Phenotypic spectrum and sex effects in eleven myoclonus‐dystonia families with ε‐sarcoglycan mutations

Myoclonus‐dystonia (M‐D) due to SGCE mutations is characterized by early onset myoclonic jerks, often associated with dystonia. Penetrance is influenced by parental sex, but other sex effects have not been established. In 42 affected individuals from 11 families with identified mutations, we found that sex was highly associated with age at onset regardless of mutation type; the median age onset for girls was 5 years versus 8 years for boys (P < 0.0097). We found no association between mutation type and phenotype. © 2007 Movement Disorder Society     

Myoclonus‐dystonia: An update

Our knowledge of the clinical, neurophysiological, and genetic aspects of myoclonus‐dystonia (M‐D) has improved markedly in the recent years. Basic research has provided new insights into the complex dysfunctions involved in the pathogenesis of M‐D. On the basis of a comprehensive literature search, this review summarizes current knowledge on M‐D, with a focus on recent findings. We also propose modified diagnostic criteria and recommendationsfor clinical management. © 2008 Movement Disorder Society     

Twenty years on: Myoclonus‐dystonia and ε‐sarcoglycan — neurodevelopment,channel, and signaling dysfunction

Myoclonus‐dystonia is a clinical syndrome characterized by a typical childhood onset of myoclonic jerks and dystonia involving the neck, trunk, and upper limbs. Psychiatric symptomatology, namely, alcohol dependence and phobic and obsessive‐compulsive disorder, is also part of the clinical picture. Zonisamide has demonstrated effectiveness at reducing both myoclonus and dystonia, and deep brain stimulation seems to be an effective and long‐lasting therapeutic option for medication‐refractory cases. In a subset of patients, myoclonus‐dystonia is associated with pathogenic variants in the epsilon‐sarcoglycan gene, located on chromosome 7q21, and up to now, more than 100 different pathogenic variants of the epsilon‐sarcoglycan gene have been described. In a few families with a clinical phenotype resembling myoclonus‐dystonia associated with distinct clinical features, variants have been identified in genes involved in novel pathways such as calcium channel regulation and neurodevelopment. Because of phenotypic similarities with epsilon‐sarcoglycan gene–related myoclonus‐dystonia, these conditions can be collectively classified as “myoclonus‐dystonia syndromes.” In the present article, we present myoclonus‐dystonia caused by epsilon‐sarcoglycan gene mutations, with a focus on genetics and underlying disease mechanisms. Second, we review those conditions falling within the spectrum of myoclonus‐dystonia syndromes, highlighting their genetic background and involved pathways. Finally, we critically discuss the normal and pathological function of the epsilon‐sarcoglycan gene and its product, suggesting a role in the stabilization of the dopaminergic membrane via regulation of calcium homeostasis and in the neurodevelopmental process involving the cerebello‐thalamo‐pallido‐cortical network. © 2019 International Parkinson and Movement Disorder Society     

“Jerky” dystonia in children: Spectrum of phenotypes and genetic testing

Hyperkinetic dystonia is characterized by phasic, tremulous, and “jerky” movements in addition to twisting postures. We studied longitudinally 23 index patients with hyperkinetic dystonia from a quaternary pediatric movement disorder clinic in Ireland. Four clinical categories emerged: (1) Eight patients were diagnosed with myoclonus‐dystonia, of whom seven carried heterozygous epsilon sarcoglycan (SGCE) mutations, including a novel deletion of exon 10. Gait disorder, unsteadiness, or frequent falls before 18 months were detected in all SGCE mutation carriers, whereas the typical neck‐predominant presentation developed only years later. (2) One patient classified as benign hereditary chorea, because jerks were choreiform and continuous rather than action‐induced, carried a heterozygous stop mutation of the TITF‐1 gene (Y114X, exon 2). (3) Three mutation‐negative patients were grouped as “myoclonic dystonia” with jerks only in the body regions affected by dystonia. (4) Eleven patients presented with a novel combination of dystonia and low amplitude poly‐mini myoclonus of the upper limbs and pectoral muscles (D‐PMM). In early childhood up to 3 years of age, an initial presentation with predominant gait impairment with only subtle jerks should prompt consideration of SGCE mutation analysis in addition to testing for DYT1 mutations. A causative gene for D‐PMM remains to be identified. © 2008 Movement Disorder Society     

