Mislocalization of syntaxin‐1 and impaired neurite growth observed in a human iPSC model for STXBP1‐related epileptic encephalopathy

Syntaxin‐binding protein 1 (STXBP1) is essential for synaptic vesicle exocytosis. Mutations of its encoding gene, STXBP1, are among the most frequent genetic causes of epileptic encephalopathies. However, the precise pathophysiology of STXBP1 haploinsufficiency has not been elucidated. Using patient‐derived induced pluripotent stem cells (iPSCs), we aimed to establish a neuronal model for STXBP1 haploinsufficiency and determine the pathophysiologic basis for STXBP1 encephalopathy. We generated iPSC lines from a patient with Ohtahara syndrome (OS) harboring a heterozygous nonsense mutation of STXBP1 (c.1099C>T; p.R367X) and performed neuronal differentiation. Both STXBP1 messenger RNA (mRNA) and STXBP1 protein expression levels of OS‐derived neurons were approximately 50% lower than that of control‐derived neurons, suggesting that OS‐derived neurons are a suitable model for elucidating the pathophysiology of STXBP1 haploinsufficiency. Through Western blot and immunocytochemistry assays, we found that OS‐derived neurons show reduced levels and mislocalization of syntaxin‐1, a component of soluble N‐ethylmaleimide‐sensitive factor attachment receptor (SNARE) proteins. In addition, OS‐derived neurons have impaired neurite outgrowth. In conclusion, this model enables us to investigate the neurobiology of STXBP1 encephalopathy throughout the stages of neurodevelopment. Reduced expression of STXBP1 leads to changes in the expression and localization of syntaxin‐1 that may contribute to the devastating phenotype of STXBP1 encephalopathy.     

Striosomal dysfunction affects behavioral adaptation but not impulsivity—Evidence from X‐linked dystonia‐parkinsonism

Background : Executive functions including behavioral adaptation and impulse control are commonly impaired in movement disorders caused by striatal pathology. However, as yet it is unclear what aspects of behavioral abnormalities are related to pathology in which striatal subcomponent, that is, the matrix and the striosomes. We therefore studied cognitive control in X‐linked dystonia‐parkinsonism, a model disease of striosomal degeneration, using behavioral paradigms and EEG. Methods : We studied genetically confirmed X‐linked dystonia‐parkinsonism patients (N = 21) in their early disease stages and healthy matched controls. Error‐related behavioral adaptation was tested in a flanker task and response inhibition in a Go/Nogo paradigm during EEG. We focused on error‐related negativity during error processing and the Nogo‐N2 and Nogo‐P3 in the response inhibition task. Source localization analyses were calculated. In addition, total wavelet power and phase‐locking factor reflecting neural synchronization processes in time and frequency across trials were calculated. Results : Error processing and behavioral adaptation predominantly engaging the anterior cingulate cortex was markedly impaired in X‐linked dystonia‐parkinsonism. This was reflected in abnormal reaction times correlating with error‐related negativity amplitudes, error related theta band activity, and the phase‐locking factor. Also, abnormal error processing correlated with dystonia severity but not with parkinsonism. Response inhibition and corresponding EEG activity were normal. Conclusions : This dissociable pattern of cognitive deficits most likely reflects predominant dysfunction of the striosomal compartment and its connections to the anterior cingulate cortex in X‐linked dystonia‐parkinsonism. The results underscore the importance of striosomes for cognitive function in humans and suggest that striosomes are relays of error‐related behavioral adaptation but not inhibitory control. © 2017 International Parkinson and Movement Disorder Society     

Pluripotent stem cell‐derived radial glia‐like cells as stable intermediate for efficient generation of human oligodendrocytes

