To assess outcomes following liver transplantation for maple syrup urine disease by determining attainment and sustainability of metabolic control and apply an “ideal” outcome composite in long-term survivors.
- Cardiac System
- Clinical Case Report
- Diagnostic Development
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- Genomic Testing
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- Neurologic System
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The primary goal of our research will always be to find effective and affordable treatments for patients. Over the years, we have shared our methods and discoveries with the broader scientific community.
In the over 30 years since the Clinic's founding, our staff have published more than 120 peer-reviewed research papers, fueled by close collaboration between our clinical and laboratory teams and effective relationships with academic, scientific, and clinical partners.
Authors: John W. Day, Jerry R Mendell, Eugenio Mercuri, Richard S Finkel, Kevin A. Strauss, Aaron Kleyn, Sitra Tauscher-Wisniewski, Francis Fonyuy Tukov, Sandra P Reyna, Deepa H Chand
This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy.
Authors: Muhammad A Usmani, Zubair M Ahmed, Magini Pamela, Victor Murcia Pienkowski, Kristen J Rasmussen, Rebecca Hernan, Faiza Rasheed, Mureed Hussain, Mohsin Shahzad, Brendan C Lanpher, Zhiyv Niu, Foong-Yen Lim, Tommaso Pippucci, Rafal Ploski, Verena Kraus, Karolina Matuszewska, Flavia Palombo, Jessica Kianmahd, UCLA Clinical Genomics Center; Julian A Martinez-Agosto, Hane Lee, Emma Colao, M Mahdi Motazacker, Karlla W Brigatti, Erik G Puffenberger, S Amer Riazuddin, Claudia Gonzaga-Jauregui, Wendy K Chung, Matias Wagner, Matthew J Schultz, Marco Seri, Anneke J A Kievit, Nicola Perrotti, J S Klein Wassink-Ruiter, Hans van Bokhoven, Sheikh Riazuddin, Saima Riazuddin
Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eight de novo heterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys∗11], c.399_400del [p.Glu133Aspfs∗37], c.747G>T [p.Gln249His], c.928-2A>C [p.?], and c.2459C>G [p.Pro820Arg]) in AP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles. In silico analysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking out ap1g1 in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-type AP1G1 mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs with de novo missense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude that de novo and bi-allelic variants in AP1G1 are associated with neurodevelopmental disorder in diverse populations.
Authors: Huiya Yang, Robert H Brown Jr, Dan Wang, Kevin A Strauss, Guangping Gao
De novo glycosphingolipid (GSL) biosynthesis defects cause severe neurological diseases, including hereditary sensory and autonomic neuropathy type 1A (HSAN1A), GM3 synthase deficiency, and hereditary spastic paraplegia type 26 (HSPG26), each lacking effective treatment. Recombinant adeno-associated virus (AAV)-mediated gene therapy has emerged as a powerful treatment for monogenic diseases and might be particularly suitable for these neurological conditions.
Authors: Torsten Joerger, Salwa Sulieman, Vincent J Carson, Michael D Fox
Authors: Tova Hershkovitz, Alina Kurolap, Galit Tal, Tamar Paperna, Adi Mory, Jeffery Staples, Karlla W. Brigatti, Regeneron Genetics Center; Claudia Gonzaga-Jauregui, Elena Dumin, Ann Saada, Hanna Mandel, Hagit Baris Feldman
Iron‑sulfur clusters (FeSCs) are vital components of a variety of essential proteins, most prominently within mitochondrial respiratory chain complexes I-III; Fe-S assembly and distribution is performed via multi-step pathways. Variants affecting several proteins in these pathways have been described in genetic disorders, including severe mitochondrial disease. Here we describe a Christian Arab kindred with two infants that died due to mitochondrial disorder involving Fe-S containing respiratory chain complexes and a third sibling who survived the initial crisis. A homozygous missense variant in NFS1: c.215G>A; p.Arg72Gln was detected by whole exome sequencing. The NFS1 gene encodes a cysteine desulfurase, which, in complex with ISD11 and ACP, initiates the first step of Fe-S formation. Arginine at position 72 plays a role in NFS1-ISD11 complex formation; therefore, its substitution with glutamine is expected to affect complex stability and function. Interestingly, this is the only pathogenic variant ever reported in the NFS1 gene, previously described once in an Old Order Mennonite family presenting a similar phenotype with intra-familial variability in patient outcomes. Analysis of datasets from both populations did not show a common haplotype, suggesting this variant is a recurrent de novo variant. Our report of the second case of NFS1-related mitochondrial disease corroborates the pathogenicity of this recurring variant and implicates it as a hot-spot variant. While the genetic resolution allows for prenatal diagnosis for the family, it also raises critical clinical questions regarding follow-up and possible treatment options of severely affected and healthy homozygous individuals with mitochondrial co-factor therapy or cysteine supplementation.
