The Old Order Mennonites of southeastern Pennsylvania are a religious isolate with origins in 16th-century Switzerland. The Swiss Mennonites immigrated to Pennsylvania over a 50-year period in the early 18th century. The history of this population in the United States provides insight into the increased incidence of several genetic diseases, most notably maple syrup urine disease (MSUD), Hirschsprung disease (HSCR), and congenital nephrotic syndrome. A comparison between the Old Order Mennonites and the Old Order Amish demonstrates the unique genetic heritage of each group despite a common religious and geographic history. Unexpectedly, several diseases in both groups demonstrate allelic and/or locus heterogeneity. The population genetics of the 1312T –> A BCKDHA gene mutation, which causes classical MSUD, are presented in detail. The incidence of MSUD in the Old Order Mennonites is estimated to be 1/358 births, yielding a corrected carrier frequency of 7.96% and a mutation allele frequency of 4.15%. Analysis of the population demonstrates that repeated cycles of sampling effects, population bottlenecks, and subsequent genetic drift were important in shaping the current allele frequencies. A linkage disequilibrium analysis of 1312T –> A mutation haplotypes is provided and discussed in the context of the known genealogical history of the population. Finally, data from microsatellite marker genotyping within the Old Order Mennonite population are provided that show a significant but modest decrease in genetic diversity and elevated levels of background linkage disequilibrium.
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Published Papers
The primary goal of our research will always be to find effective and affordable treatments for patients. One of the central focus areas of our mission is sharing our methods and discoveries with the broader scientific community.
In the over 35 years since the Clinic's founding, our staff have published more than 130 peer-reviewed research papers, fueled by close collaboration between our clinical and laboratory teams and effective relationships with academic, scientific, and clinical partners.
Authors: Jin JP, Brotto MA, Hossain MM, Huang QQ, Brotto LS, Nosek TM, Morton DH, Crawford TO
A lethal form of nemaline myopathy, named “Amish Nemaline Myopathy” (ANM), is linked to a nonsense mutation at codon Glu180 in the slow skeletal muscle troponin T (TnT) gene. We found that neither the intact nor the truncated slow TnT protein was present in the muscle of patients with ANM. The complete loss of slow TnT is consistent with the observed recessive pattern of inheritance of the disease and indicates a critical role of the COOH-terminal T2 domain in the integration of TnT into myofibrils. Expression of slow and fast isoforms of TnT is fiber-type specific. The lack of slow TnT results in selective atrophy of type 1 fibers. Slow TnT confers a higher Ca2+ sensitivity than does fast TnT in single fiber contractility assays. Despite the lack of slow TnT, individuals with ANM have normal muscle power at birth. The postnatal onset and infantile progression of ANM correspond to a down-regulation of cardiac and embryonic splice variants of fast TnT in normal developing human skeletal muscle, suggesting that the fetal TnT isoforms complement slow TnT. These results lay the foundation for understanding the molecular pathophysiology and the potential targeted therapy of ANM.
Authors: Strauss KA, Morton DH
Classic maple syrup disease can be managed to allow a benign neonatal course, normal growth, and low hospitalization rates. The majority of affected infants that are prospectively managed have good neurodevelopmental outcome; however, acute metabolic intoxication and neurologic deterioration can develop rapidly at any age. Each episode is associated with a risk for cerebral edema, cerebrovascular compromise, and brain herniation. High plasma leucine and, possibly, alpha-ketoisocaproate are the principal neurotoxins in maple syrup disease. Plasma levels rise rapidly in association with net protein catabolism provoked by common infections and injuries. Transient periods of maple syrup disease encephalopathy appear fully reversible, leaving no clinically detectable neurologic sequelae. In contrast, prolonged amino acid imbalance, particularly if occurring during the critical period of brain development, leads to neuronal hypoplasia, a paucity of synapses, and undermyelination. Stagnated maturation and inadequate nutritional maintenance of brain structure have lifelong neurologic and behavioral consequences. Core elements of effective long-term therapy include screening and identification of asymptomatic newborns, frequent plasma amino acid monitoring, careful attention to branched-chain amino acid nurtriture, prevention of cerebral essential amino acid deficiencies, adequate provision of essential omega-3 class fatty acids and micronutrients deficient in commercial formulas, methods for home monitoring of metabolic control, and a commitment to lifelong therapy. Recognizing the risk for acute leucine intoxication depends on anticipating effects of common childhood infection and physiologic stresses on whole body protein turnover. Successful management of metabolic decompensation is based on the use of home sick-day regimens, rapid availability of branched-chain amino acid-free hyperalimentation solutions for hospitalized children, prevention of hyponatremia in patients with leucinosis, and frequent adjustments of intravenous therapies guided by plasma amino acid levels and indices of metabolic and clinical response.
