Publications by authors named "Kevin A Strauss"

81 Publications

Nusinersen by subcutaneous intrathecal catheter for symptomatic spinal muscular atrophy patients with complex spine anatomy.

Muscle Nerve 2021 Oct 4. Epub 2021 Oct 4.

Clinic for Special Children, Strasburg, Pennsylvania, USA.

Introduction/aims: Intrathecal administration of nusinersen is challenging in patients with spinal muscular atrophy (SMA) who have spine deformities or fusions. We prospectively studied the safety and efficacy of nusinersen administration via an indwelling subcutaneous intrathecal catheter (SIC) for SMA patients with advanced disease.

Methods: Seventeen participants commenced nusinersen therapy between 2.7 and 31.5 years of age and received 9-12 doses via SIC. Safety was assessed in all participants. A separate efficacy analysis comprised 11 non-ambulatory, treatment-naïve SMA patients (18.1 ± 6.8 years) with three SMN2 copies and complex spine anatomy.

Results: In the safety analysis, 14 treatment-related adverse events (AEs) occurred among 12 (71%) participants; all were related to the SIC and not nusinersen. Device-related AEs interfered with 2.5% of nusinersen doses. Four SICs (24%) required surgical revision due to mechanical malfunction with or without cerebrospinal fluid leak (n = 2), and one (6%) was removed due to Staphylococcus epidermidis meningitis. In the efficacy analysis, mean performance on the Nine Hole Peg Test improved in dominant (15.9%, p = 0.0.012) and non-dominant (19.0%, p = 0.008) hands and grip strength increased 44.9% (p = 0.0.031). We observed no significant changes in motor scales, muscle force, pulmonary function, or SMA biomarkers. All participants in the efficacy cohort reported one or more subjective improvements of endurance, purposeful hand use, arm strength, head control, and/or speech.

Discussion: For SMA patients with complex spine anatomy, the SIC allows for reliable outpatient administration of nusinersen that results in meaningful improvements of upper limb function, but introduces risks of technical malfunction and iatrogenic infection. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/mus.27425DOI Listing
October 2021

Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy.

Drug Saf 2021 Oct 12;44(10):1109-1119. Epub 2021 Aug 12.

Novartis Gene Therapies, Inc., Bannockburn, IL, USA.

Introduction: This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy.

Objective: We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data.

Methods: Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated.

Results: The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients.

Conclusions: Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity.
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http://dx.doi.org/10.1007/s40264-021-01107-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473343PMC
October 2021

Metabolic Control and "Ideal" Outcomes in Liver Transplantation for Maple Syrup Urine Disease.

J Pediatr 2021 Oct 18;237:59-64.e1. Epub 2021 Jun 18.

Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center (UPMC) Children's Hospital of Pittsburgh, Pittsburgh, PA. Electronic address:

Objectives: 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.

Study Design: A single center, retrospective review collected clinical data including branched-chain amino acid (leucine, isoleucine, and valine) levels following liver transplant and determined achievement of an ideal long-term outcome profile of a first allograft stable on immunosuppression monotherapy, normal growth, and absence of common transplant-related sequelae.

Results: Of 77 patients meeting inclusion criteria identified, 23 were long-term (≥10-year) survivors and were additionally assessed for ideal outcome attainment. Patient and graft survival were 100% and 99%, respectively, and all patients were on an unrestricted protein intake diet. Although significant variation was noted in mean isoleucine (P < .01) and leucine (P < .05) levels postliver transplantation, no difference was seen in valine (P = .29) and overall clinical impact was likely negligible as metabolic stability was achieved and sustained beyond 3 years postliver transplantation and no metabolic crises were identified. Of 23 long-term survivors with available data, 9 (39%) achieved all composite metrics determined to define "ideal" outcomes in pediatric postliver transplantation populations.

Conclusions: Liver transplant enables long-term metabolic stability for patients with maple syrup urine disease. A combination of experience and improvement in both pre- and postliver transplantation care has enabled excellent survival and minimal comorbidities following transplant.
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http://dx.doi.org/10.1016/j.jpeds.2021.06.028DOI Listing
October 2021

AAV-Mediated Gene Therapy for Glycosphingolipid Biosynthesis Deficiencies.

Trends Mol Med 2021 06 10;27(6):520-523. Epub 2021 Mar 10.

Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA; Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.molmed.2021.02.004DOI Listing
June 2021

Orthopaedic manifestations of glutaric acidemia Type 1.

J Child Orthop 2020 Oct;14(5):473-479

Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.

Purpose: Glutaric acidemia type 1 (GA1), a rare hereditary metabolic disease caused by biallelic mutations of 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.

Methods: We performed a retrospective chart review spanning 28 years identifying 114 GA1 patients, most from the Old Order Amish population of Lancaster County, Pennsylvania, who were homozygous for a pathogenic founder variant of (c.1262C>T). We collected demographics, medical comorbidities, muscle tone patterns, Gross Motor Function Classification System level, gastrostomy tube status, seizure history, inpatient events, orthopaedic diagnoses and operative characteristics.

Results: Over an average follow-up of 4.7 ± 3.4 years, 24 (21%) of 114 patients had musculoskeletal problems requiring orthopaedic consultation. Scoliosis (n = 14), hip dislocation (n = 8/15 hips), hip subluxation (n = 2/three hips), and windswept hip deformity (n = 2) in the spine and hip joint were most common. In total, 35 orthopaedic surgeries were performed in 17 (71%) patients. The most common primary operations were one-stage procedures with proximal femoral varus derotation osteotomy and/or pelvic osteotomy (n = 8/14 hips) for subluxation or dislocation. In all, 11 patients had posterior spinal fusion for severe scoliosis. With the recommended metabolic management, there were no disease-specific complications in this cohort.