Neural precursor cells (NPCs) derived from human pluripotent stem cells (hPSCs) represent an attractive tool for the in vitro generation of various neural cell types. However, the developmentally early NPCs emerging during hPSC differentiation typically show a strong propensity for neuronal differentiation, with more limited potential for generating astrocytes and, in particular, for generating oligodendrocytes. This phenomenon corresponds well to the consecutive and protracted generation of neurons and GLIA during normal human development. To obtain a more gliogenic NPC type, we combined growth factor‐mediated expansion with pre‐exposure to the differentiation‐inducing agent retinoic acid and subsequent immunoisolation of CD133‐positive cells. This protocol yields an adherent and self‐renewing population of hindbrain/spinal cord radial glia (RG)‐like neural precursor cells (RGL‐NPCs) expressing typical neural stem cell markers such as nestin, ASCL1, SOX2, and PAX6 as well as RG markers BLBP, GLAST, vimentin, and GFAP. While RGL‐NPCs maintain the ability for tripotential differentiation into neurons, astrocytes, and oligodendrocytes, they exhibit greatly enhanced propensity for oligodendrocyte generation. Under defined differentiation conditions promoting the expression of the major oligodendrocyte fate‐determinants OLIG1/2, NKX6.2, NKX2.2, and SOX10, RGL‐NPCs efficiently convert into NG2‐positive oligodendroglial progenitor cells (OPCs) and are subsequently capable of in vivo myelination. Representing a stable intermediate between PSCs and OPCs, RGL‐NPCs expedite the generation of PSC‐derived oligodendrocytes with O4‐, 4860‐, and myelin basic protein (MBP)‐positive cells that already appear within 7 weeks following growth factor withdrawal‐induced differentiation. Thus, RGL‐NPCs may serve as robust tool for time‐efficient generation of human oligodendrocytes from embryonic and induced pluripotent stem cells. GLIA 2015;63:2152–2167     

Isolated and combined dystonia syndromes – an update on new genes and their phenotypes

Recent consensus on the definition, phenomenology and classification of dystonia centres around phenomenology and guides our diagnostic approach for the heterogeneous group of dystonias. Current terminology classifies conditions where dystonia is the sole motor feature (apart from tremor) as ‘isolated dystonia’, while ‘combined dystonia’ refers to dystonias with other accompanying movement disorders. This review highlights recent advances in the genetics of some isolated and combined dystonic syndromes. Some genes, such as ANO3, GNAL and CIZ1, have been discovered for isolated dystonia, but they are probably not a common cause of classic cervical dystonia. Conversely, the phenotype associated with TUBB4A mutations expanded from that of isolated dystonia to a syndrome of hypomyelination with atrophy of the basal ganglia and cerebellum (H‐ABC syndrome). Similarly, ATP1A3 mutations cause a wide phenotypic spectrum ranging from rapid‐onset dystonia‐parkinsonism to alternating hemiplegia of childhood. Other entities entailing dystonia‐parkinsonism include dopamine transporter deficiency syndrome (SLC63 mutations); dopa‐responsive dystonias; young‐onset parkinsonism (PARKIN, PINK1 and DJ‐1 mutations); PRKRA mutations; and X‐linked TAF1 mutations, which rarely can also manifest in women. Clinical and genetic heterogeneity also characterizes myoclonus‐dystonia, which includes not only the classical phenotype associated with epsilon‐sarcoglycan mutations but rarely also presentation of ANO3 gene mutations, TITF1 gene mutations typically underlying benign hereditary chorea, and some dopamine synthesis pathway conditions due to GCH1 and TH mutations. Thus, new genes are being recognized for isolated dystonia, and the phenotype of known genes is broadening and now involves different combined dystonia syndromes.     

Complicated recessive dystonia parkinsonism syndromes

In addition to pure PD and pure dystonic syndromes, there are a group of disorders with overlapping features. The differential diagnosis of these dystonia parkinsonism syndromes can be complex. In view of the growing list of recognized disorders and recent advances in genetics, we review the autosomal recessive forms of dystonia parkinsonism, summarizing clinical presentations, results of investigations, and response to treatment of gene‐proven cases. We concentrate on PANK2‐, PLA2G6‐, ATP13A2‐, FBX07, TAF1‐, and PRKRA‐associated neurodegeneration. Parkin, PINK1, and DJ‐1 are also briefly reviewed. © 2009 Movement Disorder Society     

Insights into the pathogenesis of ATP1A1‐related CMT disease using patient‐specific iPSCs