A novel mutation of the ε‐sarcoglycan gene in a Chinese family with myoclonus‐dystonia syndrome

In a Chinese myoclonus‐dystonia syndrome (MDS) family presented with a phenotype including a typical MDS, cervical dystonia, and writer's cramp, genetic analyses revealed a novel 662 + 1insG heterozygous mutation in exon 5 in the ε‐sarcoglycan (SGCE) gene, leading to a frameshift with a down stream stop codon. Low SGCE mRNA levels were detected in the mutation carriers by real‐time PCR, suggesting that the nonsense mutation might interference with the stability of SGCE mRNA. This is the first report on Chinese with a SGCE mutation leading to MDS. Our data support the fact that same mutation of SGCE gene can lead to a varied phenotype, even in the same family. © 2008 Movement Disorder Society     

A neurophysiological study of myoclonus in patients with DYT11 myoclonus‐dystonia syndrome

Mutations in the ?‐sarcoglycan (SGCE) gene have been associated with DYT11 myoclonus‐dystonia syndrome (MDS). The aim of this study was to characterize myoclonus in 9 patients with DYT11‐MDS presenting with predominant myoclonus and mild dystonia by means of neurophysiological techniques. Variously severe multifocal myoclonus occurred in all of the patients, and included short (mean 89.1 ± 13.3 milliseconds) electromyographic bursts without any electroencephalographic correlate, sometimes presenting a pseudo‐rhythmic course. Massive jerks could be evoked by sudden stimuli in 5 patients, showing a “startle‐like” muscle spreading and latencies consistent with a brainstem origin. Somatosensory evoked potentials and long‐loop reflexes were normal, as was silent period and long‐term intracortical inhibition evaluated by means of transcranial magnetic stimulation; however, short‐term intracortical inhibition revealed subtle impairment, and event‐related synchronization (ERS) in the beta band was delayed. Blink reflex recovery was strongly enhanced. Myoclonus in DYT11‐MDS seems to be generated at subcortical level, and possibly involves basal ganglia and brainstem circuitries. Cortical impairment may depend from subcortical dysfunction, but it can also have a role in influencing the myoclonic presentation. The wide distribution of the defective SCGE in DYT11‐MDS may justify the involvement of different brain areas. © 2008 Movement Disorder Society     

Evaluation of a computer‐adaptive test for the assessment of depression (D‐CAT) in clinical application

In the past, a German Computerized Adaptive Test, based on Item Response Theory (IRT), was developed for purposes of assessing the construct depression [Computer‐adaptive test for depression (D‐CAT)]. This study aims at testing the feasibility and validity of the real computer‐adaptive application. The D‐CAT, supplied by a bank of 64 items, was administered on personal digital assistants (PDAs) to 423 consecutive patients suffering from psychosomatic and other medical conditions (78 with depression). Items were adaptively administered until a predetermined reliability (r ≥ 0.90) was attained. For validation purposes, the Hospital Anxiety and Depression Scale (HADS), the Centre for Epidemiological Studies Depression (CES‐D) scale, and the Beck Depression Inventory (BDI) were administered. Another sample of 114 patients was evaluated using standardized diagnostic interviews [Composite International Diagnostic Interview (CIDI)]. The D‐CAT was quickly completed (mean 74 seconds), well accepted by the patients and reliable after an average administration of only six items. In 95% of the cases, 10 items or less were needed for a reliable score estimate. Correlations between the D‐CAT and the HADS, CES‐D, and BDI ranged between r = 0.68 and r = 0.77. The D‐CAT distinguished between diagnostic groups as well as established questionnaires do. The D‐CAT proved an efficient, well accepted and reliable tool. Discriminative power was comparable to other depression measures, whereby the CAT is shorter and more precise. Item usage raises questions of balancing the item selection for content in the future. Copyright © 2009 John Wiley & Sons, Ltd.     