Conclusions: Children with GA1 who have static striatal lesions are at risk for musculoskeletal complications, especially scoliosis and hip dislocation, and appropriate operative management requires consultation with a metabolic specialist with specific considerations for fluid management and nutrition.

Level Of Evidence: IV.
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http://dx.doi.org/10.1302/1863-2548.14.200059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666789PMC
October 2020

Biochemical phenotype and its relationship to treatment in 16 individuals with PCCB c.1606A > G (p.Asn536Asp) variant propionic acidemia.

Mol Genet Metab 2020 11 3;131(3):316-324. Epub 2020 Oct 3.

Clinic for Special Children, Strasburg, PA, USA; Department of Pediatrics, Penn Medicine-Lancaster General Hospital, Lancaster, PA, USA; Departments of Pediatrics and Molecular, Cell & Cancer Biology, University of Massachusetts School of Medicine, Worcester, MA, USA.

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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http://dx.doi.org/10.1016/j.ymgme.2020.09.006DOI Listing
November 2020

Glutaric acidemia type 1: Treatment and outcome of 168 patients over three decades.

Mol Genet Metab 2020 11 4;131(3):325-340. Epub 2020 Oct 4.

Clinic for Special Children, Strasburg, PA, USA; Department of Pediatrics, Penn Medicine-Lancaster General Hospital, Lancaster, PA, USA; Central Pennsylvania Clinic, Belleville, PA, USA.

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.
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http://dx.doi.org/10.1016/j.ymgme.2020.09.007DOI Listing
November 2020

De Novo and Inherited Variants in GBF1 are Associated with Axonal Neuropathy Caused by Golgi Fragmentation.

Am J Hum Genet 2020 10 15;107(4):763-777. Epub 2020 Sep 15.

Institute of Human Genetics, Center for Molecular Medicine Cologne, Center for Rare Diseases Cologne, and Institute for Genetics, University of Cologne, 50931 Cologne, Germany. Electronic address:

Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are clinically and genetically heterogeneous diseases characterized primarily by motor neuron degeneration and distal weakness. The genetic cause for about half of the individuals affected by HMN/CMT2 remains unknown. Here, we report the identification of pathogenic variants in GBF1 (Golgi brefeldin A-resistant guanine nucleotide exchange factor 1) in four unrelated families with individuals affected by sporadic or dominant HMN/CMT2. Genomic sequencing analyses in seven affected individuals uncovered four distinct heterozygous GBF1 variants, two of which occurred de novo. Other known HMN/CMT2-implicated genes were excluded. Affected individuals show HMN/CMT2 with slowly progressive distal muscle weakness and musculoskeletal deformities. Electrophysiological studies confirmed axonal damage with chronic neurogenic changes. Three individuals had additional distal sensory loss. GBF1 encodes a guanine-nucleotide exchange factor that facilitates the activation of members of the ARF (ADP-ribosylation factor) family of small GTPases. GBF1 is mainly involved in the formation of coatomer protein complex (COPI) vesicles, maintenance and function of the Golgi apparatus, and mitochondria migration and positioning. We demonstrate that GBF1 is present in mouse spinal cord and muscle tissues and is particularly abundant in neuropathologically relevant sites, such as the motor neuron and the growth cone. Consistent with the described role of GBF1 in Golgi function and maintenance, we observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals in this study. Our results not only reinforce the existing link between Golgi fragmentation and neurodegeneration but also demonstrate that pathogenic variants in GBF1 are associated with HMN/CMT2.
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http://dx.doi.org/10.1016/j.ajhg.2020.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491385PMC
October 2020

Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes.

Mol Genet Metab 2020 03 16;129(3):193-206. Epub 2020 Jan 16.

Clinic for Special Children, Strasburg, PA, USA; Department of Pediatrics, Penn Medicine-Lancaster General Hospital, Lancaster, PA, USA; Central Pennsylvania Clinic, Belleville, PA, USA.

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.
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http://dx.doi.org/10.1016/j.ymgme.2020.01.006DOI Listing
March 2020

Spectrum of K 2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders.

Ann Neurol 2019 12 24;86(6):899-912. Epub 2019 Oct 24.

Departments of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL.

Objective: Pathogenic variants in KCNB1, encoding the voltage-gated potassium channel K 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.

Methods: We evaluated a series of 17 KCNB1 variants associated with DEE or other neurodevelopmental disorders (NDDs) to rapidly ascertain channel dysfunction using high-throughput functional assays. Specifically, we investigated the biophysical properties and cell-surface expression of variant K 2.1 channels expressed in heterologous cells using high-throughput automated electrophysiology and immunocytochemistry-flow cytometry.

Results: Pathogenic variants exhibited diverse functional defects, including altered current density and shifts in the voltage dependence of activation and/or inactivation, as homotetramers or when coexpressed with wild-type K 2.1. Quantification of protein expression also identified variants with reduced total K 2.1 expression or deficient cell-surface expression.

