1b, M1c) or 2 (M2) copies of SMN2. DNA microsatellite and microarray data revealed structural similarities among A1, M1a, M1b, and M2. Clinical data were parsed according to both SMN1 genotype and SMN2 copy number (2 copies, n = 44; 3 copies, n = 9; or 4 copies, n = 3). No infant with 2 copies of SMN2 sat unassisted. In contrast, all 9 Mennonites with the M1a/M2 genotype (3 copies of SMN2) sat during infancy at a median age of 7 months, and 5 (56%) walked and dressed independently at median ages of 18 and 36 months, respectively. All are alive at a median age of 11 (range 2–31) years without ventilatory support. Among 13 Amish and 26 Mennonite patients with 2 copies of SMN2 who did not receive feeding or ventilatory support, A1/A1 as compared to M1a/M1a genotype was associated with earlier clinical onset (p = 0.0040) and shorter lifespan (median survival 3.9 versus 5.7 months, p = 0.0314). These phenotypic differences were not explained by variation in SMN1 deletion size or SMN2 coding sequence, which were conserved across haplotypes. Distinctive features of SMA within Plain communities provide a population-specific framework to study variations of disease expression and the impact of disease-modifying therapies administered early in life.
Vincent J. Carson, Erik G. Puffenberger, Lauren E. Bowser, Karlla W. Brigatti, Millie Young, Dominika Korulczyk, Ashlin S. Rodrigues, KaLynn K. Loeven and Kevin A. Strauss
The authors are grateful to Dr. Douglas Sproule for his critical insight and guidance during manuscript preparation and thank SMA patients and their families for their creativity, courage, and partnership in this endeavor.
About the Clinic for Special Children
The Clinic for Special Children (CSC) is a non-profit organization located in Strasburg, PA, which provides primary pediatric care and advanced laboratory services to those who suffer from genetic or other complex medical disorders. Founded in 1989, the organization provides services to over 1,050 active patients and is recognized as a world-leader in translational and precision medicine. The organization is primarily supported through community fundraising events and donations. For more information, please visit http://www.ClinicforSpecialChildren.org
The study was approved by the Penn Medicine-Lancaster General Hospital Institutional Review Board under a protocol entitled “Genetic Medicine and the Plain Communities (LGH IRB00000015; FWA00006038). Parents of all subjects consented to participate on behalf of their children and, where applicable, a separate written consent was obtained for reproduction of photographs (Fig 2). The individuals in this manuscript gave separate written informed consent (as outlined in PLOS consent form) to publish these case details.
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Spinal Muscular Atrophy (SMA) in the Amish and Mennonite communities correlates to inherited chromosome 5. A devastating genetic disease, SMA affects motor neurons that control movement, eating, and breathing. Photo from public domain.