Sidney M Gospe, Jr

Sidney M Gospe, Jr
University of Washington Seattle | UW · Department of Neurology

MD, PhD

About

122
Publications
14,567
Reads
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3,494
Citations
Introduction
Sidney M Gospe, Jr is now an emeritus professor in the Departments of Neurology and Pediatrics, University of Washington Seattle. He continues to conduct collaborative research concerning pyridoxine-dependent epilepsy, a metabolic epileptic encephalopathy caused by mutations in the ALDH7A1 gene.
Additional affiliations
June 2017 - present
University of Washington
Position
  • Professor Emeritus
August 2000 - June 2017
University of Washington Seattle
Position
  • Chair
August 2000 - June 2017
Seattle Children's Hospital
Position
  • Division Head
Education
July 1981 - June 1986
Baylor College of Medicine
Field of study
  • Pediatrics and Child Neurology
September 1975 - May 1981
Duke University
Field of study
  • Medicine
September 1975 - December 1980
Duke University
Field of study
  • Physiology and Pharmacology

Publications

Publications (122)
Article
Background and Objectives Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a developmental epileptic encephalopathy characterized by seizure improvement after pyridoxine supplementation. Adjunct lysine reduction therapies reduce the accumulation of putative neurotoxic metabolites with the goal to improve developmental outcomes. Our objective was to e...
Article
Full-text available
Background Little is known about pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) in adulthood, as the genetic basis of the disorder has only been elucidated 15 years ago. This creates a knowledge gap for physicians, pediatric patients and their parents, which was aimed to address in this study...
Article
Background Seventy-five percent of patients with pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) suffer intellectual developmental disability despite pyridoxine treatment. Adjunct lysine reduction therapies (LRT), aimed at lowering putative neurotoxic metabolites, are associated with improved c...
Article
Background Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine catabolism that presents with refractory epilepsy in newborns. Biallelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase/antiquitin, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the importa...
Preprint
Full-text available
Pyridoxine-dependent epilepsy (PDE-ALDH7A1), also known as antiquitin deficiency, is an inborn error of lysine metabolism that presents with refractory epilepsy in newborns. Bi-allelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficien...
Article
Pyridoxine‐dependent epilepsy (PDE‐ALDH7A1) is an autosomal recessive condition due to a deficiency of α‐aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE‐ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate...
Chapter
Disorders of pyridoxine metabolism include pyridoxine-dependent epilepsy (PDE) due to antiquitin (ATQ) deficiency, PDE due to abnormalities in pyridoxal 5′-phosphate (PLP) homeostasis protein (PLPHP deficiency, a PLP-responsive epileptic encephalopathy due to a deficiency of pyridox(am)ine 5′-phosphate oxidase (PNPO deficiency), and tissue nonspeci...
Article
Pyridoxine dependent epilepsy (PDE) is a treatable epileptic encephalopathy characterized by a positive response to pharmacologic doses of pyridoxine. Despite seizure control, at least 75% of individuals have intellectual disability and developmental delay. Current treatment paradigms have resulted in improved cognitive outcomes emphasizing the imp...
Chapter
Manganese transport across cell membranes is highly regulated to prevent toxic accumulation or deficiency. In recent years, three autosomal recessive disorders of manganese transport have been reported. Patients with pathogenic variants in SLC30A10 manifest hypermanganesemia, dystonia, parkinsonism, liver dysfunction, and polycythemia, whereas pati...
Article
Over the past 2 decades, various telehealth technologies, in particular synchronous video teleconferencing between provider and patient, have been incorporated into the practice of neurology. The practice of child neurology is now starting to take advantage of these rapidly evolving resources. This review describes the evolution of tele-neurology,...
Article
Pyridoxine dependent epilepsy (PDE) is a treatable epileptic encephalopathy characterized by a positive response to pharmacologic doses of pyridoxine. Despite seizure control, at least 75% of individuals have intellectual disability and developmental delay. Current treatment paradigms have resulted in improved cognitive outcomes emphasizing the imp...
Article
Objective: To evaluate the features and maturational changes in overall callosal shape in patients with pyridoxine-dependent epilepsy (PDE). Methods: Measurements were conducted through landmark-based geometric morphometrics applied on cerebral MRIs of patients with PDE and age-matched control subjects. The outline of the corpus callosum was man...
Article
Background: Channelopathies are a group of monogenic disorders that affect a single ion channel and can result in neurological disease. While a rare cause of epilepsy, channelopathies offer unique insight to the molecular basis of epilepsy and treatment opportunities. Calcium homeostasis is tightly regulated by a series of interacting subunits. CA...
