Search

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 and a considerable variability in age at onset. Here, we report on four children (aged 10-17y) who presented with neuromuscular hip dysplasia and other orthopedic abnormalities but were only later diagnosed with CMT 1A. Hip dysplasia may be the initial clinical sign in CMT, so children with late-manifesting hip disease (i.e. age >8y) should be examined for signs of peripheral neuropathy, particularly when presenting with a 'waddling' or broad-based gait. [ABSTRACT FROM AUTHOR]

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 utilizes the electrocardiogram recorded during the electroencephalogram--direct measurement of the corrected QT interval. This approach requires knowledge of the distribution of the corrected QT interval in long QT syndrome. Copyright © 2005 by Elsevier Science (USA). [ABSTRACT FROM AUTHOR]

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 whole blood manganese, with magnetic resonance imaging evidence of manganese deposition within the basal ganglia and other regions of the brain. The patient has developed neither liver failure nor parkinsonism. The pathophysiological bases of this multiorgan system disorder are described. [ABSTRACT FROM AUTHOR]

Background and Objectives: Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a developmental epileptic encephalopathy characterized by seizure improvement after pyridoxine supplementation. Adjunct lysine reduction therapies (LRTs) reduce the accumulation of putative neurotoxic metabolites with the goal to improve developmental outcomes. Our objective was to examine the association between treatment with LRTs and cognitive outcomes., Methods: Participants were recruited from within the International Registry for Patients with Pyridoxine-Dependent Epilepsy from August 2014 through March 2021. The primary outcome was standardized developmental test scores associated with overall cognitive ability. The relationship between test scores and treatment was analyzed with multivariable linear regression using a mixed-effects model. A priori, we hypothesized that treatment in early infancy with pyridoxine and LRTs would result in a normal developmental outcome. A subanalysis was performed to evaluate the association between cognitive outcome and LRTs initiated in the first 6 months of life., Results: A total of 112 test scores from 60 participants were available. On average, treatment with pyridoxine and LRTs was associated with a nonsignificant increase of 6.9 points (95% CI -2.7 to 16.5) on developmental testing compared with treatment with pyridoxine alone. For the subanalysis, a total of 14 developmental testing scores were available from 8 participants. On average, treatment with pyridoxine and LRTs in the first 6 months of life was associated with a significant increase of 21.9 points (95% CI 1.7-42.0) on developmental testing., Discussion: Pyridoxine and LRTs at any age was associated with mild improvement in developmental testing, and treatment in early infancy was associated with a clinically significant increase in developmental test scores. These results provide insight into the mechanism of intellectual and developmental disability in PDE-ALDH7A1 and emphasize the importance of treatment in early infancy with both pyridoxine and LRTs., Classification of Evidence: This study provides Class IV evidence that in PDE-ALDH7A1, pyridoxine and LRTs compared with pyridoxine alone is not significantly associated with overall higher developmental testing scores, but treatment in the first 6 months of life is associated with significantly higher developmental testing scores., (© 2022 American Academy of Neurology.)

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 cognitive outcomes. However, possibly due to timing of treatment, not all patients have normal intellectual function., Methods: This retrospective, multi-center cohort study evaluated the effect of timing of pyridoxine monotherapy and pyridoxine with adjunct LRT on neurodevelopmental outcome. Patients with confirmed PDE-ALDH7A1 with at least one sibling with PDE-ALDH7A1 and a difference in age at treatment initiation were eligible and identified via the international PDE registry, resulting in thirty-seven patients of 18 families. Treatment regimen was pyridoxine monotherapy in ten families and pyridoxine with adjunct LRT in the other eight. Primary endpoints were standardized and clinically assessed neurodevelopmental outcomes. Clinical neurodevelopmental status was subjectively assessed over seven domains: overall neurodevelopment, speech/language, cognition, fine and gross motor skills, activities of daily living and behavioral/psychiatric abnormalities., Results: The majority of early treated siblings on pyridoxine monotherapy performed better than their late treated siblings on the clinically assessed domain of fine motor skills. For siblings on pyridoxine and adjunct LRT, the majority of early treated siblings performed better on clinically assessed overall neurodevelopment, cognition, and behavior/psychiatry. Fourteen percent of the total cohort was assessed as normal on all domains., Conclusion: Early treatment with pyridoxine and adjunct LRT may be beneficial for neurodevelopmental outcome. When evaluating a more extensive neurodevelopmental assessment, the actual impairment rate may be higher than the 75% reported in literature., Take- Home Message: Early initiation of lysine reduction therapies adjunct to pyridoxine treatment in patients with PDE-ALDH7A1 may result in an improved neurodevelopmental outcome., Competing Interests: Declaration of Competing Interest The authors report no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