Authors: Carlton VE, Harris BZ, Puffenberger EG, Batta AK, Knisely AS, Robinson DL, Strauss KA, Shneider BL, Lim WA, Salen G, Morton DH, Bull LN
Familial hypercholanemia (FHC) is characterized by elevated serum bile acid concentrations, itching, and fat malabsorption. We show here that FHC in Amish individuals is associated with mutations in tight junction protein 2 (encoded by TJP2, also known as ZO-2) and bile acid Coenzyme A: amino acid N-acyltransferase (encoded by BAAT). The mutation of TJP2, which occurs in the first PDZ domain, reduces domain stability and ligand binding in vitro. We noted a morphological change in hepatic tight junctions. The mutation of BAAT, a bile acid-conjugating enzyme, abrogates enzyme activity; serum of individuals homozygous with respect to this mutation contains only unconjugated bile acids. Mutations in both TJP2 and BAAT may disrupt bile acid transport and circulation. Inheritance seems to be oligogenic, with genotype at BAAT modifying penetrance in individuals homozygous with respect to the mutation in TJP2.
Authors: Kelley RI, Robinson D, Puffenberger EG, Strauss KA, Morton DH
A new metabolic disorder characterized by severe congenital microcephaly, death within the first year, and severe 2-ketoglutaric aciduria has been found among the Old-Order Amish of Lancaster County, Pennsylvania. Amish lethal microcephaly segregates as an autosomal recessive disorder and has an unusually high incidence of at least 1 in 500 births. When the infants are well, the urine organic acid profiles show isolated, extreme elevations of 2-ketoglutaric acid. However, during otherwise simple viral illnesses, the infants often develop a metabolic acidosis, which may follow a lethal course. Cranial magnetic resonance imaging of a single patient showed a smooth, immature brain similar to that of a 20-week fetus except for a moderate degree of cerebellar vermal hypoplasia. Assay of 2-ketoglutarate dehydrogenase in cultured lymphoblasts of one patient showed normal activity. Amish lethal microcephaly maps to 17q25 and may be caused by a defect in a mitochondrial inner membrane protein functioning as a 2-ketoglutarate transporter.
Authors: Rosenberg MJ, Agarwala R, Bouffard G, Davis J, Fiermonte G, Hilliard MS, Koch T, Kalikin LM, Makalowska I, Morton DH, Petty EM, Weber JL, Palmieri F, Kelley RI, Schäffer AA, Biesecker LG
The disorder Amish microcephaly (MCPHA) is characterized by severe congenital microcephaly, elevated levels of alpha-ketoglutarate in the urine and premature death. The disorder is inherited in an autosomal recessive pattern and has been observed only in Old Order Amish families whose ancestors lived in Lancaster County, Pennsylvania. Here we show, by using a genealogy database and automated pedigree software, that 23 nuclear families affected with MCPHA are connected to a single ancestral couple. Through a whole-genome scan, fine mapping and haplotype analysis, we localized the gene affected in MCPHA to a region of 3 cM, or 2 Mb, on chromosome 17q25. We constructed a map of contiguous genomic clones spanning this region. One of the genes in this region, SLC25A19, which encodes a nuclear mitochondrial deoxynucleotide carrier (DNC), contains a substitution that segregates with the disease in affected individuals and alters an amino acid that is highly conserved in similar proteins. Functional analysis shows that the mutant DNC protein lacks the normal transport activity, implying that failed deoxynucleotide transport across the inner mitochondrial membrane causes MCPHA. Our data indicate that mitochondrial deoxynucleotide transport may be essential for prenatal brain growth.
Authors: Morton DH, Strauss KA, Robinson DL, Puffenberger EG, Kelley RI
To evaluate an approach to the diagnosis and treatment of maple syrup disease (MSD).
Authors: Kalsner LR, Rohr FJ, Strauss KA, Korson MS, Levy HL
Tyrosine supplementation has not consistently been found to improve neuropsychologic function in phenylketonuria (PKU), possibly because of failure to achieve adequate levels of tyrosine in the brain.
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