Chapter
Disorders of pyridoxine metabolism include pyridoxine-dependent epilepsy (PDE), pyridoxal-5′-phosphate- responsive epileptic encephalopathy, and tissue nonspecific isoenzyme of alkaline phosphatase deficiency. This chapter focuses on antiquitin (ATQ) deficiency, which is the main cause of autosomal recessive PDE and is characterized by early-onset...
Article
Background: In this observational study, white matter structure, functional magnetic resonance imaging (fMRI) task-based responses, and functional connectivity were assessed in four subjects with high functioning pyridoxine-dependent epilepsy and age-matched control subjects. Methods: Four male subjects with pyridoxine-dependent epilepsy (mean a...
Article
In rare diseases, the advent of potential therapies spurs early diagnosis, natural history studies, and the creation of patient registries. Succinic semialdehyde dehydrogenase (SSADH) deficiency is a relatively recently described autosomal recessive organic aciduria that is due to an inborn error of the second and final step of γ-aminobutyric acid...
Article
To improve the neurologic outcomes for infants with brain injury, neonatal providers are increasingly implementing neurocritical care approaches into clinical practice. Term infants with brain injury have been principal beneficiaries of neurologically-integrated care models to date, as evidenced by the widespread adoption of therapeutic hypothermia...
Article
To investigate the role of intragenic deletions of ALDH7A1 in patients with clinical and biochemical evidence of pyridoxine-dependent epilepsy but only a single identifiable mutation in ALDH7A1. We designed a custom oligonucleotide array with high-density probe coverage across the ALDH7A1 gene. We performed array comparative genomic hybridization i...
Article
Choline acetyltransferase catalyzes the synthesis of acetylcholine at cholinergic nerves. Mutations in human CHAT cause a congenital myasthenic syndrome (CMS) due to impaired synthesis of ACh; this severe variant of the disease is frequently associated with unexpected episodes of potentially fatal apnea. The severity of this condition varies remark...
Chapter
BACKGROUND: Seventy-five percent of patients with pyridoxine-dependent epilepsy (PDE) due to Antiquitin (ATQ) deficiency suffer from developmental delay and/or intellectual disability (IQ < 70) despite seizure control. An observational study showed that adjunct treatment with a lysine-restricted diet is safe, results in partial normalization of lys...
Article
Aim: While there have been isolated reports of callosal morphology differences in pyridoxine-dependent epilepsy (PDE), a rare autosomal disorder caused by ALDH7A1 gene mutations, no study has systematically evaluated callosal features in a large sample of patients. This study sought to overcome this knowledge gap. Method: Spanning a wide age ran...
Article
We present the case of a 14-year-old girl with a biphasic course after oxycodone ingestion. Clinically, she had a rapid return to baseline after initial ingestion and presented a week later with new onset ballism, akathisia, and encephalopathy. Neuroimaging demonstrated bilateral globi pallidi and cerebellar lesions with a relative decrease of meta...
Article
Full-text available
Background: Seventy-five percent of patients with pyridoxine-dependent epilepsy (PDE) due to Antiquitin (ATQ) deficiency suffer from developmental delay and/or intellectual disability (IQ < 70) despite seizure control. An observational study showed that adjunct treatment with a lysine-restricted diet is safe, results in partial normalization of ly...
Article
Myotonia congenita due to protein truncating CLCN1 mutations is associated with variable patterns of inheritance. Three family kindreds are described, all of whom possess protein truncating mutations (Y33X, fs503X, R894X). One lineage also has coexistent R894X, A313T, and A320V mutations. The Y33X mutation kinship has autosomal recessive inheritanc...
Article
Mutations in POMT1 lead to a group of neuromuscular conditions ranging in severity from Walker-Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, ages 19 and 14, and an unrelated 6-year old female with early onset muscular dystrophy and intellectual disability with minimal structural brain anomalies and no ocular abnor...
Article
We followed a patient with manganese transporter deficiency due to homozygous SLC30A10 mutations from age 14 years until his death at age 38 years and present the first postmortem findings of this disorder. The basal ganglia showed neuronal loss, rhodanine-positive deposits, astrocytosis, myelin loss and spongiosis. SLC30A10 protein was reduced in...
Article
The discovery of the cause of pyridoxine-dependent epilepsy (PDE), a unique autosomal recessive and treatable cause of refractory neonatal seizures, came 50 years after its first description with the identification of ALDH7A1 mutations leading to deficiency of the enzyme α-aminoadipic semialdehyde dehydrogenase (antiquitin).(1) Dysfunction of this...
Article
Objective: A high incidence of structural brain abnormalities has been reported in individuals with pyridoxine-dependent epilepsy (PDE). PDE is caused by mutations in ALDH7A1, also known as antiquitin. How antiquitin dysfunction leads to cerebral dysgenesis is unknown. In this study, we analyzed tissue from a child with PDE as well as control huma...
