Publications by authors named "Andrea Gropman"

155 Publications

Fifteen years of urea cycle disorders brain research: Looking back, looking forward.

Anal Biochem 2021 Oct 9:114343. Epub 2021 Oct 9.

Division of Neurogenetics and Neurodevelopmental Pediatrics, Children's National Hospital, Washington D.C., United States. Electronic address:

Urea cycle disorders (UCD) are inherited diseases resulting from deficiency in one of six enzymes or two carriers that are required to remove ammonia from the body. UCD may be associated with neurological damage encompassing a spectrum from asymptomatic/mild to severe encephalopathy, which results in most cases from Hyperammonemia (HA) and elevation of other neurotoxic intermediates of metabolism. Electroencephalography (EEG), Magnetic resonance imaging (MRI) and Proton Magnetic resonance spectroscopy (MRS) are noninvasive measures of brain function and structure that can be used during HA to guide management and provide prognostic information, in addition to being research tools to understand the pathophysiology of UCD associated brain injury. The Urea Cycle Rare disorders Consortium (UCDC) has been invested in research to understand the immediate and downstream effects of hyperammonemia (HA) on brain using electroencephalogram (EEG) and multimodal brain MRI to establish early patterns of brain injury and to track recovery and prognosis. This review highlights the evolving knowledge about the impact of UCD and HA in particular on neurological injury and recovery and use of EEG and MRI to study and evaluate prognostic factors for risk and recovery. It recognizes the work of others and discusses the UCDC's prior work and future research priorities.
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http://dx.doi.org/10.1016/j.ab.2021.114343DOI Listing
October 2021

DNA methylation and behavioral dysfunction in males with 47,XXY and 49,XXXXY: a pilot study.

Clin Epigenetics 2021 Jul 1;13(1):136. Epub 2021 Jul 1.

Department of Research, The Focus Foundation, Davidsonville, MD, USA.

Background: Equal dosage of X-linked genes between males and females is maintained by the X-inactivation of the second X chromosome in females through epigenetic mechanisms. Boys with aneuploidy of the X chromosome exhibit a host of symptoms such as low fertility, musculoskeletal anomalies, and cognitive and behavioral deficits that are presumed to be caused by the abnormal dosage of these genes. The objective of this pilot study is to assess the relationship between CpG methylation, an epigenetic modification, at several genes on the X chromosome and behavioral dysfunction in boys with supernumerary X chromosomes.

Results: Two parental questionnaires, the Behavior Rating Inventory of Executive Function (BRIEF) and Child Behavior Checklist (CBCL), were analyzed, and they showed expected differences in both internal and external behaviors between neurotypical (46,XY) boys and boys with 49,XXXXY. There were several CpGs in AR and MAOA of boys with 49,XXXXY whose methylation levels were skewed from levels predicted from having one active (Xa) and three inactive (Xi) X chromosomes. Further, methylation levels of multiple CpGs in MAOA showed nominally significant association with externalizing behavior on the CBCL, and the methylation level of one CpG in AR showed nominally significant association with the BRIEF Regulation Index.

Conclusions: Boys with 49,XXXXY displayed higher levels of CpG methylation at regulatory intronic regions in X-linked genes encoding the androgen receptor (AR) and monoamine oxidase A (MAOA), compared to that in boys with 47,XXY and neurotypical boys. Our pilot study results suggest a link between CpG methylation levels and behavior in boys with 49,XXXXY.
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http://dx.doi.org/10.1186/s13148-021-01123-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252231PMC
July 2021

Review of Multi-Modal Imaging in Urea Cycle Disorders: The Old, the New, the Borrowed, and the Blue.

Front Neurol 2021 28;12:632307. Epub 2021 Apr 28.

Division of Neurogenetics and Neurodevelopmental Pediatrics, Department of Neurology, Children's National Hospital, George Washington University School of Medicine, Washington, DC, United States.

The urea cycle disorders (UCD) are rare genetic disorder due to a deficiency of one of six enzymes or two transport proteins that act to remove waste nitrogen in form of ammonia from the body. In this review, we focus on neuroimaging studies in OTCD and Arginase deficiency, two of the UCD we have extensively studied. Ornithine transcarbamylase deficiency (OTCD) is the most common of these, and X-linked. Hyperammonemia (HA) in OTCD is due to deficient protein handling. Cognitive impairments and neurobehavioral disorders have emerged as the major sequelae in Arginase deficiency and OTCD, especially in relation to executive function and working memory, impacting pre-frontal cortex (PFC). Clinical management focuses on neuroprotection from HA, as well as neurotoxicity from other known and yet unclassified metabolites. Prevention and mitigation of neurological injury is a major challenge and research focus. Given the impact of HA on neurocognitive function of UCD, neuroimaging modalities, especially multi-modality imaging platforms, can bring a wealth of information to understand the neurocognitive function and biomarkers. Such information can further improve clinical decision making, and result in better therapeutic interventions. investigations of the affected brain using multimodal neuroimaging combined with clinical and behavioral phenotyping hold promise. MR Spectroscopy has already proven as a tool to study biochemical aberrations such as elevated glutamine surrounding HA as well as to diagnose partial UCD. Functional Near Infrared Spectroscopy (fNIRS), which assesses local changes in cerebral hemodynamic levels of cortical regions, is emerging as a non-invasive technique and will serve as a surrogate to fMRI with better portability. Here we review two decades of our research using non-invasive imaging and how it has contributed to an understanding of the cognitive effects of this group of genetic conditions.
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http://dx.doi.org/10.3389/fneur.2021.632307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113618PMC
April 2021

Klinefelter Syndrome and Turner Syndrome.