Interpretation: Our study establishes a platform for rapid screening of K 2.1 functional defects caused by KCNB1 variants associated with DEE and other NDDs. This will aid in establishing KCNB1 variant pathogenicity and the mechanism of dysfunction, which will enable targeted strategies for therapeutic intervention based on molecular phenotype. ANN NEUROL 2019;86:899-912.
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http://dx.doi.org/10.1002/ana.25607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025436PMC
December 2019

Crigler-Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier.

Hepatology 2020 06 5;71(6):1923-1939. Epub 2020 Feb 5.

Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.

Background And Aims: 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.

Approach And Results: Unbound ("free") bilirubin (B ) was measured in patient sera to characterize the binding of unconjugated bilirubin (B ) to albumin (A) and validate their molar concentration ratio (B /A) as an index of neurological risk. Two custom phototherapy systems were constructed from affordable materials to provide high irradiance in the outpatient setting; light dose was titrated to keep B /A at least 30% below intravascular B binding capacity (i.e., B /A = 1.0). Categorical clinical outcomes were ascertained by chart review, and a measure (L ) was used to quantify liver fibrosis. Unbound bilirubin had a nonlinear relationship to B (R  = 0.71) and B /A (R  = 0.76), and B as a percentage of B correlated inversely to the bilirubin-albumin equilibrium association binding constant (R  = 0.69), which varied 10-fold among individuals. In newborns with CN1, unconjugated bilirubin increased 4.3 ± 1.1 mg/dL per day. Four (14%) neonates developed kernicterus between days 14 and 45 postnatal days of life; peak B  ≥ 30 mg/dL and B /A ≥ 1.0 mol:mol were equally predictive of perinatal brain injury (sensitivity 100%, specificity 93.3%, positive predictive value 88.0%), and starting phototherapy after age 13 days increased this risk 3.5-fold. Consistent phototherapy with 33-103 µW/cm •nm for 9.2 ± 1.1 hours/day kept B and B /A within safe limits throughout childhood, but B increased 0.46 mg/dL per year to reach dangerous concentrations by 18 years of age. Liver transplantation (n = 17) normalized B and eliminated phototherapy dependence. Liver explants showed fibrosis ranging from mild to severe.

Conclusion: Seven decades after its discovery, CN1 remains a morbid and potentially fatal disorder.
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http://dx.doi.org/10.1002/hep.30959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909716PMC
June 2020

Clinical and genetic validity of quantitative bipolarity.

Transl Psychiatry 2019 09 16;9(1):228. Epub 2019 Sep 16.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21228, USA.

Research has yet to provide a comprehensive understanding of the genetic basis of bipolar disorder (BP). In genetic studies, defining the phenotype by diagnosis may miss risk-allele carriers without BP. The authors aimed to test whether quantitatively detected subclinical symptoms of bipolarity identifies a heritable trait that infers risk for BP. The Quantitative Bipolarity Scale (QBS) was administered to 310 Old Order Amish or Mennonite individuals from multigenerational pedigrees; 110 individuals had psychiatric diagnoses (20 BP, 61 major depressive disorders (MDD), 3 psychotic disorders, 26 other psychiatric disorders). Familial aggregation of QBS was calculated using the variance components method to derive heritability and shared household effects. The QBS score was significantly higher in BP subjects (31.5 ± 3.6) compared to MDD (16.7 ± 2.0), other psychiatric diagnoses (7.0 ± 1.9), and no psychiatric diagnosis (6.0 ± 0.65) (all p < 0.001). QBS in the whole sample was significantly heritable (h = 0.46 ± 0.15, p < 0.001) while the variance attributed to the shared household effect was not significant (p = 0.073). When subjects with psychiatric illness were removed, the QBS heritability was similar (h = 0.59 ± 0.18, p < 0.001). These findings suggest that quantitative bipolarity as measured by QBS can separate BP from other psychiatric illnesses yet is significantly heritable with and without BP included in the pedigrees suggesting that the quantitative bipolarity describes a continuous heritable trait that is not driven by a discrete psychiatric diagnosis. Bipolarity trait assessment may be used to supplement the diagnosis of BP in future genetic studies and could be especially useful for capturing subclinical genetic contributions to a BP phenotype.
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http://dx.doi.org/10.1038/s41398-019-0561-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746871PMC
September 2019

Disease burden of Crigler-Najjar syndrome: Systematic review and future perspectives.

J Gastroenterol Hepatol 2020 Apr 24;35(4):530-543. Epub 2019 Oct 24.

Audentes Therapeutics, San Francisco, CA, USA.

Background And Aim: 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.

Methods: A systematic literature review was conducted to consolidate data on the patient, caregiver, and societal burden of CNS.

Results: Twenty-eight articles on clinical aspects of CNS were identified, but no published data on its humanistic or economic burden were found. In patients with complete UGT1A1 deficiency (type 1 CNS [CNS-I]), unconjugated bilirubin levels increase 3-6 mg/dL/day during the newborn period and reach neurologically dangerous levels between 5 and 14 days of age. Phototherapy is the mainstay of treatment but poses significant challenges to patients and their families. Despite consistent phototherapy, patients with CNS-I have worsening hyperbilirubinemia with advancing age. Liver transplantation is the only definitive therapy for CNS-I and is increasingly associated with excellent long-term survival but also incurs high costs, medical and surgical morbidities, and risks of immunosuppression.

Conclusions: Crigler-Najjar syndrome is associated with a substantial burden, even with existing standards of care. The development of novel disease-modifying therapies has the potential to reduce disease burden and improve the lives of CNS patients and their families.
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http://dx.doi.org/10.1111/jgh.14853DOI Listing
April 2020

Recessive GM3 synthase deficiency: Natural history, biochemistry, and therapeutic frontier.

