An 8.5-year-old girl with classical maple syrup urine disease (MSUD) required liver transplantation for hypervitaminosis A and was effectively cured of MSUD over an 8-year clinical follow-up period. We developed a collaborative multidisciplinary effort to evaluate the effects of elective liver transplantation in 10 additional children (age range 1.9–20.5 years) with classical MSUD. Patients were transplanted with whole cadaveric livers under a protocol designed to optimize safe pre- and post-transplant management of MSUD. All patients are alive and well with normal allograft function after 106 months of follow-up in the index patient and a median follow-up period of 14 months (range 4–18 months) in the 10 remaining patients. Leucine, isoleucine and valine levels stabilized within 6 hours post-transplant and remained so on an unrestricted protein intake in all patients. Metabolic cure was documented as a sustained increase in weight-adjusted leucine tolerance, normalization of plasma concentration relationships among branched-chain and other essential and nonessential amino acids, and metabolic and clinical stability during protein loading and intercurrent illnesses. Costs and risks associated with surgery and immune suppression were similar to other pediatric liver transplant populations.
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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.
Our staff have published more than 145 peer-reviewed research papers, fueled by close collaboration between our clinical and laboratory teams and effective relationships with academic, scientific, and clinical partners.
Authors: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors
Authors: Strauss KA, Puffenberger EG, Craig DW, Panganiban CB, Lee AM, Hu-Lince D, Stephan DA, Morton DH
An Old Order Mennonite child was evaluated for gross motor delay, truncal ataxia, and slow linear growth. The diagnostic evaluation, which included sub-specialty consultations, neuroimaging, and metabolic testing, was long, costly, and did not yield a diagnosis. Recognition of a similarly affected second cousin prompted a genome-wide homozygosity mapping study using high-density single nucleotide polymorphism (SNP) arrays. SNP genotypes from two affected individuals and their parents were used to localize the disease locus to a 14.9 Mb region on chromosome 6. This region contained 55 genes, including SLC17A5, the gene encoding the lysosomal N-acetylneuraminic acid transport protein. Direct sequencing of SLC17A5 in the proband revealed homozygosity for the 115C –> T (R39C) sequence variant, the common cause of Salla disease in Finland. Three additional affected Mennonite individuals, ages 8 months to 50 years, were subsequently identified by directed molecular genetic testing. This small-scale mapping study was rapid, inexpensive, and analytically simple. In families with shared genetic heritage, genome-wide SNP arrays with relatively high marker density allow disease gene mapping studies to be incorporated into routine diagnostic evaluations.
Authors: Craig DW, Huentelman MJ, Hu-Lince D, Zismann VL, Kruer MC, Lee AM, Puffenberger EG, Pearson JM, Stephan DA
Pooling genomic DNA samples within clinical classes of disease followed by genotyping on whole-genome SNP microarrays, allows for rapid and inexpensive genome-wide association studies. Key to the success of these studies is the accuracy of the allelic frequency calculations, the ability to identify false-positives arising from assay variability and the ability to better resolve association signals through analysis of neighbouring SNPs.
Authors: Wang X, Huang QQ, Breckenridge MT, Chen A, Crawford TO, Morton DH, Jin JP
A nonsense mutation at codon Glu180 in exon 11 of slow skeletal muscle troponin T (TnT) gene (TNNT1) causes an autosomal-recessive inherited nemaline myopathy. We previously reported the absence of intact or prematurely terminated slow TnT polypeptide in Amish nemaline myopathy (ANM) patient muscle. The present study further investigates the expression and fate of mutant slow TnT in muscle cells. Intact slow TnT mRNA was readily detected in patient muscle, indicating unaffected transcription and RNA splicing. Sequence of the cloned cDNAs revealed the single nucleotide mutation in two alternatively spliced isoforms of slow TnT mRNA. Mutant TNNT1 cDNA is translationally active in Escherichia coli and non-muscle eukaryotic cells, producing the expected truncated slow TnT protein. The mutant mRNA was expressed at significant levels in differentiated C2C12 myotubes, but unlike intact exogenous TnT, truncated slow TnT protein was not detected. Transfective expression in undifferentiated myoblasts produced slow TnT mRNA but not a detectable amount of truncated or intact slow TnT proteins, indicating a muscle cell-specific proteolysis of TnT when it is not integrated into myofilaments. The slow TnT-(1–179) fragment has substantially lower affinity for binding to tropomyosin, in keeping with the loss of one of two tropomyosin-binding sites. Our findings suggest that inefficient incorporation into myofilament is responsible for the instability of mutant slow TnT in ANM muscle. Rapid degradation of the truncated slow TnT protein, rather than instability of the nonsense mRNA, provides the protective mechanism against the potential dominant negative effect of the mutant TnT fragment.