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 using clinical data as well as patient-reported outcome measures (PROMs) for the patient's perspective., Methods: Dutch, genetically confirmed PDE-ALDH7A1 patients ≥18 years were eligible for inclusion. Clinical data were collected as well as PROMs (PROMIS item banks Anxiety, Depression, Anger, Physical Functioning, Cognitive Functioning, Cognitive Abilities, Ability to Participate and Satisfaction with Social Roles)., Results: Ten out of 11 patients agreed to participate (91% response rate). Seizure control at last follow up (median age 25.2 years, range 17.8-29.8 years) was achieved with pyridoxine monotherapy in 70%, 20% with adjunct common-anti epileptic drugs and 10% did not obtain complete seizure control. Neurologic symptoms were present in all but one patient (90%) and included tremors, noted in 40%. Neuro-imaging abnormalities were present in 80%. Intellectual disability was present in 70%. One patient (10%) attended university, three maintained a job without assistance, five maintained a job with assistance or attended social daycare, and one patient never followed regular education. The cohort scored significantly lower on the PROMIS Cognitive Functioning compared to the general (age-related) population. Distribution of scores was wide on all PROMIS item banks., Discussion & Conclusion: Outcomes of this young adult cohort are heterogeneous and individualized approaches are therefore needed. Long-term seizure control with pyridoxine was achieved for almost all patients. Neurologic symptoms were noted in the majority, including tremors, as well as neuro-imaging abnormalities and intellectual disability, additionally reflected by the PROMIS Cognitive Functioning. PDE-ALDH7A1 patients scored comparable to the general population on all other PROMs, especially regarding Ability to Participate and Satisfaction with Social Roles this may indicate a positive interpretation of their functioning. The aim is to expand this pilot study to larger populations to obtain more solid data, and to advance the use of PROMs to engage patients in research and provide the opportunity for personalized care., Competing Interests: None., (© 2022 The Authors.)

BackgroundPyridoxine-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 important cofactor pyridoxal-5'-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but intellectual disability may still develop. Early diagnosis and treatment, preferably based on newborn screening, could optimize long-term clinical outcome. However, no suitable PDE-ALDH7A1 newborn screening biomarkers are currently available.MethodsWe combined the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy to discover and identify biomarkers in plasma that would allow for PDE-ALDH7A1 diagnosis in newborn screening.ResultsWe identified 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP) as a PDE-ALDH7A1 biomarker, and confirmed 6-oxopiperidine-2-carboxylic acid (6-oxoPIP) as a biomarker. The suitability of 2-OPP as a potential PDE-ALDH7A1 newborn screening biomarker in dried bloodspots was shown. Additionally, we found that 2-OPP accumulates in brain tissue of patients and Aldh7a1-knockout mice, and induced epilepsy-like behavior in a zebrafish model system.ConclusionThis study has opened the way to newborn screening for PDE-ALDH7A1. We speculate that 2-OPP may contribute to ongoing neurotoxicity, also in treated PDE-ALDH7A1 patients. As 2-OPP formation appears to increase upon ketosis, we emphasize the importance of avoiding catabolism in PDE-ALDH7A1 patients.FundingSociety for Inborn Errors of Metabolism for Netherlands and Belgium (ESN), United for Metabolic Diseases (UMD), Stofwisselkracht, Radboud University, Canadian Institutes of Health Research, Dutch Research Council (NWO), and the European Research Council (ERC).

