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Eur J Med Genet 2021 Jan 25;64(1):104117. Epub 2020 Nov 25.

Katip Çelebi University Medical Faculty, Department of Pediatrics, Division of Inborn Errors of Metabolism, Turkey.

VAC14 related childhood-onset striatonigral degeneration was first defined in 2016 in two unrelated children with sudden onset neurological disease and regression of developmental milestones. Up to now, 11 cases have been reported. VAC14 is a component of a trimolecular complex that tightly regulates the level of phosphatidylinositol 3,5-bisphosphate (PI (3, 5)P2) and PI (3, 5)P2 is critical for the survival of neural cells. Read More

Mov Disord 2021 03 6;36(3):632-641. Epub 2020 Nov 6.

Department of Clinical and Movement Neurosciences, Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, United Kingdom.

Background: Despite the considerable overlap with atypical parkinsonism, a systematic characterization of the movement disorders associated with frontotemporal lobar degeneration (FTLD) is lacking.

Objective: The aim of this study is to provide a detailed description of the phenomenology and neuropathologic correlations of movement disorders in FTLD.

Methods: In this cohort study, movement disorder clinical data were retrospectively collected from medical records of consecutive patients with a postmortem diagnosis of FTLD from the Queen Square Brain Bank between January 2010 and December 2018. Read More

Rev Neurol (Paris) 2020 May 1;176(5):353-360. Epub 2020 Apr 1.

Division of Human Pathology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan.

Progressive supranuclear palsy - Richardson syndrome (PSP-RS) was first described in 1964 by Steele et al. Tau pathology has not been reported in the hypoglossal nuclei of PSP-RS patients, whereas Steele et al. described gliosis with no remarkable neuronal losses in the hypoglossal nucleus. Read More

J Neural Transm (Vienna) 2020 02 17;127(2):205-212. Epub 2020 Feb 17.

Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder characterized by striatonigral degeneration and olivopontocerebellar atrophy. The main hallmark of MSA is the aggregation of alpha-synuclein in oligodendrocytes, which contributes to the dysfunction and death of the oligodendrocytes, followed by neurodegeneration. Studies suggested that oxidative-excitatory pathway is associated with the progression of the disease. Read More

Parkinsonism Relat Disord 2020 04 23;73:94-104. Epub 2020 Jan 23.

Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Austria. Electronic address:

Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder characterized by rapidly progressive autonomic and motor dysfunction. Pathologically, MSA is mainly characterized by the abnormal accumulation of misfolded α-synuclein in the cytoplasm of oligodendrocytes, which plays a major role in the pathogenesis of the disease. Striatonigral degeneration and olivopontecerebellar atrophy underlie the motor syndrome, while degeneration of autonomic centers defines the autonomic failure in MSA. Read More

Mol Genet Genomic Med 2020 02 26;8(2):e1101. Epub 2019 Dec 26.

Department of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, China.

Background: VAC14 is a component of a trimolecular complex that tightly regulates the level of phosphatidylinositol 3,5-bisphosphate [PI (3,5) P2]. VAC14 pathogenic variants cause prominent vacuolation of neurons in basal ganglia of patients with childhood-onset striatonigral degeneration (SNDC).

Methods: We identified two siblings with SNDC. Read More

Acta Neuropathol Commun 2019 12 23;7(1):219. Epub 2019 Dec 23.

Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.

Synucleinopathies are mostly sporadic neurodegenerative disorders of partly unexplained aetiology, and include Parkinson's disease (PD) and multiple system atrophy (MSA). We have further investigated our recent finding of somatic SNCA (α-synuclein) copy number variants (CNVs, specifically gains) in synucleinopathies, using Fluorescent in-situ Hybridisation for SNCA, and single-cell whole genome sequencing for the first time in a synucleinopathy. In the cingulate cortex, mosaicism levels for SNCA gains were higher in MSA and PD than controls in neurons (> 2% in both diseases), and for MSA also in non-neurons. Read More

Mov Disord Clin Pract 2019 Nov 6;6(8):661-666. Epub 2019 Sep 6.

Department of Pathology Columbia University Medical Center New York New York USA.