Mol Genet Metab 2019 04 21;126(4):475-488. Epub 2019 Jan 21.

Clinic for Special Children, Strasburg, PA, USA. Electronic address:

GM3 synthase, encoded by ST3GAL5, initiates synthesis of all downstream cerebral gangliosides. Here, we present biochemical, functional, and natural history data from 50 individuals homozygous for a pathogenic ST3GAL5 c.862C>T founder allele (median age 8.1, range 0.7-30.5 years). GM3 and its derivatives were undetectable in plasma. Weight and head circumference were normal at birth and mean Apgar scores were 7.7 ± 2.0 (1 min) and 8.9 ± 0.5 (5 min). Somatic growth failure, progressive microcephaly, global developmental delay, visual inattentiveness, and dyskinetic movements developed within a few months of life. Infantile-onset epileptic encephalopathy was characterized by a slow, disorganized, high-voltage background, poor state transitions, absent posterior rhythm, and spike trains from multiple independent cortical foci; >90% of electrographic seizures were clinically silent. Hearing loss affected cochlea and central auditory pathways and 76% of children tested failed the newborn hearing screen. Development stagnated early in life; only 13 (26%) patients sat independently (median age 30 months), three (6%) learned to crawl, and none achieved reciprocal communication. Incessant irritability, often accompanied by insomnia, began during infancy and contributed to high parental stress. Despite catastrophic neurological dysfunction, neuroimaging showed only subtle or no destructive changes into late childhood and hospitalizations were surprisingly rare (0.2 per patient per year). Median survival was 23.5 years. Our observations corroborate findings from transgenic mice which indicate that gangliosides might have a limited role in embryonic neurodevelopment but become vital for postnatal brain growth and function. These results have critical implications for the design and implementation of ganglioside restitution therapies.
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http://dx.doi.org/10.1016/j.ymgme.2019.01.013DOI Listing
April 2019

Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay.

Am J Hum Genet 2018 11 25;103(5):794-807. Epub 2018 Oct 25.

National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Ca signaling is vital for various cellular processes including synaptic vesicle exocytosis, muscle contraction, regulation of secretion, gene transcription, and cellular proliferation. The endoplasmic reticulum (ER) is the largest intracellular Ca store, and dysregulation of ER Ca signaling and homeostasis contributes to the pathogenesis of various complex disorders and Mendelian disease traits. We describe four unrelated individuals with a complex multisystem disorder characterized by woolly hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and global developmental delay. Through whole-exome sequencing and family-based genomics, we identified bi-allelic variants in CCDC47 that encodes the Ca-binding ER transmembrane protein CCDC47. CCDC47, also known as calumin, has been shown to bind Ca with low affinity and high capacity. In mice, loss of Ccdc47 leads to embryonic lethality, suggesting that Ccdc47 is essential for early development. Characterization of cells from individuals with predicted likely damaging alleles showed decreased CCDC47 mRNA expression and protein levels. In vitro cellular experiments showed decreased total ER Ca storage, impaired Ca signaling mediated by the IPR Ca release channel, and reduced ER Ca refilling via store-operated Ca entry. These results, together with the previously described role of CCDC47 in Ca signaling and development, suggest that bi-allelic loss-of-function variants in CCDC47 underlie the pathogenesis of this multisystem disorder.
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http://dx.doi.org/10.1016/j.ajhg.2018.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218603PMC
November 2018

Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease.

Hum Mol Genet 2019 02;28(4):525-538

Clinic for Special Children, Strasburg, PA, USA.

Aminoacyl-tRNA synthetases (ARSs) are critical for protein translation. Pathogenic variants of ARSs have been previously associated with peripheral neuropathy and multisystem disease in heterozygotes and homozygotes, respectively. We report seven related children homozygous for a novel mutation in tyrosyl-tRNA synthetase (YARS, c.499C > A, p.Pro167Thr) identified by whole exome sequencing. This variant lies within a highly conserved interface required for protein homodimerization, an essential step in YARS catalytic function. Affected children expressed a more severe phenotype than previously reported, including poor growth, developmental delay, brain dysmyelination, sensorineural hearing loss, nystagmus, progressive cholestatic liver disease, pancreatic insufficiency, hypoglycemia, anemia, intermittent proteinuria, recurrent bloodstream infections and chronic pulmonary disease. Related adults heterozygous for YARS p.Pro167Thr showed no evidence of peripheral neuropathy on electromyography, in contrast to previous reports for other YARS variants. Analysis of YARS p.Pro167Thr in yeast complementation assays revealed a loss-of-function, hypomorphic allele that significantly impaired growth. Recombinant YARS p.Pro167Thr demonstrated normal subcellular localization, but greatly diminished ability to homodimerize in human embryonic kidney cells. This work adds to a rapidly growing body of research emphasizing the importance of ARSs in multisystem disease and significantly expands the allelic and clinical heterogeneity of YARS-associated human disease. A deeper understanding of the role of YARS in human disease may inspire innovative therapies and improve care of affected patients.
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http://dx.doi.org/10.1093/hmg/ddy344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360277PMC
February 2019

Spinal muscular atrophy within Amish and Mennonite populations: Ancestral haplotypes and natural history.

PLoS One 2018 6;13(9):e0202104. Epub 2018 Sep 6.

Clinic for Special Children, Strasburg, Pennsylvania, United States of America.