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 seizure control, most patients with PDE-ALDH7A1 were reported to have developmental delay and intellectual disability. To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy. These lysine-reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients. The goal of these consensus guidelines is to re-evaluate and update the two previously published recommendations for diagnosis, treatment, and follow-up of patients with PDE-ALDH7A1. Members of the International PDE Consortium initiated evidence and consensus-based process to review previous recommendations, new research findings, and relevant clinical aspects of PDE-ALDH7A1. The guideline development group included pediatric neurologists, biochemical geneticists, clinical geneticists, laboratory scientists, and metabolic dieticians representing 29 institutions from 16 countries. Consensus guidelines for the diagnosis and management of patients with PDE-ALDH7A1 are provided., (© 2020 SSIEM.)

Background: Medical education, residency training, and the structure of child neurology residency training programs are evolving. We sought to evaluate how training program selection priorities of child neurology residency applicants have changed over time., Methods: An electronic survey was sent to child neurology residents and practicing child neurologists via the Professors of Child Neurology distribution list in the summer of 2018. It was requested that the survey be disseminated to current trainees and alumni of the programs. The survey consisted of seven questions assessing basic demographics and a list of factors applicants consider when choosing a residency., Results: There were 284 responses with a higher representation of individuals matriculating into residency in the last decade. More recent medical school graduates had a lower probability of considering curriculum as an important factor for residency selection (odds ratio [OR], 0.746; 95% confidence interval [95% CI], 0.568 to 0.98; P = 0.035) and higher priority placed on interaction with current residents over the course of the interview day (OR, 2.207; 95% CI, 1.486 to 3.278; P < 0.0001), sense of resident happiness and well-being (OR, 2.176; 95% CI, 1.494 to 3.169; P < 0.0001), and perception of city or geography of the residency program (OR, 1.710; 95% CI, 1.272 to 2.298; P < 0.001)., Conclusions: Over time, child neurology residency applicants are putting more emphasis on quality of life factors over curriculum. To accommodate these changes, child neurology residency programs should prioritize interactions with residents during the interview process and resident wellness initiatives throughout residency training., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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 importance of an early diagnosis. As genetic testing is increasingly accepted as first tier testing for epileptic encephalopathies, we aimed to provide a comprehensive overview of ALDH7A1 mutations that cause PDE. The genotypes, ethnic origin and reported gender was collected from 185 subjects with a diagnosis of PDE. The population frequency for the variants in this report and the existing literature were reviewed in the Genome Aggregation Database (gnomAD). Novel variants identified in population databases were also evaluated through in silico prediction software and select variants were over-expressed in an E.coli-based expression system to measure α-aminoadipic semialdehyde dehydrogenase activity and production of α-aminoadipic acid. This study adds 47 novel variants to the literature resulting in a total of 165 reported pathogenic variants. Based on this report, in silico predictions, and general population data, we estimate an incidence of approximately 1:64,352 live births. This report provides a comprehensive overview of known ALDH7A1 mutations that cause PDE, and suggests that PDE may be more common than initially estimated. Due to the relative high frequency of the disease, the likelihood of under-diagnosis given the wide clinical spectrum and limited awareness among clinicians as well as the cognitive improvement noted with early treatment, newborn screening for PDE may be warranted., (© 2018 SSIEM.)

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, starting with adult tele-stroke services and expanding to the management of both adults and children with a variety of chronic neurologic disorders including epilepsy, headache, movement disorders, and neurodevelopmental disabilities. Resources required for the development and sustainment of a child neurology telemedicine program are discussed together with requirements for licensure, and credentialing, and the importance of educating current and future neurology practitioners in how to provide this clinical service.

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 manually traced in the midsagittal plane. Three hundred semi-landmarks along the outline were collected and underwent statistical generalized Procrustes analysis. An allometric regression was applied to evaluate the callosal shape due to growth over time., Results: Thirty-eight patients with PDE and 38 age- and sex-matched control subjects were included. Mean age at the time of the MRI in the patient group was 9.3 years (median 6.3 years, range 0.01-48 years). Significant differences ( p < 0.01) in the mean callosal shape between patients and controls were found. The allometric regression model revealed significant shape variations ( p < 0.01) between the 2 study groups across the developmental course after controlling for the effect of callosal size on shape. This latter effect turned out to be significant as well ( p < 0.001)., Conclusions: Patients with PDE show an altered callosal shape and variations in callosal ontogeny, which are likely secondary to the underlying genetic defect with abnormal function of antiquitin, the product of the ALDH7A1 gene., (© 2018 American Academy of Neurology.)