Background: The pathological hallmark in MSA is oligodendrocytic glial cytoplasmic inclusions (GCIs) containing α-synuclein, in addition to neuronal loss and astrogliosis especially involving the striatonigral and olivopontocerebellar systems. Rarely, TAR DNA-binding protein of 43 kDa (TDP-43), a component of ubiquitinated inclusions observed mainly in amyotrophic lateral sclerosis and frontotemporal lobar degeneration has been demonstrated in cases of MSA and, more recently, was shown to colocalize with α-synuclein pathology in GCIs in 2 patients.

Methods: A 66-year-old woman presented with a syndrome characterized by spasticity, dysautonomia, bulbar dysfunction, and parkinsonism. Read More

J Parkinsons Dis 2020 ;10(1):123-130

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Both Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative disorder affecting striatonigral system. Although various lines of evidence demonstrate that dopaminergic neuron degeneration emerges before the onset of motor symptoms in PD, preclinical/prodromal progression of neurodegeneration is far less understood in MSA.

Objective: The aim of this study was to clarify the difference in the progression of dopaminergic degeneration in MSA and PD using dopamine transporter single-photon emission computed tomography (DAT SPECT). Read More

Br J Pharmacol 2020 01 3;177(1):28-47. Epub 2020 Jan 3.

Department of Medical Sciences, Section of Pharmacology, University of Ferrara and National Institute of Neuroscience, Ferrara, Italy.

The opioid-like neuropeptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP receptor) contribute to Parkinson's disease (PD) and motor complications associated with levodopa therapy. The N/OFQ-NOP receptor system is expressed in cortical and subcortical motor areas and, notably, in dopaminergic neurons of the substantia nigra compacta. Dopamine depletion, as in rodent models of PD results in up-regulation of N/OFQ transmission in the substantia nigra and down-regulation of N/OFQ transmission in the striatum. Read More

Parkinsonism Relat Disord 2020 04 10;73:85-93. Epub 2019 Oct 10.

Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford University, 300 Pasteur Dr. Room A343. MC-5235, Stanford, CA, 94305, USA. Electronic address:

Parkinson's disease is a heterogeneous disorder with both motor and non-motor symptoms that contribute to functional impairment. To develop effective, disease modifying treatments for these symptoms, biomarkers are necessary to detect neuropathological changes early in the disease course and monitor changes over time. Advances in MRI scan sequences and analytical techniques present numerous promising metrics to detect changes within the nigrostriatal system, implicated in the cardinal motor symptoms of the disease, and detect broader dysfunction involved in the non-motor symptoms, such as cognitive impairment. Read More

J Hum Genet 2019 Dec 8;64(12):1237-1242. Epub 2019 Oct 8.

Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.

VAC14-related disorders include two distinct phenotypes, striatonigral degeneration [MIM# 617054] and Yunis-Varon syndrome. Striatonigral degeneration is a recently described childhood onset dystonia caused by pathogenic variants in VAC14. It is characterized by a period of apparent normalcy followed by abrupt onset neuroregression, dystonia, involuntary movements and degenerative brain lesions involving caudate nucleus, putamen and substantia nigra. Read More

Acta Neuropathol 2020 01 18;139(1):135-156. Epub 2019 Sep 18.

The Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK.

Multiple system atrophy (MSA) is a fatal late-onset neurodegenerative disease. Although presenting with distinct pathological hallmarks, which in MSA consist of glial cytoplasmic inclusions (GCIs) containing fibrillar α-synuclein in oligodendrocytes, both MSA and Parkinson's disease are α-synucleinopathies. Pathologically, MSA can be categorized into striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA) or mixed subtypes. Read More

Cold Spring Harb Mol Case Stud 2019 12 13;5(6). Epub 2019 Dec 13.

NYS Institute for Basic Research in Developmental Disabilities (IBR), Staten Island, New York 10314, USA.

Whole-exome sequencing was used to identify the genetic etiology of a rapidly progressing neurological disease present in two of six siblings with early childhood onset of severe progressive spastic paraparesis and learning disabilities. A homozygous mutation (c.2005G>T, p, V669L) was found in , and the clinical phenotype is consistent with the recently described -related striatonigral degeneration, childhood-onset syndrome (SNDC) (MIM#617054). Read More

Mov Disord 2019 07;34(7):1085-1086

Department of Neurology and Movement Disorder Center, College of Medicine, Seoul National University, Seoul, Korea.