We correlate chromosome 5 haplotypes and SMN2 copy number with disease expression in 42 Mennonite and 14 Amish patients with spinal muscular atrophy (SMA). A single haplotype (A1) with 1 copy of SMN2 segregated among all Amish patients. SMN1 deletions segregated on four different Mennonite haplotypes that carried 1 (M1a, M1b, M1c) or 2 (M2) copies of SMN2. DNA microsatellite and microarray data revealed structural similarities among A1, M1a, M1b, and M2. Clinical data were parsed according to both SMN1 genotype and SMN2 copy number (2 copies, n = 44; 3 copies, n = 9; or 4 copies, n = 3). No infant with 2 copies of SMN2 sat unassisted. In contrast, all 9 Mennonites with the M1a/M2 genotype (3 copies of SMN2) sat during infancy at a median age of 7 months, and 5 (56%) walked and dressed independently at median ages of 18 and 36 months, respectively. All are alive at a median age of 11 (range 2-31) years without ventilatory support. Among 13 Amish and 26 Mennonite patients with 2 copies of SMN2 who did not receive feeding or ventilatory support, A1/A1 as compared to M1a/M1a genotype was associated with earlier clinical onset (p = 0.0040) and shorter lifespan (median survival 3.9 versus 5.7 months, p = 0.0314). These phenotypic differences were not explained by variation in SMN1 deletion size or SMN2 coding sequence, which were conserved across haplotypes. Distinctive 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202104PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126807PMC
February 2019

Preliminary Safety and Tolerability of a Novel Subcutaneous Intrathecal Catheter System for Repeated Outpatient Dosing of Nusinersen to Children and Adults With Spinal Muscular Atrophy.

J Pediatr Orthop 2018 Nov/Dec;38(10):e610-e617

Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE.

Background: Many patients with spinal muscular atrophy (SMA) who might benefit from intrathecal antisense oligonucleotide (nusinersen) therapy have scoliosis or spinal fusion that precludes safe drug delivery. To circumvent spinal pathology, we designed a novel subcutaneous intrathecal catheter (SIC) system by connecting an intrathecal catheter to an implantable infusion port.

Methods: Device safety and tolerability were tested in 10 SMA patients (age, 5.4 to 30.5 y; 80% with 3 copies of SMN2); each received 3 sequential doses of nusinersen (n=30 doses). Pretreatment disease burden was evaluated using the Revised Hammersmith Scale, dynamometry, National Institutes of Health pegboard, pulmonary function testing, electromyography, and 2 health-related quality of life tools.

Results: Device implantation took ≤2 hours and was well tolerated. All outpatient nusinersen doses were successfully administered via SIC within 20 minutes on the first attempt, and required no regional or systemic analgesia, cognitive distraction, ultrasound guidance, respiratory precautions, or sedation. Cerebrospinal fluid withdrawn from the SIC had normal levels of glucose and protein; cerebrospinal fluid white blood cells were slightly elevated in 2 (22%) of 9 specimens (median, 1 cell/µL; range, 0 to 12 cells/µL) and red blood cells were detected in 7 (78%) specimens (median, 4; range, 0 to 2930 cells/µL).

Discussion: Preliminary observations reveal the SIC to be relatively safe and well tolerated in SMA patients with advanced disease and spinal fusion. The SIC warrants further study and, if proven effective in larger trials of longer duration, could double the number of patients able to receive nusinersen worldwide while reducing administration costs 5- to 10-fold.
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http://dx.doi.org/10.1097/BPO.0000000000001247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211782PMC
December 2018

TNNT1 nemaline myopathy: natural history and therapeutic frontier.

Hum Mol Genet 2018 09;27(18):3272-3282

Clinic for Special Children, Strasburg, PA, USA.

We describe the natural history of 'Amish' nemaline myopathy (ANM), an infantile-onset, lethal disease linked to a pathogenic c.505G>T nonsense mutation of TNNT1, which encodes the slow fiber isoform of troponin T (TNNT1; a.k.a. TnT). The TNNT1 c.505G>T allele has a carrier frequency of 6.5% within Old Order Amish settlements of North America. We collected natural history data for 106 ANM patients born between 1923 and 2017. Over the last two decades, mean age of molecular diagnosis was 16 ± 27 days. TNNT1 c.505G>T homozygotes were normal weight at birth but failed to thrive by age 9 months. Presenting neonatal signs were axial hypotonia, hip and shoulder stiffness, and tremors, followed by progressive muscle weakness, atrophy and contractures. Affected children developed thoracic rigidity, pectus carinatum and restrictive lung disease during infancy, and all succumbed to respiratory failure by 6 years of age (median survival 18 months, range 0.2-66 months). Muscle histology from two affected children showed marked fiber size variation owing to both Type 1 myofiber smallness (hypotrophy) and Type 2 fiber hypertrophy, with evidence of nemaline rods, myofibrillar disarray and vacuolar pathology in both fiber types. The truncated slow TNNT1 (TnT) fragment (p.Glu180Ter) was undetectable in ANM muscle, reflecting its rapid proteolysis and clearance from sarcoplasm. Similar functional and histological phenotypes were observed in other human cohorts and two transgenic murine models (Tnnt1-/- and Tnnt1 c.505G>T). These findings have implications for emerging molecular therapies, including the suitably of TNNT1 gene replacement for newborns with ANM or other TNNT1-associated myopathies.
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http://dx.doi.org/10.1093/hmg/ddy233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121192PMC
September 2018

Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions.