A novel missense mutation in GTP cyclohydrolase I (GCH1) gene causes dopa‐responsive dystonia in Chinese Han population

Background: Dopa‐responsive dystonia has been shown to be caused by a number of different mutations in the GCH1 gene. Up to now, only several genetic studies of Chinese patients with Dopa‐responsive dystonia (DRD) have been reported. Methods: We performed a genetic analysis by amplifying the entire coding region of GCH1 gene and direct sequencing in four DRD families from mainland China. Results: A novel missense mutation, Gly155Ser, has been identified in a sporadic case from a consanguineous marriage family. Furthermore, two known mutations, Met137Arg and Gly203Arg, have also been detected in the other families. Conclusions: A novel missense mutation in the GCH1 gene can be associated with DRD. Our findings further expanded the mutational spectrum of GCH1 gene associated with DRD.     

Genetic labeling of steroidogenic factor‐1 (SF‐1) neurons in mice reveals ventromedial nucleus of the hypothalamus (VMH) circuitry beginning at neurogenesis and development of a separate non‐SF‐1 neuronal cluster in the ventrolateral VMH

The ventromedial nucleus of the hypothalamus (VMH) influences a wide variety of physiological responses. Here, using two distinct but complementary genetic tracing approaches in mice, we describe the development of VMH efferent projections, as marked by steroidogenic factor‐1 (SF‐1; NR5A1). SF‐1 neurons were visualized by Tau‐green fluorescent protein (GFP) expressed from the endogenous Sf‐1 locus (Sf‐1^TauGFP) or by crossing the transgenic Sf1:Cre driver to a GFP reporter strain (Z/EG^Sf1:Cre). Strikingly, VMH projections were visible early, at embryonic (E) 10.5, when few postmitotic SF1 neurons have been born, suggesting that formation of VMH circuitry begins at the onset of neurogenesis. At E14.5, comparison of these two reporter lines revealed that SF1‐positive neurons in the ventrolateral VMH (VMH_vl) persist in Z/EG^Sf1:Cre embryos but are virtually absent in Sf‐1^TauGFP. Therefore, although the entire VMH including the VMH_vl shares a common lineage, the VMH_vl further differentiates into a neuronal cluster devoid of SF‐1. At birth, extensive VMH projections to broad regions of the brain were observed in both mouse reporter lines, matching well with those previously discovered by injection of axonal anterograde tracers in adult rats. In summary, our genetic tracing studies show that VMH efferent projections are highly conserved in rodents and are established far earlier than previously appreciated. Moreover, our results imply that neurons in the VMH_vl adopt a distinct fate early in development, which might underlie the unique physiological functions associated with this VMH subregion. J. Comp. Neurol., 521:1268–1288, 2013. © 2012 Wiley Periodicals, Inc.     

Neuropathologic assessment of participants in two multi‐center longitudinal observational studies: The Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN)

It has been hypothesized that the relatively rare autosomal dominant Alzheimer disease (ADAD) may be a useful model of the more frequent, sporadic, late‐onset AD (LOAD). Individuals with ADAD have a predictable age at onset and the biomarker profile of ADAD participants in the preclinical stage may be used to predict disease progression and clinical onset. However, the extent to which the pathogenesis and neuropathology of ADAD overlaps with that of LOAD is equivocal. To address this uncertainty, two multicenter longitudinal observational studies, the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN), leveraged the expertise and resources of the existing Knight Alzheimer Disease Research Center (ADRC) at Washington University School of Medicine, St. Louis, Missouri, USA, to establish a Neuropathology Core (NPC). The ADNI/DIAN‐NPC is systematically examining the brains of all participants who come to autopsy at the 59 ADNI sites in the USA and Canada and the 14 DIAN sites in the USA (eight), Australia (three), UK (one) and Germany (two). By 2014, 41 ADNI and 24 DIAN autopsies (involving nine participants and 15 family members) had been performed. The autopsy rate in the ADNI cohort in the most recent year was 93% (total since NPC inception: 70%). In summary, the ADNI/DIAN NPC has implemented a standard protocol for all sites to solicit permission for brain autopsy and to send brain tissue to the NPC for a standardized, uniform and state‐of‐the‐art neuropathologic assessment. The benefit to ADNI and DIAN of the implementation of the NPC is very clear. The NPC provides final “gold standard” neuropathological diagnoses and data against which the antecedent observations and measurements of ADNI and DIAN can be compared.     