Front Neurosci 2019 11;13:590. Epub 2019 Jun 11.

Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.

Cerebral dopamine neurotrophic factor (CDNF) has shown therapeutic potential in rodent and non-human primate models of Parkinson's disease by protecting the dopamine neurons from degeneration and even restoring their phenotype and function. Previously, neurorestorative efficacy of CDNF in the 6-hydroxydopamine (6-OHDA) model of Parkinson's disease as well as diffusion of the protein in the striatum (STR) has been demonstrated and studied. Here, experiments were performed to characterize the diffusion and transport of supra-nigral CDNF in non-lesioned rats. Read More

PLoS One 2019 10;14(6):e0218130. Epub 2019 Jun 10.

Division of Neurobiology, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.

Background: Unresponsiveness to dopaminergic therapies is a key feature in the diagnosis of multiple system atrophy (MSA) and a major unmet need in the treatment of MSA patients caused by combined striatonigral degeneration (SND). Transgenic, alpha-synuclein animal models do not recapitulate this lack of levodopa responsiveness. In order to preclinically study interventions including striatal cell grafts, models that feature SND are required. Read More

Br J Pharmacol 2019 07 21;176(13):2146-2161. Epub 2019 May 21.

Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Madrid, Spain.

Background And Purpose: L-DOPA-induced dyskinesia (LID) remains a major complication of L-DOPA therapy in Parkinson's disease. LID is believed to result from inhibition of substantia nigra reticulata (SNr) neurons by GABAergic striatal projection neurons that become supersensitive to dopamine receptor stimulation after severe nigrostriatal degeneration. Here, we asked if stimulation of direct medium spiny neuron (dMSN) GABAergic terminals at the SNr can produce a full dyskinetic state similar to that induced by L-DOPA. Read More

Mol Genet Metab 2019 03 5;126(3):250-258. Epub 2019 Jan 5.

Department of Child Neurology, Hospital Vall d'Hebron - Institut de Recerca (VHIR), Barcelona, Spain; CIBERER, Centro de Investigaciones Biomédicas en Red de Enfermedades Raras, Madrid, Spain; Faculty of Medicine, Universitat Autónoma de Barcelona, Unitat Docent Vall d'Hebrón, Spain. Electronic address:

Aim: To perform a deep phenotype characterisation in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations.

Method: A multi-gene panel of childhood-onset basal ganglia neurodegeneration inherited conditions was analysed followed by functional studies in fibroblasts.

Results: Three siblings developed gait dystonia in infancy followed by rapid progression to generalised dystonia and psychomotor regression. Read More

Mol Genet Genomic Med 2019 03 8;7(3):e541. Epub 2019 Jan 8.

Department of Neurology, Peking University People's Hospital, Beijing, China.

Background: Heteroplasmic mitochondrial 3697G>A mutation has been associated with leber hereditary optic neuropathy (LHON), mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and LHON/MELAS overlap syndrome. However, homoplasmic m.3697G>A mutation was only found in a family with Leigh syndrome, and the phenotype and pathogenicity of this homoplasmic mutation still need to be investigated in new patients. Read More

Gene Ther 2019 02 7;26(1-2):57-64. Epub 2018 Dec 7.

CNS Gene Therapy, Department of Experimental Medical Science, Lund University, Lund, Sweden.

Glial cell-line derived neurotrophic factor (GDNF) is a promising therapeutic molecule to treat Parkinson's disease. Despite an excellent profile in experimental settings, clinical trials testing GDNF have failed. One of the theories to explain these negative outcomes is that the clinical trials were done in late-stage patients that have advanced nigrostriatal degeneration and may therefore not respond to a neurotrophic factor therapy. Read More

Parkinsonism Relat Disord 2019 04 15;61:170-178. Epub 2018 Oct 15.

Department of Neurology, University of Luebeck, Luebeck, Germany. Electronic address:

Background: X-linked dystonia-parkinsonism (XDP) is characterized by the unique transition of dystonia to parkinsonism and striatal degeneration. Slowing of saccades on clinical examination has been taken as suggestive of a progressive supranuclear palsy (PSP) phenotype.