Am J Hum Genet 2017 Dec 30;101(6):985-994. Epub 2017 Nov 30.

Institute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland.

Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-β-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.
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http://dx.doi.org/10.1016/j.ajhg.2017.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812889PMC
December 2017

Management of Congenital Heart Disease Associated with Ellis-van Creveld Short-rib Thoracic Dysplasia.

J Pediatr 2017 12;191:145-151

Clinic for Special Children, Strasburg, PA. Electronic address:

Objective: To evaluate clinical outcome of patients with Ellis-van Creveld syndrome (EVC) in whom congenital heart disease (CHD) repair was delayed intentionally to reduce the risk of postoperative respiratory morbidity and mortality.

Study Design: This retrospective review of 51 EVC c.1886+5G>T homozygotes born between 2005 and 2014 focused on 18 subjects who underwent surgery for CHD, subdivided into early (mean, 1.3 months) vs delayed (mean, 50.1 months) repair.

Results: Growth trajectories differed between control subjects and patients with EVC, and CHD was associated with slower weight gain. Relative to controls, infants with EVC had a 40%-75% higher respiratory rates (independent of CHD) accompanied by signs of compensated respiratory acidosis. Blood gases and respiratory rates approached normal values by age 4 years. Hemodynamically significant CHD was present in 23 children, 18 (78%) of whom underwent surgical repair. Surgery was performed at 1.3 ± 1.3 months for children born between 2005 and 2009 (n = 9) and 50.1 ± 40.2 months (P = .009) for children born between 2010 and 2014 (n = 9). The latter had shorter postoperative mechanical ventilation (1.1 ± 2.4 days vs 49.6 ± 57.1 days; P = .075), shorter intensive care duration of stay (16 ± 24 days vs 48.6 ± 44.2 days; P = .155), and no postoperative tracheostomies (vs 60%; P = .028) or deaths (vs 44%; P = .082).

Conclusion: Among children with EVC and possibly other short-rib thoracic dysplasias, delayed surgical repair of CHD reduces postoperative morbidity and improves survival. Respiratory rate serves as a simple indicator for optimal timing of surgical repair.
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http://dx.doi.org/10.1016/j.jpeds.2017.08.073DOI Listing
December 2017

Genomic diagnostics within a medically underserved population: efficacy and implications.

Genet Med 2018 01 20;20(1):31-41. Epub 2017 Jul 20.

Clinic for Special Children, Strasburg, Pennsylvania, USA.

PurposeWe integrated whole-exome sequencing (WES) and chromosomal microarray analysis (CMA) into a clinical workflow to serve an endogamous, uninsured, agrarian community.MethodsSeventy-nine probands (newborn to 49.8 years) who presented between 1998 and 2015 remained undiagnosed after biochemical and molecular investigations. We generated WES data for probands and family members and vetted variants through rephenotyping, segregation analyses, and population studies.ResultsThe most common presentation was neurological disease (64%). Seven (9%) probands were diagnosed by CMA. Family WES data were informative for 37 (51%) of the 72 remaining individuals, yielding a specific genetic diagnosis (n = 32) or revealing a novel molecular etiology (n = 5). For five (7%) additional subjects, negative WES decreased the likelihood of genetic disease. Compared to trio analysis, "family" WES (average seven exomes per proband) reduced filtered candidate variants from 22 ± 6 to 5 ± 3 per proband. Nineteen (51%) alleles were de novo and 17 (46%) inherited; the latter added to a population-based diagnostic panel. We found actionable secondary variants in 21 (4.2%) of 502 subjects, all of whom opted to be informed.ConclusionCMA and family-based WES streamline and economize diagnosis of rare genetic disorders, accelerate novel gene discovery, and create new opportunities for community-based screening and prevention in underserved populations.
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http://dx.doi.org/10.1038/gim.2017.76DOI Listing
January 2018

Defects in lymphocyte telomere homeostasis contribute to cellular immune phenotype in patients with cartilage-hair hypoplasia.

J Allergy Clin Immunol 2017 Oct 23;140(4):1120-1129.e1. Epub 2017 Jan 23.

Section of Immunology, Allergy and Rheumatology, Texas Children's Hospital, Baylor College of Medicine, Houston, Tex. Electronic address:

Background: Mutations in the long noncoding RNA RNase component of the mitochondrial RNA processing endoribonuclease (RMRP) give rise to the autosomal recessive condition cartilage-hair hypoplasia (CHH). The CHH disease phenotype has some overlap with dyskeratosis congenita, a well-known "telomere disorder." RMRP binds the telomerase reverse transcriptase (catalytic subunit) in some cell lines, raising the possibility that RMRP might play a role in telomere biology.

Objective: We sought to determine whether a telomere phenotype is present in immune cells from patients with CHH and explore mechanisms underlying these observations.

Methods: We assessed proliferative capacity and telomere length using flow-fluorescence in situ hybridization (in situ hybridization and flow cytometry) of primary lymphocytes from patients with CHH, carrier relatives, and control subjects. The role of telomerase holoenzyme components in gene expression and activity were assessed by using quantitative PCR and the telomere repeat amplification protocol from PBMCs and enriched lymphocyte cultures.

Results: Lymphocyte cultures from patients with CHH display growth defects in vitro, which is consistent with an immune deficiency cellular phenotype. Here we show that telomere length and telomerase activity are impaired in primary lymphocyte subsets from patients with CHH. Notably, telomerase activity is affected in a gene dose-dependent manner when comparing heterozygote RMRP carriers with patients with CHH. Telomerase deficiency in patients with CHH is not mediated by abnormal telomerase gene transcript levels relative to those of endogenous genes.