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. CACNA1A encodes the principal pore-forming subunit of the voltage-gated P/Q-type calcium channel, alpha1. Patients with epileptic encephalopathy due to pathogenic variants in CACNA1A have been previously described and are challenging to treat., Patient Description: We describe a child with epileptic encephalopathy, ataxia, cognitive impairment, and significant social-behavioral abnormalities due to a de novo pathogenic variant, p.S1373L in the CACNA1A gene. After failing zonisamide and divalproex sodium, she had a dramatic response to lamotrigine with a precipitous decrease in seizure frequency and severity. This improvement has persisted over one year., Conclusion: While classically thought to act at sodium channels, lamotrigine also modulates the activity of the P/Q-type calcium channel, making it a candidate for precision therapy for patients with epileptic encephalopathy due to CACNA1A pathogenic variants. The rarity and clinical heterogeneity of epilepsy due to variants in CACNA1A presents challenges to clinical diagnosis. However, genetic analysis for patients with epilepsy continues to expand; additional patients are likely to be identified molecularly. Lamotrigine should be considered as a first-line treatment in patients with epileptic encephalopathy due to pathogenic variants in CACNA1A., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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 age 31 years 8 months, standard deviation 12 years 3 months) and age-matched control subjects (32 years 4 months, standard deviation 13 years) were recruited to participate in the study. Diffusion tensor data were collected and postprocessed in Functional Magnetic Resonance Imaging of the Brain Software Library to quantify corpus callosum tracts as a means to assess white matter structure. Task-based fMRI data were collected and Functional Magnetic Resonance Imaging of the Brain Software Library used to assess task response. The fMRI resting-state data were analyzed with the functional connectivity toolbox Conn to determine functional connectivity., Results: Subjects with high functioning pyridoxine-dependent epilepsy retained structural white matter connectivity compared with control subjects, despite morphologic differences in the posterior corpus callosum. fMRI task-based results did not differ between subjects with pyridoxine-dependent epilepsy and control subjects; functional connectivity as measured with resting-state fMRI was lower in subjects with pyridoxine-dependent epilepsy for several systems (memory, somatosensory, auditory)., Conclusion: Although corpus callosum morphology is diminished in the posterior portions, structural connectivity was retained in subjects with pyridoxine-dependent epilepsy, while functional connectivity was diminished for memory, somatosensory, and auditory systems., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: 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., Methods: We designed a custom oligonucleotide array with high-density probe coverage across the ALDH7A1 gene. We performed array comparative genomic hybridization in 6 patients with clinical and biochemical evidence of pyridoxine-dependent epilepsy but only a single detectable mutation in ALDH7A1 by sequence analysis., Results: We found partial deletions of ALDH7A1 in 5 of 6 patients. Breakpoint analysis reveals that the deletions are likely a result of Alu-Alu recombination in all cases. The density of Alu elements within introns of ALDH7A1 suggests susceptibility to recurrent rearrangement., Conclusion: Patients with clinical pyridoxine-dependent epilepsy and a single identifiable mutation in ALDH7A1 warrant further investigation for copy number changes involving the ALHD7A1 gene., (© 2015 American Academy of Neurology.)

Choline acetyltransferase catalyzes the synthesis of acetylcholine at cholinergic nerves. Mutations in human CHAT cause a congenital myasthenic syndrome 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 remarkably, and the molecular factors determining this variability are poorly understood. Furthermore, genotype-phenotype correlations have been difficult to establish in patients with biallelic mutations. We analyzed the protein expression of phosphorylated ChAT of seven CHAT mutations, p.Val136Met, p.Arg207His, p.Arg186Trp, p.Val194Leu, p.Pro211Ala, p.Arg566Cys, and p.Ser694Cys, in HEK-293 cells to phosphorylated ChAT, determined their enzyme kinetics and thermal stability, and examined their structural changes. Three mutations, p.Arg207His, p.Arg186Trp, and p.Arg566Cys, are novel, and p.Val136Met and p.Arg207His are homozygous in three families and associated with severe disease. The characterization of mutants showed a decrease in the overall catalytic efficiency of ChAT; in particular, those located near the active-site tunnel produced the most seriously disruptive phenotypic effects. On the other hand, p.Val136Met, which is located far from both active and substrate-binding sites, produced the most drastic reduction of ChAT expression. Overall, CHAT mutations producing low enzyme expression and severe kinetic effects are associated with the most severe phenotypes., (© 2015 WILEY PERIODICALS, INC.)