Objectives: To elucidate whether eye movement abnormalities in XDP patients reflect striatonigral impairment or deficits in the brainstem saccade generator as present in PSP. Read More

Mov Disord 2018 07;33(7):1099-1107

University College London (UCL) Institute of Neurology, London, UK.

Background: The onset of multiple system atrophy (MSA) before age 40 years is referred to as "young-onset MSA." We identified clinical and pathological characteristics that might help with its early diagnosis and distinction from young-onset Parkinson's disease and late-onset MSA.

Methods: We reviewed the available clinical and pathological features in cases that fulfilled consensus criteria for diagnosis of probable MSA or had autopsy confirmed MSA with an onset before age 40 years and compared the clinical features with 16 autopsy confirmed cases with young-onset Parkinson's disease and a large published series of late-onset MSA from the European MSA Study Group. Read More

J Neuroinflammation 2018 Aug 13;15(1):227. Epub 2018 Aug 13.

Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: The first pathology observed in Parkinson's disease (PD) is 'dying back' of striatal dopaminergic (DA) terminals. Connexin (Cx)30, an astrocytic gap junction protein, is upregulated in the striatum in PD, but its roles in neurodegeneration remain elusive. We investigated Cx30 function in an acute PD model by administering 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to wild-type (WT) and Cx30 knockout (KO) mice. Read More

Sci Rep 2018 07 3;8(1):10068. Epub 2018 Jul 3.

Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.

Dendritic regression of striatal spiny projection neurons (SPNs) is a pathological hallmark of Parkinson's disease (PD). Here we investigate how chronic dopamine denervation and dopamine replacement with L-DOPA affect the morphology and physiology of direct pathway SPNs (dSPNS) in the rat striatum. We used a lentiviral vector optimized for retrograde labeling (FuG-B-GFP) to identify dSPNs in rats with 6-hydroxydopamine (6-OHDA) lesions. Read More

J Neuropathol Exp Neurol 2018 07;77(7):598-607

Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease characterized by aggregation of α-synuclein in oligodendrocytes to form glial cytoplasmic inclusions. According to the distribution of neurodegeneration, MSA is subtyped as striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), or as combination of these 2 (mixed MSA). In the current study, we aimed to investigate regional microglial populations and gene expression in the 3 different MSA subtypes. Read More

J Neurol 2018 Jul 25;265(7):1540-1547. Epub 2018 Apr 25.

Department of Neurology, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Beomo-ri, Mulgum-eup, Yangsan, Gyeongsangnam-do, 626-770, Republic of Korea.

Objective: The variability of the severity and regional distribution of pathological process in basal ganglia (BG) and brainstem-cerebellar systems results in clinical heterogeneity and represents the motor subtype of multiple system atrophy (MSA). This study aimed to quantify spatial patterns of multimodal MRI abnormalities in BG and stem-CB regions and define structural MRI findings that correlate with clinical characteristics.

Methods: We simultaneously measured R2*, mean diffusivity (MD), and volume in the subcortical structures (BG, thalamus, brainstem-cerebellar regions) of 39 probable MSA and 22 control subjects. Read More

Br J Dermatol 2018 08 29;179(2):509-511. Epub 2018 May 29.

Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Acta Neurol Scand 2018 Aug 24;138(2):170-176. Epub 2018 Mar 24.

Department of Neurology & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.

Objectives: To investigate the differences in the pattern of striatal (caudate and putamen) dopamine transporter (DAT) loss in a multiple system atrophy (MSA) cohort, based on the clinical variants parkinsonian subtype (MSA-P) and cerebellar subtype (MSA-C) via (11)C-N-2-carbomethoxy-3-(4-fluorophenyl)-tropane ( C-CFT) positron emission tomography (PET) imaging.

Materials And Methods: One hundred and six subjects (forty-one patients with probable MSA-P; forty patients with probable MSA-C; twenty-five healthy controls) underwent C-CFT PET. Subregional C-CFT uptake of bilateral caudate, anterior putamen, and posterior putamen was calculated respectively to measure the striatal dopaminergic function. Read More