Pediatr Rev 2021 05;42(5):272-274

George Washington University, Washington, DC.

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http://dx.doi.org/10.1542/pir.2020-004028DOI Listing
May 2021

Management considerations for stroke-like episodes in MELAS with concurrent COVID-19 infection.

J Neurol 2021 Nov 1;268(11):3988-3991. Epub 2021 Apr 1.

Center for Neuroscience and Behavioral Medicine, Children's National Hospital, Washington, DC, USA.

There have been considerations since the beginning of the Coronavirus pandemic that COVID-19 infection, like any other viral illness, can trigger neurological and metabolic decompensation in patients with mitochondrial diseases. At the time of writing, there were no published reports reviewing experiences and guidelines about management of COVID-19 infection in this patient population. We present a challenging case of an adult patient with a known diagnosis of Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like Episodes (MELAS) complicated by COVID-19 infection. She initially presented with altered mental status and vomiting and went on to develop a stroke-like episode, pancreatitis, and pneumatosis intestinalis. We review salient features of her hospitalization, including initiation of thromboprophylaxis in relation to intravenous arginine therapy, caution regarding medications such as remdesivir, and the incidence of gastrointestinal complications.
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http://dx.doi.org/10.1007/s00415-021-10538-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016504PMC
November 2021

Clinical diagnosis of presumed SOX2 gonadosomatic mosaicism.

Ophthalmic Genet 2021 06 15;42(3):320-325. Epub 2021 Mar 15.

Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.

: To describe a family with presumed gonadosomatic mosaicism diagnosed upon ophthalmic examination of the proband's mother.: The family underwent comprehensive ophthalmic and physical examination. Variant detection was performed using trio exome analysis on peripheral leukocyte DNA from blood and saliva samples. Variant segregation analysis was performed using a custom panel NGS sequencing. An identified variant in the gene was confirmed in the proband by Sanger sequencing.: We report an individual with bilateral microphthalmia, developmental delay, hearing loss, and dysmorphic features. Her mother was found to have asymptomatic uveal coloboma affecting her anterior segment. Her father, aunt, and sisters were unaffected. Trio exome sequence analysis showed an apparent heterozygous deletion in the proband, NM_003106.3:c.70_89del, NP_003097.1:p.(Asn24Argfs*65), classified as pathogenic. Testing of the other family members' peripheral blood and saliva was negative for this variant. The iris transillumination abnormalities in the proband's mother supports a gonadosomatic mosaicism scenario.: The results from this family underscore the importance of performing detailed evaluations of the parents of apparently sporadically affected individuals with heritable ophthalmic disorders. The identification of mildly affected individuals could substantially alter recurrence risks.
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http://dx.doi.org/10.1080/13816810.2021.1888127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154737PMC
June 2021

The Application of Neurodiagnostic Studies to Inform the Acute Management of a Newborn Presenting With Sarbamoyl Shosphate Synthetase 1 Deficiency.

Child Neurol Open 2021 Jan-Dec;8:2329048X20985179. Epub 2021 Jan 22.

Neurology, Children's National Hospital, George Washington University School of Medicine, Washington, DC, USA.

Neonatal-onset urea cycle disorders (UCDs) may result in hyperammonemic (HA) encephalopathy presenting with several neurologic sequelae including seizures, coma, and death. However, no recommendations are given in how and when neurodiagnostic studies should be used to screen or assess for these neurologic complications. We present a case of carbamoyl phosphate synthetase 1 (CPS1) deficiency in a newborn female in which electroencephalogram monitoring to assess encephalopathy and seizures, and magnetic resonance imaging measurements of brain metabolites were used to guide care during her hyperammonemic crisis. Her neurologic course and response to treatment characterizes the significant neurologic impact of HA encephalopathy. Our group herein proposes a clinical neurodiagnostic pathway for managing acute HA encephalopathy.
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http://dx.doi.org/10.1177/2329048X20985179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841664PMC
January 2021

The effect of early hormonal treatment (EHT) on expressive and receptive language capabilities in boys with 47,XXY (Klinefelter syndrome) during infancy and early childhood.

Genet Med 2021 06 24;23(6):1017-1022. Epub 2021 Feb 24.

Department of Neurology, George Washington University, Washington, DC, USA.

Purpose: 47,XXY is associated with variable neurodevelopmental outcomes including deficits in expressive and receptive language development. Early hormonal treatment (EHT) has been associated with mitigating some deficiencies in boys with 47,XXY. This study investigates these language capabilities of 47,XXY boys in the first five years of life and the associated effects of EHT on these capabilities.

Methods: One hundred and seventy-five boys with 47,XXY between the ages of 0 and 5 years, 11 months completed neurodevelopmental assessments specific to age examining their expressive and receptive language capabilities. Subjects were grouped by treatment (EHT and No-T) and differences were analyzed.

