SMA Type 1 Shows Different Disease Course Between Plain Communities, Study Shows

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Spinal muscular atrophy (SMA) type 1 has different disease courses between Plain (Amish and conservative Mennonite) communities, a recent natural history study shows.

The study, “Spinal muscular atrophy within Amish and Mennonite populations: Ancestral haplotypes and natural history,” was published in the journal Plos One.

SMA is inherited in an autosomal recessive manner, meaning a child has to inherit two defective copies of the survival motor neuron 1 (SMN1) gene (one from each parent) to develop the disease. People who carry one mutated gene and one healthy gene will not have the condition, but will be carriers who may pass the disease to their children.

A second survival motor neuron gene (SMN2) also is capable of producing SMN, but only 10 percent of the protein it produces is functional. The number of SMN2 gene copies that a patient carries is inversely associated with disease severity. Two SMN2 copies are associated with a severe form of SMA (type 1). Three or more copies are linked to later disease onset and slower disease progression.

Members of endogamous communities — in which it is custom to marry within the same ethnic, social, cultural, religious, or tribal group — such as Amish and conservative Mennonite, may descend from a limited pool of “founder” ancestors who have specific genetic profiles that are transmitted from generation to generation.

In Amish and Mennonite communities, SMA is relatively common, and the carrier frequencies for SMN1 mutations are higher than those of the general population. SMA patients within these populations tend to have the same SMN1 mutation, share a large proportion of genetic material, and have similar dietary, environmental, and socioeconomic conditions.

Also, genetic variations in the SMN1 and SMN2 genes are often inherited from a parent together in a bulk, which is called a haplotype.

Researchers at the Clinic for Special Children, in Strasburg, Pennsylvania, analyzed the SMN1SMN2 haplotypes and their associations with different forms of SMA in 14 Amish and 42 conservative Mennonite SMA patients.

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Amish patients shared SMN1 mutations that traced back several generations, while Mennonites had SMN1 mutations that traced to a common ancestor across 11 generations. Among the 56 patients, 44 carried two SMN2 copies, nine carried three copies, and three carried four copies.

Amish patients had a single haplotype (named A1) with SMN1 mutations and one copy of SMN2 being transmitted throughout generations. Among Mennonite patients, the shared SMN1 mutations were transmitted through four haplotypes, three with one SMN2 copy (named M1a, M1b and M1c) and one with two copies of SMN2 (named M2).

As expected, patients carrying two copies of SMN2 — those with the A1/A1, M1a/M1a, M1a/M1b, and M1a/M1c haplotype combinations — had earlier disease onset, worse motor function and shorter survival than those with three (M1a/M2 combination), or four (M2/M2 combination) SMN2 copies.

Patients with three or four copies of SMN2 showed a higher variability in motor development, which the researchers noted is not uncommon.

However, to researchers’ surprise, patients with two copies of SMN2 showed differences in disease severity and survival depending on their haplotype combination.

Amish patients with A1/A1 combination had a more severe SMA, with a significantly earlier disease onset and shorter lifespan, compared to Mennonite patients with M1a/M1a — the most common haplotype combination of two SMN2 copies in this patient population.

Since A1 and M1a haplotypes were found to be similar in their SMN1 mutation and SMN2 DNA sequence, the team plans to conduct a more profound genetic analysis to see if they can discover the cause of these discrepancies in disease development.

Researchers noted their results highlight that SMA type 1 follows a different disease course within and between Amish and Mennonite communities, and that this also may be true for other endogamous communities.

These different 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,” they wrote.