Article
Head-shaking stereotypies have been described in patients with neurological impairment. We noted an unusual preponderance of head shaking in patients with rhombencephalosynapsis (RES). We sought to delineate the movements further and determine whether oculomotor and vestibular testing could reveal their cause. Information was collected from direct...
Article
α-AASA and P6C were measured retrospectively in original newborn DBS of five patients with PDE using a LC-MS/MS method we developed previously. Both α-AASA and P6C were elevated markedly in the three newborn DBS stored at -20°C. At room temperature, α-AASA and P6C in DBS appeared stable for 3days and then decreased by up to 70% after 14days but rem...
Article
Using vignettes of real cases and the SimulConsult diagnostic decision support software, neurologists listed a differential diagnosis and workup before and after using the decision support. Using the software, there was a significant reduction in error, up to 75% for diagnosis and 56% for workup. This error reduction occurred despite the baseline b...
Article
We have identified an autosomal recessively inherited disorder of manganese metabolism that causes manganese accumulation in liver and brain with characteristic MRI brain appearances of hyperintense basal ganglia on T1-weighted sequences. Most affected individuals present in childhood with difficulties walking and fine motor impairment due to dysto...
Article
A cause of antiepileptic medication resistant seizures presenting in neonates and young infants is pyridoxine-dependent epilepsy (PDE), an organic aciduria, which is due to recessive mutations in the ALDH7A1 gene, resulting in deficiency of antiquitin. Since the discovery of molecular basis of this disorder, a few patients have been reported with a...
Article
Full-text available
OBJECTIVE: To evaluate the efficacy and safety of dietary lysine restriction as an adjunct to pyridoxine therapy on biochemical parameters, seizure control, and developmental/cognitive outcomes in children with pyridoxine-dependent epilepsy (PDE) caused by antiquitin (ATQ) deficiency. METHODS: In this observational study, seven children with confir...
Article
This commentary is on the original article by Bok et al. on pages 849‐854 of this issue.
Article
Full-text available
Environmental manganese (Mn) toxicity causes an extrapyramidal, parkinsonian-type movement disorder with characteristic magnetic resonance images of Mn accumulation in the basal ganglia. We have recently reported a suspected autosomal recessively inherited syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia in cases without...
Article
A 2-year-old girl from a consanguineous marriage was evaluated for refractory seizures that had presented at birth. Since her presentation, she had been treated with pyridoxine and antiepileptic medications. Because she did not manifest the expected clinical response, pyridoxine was discontinued, which led to an increase in clinical events. Cerebro...
Chapter
The causal disease Definitions and epidemiology Pyridoxine-dependent epilepsy (PDE) is a familial autosomal recessive disorder that results in intractable seizures presenting in newborns and older infants that come under control only after the administration of large doses of pyridoxine (vitamin B6). Untreated, the disorder results in death from st...
Article
Full-text available
Seizures are common in children, but the causes and recurrence risk for children with a nonfebrile first seizure remain poorly understood. In a prospective longitudinal study of children who presented with a first-time seizure, we investigated the viral etiology of associated infectious illnesses and sought to determine the risk of recurrent seizur...
Article
Manifesting carriers of DMD gene mutations may present diagnostic challenges, particularly in the absence of a family history of dystrophinopathy. We review the clinical and genetic features in 15 manifesting carriers identified among 860 subjects within the United Dystrophinopathy Project, a large clinical dystrophinopathy cohort whose members und...
Article
Full-text available
The treatment of neonatal seizures generally relies on the use of one or more anticonvulsant medications along with evaluation and management of any underlying etiology. In some circumstances, neonatal seizures are refractory to therapy and result in poor outcomes, including death. Certain rare vitamin- responsive inborn errors of metabolism may pr...
Article
Pyridoxine-dependent seizures (PDS) is an autosomal recessive disorder characterized by seizures presenting in neonates or infants up to 3 years of age which respond to pharmacological doses of pyridoxine. Alpha-aminoadipic semialdehyde dehydrogenase (antiquitin) deficiency was identified as an underlying defect in PDS characterized by accumulation...
Article
Full-text available
Charcot–Marie–Tooth disease (CMT) is one of the most common inherited neurological disorders, affecting 36 in 100 000 people. CMT type 1A (hereditary motor and sensory neuropathy) is the most frequent form of this disease, affecting 60 to 80% of the CMT population, but its diagnosis may be delayed because of inconsistent clinical signs and symptoms...
Article
While there is evidence that human perinatal exposure to environmental tobacco smoke (ETS) can result in an increased risk of respiratory disorders and sudden infant death syndrome, evidence linking ETS exposure to neurodevelopmental handicaps is suggestive but less compelling. We previously noted that postnatal ETS exposure, rather than prenatal e...