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 range from birth to 48 years, corpus callosum morphology and cross-sectional cerebral area were measured in 30 individuals with PDE (12 males, 18 females, median age 3.92y; 25th centile 0.27, 75th centile 15.25) compared to 30 age-matched comparison individuals (11 males, 19 females, median age 3.85y; 25th centile 0.26, 75th centile 16.00). Individuals with PDE were also divided into age groups to evaluate findings across development. As delay to treatment may modulate clinical severity, groups were stratified by treatment delay (less than or greater than 2wks from birth)., Results: Markedly reduced callosal area expressed as a ratio of mid-sagittal cerebral area was observed for the entire group with PDE (p<0.001). Stratifying by age (<1y, 1-10y, >10y) demonstrated posterior abnormalities to be a consistent feature, with anterior regions increasingly involved across the developmental trajectory. Splitting the PDE group by treatment lag did not reveal overall or sub-region callosal differences., Interpretation: Callosal abnormalities are a common feature of PDE not explained by treatment lag. Future work utilizing tract-based approaches to understand inter- and intra-hemispheric connectivity patterns will help in the better understanding the structural aspects of this disease., (© 2014 Mac Keith Press.)

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 metabolite peaks on magnetic resonance spectroscopy. Her movement disorder was treated successfully with valproic acid and clonidine. Her cognitive functioning returned to baseline 3 months after ingestion., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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 residual basal ganglia neurons. Depigmentation of the substantia nigra and other brainstem nuclei was present. Manganese content of basal ganglia and liver was increased 16-fold and 9-fold, respectively. Our study provides a pathological foundation for further investigation of central nervous system toxicity secondary to deregulation of manganese metabolism., (© 2014 American Neurological Association.)

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 abnormalities. Compound heterozygous mutations in POMT1 were identified including a previously reported nonsense mutation (c.2167dupG; p.Asp723Glyfs*8) associated with Walker-Warburg syndrome and a novel missense mutation in a highly conserved region of the protein O-mannosyltransferase 1 protein (c.1958C>T; p.Pro653Leu). This novel variant reduces the phenotypic severity compared to patients with homozygous c.2167dupG mutations or compound heterozygous patients with a c.2167dupG mutation and a wide range of other mutant POMT1 alleles., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Introduction: Myotonia congenita due to protein truncating CLCN1 mutations is associated with variable patterns of inheritance., Methods: 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., Results: The Y33X mutation kinship has autosomal recessive inheritance and a severe phenotype when homozygous. The fs503X family has autosomal dominant inheritance and a moderate-to-severe phenotype. The A313T mutation kindred also has autosomal dominant inheritance but expresses a mild phenotype, except for the more severely affected compound heterozygotes., Conclusions: Early truncating mutations precluding dimerization are expected to be autosomal recessive and express a severe phenotype, while later mutations may be variable. The pedigrees presented here demonstrate that intrafamilial phenotypic variability may result from a dosage effect of an additional mutation, not necessarily variable expressivity. Mutations that have unexpected patterns of inheritance may represent allelic variability., (Copyright © 2013 Wiley Periodicals, Inc.)

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 being one in which testers were allowed to use narrative resources and Web searching. A key factor that improved performance was taking enough time (>2 minutes) to enter clinical findings into the software accurately. Under these conditions and for instances in which the diagnoses changed based on using the software, diagnostic accuracy improved in 96% of instances. There was a 6% decrease in the number of workup items accompanied by a 34% increase in relevance. The authors conclude that decision support for a neurological diagnosis can reduce errors and save on unnecessary testing.