Results: In the age groups of under 12 months, 24-35 months, 36-47 months, and 60-71 months, the EHT group scored significantly higher on expressive language assessments than the No-T group (p = 0.09, p = 0.0002, p = 0.009, and p = 0.02, respectively). In the age groups of under 12 months and 24-35 months, the EHT group scored significantly better on the auditory comprehension domain of the PLS-4/5 (p = 0.02 and p = 0.05, respectively) than the No-T group.

Conclusion: Study data suggest EHT may be essential in optimizing receptive and expressive language development in 47,XXY boys during early childhood, which is critical in fostering reading skills and later academic success.
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http://dx.doi.org/10.1038/s41436-021-01098-wDOI Listing
June 2021

Novel presentations associated with a PDHA1 variant - Alternating hemiplegia in Hemizygote proband and Guillain Barre Syndrome in Heterozygote mother.

Eur J Paediatr Neurol 2021 Mar 22;31:27-30. Epub 2021 Jan 22.

Division of Neurogenetics and Developmental Pediatrics, Children's National Hospital, Washington DC, USA.

We report a 5-year-old male with a PDHA1 variant who presented with alternating hemiplegia of childhood and later developed developmental regression, basal ganglia injury and episodic lactic acidosis. Enzyme assay in lymphocytes confirmed a diagnosis of Pyruvate Dehydrogenase Complex (PDC) deficiency. His mother who was heterozygous for the same variant suffered from ophthalmoplegia, chronic migraine and developed flaccid paralysis at 36 years of age. PDHA1 is the most common genetic cause of PDC deficiency and presents with a myriad of neurological phenotypes including neonatal form with lactic acidosis, non-progressive infantile encephalopathy, Leigh syndrome subtype and intermittent ataxia. The presentations in our 2 patients contribute to the clinical heterogeneity of this neurogenetic condition.
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http://dx.doi.org/10.1016/j.ejpn.2021.01.006DOI Listing
March 2021

Expanding Role of Proton Magnetic Resonance Spectroscopy: Timely Diagnosis and Treatment Initiation in Partial Ornithine Transcarbamylase Deficiency.

J Pediatr Genet 2021 Mar 23;10(1):77-80. Epub 2020 Apr 23.

Division of Neurogenetics and Developmental Pediatrics, Center for Neuroscience and Behavioral Medicine, Children's National Hospital, Washington, District of Columbia, United States.

We report the case of a 3-year-old male patient who presented with a 3-day history of altered mental status, emesis, and abdominal pain in the setting of a viral illness. A rapid screening revealed a high ammonia level and after reviewing his proton magnetic resonance spectroscopy (1H MRS) which showed the classic triad of high glutamate, low choline, and myoinositol, a diagnosis of ornithine transcarbamylase deficiency (OTCD) was made within 6 hours of presentation. Therapy with sodium phenylbutyrate and sodium benzoate was initiated and patient was discharged after 3 days with no neurologic disability. Biochemical and molecular testing eventually confirmed the diagnosis. 1H MRS is a practical and fast neuroimaging modality that can aid in diagnosis of OTCD and enables faster initiation of treatment in acute settings.
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http://dx.doi.org/10.1055/s-0040-1709670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853912PMC
March 2021

Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia.

Genet Med 2021 05 20;23(5):881-887. Epub 2021 Jan 20.

Duke University Health System, Durham, NC, USA.

Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene.

Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual.

Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy.

Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.
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http://dx.doi.org/10.1038/s41436-020-01076-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107131PMC
May 2021

Differentiating Moebius syndrome and other congenital facial weakness disorders with electrodiagnostic studies.

Muscle Nerve 2021 04 19;63(4):516-524. Epub 2021 Jan 19.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Introduction: Congenital facial weakness (CFW) can result from facial nerve paresis with or without other cranial nerve and systemic involvement, or generalized neuropathic and myopathic disorders. Moebius syndrome is one type of CFW. In this study we explored the utility of electrodiagnostic studies (EDx) in the evaluation of individuals with CFW.

Methods: Forty-three subjects enrolled prospectively into a dedicated clinical protocol and had EDx evaluations, including blink reflex and facial and peripheral nerve conduction studies, with optional needle electromyography.

Results: MBS and hereditary congenital facial paresis (HCFP) subjects had low-amplitude cranial nerve 7 responses without other neuropathic or myopathic findings. Carriers of specific pathogenic variants in TUBB3 had, in addition, a generalized sensorimotor axonal polyneuropathy with demyelinating features. Myopathic findings were detected in individuals with Carey-Fineman-Ziter syndrome, myotonic dystrophy, other undefined myopathies, or CFW with arthrogryposis, ophthalmoplegia, and other system involvement.

Discussion: EDx in CFW subjects can assist in characterizing the underlying pathogenesis, as well as guide diagnosis and genetic counseling.
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http://dx.doi.org/10.1002/mus.27159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353595PMC
April 2021

Insight versus hindsight: What we have learned after 17 years of research with sex chromosome abnormalities.

Am J Med Genet A 2021 03 24;185(3):1004-1005. Epub 2020 Dec 24.