The development of patient‐specific induced pluripotent stem cells (iPSCs) offered interesting insights in modeling the pathogenesis of Charcot‐Marie‐Tooth (CMT) disease and thus we decided to explore the phenotypes of iPSCs derived from a single CMT patient carrying a mutant ATP1A1 allele (p.Pro600Ala). iPSCs clones generated from CMT and control fibroblasts, were induced to differentiate into neural precursors and then into post‐mitotic neurons. Control iPSCs differentiated into neuronal precursors and then into post‐mitotic neurons within 6‐8 days. On the contrary, the differentiation of CMT iPSCs was clearly defective. Electrophysiological properties confirmed that post‐mitotic neurons were less mature compared to the normal counterpart. The impairment of in vitro differentiation of CMT iPSCs only concerned with the neuronal pathway, because they were able to differentiate into mesendodermal cells and other ectodermal derivatives. ATP1A1 was undetectable in the few neuronal cells derived from CMT iPSCs. ATP1A1 gene mutation (p.Pro600Ala), responsible for a form of axonal CMT disease, is associated in vitro with a dramatic alteration of the differentiation of patient‐derived iPSCs into post‐mitotic neurons. Thus, the defect in neuronal cell development might lead in vivo to a decreased number of mature neurons in ATP1A1‐CMT disease.     

Fragile X Syndrome Patient–Derived Neurons Developing in the Mouse Brain Show FMR1-Dependent Phenotypes

BackgroundFragile X syndrome (FXS) is characterized by physical abnormalities, anxiety, intellectual disability, hyperactivity, autistic behaviors, and seizures. Abnormal neuronal development in FXS is poorly understood. Data on patients with FXS remain scarce, and FXS animal models have failed to yield successful therapies. In vitro models do not fully recapitulate the morphology and function of human neurons.MethodsTo mimic human neuron development in vivo, we coinjected neural precursor cells derived from FXS patient–derived induced pluripotent stem cells and neural precursor cells derived from corrected isogenic control induced pluripotent stem cells into the brain of neonatal immune-deprived mice.ResultsThe transplanted cells populated the brain and a proportion differentiated into neurons and glial cells. Immunofluorescence and single and bulk RNA sequencing analyses showed accelerated maturation of FXS neurons after an initial delay. Additionally, we found increased percentages of Arc- and Egr-1–positive FXS neurons and wider dendritic protrusions of mature FXS striatal medium spiny neurons.ConclusionsThis transplantation approach provides new insights into the alterations of neuronal development in FXS by facilitating physiological development of cells in a 3-dimensional context.     

Novel Dystonia Genes: Clues on Disease Mechanisms and the Complexities of High‐Throughput Sequencing

Dystonia is a genetically heterogenous disease and a prototype disorder where next‐generation sequencing has facilitated the identification of new pathogenic genes. This includes the first two genes linked to recessively inherited isolated dystonia, that is, HPCA (hippocalcin) and COL6A3 (collagen VI alpha 3). These genes are proposed to underlie cases of the so‐called DYT2‐like dystonia, while also reiterating two distinct pathways in dystonia pathogenesis. First, deficiency in HPCA function is thought to alter calcium homeostasis, a mechanism that has previously been forwarded for CACNA1A and ANO3. The novel myoclonus‐dystonia genes KCTD17 and CACNA1B also implicate abnormal calcium signaling in dystonia. Second, the phenotype in COL6A3‐loss‐of‐function zebrafish models argues for a neurodevelopmental defect, which has previously been suggested as a possible biological mechanism for THAP1, TOR1A, and TAF1 based on expression data. The newly reported myoclonus‐dystonia gene, RELN, plays also a role in the formation of brain structures. Defects in neurodevelopment likewise seem to be a recurrent scheme underpinning mainly complex dystonias, for example those attributable to biallelic mutations in GCH1, TH, SPR, or to heterozygous TUBB4A mutations. To date, it remains unclear whether dystonia is a common phenotypic outcome of diverse underlying disease mechanisms, or whether the different genetic causes converge in a single pathway. Importantly, the relevance of pathways highlighted by novel dystonia genes identified by high‐throughput sequencing depends on the confirmation of mutation pathogenicity in subsequent genetic and functional studies. However, independent, careful validation of genetic findings lags behind publications of newly identified genes. We conclude with a discussion on the characteristics of true‐positive reports. © 2016 International Parkinson and Movement Disorder Society     

Engineering synucleinopathy‐resistant human dopaminergic neurons by CRISPR‐mediated deletion of the SNCA gene