Article
Pyridoxine-dependent seizure (PDS) is a rare disorder characterized by seizures that are resistant to common anticonvulsants, and that are ultimately controlled by daily pharmacologic doses of pyridoxine (vitamin B6). Mutations of the antiquitin gene (ALDH7A1) are now recognized as the molecular basis of cases of neonatal-onset PDS. Bidirectional D...
Article
Full-text available
To facilitate clinical research on pyridoxine-dependent seizures (PDS), a rare disease registry was established for affected patients in the United States and Canada. From 1999 to 2007, 63 cases, ranging in age from 11 months to 40 years, were registered. All registered cases were diagnosed with PDS by their physicians using clinical criteria. Seve...
Article
Nemaline myopathy is a rare disorder of varying severity and genetic etiology. We present two cases, a father and son, with a novel missense mutation in the alpha actin gene. Both have a history of early motor impairment, with the son's course being considerably more severe. This pair illustrates the clinical variability of nemaline myopathy, highl...
Article
Pyridoxine dependency is an uncommon but important cause of intractable seizures presenting in infancy and early childhood. This paper discusses recent clinical, biochemical and genetic studies and how the findings should change our approach in evaluating young patients with antiepileptic drug-resistant seizures. Originally thought to be due to abn...
Article
Full-text available
Congenital human cytomegalovirus (HCMV) infection has long been recognized as a threat to the developing fetus, even though studies have shown that only a subset of congenital infections results in clinical signs of disease. Among the estimated 8000 children who develop sequelae from congenital CMV infection each year in the United States alone, mo...
Article
Pyridoxine is a recommended antidote that should be available in emergency departments (EDs). A pediatric use of this preparation is the treatment of acute seizures secondary to pyridoxine dependency or responsiveness. Two cases of children with pyridoxine-dependent and pyridoxine-responsive seizures whose treatment was affected by the unavailabili...
Article
Pyridoxine-dependent seizure (PDS) is a rare autosomal recessive intractable seizure disorder only controlled by a daily supplementation of pharmacological doses of pyridoxine (Vitamin B6). Although glutamate decarboxylase utilizes pyridoxal phosphate as a cofactor during conversion of the excitatory amino acid, glutamate, to the inhibitory neurotr...
Article
To describe the clinical characteristics of children with a first-time nonfebrile seizure in the setting of mild illness and to test the hypothesis that these seizures are associated with illness characterized by diarrhea. This retrospective cohort study was performed in a pediatric emergency department. Patients ages 6 months to 6 years who were e...
Article
Using case reports from their own experience and in the literature the authors illustrate the difficulty in distinguishing non-life threatening causes, including epilepsy, from a serious cardiac arrythmia when evaluating children with paroxysmal events. Focusing on long QT syndrome, they suggest an approach for the pediatric neurologist that utiliz...
Article
A case report of neonatal onset pyridoxine-dependent seizures in a male patient with early diagnosis and treatment is presented. The patient's epilepsy was recognized and treated with pyridoxine (vitamin B6) within 8 hours of birth. Treatment has been nearly continuous since that time. This paper reports the results of a full neuropsychological eva...
Article
Pyridoxine-dependent seizures, although a rare clinical entity, have been recognized as an etiology of intractable seizures in neonates and infants for more than 45 years. Recent research has focused on the molecular and neurochemical aspects of this disorder, as well as the optimal treatment of the condition. This review discusses the clinical fea...
Article
Full-text available
Progressive myelopathy is a rare complication of chronic hepatic disease which has never been reported in the paediatric age group. We describe the 11 year course of an adolescent male with hepatic myelopathy caused by cryptogenic micronodular cirrhosis. His condition has been associated with persistent polycythaemia and extraordinary increases of...
Article
Several aspects of pyridoxine-dependent seizure (PDS) suggest a mutation affecting glutamate decarboxylase (GAD) as a possible cause. To examine the possibility of GAD linkage with PDS, the authors performed genotype analyses of three families using polymorphic markers near the GAD genes (GAD1 and GAD2). In each family, the affected siblings exhibi...
Article
Toluene inhalant abuse during pregnancy may result in growth-retarded microcephalic newborns who subsequently demonstrate developmental impairment. By using a rat model of toluene-abuse embryopathy, we studied the effects of prenatal toluene exposure on the generation and migration of cortical neurons. Dams were exposed by gavage to either corn oil...
Article
The authors describe a double labeling immunohistochemical technique to facilitate the study of neuronal proliferation and migration. Proliferating fetal neuroblasts were labeled with 5-bromo-2′-deoxyuridine (BrdU), and the labeled mature neurons were identified with a monoclonal anti-BrdU antibody. To differentiate neurons from glia, the tissue wa...
Article
Pyridoxine dependency is an uncommon familial cause of intractable seizures in newborns and infants. Fewer than 100 patients have been reported, and only four reports have included examples of brain imaging findings. We report the first longitudinal MRI findings in two patients with this condition. Six brain MR scans, three each from two patients w...