Aicardi-Goutières syndrome may present with positive newborn screen for X-linked adrenoleukodystrophy.
American journal of medical genetics. Part A
We report three unrelated probands, two male and one female, diagnosed with Aicardi-Goutières syndrome (AGS) after screening positive on California newborn screening (CA NBS) for X-linked adrenoleukodystrophy (X-ALD) due to elevated C26:0 lysophosphatidylcholine (C26:0-LPC). Follow-up evaluation was notable for elevated C26:0, C26:1, and C26:0/C22:0 ratio, and normal red blood cell plasmalogens levels in all three probands. Diagnoses were confirmed by molecular sequencing prior to 12?months of age after clinical evaluation was inconsistent with X-ALD or suggestive of AGS. For at least one proband, the early diagnosis of AGS enabled candidacy for enrollment into a therapeutic clinical trial. This report demonstrates the importance of including AGS on the differential diagnosis for individuals who screen positive for X-ALD, particularly infants with abnormal neurological features, as this age of onset would be highly unusual for X-ALD. While AGS is not included on the Recommended Universal Screening Panel, affected individuals can be identified early through state NBS programs so long as providers are aware of a broader differential that includes AGS. This report is timely, as state NBS algorithms for X-ALD are actively being established, implemented, and refined.
View details for DOI 10.1002/ajmg.a.62160
View details for PubMedID 33683010
A Case of Abulia From Left Middle Cerebral Artery Stroke in an Adolescent Treated Successfully With Short Duration Olanzapine.
; 43 (3): 86?89
Abulia is defined as a pathological state of amotivation, apathy, and global absence of willpower. It presents with a challenging array of overlapping symptoms, making effective identification and treatment difficult.We describe the first known report of an adolescent with a ventricular assist device who developed abulia following a left middle cerebral artery (MCA) stroke who responded successfully to treatment with olanzapine.The neurobiological etiology of abulia is still unclear but is postulated to be related to deficits in the dopaminergic reward circuitry in the frontal-subcortical-mesolimbic regions. There have been reports of poststroke patients with abulia being treated by modulating this dopamine circuitry and in some cases with short-term low-dose olanzapine.Further research is needed to develop a better understanding of the pathophysiology of abulia leading to more effective treatment algorithms including more specific diagnostic tools and effective pharmacological interventions.
View details for DOI 10.1097/WNF.0000000000000389
View details for PubMedID 32384311
Acute Hyperextension "Surfer's" Myelopathy in a Gymnast: Bending over Backwards for Diagnosis
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for Web of Science ID 000536058004287
Continuous EEG for Seizure Detection in Neonates after Cardiac Bypass without Deep Hypothermic Cardiac Arrest
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for Web of Science ID 000536058004299
A Previously Healthy Adolescent With Acute Psychosis and Severe Hyperhidrosis.
A previously healthy 15-year-old boy presented with 3 months of progressive psychosis, insomnia, back and groin pain, and hyperhidrosis. On examination, the patient was disheveled, agitated, and soaked with sweat, with systolic blood pressure in the 160s and heart rate in the 130s. Aside from occasional auditory and visual hallucinations, his neurologic examination was normal. The patient was admitted for an extensive workup, including MRI of the brain and spine and lumbar puncture, which were normal. Through collaboration with various pediatric specialists, including psychiatry and neurology, a rare diagnosis was ultimately unveiled.
View details for DOI 10.1542/peds.2019-3786
View details for PubMedID 32444380
- Differentiation and maturation of oligodendrocytes in human three-dimensional neural cultures NATURE NEUROSCIENCE 2019; 22 (3): 484-+
Deoxycytidine and deoxythymidine treatment for thymidine kinase 2 deficiency.