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 lysine intermediates in body fluids, and may have beneficial effects on seizure control and psychomotor development., Methods: In analogy to the NICE guideline process, the international PDE Consortium, an open platform uniting scientists and clinicians working in the field of this metabolic epilepsy, during four workshops (2010-2013) developed a recommendation for a lysine-restricted diet in PDE, with the aim of standardizing its implementation and monitoring of patients. Additionally, a proposal for a further observational study is suggested., Results: (1) All patients with confirmed ATQ deficiency are eligible for adjunct treatment with lysine-restricted diet, unless treatment with pyridoxine alone has resulted in complete symptom resolution, including normal behavior and development. (2) Lysine restriction should be started as early as possible; the optimal duration remains undetermined. (3) The diet should be implemented and the patient be monitored according to these recommendations in order to assure best possible quality of care and safety., Discussion: The implementation of this recommendation will provide a unique and a much needed opportunity to gather data with which to refine the recommendation as well as improve our understanding of outcomes of individuals affected by this rare disease. We therefore propose an international observational study that would utilize freely accessible, online data sharing technologies to generate more evidence.

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 human and murine brain to determine the normal distribution of antiquitin, its distribution in PDE, and associated brain malformations., Methods: Formalin-fixed human brain sections were subjected to histopathology and fluorescence immunohistochemistry studies. Frozen brain tissue was utilized for measurement of PDE-associated metabolites and Western blot analysis. Comparative studies of antiquitin distribution were performed in developing mouse brain sections., Results: Histologic analysis of PDE cortex revealed areas of abnormal radial neuronal organization consistent with type Ia focal cortical dysplasia. Heterotopic neurons were identified in subcortical white matter, as was cortical astrogliosis, hippocampal sclerosis, and status marmoratus of the basal ganglia. Highly elevated levels of lysine metabolites were present in postmortem PDE cortex. In control human and developing mouse brain, antiquitin immunofluorescence was identified in radial glia, mature astrocytes, ependyma, and choroid plexus epithelium, but not in neurons. In PDE cortex, antiquitin immunofluorescence was greatly attenuated with evidence of perinuclear accumulation in astrocytes., Interpretation: Antiquitin is expressed within glial cells in the brain, and its dysfunction in PDE is associated with neuronal migration abnormalities and other structural brain defects. These malformations persist despite postnatal pyridoxine supplementation and likely contribute to neurodevelopmental impairments., (© 2014 Child Neurology Society/American Neurological Association.)

Background: 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., Methods: Information was collected from direct observation, video review and parental questionnaire from 59 patients with RES. Oculomotor and vestibular testing was performed in 4 children., Results: Of 59 patients, 50 had persistent head shaking that was often observed years before RES was recognized. Three affected children demonstrated abnormal central vestibular processing., Conclusions: Head-shaking is common in RES. These characteristic movements may provide input to a defective vestibular system or may represent a motor pattern that is usually suppressed by vestibular feedback. Persistent head shaking should alert clinicians to the possible presence of a congenital hindbrain abnormality that affects the vestibulocerebellum, particularly RES., (© 2013 Movement Disorder Society.)

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 3 days and then decreased by up to 70% after 14 days but remained much higher than control, indicating newborn screening for PDE is feasible., (© 2013.)

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 similar clinical phenotype but without evidence of antiqutin dysfunction. We report on a patient who had carried a clinical diagnosis of PDE for 7 years, but who was than shown to have normal ALDH7A1 sequencing and the absence of biomarkers characteristic of this familial epilepsy. Array comparative genomic hybridization (CGH) demonstrated a 1.5-Mb terminal deletion of the long arm of chromosome 20, which included deletion of the KCNQ2 and CHRNA4 genes, both of which have been associated with specific epilepsy syndromes. We suggest that this boy's neonatal epilepsy and neurodevelopmental disabilities are secondary to this deletion and that his clinical response to pyridoxine was coincidental. This patient's history emphasizes the utility of array CGH in the evaluation of children with epilepsy of unknown etiology., (Copyright © 2012 Wiley Periodicals, Inc.)