An emerging treatment for Parkinson's disease (PD) is cell replacement therapy. Authentic midbrain dopaminergic (mDA) neuronal precursors can be differentiated from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (iPSCs). These laboratory‐generated mDA cells have been demonstrated to mature into functional dopaminergic neurons upon transplantation into preclinical models of PD. However, clinical trials with human fetal mesenchephalic cells have shown that cell replacement grafts in PD are susceptible to Lewy body formation suggesting host‐to‐graft transfer of α‐synuclein pathology. Here, we have used CRISPR/Cas9n technology to delete the endogenous SNCA gene, encoding for α‐synuclein, in a clinical‐grade hESC line to generate SNCA^+/? and SNCA^?/? cell lines. These hESC lines were first differentiated into mDA neurons, and then challenged with recombinant α‐synuclein preformed fibrils (PFFs) to seed the formation for Lewy‐like pathology as measured by phosphorylation of serine‐129 of α‐synuclein (pS129‐αSyn). Wild‐type neurons were fully susceptible to the formation of protein aggregates positive for pS129‐αSyn, while SNCA^+/? and SNCA^?/? neurons exhibited significant resistance to the formation of this pathological mark. This work demonstrates that reducing or completely removing SNCA alleles by CRISPR/Cas9n‐mediated gene editing confers a measure of resistance to Lewy pathology.     

Blepharospasm and limb dystonia caused by Mohr‐Tranebjaerg syndrome with a novel splice‐site mutation in the deafness/dystonia peptide gene

Mohr‐Tranebjaerg syndrome (MTS) is an X‐linked disorder characterized by childhood‐onset progressive deafness, dystonia, spasticity, mental deterioration, and blindness. It is due to mutations in the deafness/dystonia peptide (DDP1) gene. We describe a sporadic 42‐year‐old man with MTS presenting with postlingual deafness, adult‐onset progressive dystonia with marked arm tremor, mild spasticity of the legs, and visual disturbance due to a novel mutation (g to a transition at the invariant gt of the 5′ splice donor site of exon 1) in the DDP1 gene. This case, and a review of previously reported cases, highlights a variety of potential diagnostic pitfalls in this condition. © 2007 Movement Disorder Society     

Novel Disabled‐1‐expressing neurons identified in adult brain and spinal cord

Components of the Reelin‐signaling pathway are highly expressed in embryos and regulate neuronal positioning, whereas these molecules are expressed at low levels in adults and modulate synaptic plasticity. Reelin binds to Apolipoprotein E receptor 2 and Very‐low‐density lipoprotein receptors, triggers the phosphorylation of Disabled‐1 (Dab1), and initiates downstream signaling. The expression of Dab1 marks neurons that potentially respond to Reelin, yet phosphorylated Dab1 is difficult to detect due to its rapid ubiquitination and degradation. Here we used adult mice with a lacZ gene inserted into the dab1 locus to first verify the coexpression of β‐galactosidase (β‐gal) in established Dab1‐immunoreactive neurons and then identify novel Dab1‐expressing neurons. Both cerebellar Purkinje cells and spinal sympathetic preganglionic neurons have coincident Dab1 protein and β‐gal expression in dab1^lacZ/+ mice. Adult pyramidal neurons in cortical layers II–III and V are labeled with Dab1 and/or β‐gal and are inverted in the dab1^lacZ/lacZ neocortex, but not in the somatosensory barrel fields. Novel Dab1 expression was identified in GABAergic medial septum/diagonal band projection neurons, cerebellar Golgi interneurons, and small neurons in the deep cerebellar nuclei. Adult somatic motor neurons also express Dab1 and show ventromedial positioning errors in dab1‐null mice. These findings suggest that: (i) Reelin regulates the somatosensory barrel cortex differently than other neocortical areas, (ii) most Dab1 medial septum/diagonal band neurons are probably GABAergic projection neurons, and (iii) positioning errors in adult mutant Dab1‐labeled neurons vary from subtle to extensive.     

Sustained quality‐of‐life improvements over 10 years after deep brain stimulation for dystonia

