Glutaric acidemia type 1 (GA1), a rare hereditary metabolic disease caused by biallelic mutations of GCDH, can result in acute or insidious striatal degeneration within the first few years of life. We reviewed the orthopaedic sequelae and management of 114 neurologically injured patients with a confirmed molecular diagnosis of GA1.
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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: Strauss KA, Ahlfors CE, Soltys K, Mazariegos GV, Young M, Bowser LE, Fox MD, Squires JE, McKiernan P, Brigatti KW, Puffenberger EG, Carson VJ, Vreman HJ
We describe the pathophysiology, treatment, and outcome of Crigler-Najjar type 1 syndrome (CN1) in 28 UGT1A1 c.222C>A homozygotes followed for 520 aggregate patient-years.
Authors: Dhawan A, Lawlor MW, Mazariegos GV, McKiernan P, Squires JE, Strauss KA, Gupta D, James E, Prasad S
Crigler-Najjar syndrome (CNS) results from biallelic mutations of UGT1A1 causing partial or total loss of uridine 5′-diphosphate glucuronyltransferase activity leading to unconjugated hyperbilirubinemia and its attendant risk for irreversible neurological injury (kernicterus). CNS is exceedingly rare and has been only partially characterized through relatively small studies, each comprising between two and 57 patients.
Authors: Marcello Scala, Majid Mojarrad, Saima Riazuddin, Karlla W. Brigatti, Zineb Ammous, Julie S Cohen, Heba Hosny, Muhammad A Usmani, Mohsin Shahzad, Sheikh Riazuddin, Valentina Stanley, Atiye Eslahi, Richard E Person, Hasnaa M Elbendary, Anne M Comi, Laura Poskitt, Vincenzo Salpietro, Queen Square Genomics, Jill A Rosenfeld, Katie B Williams, Dana Marafi, Fan Xia, Marta Biderman Waberski, Maha S Zaki, Joseph Gleeson, Erik Puffenberger, Henry Houlden, Reza Maroofian
Authors: Kevin A. Strauss, Vincent J. Carson, Kyle Soltys, Millie E. Young, Lauren E. Bowser, Erik G. Puffenberger, Karlla W. Brigatti, Katie B. Williams, Donna L. Robinson, Christine Hendrickson, Keturah Beiler, Cora M. Taylor, Barbara Haas-Givler, Stephanie Chopko, Jennifer Hailey, Emilie R. Muelly, Diana A. Shellmer, Zachary Radcliff, Ashlin Rodrigues, KaLynn Loeven, Adam D. Heaps, George V. Mazariegos, D. Holmes Morton
Over the past three decades, we studied 184 individuals with 174 different molecular variants of branched-chain α-ketoacid dehydrogenase activity, and here delineate essential clinical and biochemical aspects of the maple syrup urine disease (MSUD) phenotype. We collected data about treatment, survival, hospitalization, metabolic control, and liver transplantation from patients with classic (i.e., severe; n = 176), intermediate (n = 6) and intermittent (n = 2) forms of MSUD. A total of 13,589 amino acid profiles were used to analyze leucine tolerance, amino acid homeostasis, estimated cerebral amino acid uptake, quantitative responses to anabolic therapy, and metabolic control after liver transplantation. Standard instruments were used to measure neuropsychiatric outcomes. Despite advances in clinical care, classic MSUD remains a morbid and potentially fatal disorder. Stringent dietary therapy maintains metabolic variables within acceptable limits but is challenging to implement, fails to restore appropriate concentration relationships among circulating amino acids, and does not fully prevent cognitive and psychiatric disabilities. Liver transplantation eliminates the need for a prescription diet and safeguards patients from life-threatening metabolic crises, but is associated with predictable morbidities and does not reverse pre-existing neurological sequelae. There is a critical unmet need for safe and effective disease-modifying therapies for MSUD which can be implemented early in life. The biochemistry and physiology of MSUD and its response to liver transplantation afford key insights into the design of new therapies based on gene replacement or editing.
Authors: Kang SK, Vanoye CG, Misra SN, Echevarria DM, Calhoun JD, O’Connor JB, Fabre KL, McKnight D, Demmer L, Goldenberg P, Grote LE, Tiffault I, Saunders C, Strauss KA, Torkamani A, van der Smagt J, van Gassen K, Carson RP, Diaz J, Leon E, Jacher JE, Hannibal MC, Litwin J, Friedman NR, Schreiber A, Lynch B, Poduri A, Marsh ED, Goldberg EM, Millichap JJ, George AL Jr, Kearney JA
Pathogenic variants in KCNB1, encoding the voltage-gated potassium channel KV 2.1, are associated with developmental and epileptic encephalopathy (DEE). Previous functional studies on a limited number of KCNB1 variants indicated a range of molecular mechanisms by which variants affect channel function, including loss of voltage sensitivity, loss of ion selectivity, and reduced cell-surface expression.
Authors: Kazuhiro Aoki, Adam D. Heaps, Kevin A. Strauss, Michael Tiemeyer
Among Amish communities of North America, biallelic mutations of ST3GAL5 (c.694C > T) eliminate synthesis of GM3 and its derivative downstream a- and b-series gangliosides. Systemic ganglioside deficiency is associated with infantile onset psychomotor retardation, slow brain growth, intractable epilepsy, deafness, and cortical visual impairment. We developed a robust quantitative assay to simultaneously characterize glycan and ceramide moieties of plasma glycosphingolipids (GSLs) among ST3GAL5 c.694C > T homozygotes (n = 8), their heterozygous siblings (n = 24), and wild type control (n = 19) individuals.
Authors: Iffland PH 2nd, Carson V, Bordey A, Crino PB
The mechanistic target of rapamycin (mTOR) pathway has been implicated in a growing number of malformations of cortical development (MCD) associated with intractable epilepsy. Mutations in single genes encoding mTOR pathway regulatory proteins have been linked to MCD such as focal cortical dysplasia (FCD) types IIa and IIb, hemimegalencephaly (HME), and megalencephaly. Recent studies have demonstrated that the GATOR1 protein complex, comprised of DEPDC5, NPRL3, and NPRL2, plays a pivotal role in regulating mTOR signaling in response to cellular amino acid levels and that mutations in DEPDC5, NPRL3, or NPRL2 are linked to FCD, HME, and seizures. Histopathological analysis of FCD and HME tissue specimens resected from individuals harboring DEPDC5, NPRL3, or NPRL2 gene mutations reveals hyperactivation of mTOR pathway signaling. Family pedigrees carrying mutations in either DEPDC5 or NPRL3 share clinical phenotypes of epilepsy and MCD, as well as intellectual and neuropsychiatric disabilities. Interestingly, some individuals with seizures associated with DEPDC5, NPRL3, or NPRL2 variants exhibit normal brain imaging suggesting either occult MCD or a role for these genes in non-lesional neocortical epilepsy. Mouse models resulting from knockdown or knockout of either Depdc5 or Nprl3 exhibit altered cortical lamination, neuronal dysmorphogenesis, and enhanced neuronal excitability as reported in models resulting from direct mTOR activation through expression of its canonical activator RHEB. The role of the GATOR1 proteins in regulating mTOR signaling suggest plausible options for mTOR inhibition in the treatment of epilepsy associated with mutations in DEPDC5, NPRL3, or NPRL2.
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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.