Department of Research, The Focus Foundation, Davidsonville, Maryland, USA.

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http://dx.doi.org/10.1002/ajmg.a.62022DOI Listing
March 2021

Multimodal imaging in urea cycle-related neurological disease - What can imaging after hyperammonemia teach us?

Transl Sci Rare Dis 2020 Aug 3;5(1-2):87-95. Epub 2020 Aug 3.

Division of Neurogenetics and Developmental Pediatrics, Center for Neuroscience and Behavioral Medicine, Children's National Hospital, Washington, DC, USA.

Background: Urea cycle-related brain disease may take on variable neuroimaging manifestations, ranging from normal to abnormal with or without a signature appearance. In the past, we have described the usefulness of multimodal imaging in identifying biomarkers of neuronal injury in UCD patients. In this study, we report unique findings in an adolescent male with neonatal-onset OTC deficiency after an episode of hyperammonemia.

Materials And Methods: Multiplanar, multisequence MR imaging (T1WI, T2WI, T2 FLAIR, diffusion weighted images and gradient echo) of the brain was performed on seven separate occasions over the course following the acute illness; first five exams were performed within 28 days of admission and the final two exams were performed approximately 3 and 5 months later.

Results: 1.The initial MR revealed increased signal on T2WI in the basal ganglia, claustrum and frontoparietal white matter; which remained stable over time. By the 5th exam, signal changes had developed in frontal cortex; reflecting permanent injury. 2. DTI tractography of the corticospinal tracts displayed revealed diminution of the number of projectional and commissural fibers over time. 3. Blood flow measurements demonstrated hypoperfusion on the fifth exams followed by hyperperfusion on the final two studies. 4. MR spectroscopy demonstrated that glutamine was elevated during hyperammonemia with myoinositol reduction, reflecting osmotic buffering.

Conclusion: This particular multimodal magnetic resonance neuroimaging showed novel, temporally specific manifestations over the disease course in OTC deficiency. This prospective imaging study expands our understanding of the effect of hyperammonemia on the structure and biochemistry of the nervous system.
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http://dx.doi.org/10.3233/TRD-200048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739971PMC
August 2020

Severity-adjusted evaluation of newborn screening on the metabolic disease course in individuals with cytosolic urea cycle disorders.

Mol Genet Metab 2020 12 7;131(4):390-397. Epub 2020 Nov 7.

Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany; Heidelberg Research Center for Molecular Medicine (HRCMM), Heidelberg, Germany. Electronic address:

Objective: The implementation of newborn screening (NBS) programs for citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) is subject to controversial debate. The aim of this study was to assess the impact of NBS on the metabolic disease course and clinical outcome of affected individuals.

Methods: In 115 individuals with CTLN1 and ASA, we compared the severity of the initial hyperammonemic episode (HAE) and the frequency of (subsequent) HAEs with the mode of diagnosis. Based on a recently established functional disease prediction model, individuals were stratified according to their predicted severe or attenuated phenotype.

Results: Individuals with predicted attenuated forms of CTLN1 and ASA were overrepresented in the NBS group, while those with a predicted severe phenotype were underrepresented compared to individuals identified after the manifestation of symptoms (SX). Identification by NBS was associated with reduced severity of the initial HAE both in individuals with predicted severe and attenuated phenotypes, while it was not associated with lower frequency of (subsequent) HAEs. Similar results were obtained when including some patients diagnosed presymptomatically (i.e. prenatal testing, and high-risk family screening) in this analysis.

Conclusion: Since one of the major challenges of NBS outcome studies is the potential overrepresentation of individuals with predicted attenuated phenotypes in NBS cohorts, severity-adjusted evaluation of screened and unscreened individuals is important to avoid overestimation of the NBS effect. NBS enables the attenuation of the initial HAE but does not affect the frequency of subsequent metabolic decompensations in individuals with CTLN1 and ASA. Future long-term studies will need to evaluate the clinical impact of this finding, especially with regard to mortality, as well as cognitive outcome and quality of life of survivors.
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http://dx.doi.org/10.1016/j.ymgme.2020.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315358PMC
December 2020

Response to Finsterer's "Exclude hereditary and acquired differential disorders before attributing retinoschisis to Kears-Sayre syndrome".

Ophthalmic Genet 2021 02 24;42(1):100. Epub 2020 Nov 24.

Ophthalmic Genetics & Visual Function Branch, National Eye Institute, National Institutes of Health , Bethesda, Maryland, USA.

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http://dx.doi.org/10.1080/13816810.2020.1832295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127728PMC
February 2021

Developing a New Set of ACGME Milestones for Child Neurology Residency.

Pediatr Neurol 2021 01 24;114:47-52. Epub 2020 Oct 24.

Accreditation Council for Graduate Medical Education, Chicago, Illinois.

Background: The Educational Milestones developed by the Accreditation Council for Graduate Medical Education (ACGME) are a construct used to evaluate the development of core competencies during residency and fellowship training. The milestones were developed to create a framework for professional development during graduate medical education. The first iteration of milestones for the child neurology residency was implemented in 2015. In the years that followed, the ACGME received and reviewed feedback about the milestones and set out to revise them.