Background : Little is known about the quality of life of people with dystonia and DBS beyond 5 years. The objectives of this study were (1) to examine the long‐term quality‐of‐life outcomes in a large cohort of people with dystonia and DBS, (2) to determine the incidence of stimulation‐induced parkinsonism, and (3) to elucidate the potential long‐term cognitive impact of DBS in this cohort. Methods : Fifty‐four subjects with dystonia and DBS for more than 5 years were contacted via social media and were offered to complete a quality‐of‐life survey comparing current‐day life and life prior to DBS. The primary study outcomes were the Short Form survey, a parkinsonian symptoms questionnaire, the Telephone Montreal Cognitive Assessment, and the Measurement of Every Day Cognition. Results : Thirty‐seven of 54 subjects consented to the study. Average age was 39.7 ± 16.6 years, 16 were female, and 23 were DYT1+. Average time from implantation was 10.5 years. Average total Short Form survey scores improved, from 43.7 pre‐DBS to 69.5 current day (P < 0.0005). Mean total self‐reported parkinsonian symptom score was 13.8 ± 14.7, with worsening balance and hypophonia the most common. Average Telephone Montreal Cognitive Assessment was 20.1 ± 1.6, with 3 of 29 scores (10.3%) in the impaired range (score of 18 or less). Average total Every Day Cognition score was 1.25 ± 0.35, with 3 subjects (10.3%) scoring in the range of impaired cognition (>1.81). Conclusions : DBS for dystonia results in long‐term quality‐of‐life improvements that persist on average 10 years or more after surgery. The prevalence of stimulation‐induced parkinsonism and cognitive impairment is low. © 2018 International Parkinson and Movement Disorder Society     

Molecular mechanisms of cross‐inhibition between nicotinic acetylcholine receptors and P2X receptors in myenteric neurons and HEK‐293 cells

Background P2X₂ and nicotinic acetylcholine receptors (nAChRs) mediate fast synaptic excitation in the enteric nervous system. P2X receptors and nAChRs are functionally linked. This study examined the mechanisms responsible for interactions between P2X2 and α3β4subunit‐containing nAChRs. Methods The function of P2X2 and α3β4 nAChRs expressed by HEK‐293 cells and guinea pig ileum myenteric neurons in culture was studied using whole‐cell patch clamp techniques. Key Results In HEK‐293 cells expressing α3β4 nAChRs and P2X2 receptors, co‐application of ATP and acetylcholine caused inward currents that were 56 ± 7% of the current that should occur if these channels functioned independently (P < 0.05, n = 9); we call this interaction cross‐inhibition. Cross‐inhibition did not occur in HEK‐293 cells expressing α3β4 nAChRs and a C‐terminal tail truncated P2X2 receptor (P2X2TR) (P > 0.05, n = 8). Intracellular application of the C‐terminal tail of the P2X2 receptor blocked nAChR‐P2X receptor cross‐inhibition in HEK‐293 cells and myenteric neurons. In the absence of ATP, P2X2 receptors constitutively inhibited nAChR currents in HEK‐293 cells expressing both receptors. Constitutive inhibition did not occur in HEK‐293 cells expressing α3β4 nAChRs transfected with P2X2TR. Currents caused by low (≤30 μmol L^?1), but not high (≥100 μmol L^?1) concentrations of ATP in cells expressing P2X2 receptors were inhibited by co‐expression with α3β4 nAChRs. Conclusions & Inferences The C‐terminal tail of P2X2 receptors mediates cross‐inhibition between α3β4 nAChR‐P2X2 receptors. The closed state of P2X2 receptors and nAChRs can also cause cross‐inhibition. These interactions may modulate transmission at enteric synapses that use ATP and acetylcholine as co‐transmitters.     

An epilepsy‐associated ACTL6B variant captures neuronal hyperexcitability in a human induced pluripotent stem cell model

ACTL6B is a component of the neuronal BRG1/brm‐associated factor (nBAF) complex, which is required for chromatin remodeling in postmitotic neurons. We recently reported biallelic pathogenic variants in ACTL6B in patients diagnosed with early infantile epileptic encephalopathy, subtype 76 (EIEE‐76), presenting with severe, global developmental delay, epileptic encephalopathy, cerebral atrophy, and abnormal central nervous system myelination. However, the pathophysiological mechanisms underlying their phenotype is unknown. Here, we investigate the molecular pathogenesis of ACTL6B p.(Val421_Cys425del) using in silico 3D protein modeling predictions and patient‐specific induced pluripotent stem cell‐derived neurons. We found neurons derived from EIEE‐76 patients showed impaired accumulation of ACTL6B compared to unaffected relatives, caused by reduced protein stability. Furthermore, EIEE‐76 patient‐derived neurons had dysregulated nBAF target gene expression, including genes important for neuronal development and disease. Multielectrode array system analysis unveiled elevated electrophysiological activity of EIEE‐76 patients‐derived neurons, consistent with the patient phenotype. Taken together, our findings validate a new model for EIEE‐76 and reveal how reduced ACTL6B expression affects neuronal function.     