Authors: Kevin A. Strauss, Katie B. Williams, Vincent J. Carson, Laura Poskitt, Lauren E. Bowser, Millie Young, Donna L. Robinson, Christine Hendrickson, Keturah Beiler, Cora M. Taylor, Barbara Haas-Givler, Jennifer Hailey, Stephanie Chopko, Erik G. Puffenberger, Karlla W. Brigatti, Freeman Miller, D. Holmes Morton
Glutaric acidemia type 1 (GA1) is a disorder of cerebral organic acid metabolism resulting from biallelic mutations of GCDH. Without treatment, GA1 causes striatal degeneration in >80% of affected children before two years of age. We analyzed clinical, biochemical, and developmental outcomes for 168 genotypically diverse GA1 patients managed at a single center over 31 years, here separated into three treatment cohorts: children in Cohort I (n = 60; DOB 2006–2019) were identified by newborn screening (NBS) and treated prospectively using a standardized protocol that included a lysine-free, arginine-enriched metabolic formula, enteral l-carnitine (100 mg/kg•day), and emergency intravenous (IV) infusions of dextrose, saline, and l-carnitine during illnesses; children in Cohort II (n = 57; DOB 1989–2018) were identified by NBS and treated with natural protein restriction (1.0–1.3 g/kg•day) and emergency IV infusions; children in Cohort III (n = 51; DOB 1973–2016) did not receive NBS or special diet. The incidence of striatal degeneration in Cohorts I, II, and III was 7%, 47%, and 90%, respectively (p < .0001). No neurologic injuries occurred after 19 months of age. Among uninjured children followed prospectively from birth (Cohort I), measures of growth, nutritional sufficiency, motor development, and cognitive function were normal. Adherence to metabolic formula and l-carnitine supplementation in Cohort I declined to 12% and 32%, respectively, by age 7 years. Cessation of strict dietary therapy altered plasma amino acid and carnitine concentrations but resulted in no serious adverse outcomes. In conclusion, neonatal diagnosis of GA1 coupled to management with lysine-free, arginine-enriched metabolic formula and emergency IV infusions during the first two years of life is safe and effective, preventing more than 90% of striatal injuries while supporting normal growth and psychomotor development. The need for dietary interventions and emergency IV therapies beyond early childhood is uncertain.
Authors: Olivia Wenger, Miraides Brown, Brandon Smith, Devyani Chowdhury, Andrew H Crosby, Emma L Baple, Mark Yoder, William Laxen, Silvia Tortorelli, Kevin A Strauss
Propionic acidemia (PA) is caused by inherited deficiency of mitochondrial propionyl-CoA carboxylase (PCC) and results in significant neurodevelopmental and cardiac morbidity. However, relationships among therapeutic intervention, biochemical markers, and disease progression are poorly understood. Sixteen individuals homozygous for PCCB c.1606A > G (p.Asn536Asp) variant PA participated in a two-week suspension of therapy. Standard metabolic markers (plasma amino acids, blood spot methylcitrate, plasma/urine acylcarnitines, urine organic acids) were obtained before and after stopping treatment. These same markers were obtained in sixteen unaffected siblings. Echocardiography and electrocardiography were obtained from all subjects. We characterized the baseline biochemical phenotype of untreated PCCB c.1606A > G homozygotes and impact of treatment on PCC deficiency biomarkers. Therapeutic regimens varied widely. Suspension of therapy did not significantly alter branched chain amino acid levels, their alpha-ketoacid derivatives, or urine ketones. Carnitine supplementation significantly increased urine propionylcarnitine and its ratio to total carnitine. Methylcitrate blood spot and urine levels did not correlate with other biochemical measures or cardiac outcomes. Treatment of PCCB c.1606A > G homozygotes with protein restriction, prescription formula, and/or various dietary supplements has a limited effect on core biomarkers of PCC deficiency. These patients require further longitudinal study with standardized approaches to better understand the relationship between biomarkers and disease burden.
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Our clinic serves as a trusted medical home for families working to prevent and treat genetic illness in their children. Serving predominantly Amish and Mennonite families, the sturdy, timber-framed building was "raised" by the hands of those in the Anabaptist community outside of Strasburg, PA. Inside the clinic is filled with an array of high-tech gene sequencing that allows us to deliver state of the art care in a nurturing environment.