Methods: A committee was assembled to review the original milestones and develop a new set of milestones. The group was also encouraged to not only consider the child neurology residency graduate of today but also the graduate of tomorrow, taking into account growing fields such as genetics and technology.

Results: A diverse group of 12 individuals, including 10 child neurologists (all of whom were current or previous program directors or associate program directors), one child neurology resident, and one non-physician program coordinator, were recruited from programs of varying size across the country.

Conclusions: The committee developed a revision to the child neurology milestones. All changes made were with a focus on how the milestones can be useful to trainees, program directors, and clinical competency committee members. Implementation and further feedback should help guide future revisions. These changes should help trainees, clinical competency committee members, and program directors find more meaning from their use.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.10.008DOI Listing
January 2021

Soy-Based Infant Formula is Associated with an Increased Prevalence of Comorbidities in Fragile X Syndrome.

Nutrients 2020 Oct 14;12(10). Epub 2020 Oct 14.

Department of Pediatrics, Rush University Medical Center, Chicago, IL 60612, USA.

A large number of adults and children consume soy in various forms, but little information is available regarding potential neurological side effects. Prior work indicates an association between the consumption of soy-based diets and seizure prevalence in mouse models of neurological disease and in children with autism. Herein, we sought to evaluate potential associations between the consumption of soy-based formula during infancy and disease comorbidities in persons with fragile X syndrome (FXS), while controlling for potentially confounding issues, through a retrospective case-control survey study of participants with FXS enrolled in the Fragile X Online Registry with Accessible Research Database (FORWARD). There was a 25% usage rate of soy-based infant formula in the study population. We found significant associations between the consumption of soy-based infant formula and the comorbidity of autism, gastrointestinal problems (GI) and allergies. Specifically, there was a 1.5-fold higher prevalence of autism, 1.9-fold GI problems and 1.7-fold allergies in participants reporting the use of soy-based infant formula. The major reason for starting soy-based infant formula was GI problems. The average age of seizure and allergy onset occurred long after the use of soy-based infant formula. We conclude that early-life feeding with soy-based infant formula is associated with the development of several disease comorbidities in FXS.
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http://dx.doi.org/10.3390/nu12103136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602206PMC
October 2020

Hemodynamics of Prefrontal Cortex in Ornithine Transcarbamylase Deficiency: A Twin Case Study.

Front Neurol 2020 14;11:809. Epub 2020 Aug 14.

National Institutes of Health (NIH), National Institute of Child Health and Human Development, Bethesda, MD, United States.

Ornithine transcarbamylase deficiency (OTCD) is the most common form of urea cycle disorder characterized by the presence of hyperammonemia (HA). In patients with OTCD, HA is known to cause impairments in domains of executive function and working memory. Monitoring OTCD progression and investigating neurocognitive biomarkers can, therefore, become critical in understanding the underlying brain function in a population with OTCD. We used functional near infrared spectroscopy (fNIRS) to examine the hemodynamics of prefrontal cortex (PFC) in a fraternal twin with and without OTCD. fNIRS is a non-invasive and wearable optical technology that can be used to assess cortical hemodynamics in a realistic clinical setting. We quantified the hemodynamic variations in total-hemoglobin as assessed by fNIRS while subjects performed the -back working memory (WM) task. Our preliminary results showed that the sibling with OTCD had higher variation in a very low frequency band (<0.03 Hz, related to mechanism of cerebral autoregulation) compared to the control sibling. The difference between these variations was not as prominent in the higher frequency band, indicating the possible role of impaired autoregulation and cognitive function due to presence of HA. We further examined the functional connectivity in PFC, where the OTCD sibling showed lower interhemispheric functional connectivity as the task load increased. Our pilot results are the first to show the utility of fNIRS in monitoring OTCD cortical hemodynamics, indicating the possibility of inefficient neurocognitive function. This study provides a novel insight into the monitoring of OTCD focusing on the contribution of physiological process and neurocognitive function in this population.
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http://dx.doi.org/10.3389/fneur.2020.00809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456944PMC
August 2020

Retinoschisis associated with Kearns-Sayre syndrome.

Ophthalmic Genet 2020 10 13;41(5):497-500. Epub 2020 Aug 13.

Ophthalmic Genetics & Visual Function Branch, National Eye Institute, National Institutes of Health , Bethesda, Maryland, USA.

Background: Kearns-Sayre Syndrome (KSS) is characterized by pigmentary retinopathy, external ophthalmoplegia and heart block. We report on a now 24-year-old male with clinical retinoschisis and molecularly confirmed KSS.

Materials And Methods: Physical and complete ophthalmic examination, molecular diagnosis.

Results: Over nine years of follow-up, the subject manifested progressive signs and symptoms of KSS, including external ophthalmoplegia/strabismus, ptosis, pigmentary retinopathy, corneal edema, Type I diabetes mellitus, gut dysmotility, sensorineural deafness and heart block. At age 21 he was incidentally found to have retinoschisis on optical coherence tomography that remained stable over three years follow-up. Sequencing of the gene revealed no pathogenic variants, effectively ruling out co-existing X-linked retinoschisis.

