Delayed Onset of Chorea After Extrapontine Myelinolysis.
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ABSTRACT:
SUBMITTER: Cury RG
PROVIDER: S-EPMC6353359 | biostudies-literature | 2014 Dec
REPOSITORIES: biostudies-literature
Publications
Delayed Onset of Chorea After Extrapontine Myelinolysis.
Cury Rubens Gisbert RG Caldas Vitor M VM Dornelas Gilmar O GO Haddad Mônica Santoro MS
Movement disorders clinical practice 20140909 4
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Project description:Benign hereditary chorea (BHC) is an autosomal dominant disorder characterized by an early-onset nonprogressive chorea. The early onset and the benign course distinguishes BHC from the more common Huntington disease (HD). Previous studies on families with BHC have shown that BHC and HD are not allelic. We studied a large Dutch kindred with BHC and obtained strong evidence for linkage between the disorder and markers on chromosome 14q (maximum LOD score 6.32 at recombination fraction 0). The BHC locus in this family was located between markers D14S49 and D14S1064, a region spanning approximately 20.6 cM that contains several interesting candidate genes involved in the development and/or maintenance of the CNS: glia maturation factor-beta, GTP cyclohydrolase 1 and the survival of motor neurons (SMN)-interacting protein 1. The mapping of the BHC locus to 14q is a first step toward identification of the gene involved, which might, subsequently, shed light on the pathogenesis of this and other choreatic disorders.
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Project description:Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C [p.Phe300Leu] in two individuals and c.1000T>C [p.Phe334Leu] in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions affect highly conserved amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders.
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Project description:IntroductionCentral pontine myelinolysis (CPM) is an acquired demyelinating lesion of the basis pontis that typically occurs after rapid correction of hyponatremia. There are only a few reported cases of patients without symptoms that have demonstrated CPM on imaging.Case presentationWe report the case of a 26-year-old Hispanic male with history of alcohol abuse who was transferred to our medical center for acute onset diffuse abdominal pain. During his work up, a computed tomography scan demonstrated a large pancreatic mass. He underwent an endoscopic guided biopsy which demonstrated a rare and aggressive natural killer T cell lymphoma. His laboratory values were consistent with hyponatremia, which the medical team gently corrected. An MRI was performed for staging purposes which revealed findings consistent with CPM. A full neurological exam demonstrated no deficits.Materials and methodsWE CONDUCTED A PUBMED SEARCH USING THE FOLLOWING KEYWORDS: asymptomatic, central, pontine, and myelinolysis in order to find other case reports of asymptomatic CPM.ResultsOf the 29 results, only 6 previous case reports with English language abstracts of asymptomatic CPM were present since 1995.ConclusionDespite slow correction of hyponatremia, CPM can be an important consequence, especially in patients with chronic alcoholism. Although this patient did not demonstrate any neurological deficits, the fact that there were changes seen on MRI should caution physicians in aggressively treating hyponatremia. Furthermore, if there is a decision to treat, then fluid restriction and reversal of precipitating factors (i.e. diuretics) should be used initially, unless there is concern for hypovolemia.
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Project description:BACKGROUND:We investigated a family that presented with an infantile-onset chorea-predominant movement disorder, negative for NKX2-1, ADCY5, and PDE10A mutations. METHODS:Phenotypic characterization and trio whole-exome sequencing was carried out in the family. RESULTS:We identified a homozygous mutation affecting the GAF-B domain of the 3',5'-cyclic nucleotide phosphodiesterase PDE2A gene (c.1439A>G; p.Asp480Gly) as the candidate novel genetic cause of chorea in the proband. PDE2A hydrolyzes cyclic adenosine/guanosine monophosphate and is highly expressed in striatal medium spiny neurons. We functionally characterized the p.Asp480Gly mutation and found that it severely decreases the enzymatic activity of PDE2A. In addition, we showed equivalent expression in human and mouse striatum of PDE2A and its homolog gene, PDE10A. CONCLUSIONS:We identified a loss-of-function homozygous mutation in PDE2A associated to early-onset chorea. Our findings possibly strengthen the role of cyclic adenosine monophosphate and cyclic guanosine monophosphate metabolism in striatal medium spiny neurons as a crucial pathophysiological mechanism in hyperkinetic movement disorders. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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Project description:ObjectiveTo characterize clinical and radiologic features of patients with central pontine myelinolysis (CPM) and identify variables that predict outcome.Patients and methodsWe retrospectively studied patients diagnosed as having CPM identified by a search of Mayo Clinic medical records from January 1, 1999, through December 31, 2010. Diagnosis was made by clinical and radiologic features. Favorable outcome was defined by a modified Rankin Scale score of 2 or lower. Volume of signal abnormality on brain magnetic resonance imaging (MRI) was quantified by a neuroradiologist blinded to outcomes. Wilcoxon rank sum tests were used to assess association between volume of signal abnormality and outcomes at discharge and last follow-up.ResultsOf 24 patients, 14 (58%) had only CPM, and 10 (42%) had extrapontine involvement. Hyponatremia was documented in 18 patients (75%), with median sodium nadir of 114 mmol/L. Eighteen patients (75%) had alcoholism, and malnutrition was documented in 12 (50%). Presenting symptoms included encephalopathy (n=18 [75%]), ataxia (n=11 [46%]), dysarthria (n=7 [29%]), eye movement abnormalities (n=6 [25%]), and seizures (n=5 [21%]). Favorable outcome was seen in 15 patients (63%) at last follow-up. Findings on initial brain MRI were normal in 5 patients, but all MRI scans were abnormal with serial imaging. The volume of radiologic signal abnormality was not associated with outcome at discharge or last follow-up (P=.67 and P=.37, respectively).ConclusionClinical outcome in patients with CPM is not predicted by the volume of radiologic T2 signal abnormality on MRI or the severity of hyponatremia. Serial brain imaging is of value because a substantial proportion of patients have normal findings on initial MRI.
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