Annals of neurology
Thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial pyrimidine salvage pathway, is essential for mitochondrial DNA (mtDNA) maintenance. Mutations in the nuclear gene TK2 cause TK2 deficiency, which manifests predominantly in children as myopathy with mtDNA depletion. Molecular bypass therapy with the TK2 products, dCMP and dTMP, prolongs the lifespan of Tk2-deficient (Tk2(-/-) ) mice by 2-3 fold. Because we observed rapid catabolism of the deoxynucleoside monophosphates to deoxythymidine (dT) and deoxycytidine (dC), we hypothesized that: 1) deoxynucleosides might be the major active agents and 2) inhibition of deoxycytidine deamination might enhance dTMP+dCMP therapy.To test these hypotheses, we assessed two therapies in Tk2(-/-) mice: 1) dT+dC and 2) co-administration of the deaminase inhibitor, tetrahydrouridine (THU), with dTMP+dCMP.We observed that dC+dT delayed disease onset, prolonged lifespan of Tk2-deficient mice, and restored mtDNA copy number as well as respiratory chain enzyme activities and levels. In contrast, dCMP+dTMP+THU therapy decreased lifespan of Tk2(-/-) animals compared to dCMP+dTMP.Our studies demonstrate that deoxynucleoside substrate enhancement is a novel therapy, which may ameliorate TK2 deficiency in patients. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/ana.24922
View details for PubMedID 28318037
Deletion of Rapgef6, a candidate schizophrenia susceptibility gene, disrupts amygdala function in mice
In human genetic studies of schizophrenia, we uncovered copy-number variants in RAPGEF6 and RAPGEF2 genes. To discern the effects of RAPGEF6 deletion in humans, we investigated the behavior and neural functions of a mouse lacking Rapgef6. Rapgef6 deletion resulted in impaired amygdala function measured as reduced fear conditioning and anxiolysis. Hippocampal-dependent spatial memory and prefrontal cortex-dependent working memory tasks were intact. Neural activation measured by cFOS phosphorylation demonstrated a reduction in hippocampal and amygdala activation after fear conditioning, while neural morphology assessment uncovered reduced spine density and primary dendrite number in pyramidal neurons of the CA3 hippocampal region of knockout mice. Electrophysiological analysis showed enhanced long-term potentiation at cortico-amygdala synapses. Rapgef6 deletion mice were most impaired in hippocampal and amygdalar function, brain regions implicated in schizophrenia pathophysiology. The results provide a deeper understanding of the role of the amygdala in schizophrenia and suggest that RAPGEF6 may be a novel therapeutic target in schizophrenia.
View details for DOI 10.1038/tp.2015.75
View details for Web of Science ID 000367658600001
View details for PubMedID 26057047
Long Survival in Patients With Leigh Syndrome and the m.10191T > C Mutation in MT-ND3: A Case Report and Review of the Literature
JOURNAL OF CHILD NEUROLOGY
2014; 29 (10): NP105-NP110
We report an unusual case of Leigh syndrome due to the m.10191T>C mutation in the complex I gene MT-ND3. This mutation has been associated with a spectrum of clinical phenotypes ranging from infant lethality to adult onset. Despite infantile onset and severe symptoms, our patient has survived to early adulthood because of a strict dietary regimen and parental care. This patient is an extreme example of the frequently prolonged course of Leigh syndrome due to this particular mutation.
View details for DOI 10.1177/0883073813506783
View details for Web of Science ID 000342823700005
View details for PubMedID 24284231
Copy number variation and psychiatric disease risk.
Methods in molecular biology (Clifton, N.J.)
2012; 838: 97-113
Psychiatric disorders are multifactorial in nature with complex genetic architecture. A number of recent studies, building upon earlier findings of copy number variants (CNVs) at the 22q11.2 locus, suggest that rare CNVs represent an important component of genetic heterogeneity in the etiology of complex psychiatric diseases, such as schizophrenia. De novo CNVs are found with higher frequency among sporadic cases, whereas inherited CNVs are enriched among familial cases. Despite substantial progress, a number of challenges remain, such as pinpointing causative relationships between specific gene(s) affected by CNVs and disease phenotypes as well as distinguishing abnormal structural mutations from neutral polymorphisms and establishing a clear association between individual pathogenic CNV and disease phenotypes.
View details for DOI 10.1007/978-1-61779-507-7_4
View details for PubMedID 22228008
Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2011; 108 (49): E1349-E1358
Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophrenia-predisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growth-promoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations.
View details for DOI 10.1073/pnas.1114113108
View details for Web of Science ID 000297683800012
View details for PubMedID 22049344