Conclusions: These findings suggest retinoschisis may be a rare manifestation of KSS. A trial of a carbonic anhydrase inhibitor was frustrated by coexisting corneal edema associated with the condition.
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http://dx.doi.org/10.1080/13816810.2020.1799416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127726PMC
October 2020

Speech and language development in children with 49,XXXXY syndrome.

Am J Med Genet A 2020 Jul 28. Epub 2020 Jul 28.

Division of Neurogenetics and Developments Pediatrics, Children's National Health System, Washington, District of Columbia, USA.

49,XXXXY is the rarest X and Y chromosomal variation and is frequently characterized by expressive and receptive language dysfunction, low muscle tonus, and intellectual deficits. Due to the low incidence of this disorder, comprehensive studies analyzing the specific aspects of the speech and language phenotype in these boys have been uncommon. This is the first in-depth investigation of the speech and language profiles in a large cohort of boys with 49,XXXXY. Based on the clinical judgment of speech and language pathologists, there was an increased incidence (91.8%) of Childhood Apraxia of Speech (CAS), which has not been previously described in this disorder. In preschool boys, some significant differences were demonstrated between boys who received early hormonal treatment (n = 16) and untreated boys (n = 4) on the language scales (p = .047) on the Bayley Scales of Infants and Toddlers, as well as significant differences between treated (n = 13) and untreated boys (n = 8) on the Expressive One Word Picture Vocabulary Test (p = .008). No significant differences between treatment groups were found in school age children, however, treated groups demonstrated less discrepancies between expressive and receptive language. More research and larger samples are needed to determine the extent of the impact of testosterone treatment on boys with 49,XXXXY. This study identifies CAS as a potential explanation for the significant expressive language dysfunction and subsequent behavioral dysfunction. These findings may assist in facilitating more targeted treatment and improved outcomes for boys with 49,XXXXY.
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http://dx.doi.org/10.1002/ajmg.a.61767DOI Listing
July 2020

Long-term effects of medical management on growth and weight in individuals with urea cycle disorders.

Sci Rep 2020 07 20;10(1):11948. Epub 2020 Jul 20.

Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs.
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http://dx.doi.org/10.1038/s41598-020-67496-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371674PMC
July 2020

Neurocognitive development and capabilities in boys with 49,XXXXY syndrome.

Am J Med Genet A 2020 Jul 14. Epub 2020 Jul 14.

Research Department, The Focus Foundation, Davidsonville, Maryland, USA.

49,XXXXY was previously associated with profound to severe intellectual deficits. However, prior research papers on the cognitive profiles of this population were confounded by small samples sizes, wide age spreads, and incomplete histories of testosterone replacement therapy. This study is the first comprehensive, international investigation of the neurocognitive aspects of 49,XXXXY, and the potential effects of biological treatment on this profile. Sixty-seven boys from infancy to 11 years of age were enrolled in this longitudinal study, with the majority of boys postnatally diagnosed though chromosomal analysis. These boys received a comprehensive neurocognitive evaluation tailored to specific language-based deficits and cognitive challenges. Results revealed higher neurocognitive capacities, both verbally and nonverbally, than previously reported in this disorder. Infant boys with 49,XXXXY who received early hormonal therapy (EHT) had significantly higher scores on the cognitive domain of the Bayley Scales of Infant Development than untreated infants (p = .013). In addition, treated school-aged participants had significantly better scaled scores than untreated boys in form completion (p = .042), a task that requires deductive reasoning, on nonverbal testing on the Leiter International Performance Scales. This study indicates greater cognitive capacities with a wide range of abilities in the child with 49,XXXXY, thus warranting further investigation to identify and understand the critical influences on the etiology and the variability of those capacities.
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http://dx.doi.org/10.1002/ajmg.a.61736DOI Listing
July 2020

49,XXXXY syndrome: A study of neurological function in this uncommon X and Y chromosomal disorder.

Am J Med Genet A 2020 Jul 13. Epub 2020 Jul 13.

Division of Neurogenetics and Developments Pediatrics, Children's National Health System, Washington, District of Columbia, USA.

49,XXXXY is a rare chromosomal variation characterized by deficits in motor, language, and cognitive domains. This study reports on the neurological function and dysmorphic features in the largest cohort to date. Seventy-two boys with 49,XXXXY were evaluated on a variety of domains including a neurological examination and neuromotor assessments including the Beery Buktenica Developmental Test of Visual-Motor Integration, Sixth Edition, the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), and the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition. Results supported previous literature by describing high occurrences of truncal and extremity hypotonia, which significantly impacts on motor milestones and ambulation in this population. The boys presented with dysmorphic features including epicanthal folds, frontal bossing, and synophrys. Visual perception skills were mildly impaired and cranial nerves were typically intact, however capabilities in motor coordination and fine motor precision were greatly delayed, supporting deficits in refined and controlled hand movements versus widespread visual deficits. Preschool boys treated with testosterone replacement had significantly increased scores when compared to the untreated group on the BSID-III Psychomotor Development Index, further supporting previous research indicating that testosterone replacement may have a positive impact on neurodevelopmental outcomes in males with additional X chromosomes. Boys with 49,XXXXY may benefit from hormonal treatment in conjunction with early intervention services to address their significant motor deficits.
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http://dx.doi.org/10.1002/ajmg.a.61742DOI Listing
July 2020

Introduction: Comprehensive investigation into an international cohort of boys with 49,XXXXY.