Genetic epidemiology,demographic, and clinical characteristics of Charcot‐Marie‐tooth disease in the island of Gran Canaria (Spain)

Charcot‐Marie‐Tooth (CMT) disease is the most common hereditary neuromuscular disorder. This study involves the entire known CMT patient registry in Gran Canaria, represented by 256 patients belonging to 79 unrelated families, who were clinically and genetically characterized, along with physical and neurophysiological evaluation on 181 and 165 patients, respectively. Complete genotyping showed an estimated prevalence of CMT disease of 30.08/100 000 (95% confidence interval [CI] = 26.5;33.9), corresponding mainly (78.5%) to CMT1A (23.6/100 000) and hereditary neuropathy with liability to pressure palsies [HNPP] 17.5%; 5.29/100 000). Most patients (198) with CMT1A carried the 17p11.2 duplication including the PMP22 gene, 45 patients with HNPP were all affected by deletion of the 17p11.2 locus, and 10 patients presented with axonal phenotypes: CMT2A (MFN2), CMT2N (AARS), and CMT1X (GJB1). Despite showing a classical CMT1A phenotype, we found a much earlier age of onset in our CMT1A patients, along with increased frequency of appearance of postural hand tremor. Bilateral tongue atrophy was an additional phenotype observed. Being this CMT1A group, one of the largest cohorts known to date, this study provided a unique opportunity to further define the clinical phenotype of CMT1A patients carrying the 17p11.2 duplication in a homogeneous ethnic group.     

Deletion of Cav2.1(α1A) subunit of Ca2+‐channels impairs synaptic GABA and glutamate release in the mouse cerebellar cortex in cultured slices

Deletion of both alleles of the P/Q‐type Ca²⁺‐channel Ca_v2.1(α_1A) subunit gene in mouse leads to severe ataxia and early death. Using cerebellar slices obtained from 10 to 15 postnatal days mice and cultured for at least 3 weeks in vitro, we have analysed the synaptic alterations produced by genetically ablating the P/Q‐type Ca²⁺‐channels, and compared them with the effect of pharmacological inhibition of the P/Q‐ or N‐type channels on wild‐type littermate mice. Analysis of spontaneous synaptic currents recorded in Purkinje cells (PCs) indicated that the P/Q‐type channels play a prominent role at the inhibitory synapses afferent onto the PCs, with the effect of deleting Ca_v2.1(α_1A) partially compensated. At the granule cell (GC) to PC synapses, both N‐ and P/Q‐type Ca²⁺‐channels were found playing a role in glutamate exocytosis, but with no significant phenotypic compensation of the Ca_v2.1(α_1A) deletion. We also found that the P/Q‐ but not N‐type Ca²⁺‐channel is indispensable at the autaptic contacts between PCs. Tuning of the GC activity implicates both synaptic and sustained extrasynaptic γ‐aminobutyric acid (GABA) release, only the former was greatly impaired in the absence of P/Q‐type Ca²⁺‐channels. Overall, our data demonstrate that both P/Q‐ and N‐type Ca²⁺‐channels play a role in glutamate release, while the P/Q‐type is essential in GABA exocytosis in the cerebellum. Contrary to the other regions of the CNS, the effect of deleting the Ca_v2.1(α_1A) subunit is partially or not compensated at the inhibitory synapses. This may explain why cerebellar ataxia is observed at the mice lacking functional P/Q‐type channels.     