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 confirmed ATQ deficiency were started on dietary lysine restriction with regular nutritional monitoring. Biochemical outcomes were evaluated using pipecolic acid and α-aminoadipic semialdehyde (AASA) levels in body fluids; developmental/cognitive outcomes were evaluated using age-appropriate tests and parental observations., Results: Lysine restriction was well tolerated with good compliance; no adverse events were reported. Reduction in biomarker levels (measurement of the last value before and first value after initiation of dietary lysine restriction) ranged from 20 to 67% for plasma pipecolic acid, 13 to 72% for urinary AASA, 45% for plasma AASA and 42% for plasma P6C. For the 1 patient in whom data were available and who showed clinical deterioration upon interruption of diet, cerebrospinal fluid levels decreased by 87.2% for pipecolic acid and 81.7% for AASA. Improvement in age-appropriate skills was observed in 4 out of 5 patients showing pre-diet delays, and seizure control was maintained or improved in 6 out 7 children., Conclusions: This observational study provides Level 4 evidence that lysine restriction is well tolerated with significant decrease of potentially neurotoxic biomarkers in different body compartments, and with the potential to improve developmental outcomes in children with PDE caused by ATQ deficiency. To generate a strong level of evidence before this potentially burdensome dietary therapy becomes the mainstay treatment, we have established: an international PDE consortium to conduct future studies with an all-inclusive integrated study design; a website containing up-to-date information on PDE; a methodological toolbox; and an online registry to facilitate the participation of interested physicians, scientists, and families in PDE research., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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 environmental Mn exposure. Whole-genome mapping of two consanguineous families identified SLC30A10 as the affected gene in this inherited type of hypermanganesemia. This gene was subsequently sequenced in eight families, and homozygous sequence changes were identified in all affected individuals. The function of the wild-type protein and the effect of sequence changes were studied in the manganese-sensitive yeast strain Δpmr1. Expressing human wild-type SLC30A10 in the Δpmr1 yeast strain rescued growth in high Mn conditions, confirming its role in Mn transport. The presence of missense (c.266T>C [p.Leu89Pro]) and nonsense (c.585del [p.Thr196Profs(∗)17]) mutations in SLC30A10 failed to restore Mn resistance. Previously, SLC30A10 had been presumed to be a zinc transporter. However, this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain. This is an important step toward understanding Mn transport and its role in neurodegenerative processes., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Antiquitin (ATQ) deficiency is the main cause of pyridoxine dependent epilepsy characterized by early onset epileptic encephalopathy responsive to large dosages of pyridoxine. Despite seizure control most patients have intellectual disability. Folinic acid responsive seizures (FARS) are genetically identical to ATQ deficiency. ATQ functions as an aldehyde dehydrogenase (ALDH7A1) in the lysine degradation pathway. Its deficiency results in accumulation of α-aminoadipic semialdehyde (AASA), piperideine-6-carboxylate (P6C) and pipecolic acid, which serve as diagnostic markers in urine, plasma, and CSF. To interrupt seizures a dose of 100 mg of pyridoxine-HCl is given intravenously, or orally/enterally with 30 mg/kg/day. First administration may result in respiratory arrest in responders, and thus treatment should be performed with support of respiratory management. To make sure that late and masked response is not missed, treatment with oral/enteral pyridoxine should be continued until ATQ deficiency is excluded by negative biochemical or genetic testing. Long-term treatment dosages vary between 15 and 30 mg/kg/day in infants or up to 200 mg/day in neonates, and 500 mg/day in adults. Oral or enteral pyridoxal phosphate (PLP), up to 30 mg/kg/day can be given alternatively. Prenatal treatment with maternal pyridoxine supplementation possibly improves outcome. PDE is an organic aciduria caused by a deficiency in the catabolic breakdown of lysine. A lysine restricted diet might address the potential toxicity of accumulating αAASA, P6C and pipecolic acid. A multicenter study on long term outcomes is needed to document potential benefits of this additional treatment. The differential diagnosis of pyridoxine or PLP responsive seizure disorders includes PLP-responsive epileptic encephalopathy due to PNPO deficiency, neonatal/infantile hypophosphatasia (TNSALP deficiency), familial hyperphosphatasia (PIGV deficiency), as well as yet unidentified conditions and nutritional vitamin B6 deficiency. Commencing treatment with PLP will not delay treatment in patients with pyridox(am)ine phosphate oxidase (PNPO) deficiency who are responsive to PLP only., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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. Cerebrospinal fluid neurotransmitter metabolite chromatography and an assay of serum biomarkers, including pipecolic acid and α-aminoadipic semialdehyde, confirmed the diagnosis of pyridoxine-dependent epilepsy, and genetic testing identified a homozygous mutation in our patient, and in a first cousin with epilepsy. The reintroduction of pyridoxine and addition of folinic acid eventually led to control of her seizures. Early testing of biomarkers may prevent delays in diagnosing pyridoxine-dependent epilepsy. We recommend that all patients presenting with cryptogenic seizures before age 18 months undergo this evaluation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Seizures are common in children, but the causes and recurrence risk for children with a nonfebrile first seizure remain poorly understood., Objective: 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 seizures stratified by fever and type of illness., Patients and Methods: Children (aged 6 months to 6 years) were enrolled at the time of evaluation for their first seizure and followed monthly for up to 5 years. Seizure and illness data were collected through parent interviews and medical-record reviews. Stool, serum, and cerebrospinal fluid collected within 48 hours of the first seizure were evaluated for viral gastrointestinal pathogens., Results: Of the 117 children enrolled, 78 (67%) had febrile seizures, 34 (29%) had nonfebrile-illness seizures, and 5 (4%) had unprovoked seizures. Children with nonfebrile-illness seizures were more likely than those with febrile seizures to have acute gastroenteritis (47% and 28%, respectively; P = .05). No significant differences in seizure recurrence were found between children with or without a fever at first seizure. Children with acute gastroenteritis at first seizure, regardless of fever, had a lower risk of seizure recurrence compared with children with other acute illnesses (hazard ratio: 0.28; 95% confidence interval: 0.09-0.80)., Conclusions: Our results confirm the role of gastrointestinal illness as a distinguishing feature in childhood seizures. Children with this distinct presentation have a low rate of seizure recurrence and few neurologic complications.