Familial paroxysmal exercise‐induced dystonia: atypical presentation of autosomal dominant GTP‐cyclohydrolase 1 deficiency

Paroxysmal exercise‐induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise‐induced dystonia. The dystonia began in childhood and was only ever induced after many minutes of exercise, and was never present at rest, or on initiation of movements. In addition, family members suffered restless legs syndrome (RLS), depression, and adult‐onset Parkinsonism. The index case had low cerebrospinal fluid neurotransmitters and pterins. The PED and RLS stopped on initiation of l ‐Dopa therapy. Both live family members were found to have a nonsense mutation (p.E84X) in exon 1 of the GTP‐cyclohydrolase 1 (GCH‐1) gene. We propose that GCH‐1 mutations should be considered a genetic cause of familial PED, especially if additional clinical features of monoaminergic deficiency are present in affected individuals.     

Mechanisms of status epilepticus: α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor hypothesis

Prolonged seizures of status epilepticus (SE) result from failure of mechanisms of seizure termination or activation of mechanisms that sustain seizures. Reduced γ‐aminobutyric acid type A receptor–mediated synaptic transmission contributes to impairment of seizure termination. However, mechanisms that sustain prolonged seizures are not known. We propose that insertion of GluA1 subunits at the glutamatergic synapses causes potentiation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic receptor (AMPAR)‐mediated neurotransmission, which helps to spread and sustain seizures. The AMPAR‐mediated neurotransmission of CA1 pyramidal neurons was increased in animals in SE induced by pilocarpine. The surface membrane expression of GluA1 subunit–containing AMPARs on CA1 pyramidal neurons was also increased. Blockade of N‐methyl‐d ‐aspartate receptors 10 minutes after the onset of continuous electrographic seizure activity prevented the increase in the surface expression of GluA1 subunits. N‐methyl‐d ‐aspartate receptor antagonist MK‐801 in conjunction with diazepam also terminated seizures that were refractory to MK‐801 or diazepam alone. Future studies using mice lacking the GluA1 subunit expression will provide further insights into the role of GluA1 subunit–containing AMPAR plasticity in sustaining seizures of SE.     

Parkinsonism without dopamine neuron degeneration in aged l‐dopa‐responsive dystonia knockin mice

Background : Recent neuroimaging studies implicate nigrostriatal degeneration as a critical factor in producing late‐onset parkinsonism in patients with l ‐dopa‐responsive dystonia‐causing mutations. However, postmortem anatomical studies do not reveal neurodegeneration in l ‐dopa‐responsive dystonia patients. These contrasting findings make it unclear how parkinsonism develops in l ‐dopa‐responsive dystonia mutation carriers. Methods : We prospectively assessed motor dysfunction, responses to dopaminergic challenge, and dopamine neuron degeneration with aging in a validated knockin mouse model bearing a l ‐dopa‐responsive dystonia‐causing mutation found in humans. Results : As l ‐dopa‐responsive dystonia mice aged, dystonic movements waned while locomotor activity decreased and initiation of movements slowed. Despite the age‐related reduction in movement, there was no evidence for degeneration of midbrain dopamine neurons. Presynaptically mediated dopaminergic responses did not change with age in l ‐dopa‐responsive dystonia mice, but responses to D1 dopamine receptor agonists decreased with age. Conclusions : We have demonstrated for the first time the co‐occurrence of dystonia and Parkinson's‐like features (mainly consisting of hypokinesia) in a genetic mouse model. In this model we show that these features evolve without dopaminergic neurodegeneration, suggesting that postsynaptic plasticity, rather than presynaptic degeneration, may contribute to the development of parkinsonism in patients with l ‐dopa‐responsive dystonia. © 2017 International Parkinson and Movement Disorder Society     

A homozygous loss‐of‐function mutation in PDE2A associated to early‐onset hereditary chorea

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.     

Dopa‐responsive dystonia presenting with prominent isolated bilateral resting leg tremor: Evidence for a role of parkin?

We report on a GTP cyclohydrolase 1 mutation‐confirmed case of dopa‐responsive dystonia who presented with an isolated parkinsonian rest tremor starting at the age of 15 years. There was no dystonia or other features of parkinsonism. Sequencing of the parkin gene demonstrated polymorphisms in a compound heterozygous state. The spectrum of unusual clinical presentations of dopa‐responsive dystonia is discussed. © 2003 Movement Disorder Society