Conclusion: These findings suggest that telomere deficiency is implicated in the CHH disease phenotype through an as yet unidentified mechanism.
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http://dx.doi.org/10.1016/j.jaci.2016.11.051DOI Listing
October 2017

Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant.

Am J Hum Genet 2016 Nov 20;99(5):1117-1129. Epub 2016 Oct 20.

Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA. Electronic address:

Lissencephaly is a malformation of cortical development typically caused by deficient neuronal migration resulting in cortical thickening and reduced gyration. Here we describe a "thin" lissencephaly (TLIS) variant characterized by megalencephaly, frontal predominant pachygyria, intellectual disability, and seizures. Trio-based whole-exome sequencing and targeted re-sequencing identified recessive mutations of CRADD in six individuals with TLIS from four unrelated families of diverse ethnic backgrounds. CRADD (also known as RAIDD) is a death-domain-containing adaptor protein that oligomerizes with PIDD and caspase-2 to initiate apoptosis. TLIS variants cluster in the CRADD death domain, a platform for interaction with other death-domain-containing proteins including PIDD. Although caspase-2 is expressed in the developing mammalian brain, little is known about its role in cortical development. CRADD/caspase-2 signaling is implicated in neurotrophic factor withdrawal- and amyloid-β-induced dendritic spine collapse and neuronal apoptosis, suggesting a role in cortical sculpting and plasticity. TLIS-associated CRADD variants do not disrupt interactions with caspase-2 or PIDD in co-immunoprecipitation assays, but still abolish CRADD's ability to activate caspase-2, resulting in reduced neuronal apoptosis in vitro. Homozygous Cradd knockout mice display megalencephaly and seizures without obvious defects in cortical lamination, supporting a role for CRADD/caspase-2 signaling in mammalian brain development. Megalencephaly and lissencephaly associated with defective programmed cell death from loss of CRADD function in humans implicate reduced apoptosis as an important pathophysiological mechanism of cortical malformation. Our data suggest that CRADD/caspase-2 signaling is critical for normal gyration of the developing human neocortex and for normal cognitive ability.
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http://dx.doi.org/10.1016/j.ajhg.2016.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097945PMC
November 2016

Abnormal Hypermethylation at Imprinting Control Regions in Patients with S-Adenosylhomocysteine Hydrolase (AHCY) Deficiency.

PLoS One 2016 14;11(3):e0151261. Epub 2016 Mar 14.

Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

S-adenosylhomocysteine hydrolase (AHCY) deficiency is a rare autosomal recessive disorder in methionine metabolism caused by mutations in the AHCY gene. Main characteristics are psychomotor delay including delayed myelination and myopathy (hypotonia, absent tendon reflexes etc.) from birth, mostly associated with hypermethioninaemia, elevated serum creatine kinase levels and increased genome wide DNA methylation. The prime function of AHCY is to hydrolyse and efficiently remove S-adenosylhomocysteine, the by-product of transmethylation reactions and one of the most potent methyltransferase inhibitors. In this study, we set out to more specifically characterize DNA methylation changes in blood samples from patients with AHCY deficiency. Global DNA methylation was increased in two of three analysed patients. In addition, we analysed the DNA methylation levels at differentially methylated regions (DMRs) of six imprinted genes (MEST, SNRPN, LIT1, H19, GTL2 and PEG3) as well as Alu and LINE1 repetitive elements in seven patients. Three patients showed a hypermethylation in up to five imprinted gene DMRs. Abnormal methylation in Alu and LINE1 repetitive elements was not observed. We conclude that DNA hypermethylation seems to be a frequent but not a constant feature associated with AHCY deficiency that affects different genomic regions to different degrees. Thus AHCY deficiency may represent an ideal model disease for studying the molecular origins and biological consequences of DNA hypermethylation due to impaired cellular methylation status.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151261PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790936PMC
August 2016

Living related versus deceased donor liver transplantation for maple syrup urine disease.

Mol Genet Metab 2016 Mar 12;117(3):336-43. Epub 2016 Jan 12.

Clinic for Special Children, Strasburg, PA, USA; Franklin & Marshall College, Lancaster, PA, USA; Lancaster General Hospital, Lancaster, PA, USA. Electronic address:

Maple syrup urine disease (MSUD) is an inherited disorder of branched chain ketoacid (BCKA) oxidation associated with episodic and chronic brain disease. Transplantation of liver from an unrelated deceased donor restores 9-13% whole-body BCKA oxidation capacity and stabilizes MSUD. Recent reports document encouraging short-term outcomes for MSUD patients who received a liver segment from mutation heterozygous living related donors (LRDT). To investigate effects of living related versus deceased unrelated grafts, we studied four Brazilian MSUD patients treated with LRDT who were followed for a mean 19 ± 12 postoperative months, and compared metabolic and clinical outcomes to 37 classical MSUD patients treated with deceased donor transplant. Patient and graft survival for LRDT were 100%. Three of 4 MSUD livers were successfully domino transplanted into non-MSUD subjects. Following LRDT, all subjects resumed a protein-unrestricted diet as mean plasma leucine decreased from 224 ± 306 μM to 143 ± 44 μM and allo-isoleucine decreased 91%. We observed no episodes of hyperleucinemia during 80 aggregate postoperative patient-months. Mean plasma leucine:isoleucine:valine concentration ratios were ~2:1:4 after deceased donor transplant compared to ~1:1:1.5 following LRDT, resulting in differences of predicted cerebral amino acid uptake. Mutant heterozygous liver segments effectively maintain steady-state BCAA and BCKA homeostasis on an unrestricted diet and during most catabolic states, but might have different metabolic effects than grafts from unrelated deceased donors. Neither living related nor deceased donor transplant affords complete protection from metabolic intoxication, but both strategies represent viable alternatives to nutritional management.
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http://dx.doi.org/10.1016/j.ymgme.2016.01.005DOI Listing
March 2016

Intraventricular Baclofen for Treatment of Severe Dystonia Associated with Glutaryl-CoA Dehydrogenase Deficiency (GA1): Report of Two Cases.