Independent component analysis (ICA) of generalized spike wave discharges in fMRI: Comparison with general linear model‐based EEG‐fMRI

Most EEG‐fMRI studies in epileptic patients are analyzed using the general linear model (GLM), which assumes a known hemodynamic response function (HRF) to epileptic spikes. In contrast, independent component analysis (ICA) can extract blood‐oxygenation level dependent (BOLD) responses without imposing constraints on the HRF. ICA might therefore detect responses that vary in time and shape, and that are not detected in the GLM analysis. In this study, we compared the findings of ICA and GLM analyses in 12 patients with idiopathic generalized epilepsy. Spatial ICA was used to extract independent components from the functional magnetic resonance imaging (fMRI) data. A deconvolution method identified component time courses significantly related to the generalized EEG discharges, without constraining the shape of the HRF. The results from the ICA analysis were compared to those from the GLM analysis. GLM maps and ICA maps showed significant correlation and revealed BOLD responses in the thalamus, caudate nucleus, and default mode areas. In patients with a low rate of discharges per minute, the GLM analysis detected BOLD signal changes within the thalamus and the caudate nucleus that were not revealed by the ICA. In conclusion, ICA is a viable alternative technique to GLM analyses in EEG‐fMRI studies related to generalized discharges. This study demonstrated that the BOLD response largely resembles the standard HRF and that GLM analysis is adequate. However, ICA is more dependent on a sufficient number of events than GLM analysis. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.     

The stressed brain: regional and stress‐related corticosterone and stress‐regulated gene expression in the adult zebra finch (Taeniopygia guttata)

Glucocorticoids (CORT) are well‐known as important regulators of behaviour and cognition at basal levels and under stress. However, the precise mechanisms governing CORT action and functional outcomes of this action in the brain remain unclear, particularly in model systems other than rodents. In the present study, we investigated the dynamics of CORT regulation in the zebra finch, an important model system for vocal learning, neuroplasticity and cognition. We tested the hypothesis that CORT is locally regulated in the zebra finch brain by quantifying regional and stress‐related variation in total CORT across brain regions. In addition, we used an ex vivo slice culture system to test whether CORT regulates target gene expression uniquely in discrete regions of the brain. We documented a robust increase in brain CORT across regions after 30 minutes of restraint stress but, interestingly, baseline and stress‐induced CORT levels varied between regions. In addition, CORT treatment of brain slice cultures differentially affected expression of three CORT target genes: it up‐regulated expression of FKBP5 in most regions and SGK1 in the hypothalamus only, whereas GILZ was unaffected by CORT treatment across all brain regions investigated. The specific mechanisms producing regional variation in CORT and CORT‐dependent downstream gene expression remain unknown, although these data provide additional support for the hypothesis that the songbird brain employs regulatory mechanisms that result in precise control over the influence of CORT on glucocorticoid‐sensitive neural circuits.     

Searching for cognitive enhancement in the Morris water maze: better and worse performance in D‐amino acid oxidase knockout (Dao−/−) mice

A common strategy when searching for cognitive‐enhancing drugs has been to target the N‐methyl‐d ‐aspartate receptor (NMDAR), given its putative role in synaptic plasticity and learning. Evidence in favour of this approach has come primarily from studies with rodents using behavioural assays like the Morris water maze. D‐amino acid oxidase (DAO) degrades neutral D‐amino acids such as D‐serine, the primary endogenous co‐agonist acting at the glycine site of the synaptic NMDAR. Inhibiting DAO could therefore provide an effective and viable means of enhancing cognition, particularly in disorders like schizophrenia, in which NMDAR hypofunction is implicated. Indirect support for this notion comes from the enhanced hippocampal long‐term potentiation and facilitated water maze acquisition of ddY/Dao⁻ mice, which lack DAO activity due to a point mutation in the gene. Here, in Dao knockout (Dao^−/−) mice, we report both better and worse water maze performance, depending on the radial distance of the hidden platform from the side wall of the pool. Dao^−/− mice displayed an increased innate preference for swimming in the periphery of the maze (possibly due to heightened anxiety), which facilitated the discovery of a peripherally located platform, but delayed the discovery of a centrally located platform. By contrast, Dao^−/− mice exhibited normal performance in two alternative assays of long‐term spatial memory: the appetitive and aversive Y‐maze reference memory tasks. Taken together, these results question the proposed relationship between DAO inactivation and enhanced long‐term associative spatial memory. They also have generic implications for how Morris water maze studies are performed and interpreted.