Am J Med Genet A 2020 Jul 13. Epub 2020 Jul 13.

Division of Neurogenetics and Developments Pediatrics, Children's National Health System, Washington, District of Columbia, USA.

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http://dx.doi.org/10.1002/ajmg.a.61739DOI Listing
July 2020

Evidence of intrauterine growth restriction and growth hormone deficiency in 49,XXXXY syndrome.

Am J Med Genet A 2020 Jul 2. Epub 2020 Jul 2.

Division of Research, The Focus Foundation, Davidsonville, Maryland, USA.

49,XXXXY is an X and Y chromosome variation that occurs in 1:85,000 to 1:100,000 live male births. Previous case studies have described boys with this disorder to be shorter than average when compared with boys with only one extra chromosome and with the mean stature in a small cohort reported to range from the seventh to 33rd percentile. The origin behind the possible differences in height between boys with 47,XXY and 49,XXXXY is currently unknown, however one study hypothesized that it was due to a difference in the expression of the SHOX gene. This study reports on the anthropometric measurements of 84 boys with 49,XXXXY. Forty-five percent of children with 49,XXXXY were found to be below the third percentile in height at the time of evaluation. In addition, 7.14% of the cohort were diagnosed and given treatment for growth hormone deficiency (GHD). The analysis of this cohort demonstrates that the below average heights seen throughout childhood in this population potentially begins prenatally and suggests that boys with 49,XXXXY may be at a higher risk for intrauterine growth restriction (IUGR) and GHD. Future research is needed to investigate the etiology of the poor growth in boys with 49,XXXXY and evaluate the incidence of GHD and IUGR in this population.
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http://dx.doi.org/10.1002/ajmg.a.61738DOI Listing
July 2020

Molecular genetic and mitochondrial metabolic analyses confirm the suspected mitochondrial etiology in a pediatric patient with an atypical form of alternating hemiplegia of childhood.

Mol Genet Metab Rep 2020 Sep 28;24:100609. Epub 2020 May 28.

Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.

Alternative hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder with an extensive phenotypic variability, resulting in a challenging clinical diagnosis. About 75% of AHC cases are caused by pathogenic variants mapping in the , or gene, leaving many AHC patients clinically and genetically undiagnosed. In this study, we report the case of a 9-year old proband clinically diagnosed with an atypical form of AHC presenting a suspected mitochondrial etiology and an obscure genetic diagnosis. Long-range PCR followed by next generation sequencing of the proband's mitochondrial genome identified a novel mitochondrial variant, m.12302C > A, mapping in the gene with a low heteroplasmic level in blood and fibroblasts. Whole exome sequencing revealed three known and novel pathogenic variants with different parental inheritance, all involved in the mitochondrial energy metabolism and thus far not associated with AHC. Live-cell mitochondrial metabolic study showed dysregulated mitochondrial oxidative phosphorylation pathway and metabolic plasticity preventing an efficient switch to glycolysis to sustain ATP homeostasis, congruent with the suspected mitochondrial etiology. In conclusion, our comprehensive genetic and metabolic analyses suggest an oligogenic inheritance among the nuclear and mitochondrial variants for the mitochondrial etiology of proband's atypical form of AHC, thereby providing critical insight in terms of genetic clues and bioenergetic deficit. This approach also improves the diagnostic process of atypical form of AHC with an unclear genotype-phenotype correlation to personalize therapeutic interventions.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262444PMC
September 2020

Mitochondrial diseases in North America: An analysis of the NAMDC Registry.

Neurol Genet 2020 Apr 2;6(2):e402. Epub 2020 Mar 2.

Department of Neurology (E.B., V.E., S.D., K.E., X.Q.R., M.H.), Columbia University Medical Center, New York; Department of Biostatistics (Y.L., V.C., J.K., J. Grier, R.B., J.L.P.T.), Mailman School of Public Health, Columbia University, New York; Radboudumc (R.S.), Nijmegen, The Netherlands; Department of Pediatrics (B.H.C.), Northeast Ohio Medical University and Akron Children's Hospital; Genetics Unit (A.K.), Massachusetts General Hospital, Boston; Department of Pediatrics (G.D.V.), State University of New York at Buffalo; Departments of Neurosciences and Pediatrics (R.H.), University of California at San Diego; Department of Pediatrics (J.L.K.V.H., A.L.), University of Colorado School of Medicine, Aurora; Department of Molecular and Human Genetics (F.S.), Baylor College of Medicine, Houston, TX; Texas Children's Hospital (F.S.), Houston; Joint BCM-CUHK Center of Medical Genetics (F.S.), Prince of Wales Hospital, ShaTin, New Territories, Hong Kong; Department of Neurology (S.P.), Cleveland Clinic, OH; Departments of Genetics and Genome Sciences and Pediatrics (J.K.B., S.D.D.), and Center for Human Genetics, University Hospitals Cleveland Medical Center, Case Western Reserve University, OH; Departments of Neurology and Clinical Genomics (R.H.G.), Mayo Clinic, Rochester, MN; Department of Neurology (R.P.S.), University of Washington, Seattle Children's Hospital; Department of Pediatrics (G.M.E.), Stanford University, Palo Alto, CA; Department of Medicine (P.W.S.), University of Florida at Gainesville; Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai (J. Ganesh), New York; Mitochondrial Medicine Frontier Program (Z.Z.-C., M.J.F., A.C.G.), Division of Human Genetics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine; University of Pennsylvania Perelman School of Medicine (Z.Z.-C.), Philadelphia; Department of Neurology (M.T.), McMasters University, Toronto, Ontario, Canada; Department of Neurology (A.G.), Children's National Health Network, Washington, DC; Office of Dietary Supplements (K.C.), National Institutes of Health, Bethesda, MD; and Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.K.), National Institutes of Health, Bethesda, MD.