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 undergo comprehensive DMD mutation analysis. We defined manifesting carriers as females with significant weakness, excluding those with only myalgias/cramps. DNA extracted from peripheral blood was used to study X-chromosome inactivation patterns. Among these manifesting carriers, age at symptom onset ranged from 2 to 47 years. Seven had no family history and eight had male relatives with Duchenne muscular dystrophy (DMD). Clinical severity among the manifesting carriers varied from a DMD-like progression to a very mild Becker muscular dystrophy-like phenotype. Eight had exonic deletions or duplications and six had point mutations. One patient had two mutations (an exonic deletion and a splice site mutation), consistent with a heterozygous compound state. The X-chromosome inactivation pattern was skewed toward non-random in four out of seven informative deletions or duplications but was random in all cases with nonsense mutations. We present the results of DMD mutation analysis in this manifesting carrier cohort, including the first example of a presumably compound heterozygous DMD mutation. Our results demonstrate that improved molecular diagnostic methods facilitate the identification of DMD mutations in manifesting carriers, and confirm the heterogeneity of mutational mechanisms as well as the wide spectrum of phenotypes., (2010 Elsevier B.V. All rights reserved.)

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 present as neonatal encephalopathy with anticonvulsant-resistant seizures. Therefore, it is vital for the clinicians of caring for seizing encephalopathic newborns to consider these particular disorders early in the hospital course. Pyridoxine-dependent seizures are due to deficiency of alpha-aminoadipic semialdehyde dehydrogenase (antiquitin) which is encoded by ALDH7A1. Seizures in infants who are pyridoxine-dependent must be treated using pharmacologic doses of pyridoxine (vitamin B(6)), and life-long therapy is required. Despite medical therapy, developmental handicaps, particularly in expressive language, are common. Folinic acidresponsive seizures are treated with supplements of folinic acid (5-formyltetrahydrofolate). Recently, patients with this condition were also demonstrated to be antiquitin deficient. Pyridoxal phosphate-dependent seizures result from a deficiency of pyridox(am)ine 5'-phosphate oxidase which is encoded by PNPO. Patients with this cause of seizures respond to pyridoxal phosphate but not to pyridoxine. This review discusses our current understanding of these three neonatal vitamin-responsive epileptic encephalopathies and a diagnostic and treatment protocol is proposed.