Authors: Strauss KA
Authors: Nakabayashi K, Amann D, Ren Y, Saarialho-Kere U, Avidan N, Gentles S, MacDonald JR, Puffenberger EG, Christiano AM, Martinez-Mir A, Salas-Alanis JC, Rizzo R, Vamos E, Raams A, Les C, Seboun E, Jaspers NG, Beckmann JS, Jackson CE, Scherer SW
We have identified C7orf11, which localizes to the nucleus and is expressed in fetal hair follicles, as the first disease gene for nonphotosensitive trichothiodystrophy (TTD). C7orf11 maps to chromosome 7p14, and the disease locus has been designated “TTDN1” (TTDnonphotosensitive 1). Mutations were found in patients with Amish brittle-hair syndrome and in other nonphotosensititive TTD cases with mental retardation and decreased fertility but not in patients with Sabinas syndrome or Pollitt syndrome. Therefore, genetic heterogeneity in nonphotosensitive TTD is a feature similar to that observed in photosensitive TTD, which is caused by mutations in transcription factor II H (TFIIH) subunit genes. Comparative immunofluorescence analysis, however, suggests that C7orf11 does not influence TFIIH directly. Given the absence of cutaneous photosensitivity in the patients with C7orf11 mutations, together with the protein’s nuclear localization, C7orf11 may be involved in transcription but not DNA repair.
Authors: Puffenberger EG, Hu-Lince D, Parod JM, Craig DW, Dobrin SE, Conway AR, Donarum EA, Strauss KA, Dunckley T, Cardenas JF, Melmed KR, Wright CA, Liang W, Stafford P, Flynn CR, Morton DH, Stephan DA
We have identified a lethal phenotype characterized by sudden infant death (from cardiac and respiratory arrest) with dysgenesis of the testes in males [Online Mendelian Inheritance in Man (OMIM) accession no. 608800]. Twenty-one affected individuals with this autosomal recessive syndrome were ascertained in nine separate sibships among the Old Order Amish. High-density single-nucleotide polymorphism (SNP) genotyping arrays containing 11,555 single-nucleotide polymorphisms evenly distributed across the human genome were used to map the disease locus. A genome-wide autozygosity scan localized the disease gene to a 3.6-Mb interval on chromosome 6q22.1-q22.31. This interval contained 27 genes, including two testis-specific Y-like genes (TSPYL and TSPYL4) of unknown function. Sequence analysis of the TSPYL gene in affected individuals identified a homozygous frameshift mutation (457_458insG) at codon 153, resulting in truncation of translation at codon 169. Truncation leads to loss of a peptide domain with strong homology to the nucleosome assembly protein family. GFP-fusion expression constructs were constructed and illustrated loss of nuclear localization of truncated TSPYL, suggesting loss of a nuclear localization patch in addition to loss of the nucleosome assembly domain. These results shed light on the pathogenesis of a disorder of sexual differentiation and brainstem-mediated sudden death, as well as give insight into a mechanism of transcriptional regulation.
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Our clinic serves as a trusted medical practice for children and adults facing rare genetic disorders. Our dedicated team works every day to prevent and treat genetic illnesses. Our facility is in the heart of the Amish and Mennonite communities in Lancaster County. Inside is filled with cutting-edge gene sequencing tools that allow us to deliver highly personalized care—a precise treatment option for the right patient at the right time.