Mov Disord Clin Pract 2016 May-Jun;3(3):296-299. Epub 2016 Jan 5.

Clinic for Special Children Strasburg Pennsylvania USA.

Two individuals with intractable generalized dystonia secondary to glutaric aciduria type 1 (GA1) were treated with continuous intraventricular baclofen (IVB) infusion. On IVB of 220 μg/day, one 10-year-old girl had an 85% reduction in dystonia, from Barry-Albright Dystonia Scale (BADS) score 30.7 to 4.5 (maximum score: 32) at 30 postoperative months. Her enteral dystonia medications were reduced >60%, and she discontinued medications for pain, anxiety, and depression. A second GA1 patient, age 23, experienced a more modest 18% reduction in dystonia (BADS decrease from 29.7 to 24.3) on IVB of 1,665 μg/day at 14 postoperative months. He substantially reduced his enteral dystonia medications and reported meaningful pain relief. These cases demonstrate that IVB may be a palliative option in the intractable dystonia of GA1. Our provisional observations suggest that IVB may be more beneficial in younger GA1 patients.
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http://dx.doi.org/10.1002/mdc3.12278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353460PMC
January 2016

Heritability of complex white matter diffusion traits assessed in a population isolate.

Hum Brain Mapp 2016 Feb 5;37(2):525-35. Epub 2015 Nov 5.

Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland.

Introduction: Diffusion weighted imaging (DWI) methods can noninvasively ascertain cerebral microstructure by examining pattern and directions of water diffusion in the brain. We calculated heritability for DWI parameters in cerebral white (WM) and gray matter (GM) to study the genetic contribution to the diffusion signals across tissue boundaries.

Methods: Using Old Order Amish (OOA) population isolate with large family pedigrees and high environmental homogeneity, we compared the heritability of measures derived from three representative DWI methods targeting the corpus callosum WM and cingulate gyrus GM: diffusion tensor imaging (DTI), the permeability-diffusivity (PD) model, and the neurite orientation dispersion and density imaging (NODDI) model. These successively more complex models represent the diffusion signal modeling using one, two, and three diffusion compartments, respectively.

Results: We replicated the high heritability of the DTI-based fractional anisotropy (h(2)  = 0.67) and radial diffusivity (h(2)  = 0.72) in WM. High heritability in both WM and GM tissues were observed for the permeability-diffusivity index from the PD model (h(2)  = 0.64 and 0.84), and the neurite density from the NODDI model (h(2)  = 0.70 and 0.55). The orientation dispersion index from the NODDI model was only significantly heritable in GM (h(2)  = 0.68).

Conclusion: DWI measures from multicompartmental models were significantly heritable in WM and GM. DWI can offer valuable phenotypes for genetic research; and genes thus identified may reveal mechanisms contributing to mental and neurological disorders in which diffusion imaging anomalies are consistently found. Hum Brain Mapp 37:525-535, 2016. © 2015 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hbm.23047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718876PMC
February 2016

A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 2: cobalamin C deficiency.

Genet Med 2016 Apr 13;18(4):396-404. Epub 2015 Aug 13.

Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Purpose: Cobalamin C (cblC) deficiency impairs the biosynthesis of 5'-deoxyadenosyl-adenosyl- and methyl-cobalamin, resulting in methylmalonic acidemia combined with hyperhomocysteinemia and hypomethioninemia. However, some patients with cblC deficiency are treated with medical foods, devoid of methionine and high in leucine content, that are formulated for patients with isolated propionate oxidative defects. We examined the effects of imbalanced branched-chain amino acid intake on growth outcomes in cblC-deficient patients.

Methods: Dietary intake was correlated with biochemical, anthropometric, and body composition measurements and other disease parameters in a cohort of 28 patients with early-onset cblC deficiency.

Results: Protein-restricted diets were followed by 21% of the patients, whereas 32% received medical foods. Patients on protein-restricted diets had lower height-for-age z-score (P = 0.034), whereas patients consuming medical foods had lower head circumference Z-scores (P = 0.037), plasma methionine concentrations (P = 0.001), and predicted methionine influx through the blood-brain barrier Z-score (-1.29 vs. -0.0617; P = 0.007). The combination of age at diagnosis, a history of seizures, and the leucine-to-valine dietary intake ratio best predicted head circumference Z-score based on multiple regression modeling (R(2) = 0.945).

Conclusions: Patients with cblC deficiency treated with medical foods designed for isolated methylmalonic acidemia are at risk for iatrogenic methionine deficiency that could adversely affect brain growth and development.Genet Med 18 4, 396-404.
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http://dx.doi.org/10.1038/gim.2015.107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752912PMC
April 2016
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