Objective: To describe clinical, biochemical, and genetic features of participants with mitochondrial diseases (MtDs) enrolled in the North American Mitochondrial Disease Consortium (NAMDC) Registry.

Methods: This cross-sectional, multicenter, retrospective database analysis evaluates the phenotypic and molecular characteristics of participants enrolled in the NAMDC Registry from September 2011 to December 2018. The NAMDC is a network of 17 centers with expertise in MtDs and includes both adult and pediatric specialists.

Results: One thousand four hundred ten of 1,553 participants had sufficient clinical data for analysis. For this study, we included only participants with molecular genetic diagnoses (n = 666). Age at onset ranged from infancy to adulthood. The most common diagnosis was multisystemic disorder (113 participants), and only a minority of participants were diagnosed with a classical mitochondrial syndrome. The most frequent classical syndromes were Leigh syndrome (97 individuals) and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (71 individuals). Pathogenic variants in the mitochondrial DNA were more frequently observed (414 participants) than pathogenic nuclear gene variants (252 participants). Pathogenic variants in 65 nuclear genes were identified, with and being the most commonly affected. Pathogenic variants in 38 genes were reported only in single participants.

Conclusions: The NAMDC Registry data confirm the high variability of clinical, biochemical, and genetic features of participants with MtDs. This study serves as an important resource for future enhancement of MtD research and clinical care by providing the first comprehensive description of participant with MtD in North America.
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http://dx.doi.org/10.1212/NXG.0000000000000402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164977PMC
April 2020

Musculoskeletal abnormalities in a large international cohort of boys with 49,XXXXY.

Am J Med Genet A 2020 Apr 3. Epub 2020 Apr 3.

The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.

49,XXXXY is the rarest X and Y chromosomal variation, with an incidence of 1 in 80,000-100,000 live male births and has been associated with numerous musculoskeletal abnormalities. Data was collected from an international cohort of boys with 49,XXXXY over 10 years. Children were evaluated by a multidisciplinary team consisting of a pediatric orthopedist, a neurogeneticist, a neurodevelopmentalist, and two physical therapists. Increased rates of torticollis (32.4%), hamstring tightness (42%), radioulnar synostosis (67.6%), pes planus (65.2%), and other foot abnormalities (86.9%) were observed. Several anomalies increased with age, specifically hamstring tightness, kyphosis, and scoliosis. The elucidation of the orthopedic profile of this population is necessary in order to provide healthcare providers with current medical information. This research further supports the necessity for the comprehensive multidisciplinary treatment of boys with 49,XXXXY.
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http://dx.doi.org/10.1002/ajmg.a.61578DOI Listing
April 2020

Neurodevelopmental outcome of prenatally diagnosed boys with 47,XXY (Klinefelter syndrome) and the potential influence of early hormonal therapy.

Am J Med Genet A 2020 08 27;182(8):1881-1889. Epub 2020 Mar 27.

Division of Neurogenetics and Developmental Pediatrics, Children's National Health System, Washington, District of Columbia, USA.

This cross-sectional study examined the neurodevelopment of a large, prenatally diagnosed population of boys with 47,XXY; investigated the potentially positive effects of early hormonal therapy (EHT) on language, cognition, and motor in this population; and identified novel at risk biomarkers associated with 47,XXY. Two-hundred and seventy two evaluations were collected from 148 prenatally diagnosed boys with 47,XXY between 0 and 36 months and separated into one of three groups, depending on visit age: Y1 (0-12 months; n = 100), Y2 (13-24 months; n = 90), and Y3 (25-36 months; n = 82). Those who received EHT (administered by 12 months) were further separated (Y1, n = 37; Y2, n = 34; Y3, n = 30). Neurodevelopmental evaluations consisted of Preschool Language Scales, Early Language Milestone Scale, and Bayley Scales of Infant and Toddler Development and evaluated the effect of EHT on auditory comprehension, expressive communication, receptive language, cognition, and motor. EHT was found to be associated with a positive effect within the first year of life in these domains, as well as in the second and third year of life. Additionally, three novel at-risk biomarkers were identified in this cohort: feeding difficulties in infancy, positional torticollis, and the need for orthotics. The positive effects of EHT observed in language, cognition, and motor at variable stages within the first 3 years of life provide additional evidence into the possible efficacy of early biological treatment for boys with 47,XXY to address the neurodevelopmental dysfunction.
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http://dx.doi.org/10.1002/ajmg.a.61561DOI Listing
August 2020
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