Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Neurology
Published in: Journal of Neurology 12/2021

01-12-2021 | Opioids | Review

Spinocerebellar ataxia type 23 (SCA23): a review

Authors: Fan Wu, Xu Wang, Xiaohan Li, Huidi Teng, Tao Tian, Jing Bai

Published in: Journal of Neurology | Issue 12/2021

Login to get access

Abstract

Spinocerebellar ataxias (SCAs), formerly known as autosomal dominant cerebellar ataxias (ADCAs), are a group of hereditary heterogeneous neurodegenerative diseases. Gait, progressive ataxia, dysarthria, and eye movement disorder are common symptoms of spinocerebellar ataxias. Other symptoms include peripheral neuropathy, cognitive impairment, psychosis, and seizures. Patients may lose their lives due to out of coordinated respiration and/or swallowing. Neurological signs cover pyramidal or extrapyramidal signs, spasm, ophthalmoplegia, hyperactive deep tendon reflexes, and so on. Different subtypes of SCAs present various clinical features. Spinocerebellar ataxia type 23 (SCA23), one subtype of the SCA family, is characterized by mutant prodynorphin (PDYN) gene. Based on literatures, this review details a series of SCA23, to improve a whole understanding of clinicians and point out the potential research direction of this dysfunction, including a history, pathophysiological mechanism, diagnosis and differential diagnosis, epigenetics, penetrance and prevalence, genetic counseling, treatment and prognosis.
Literature
1.
Harding AE (1983) Classification of the hereditary ataxias and paraplegias. Lancet 1(8334):1151–1155PubMedCrossRef
2.
Sullivan R, Yau WY, O’Connor E, Houlden H (2019) Spinocerebellar ataxia: an update. J Neurol 266(2):533–544PubMedCrossRef
3.
Paulson HL, Shakkottai VG, Clark HB, Orr HT (2017) Polyglutamine spinocerebellar ataxias—from genes to potential treatments. Nat Rev Neurosci 18(10):613–626PubMedPubMedCentralCrossRef
4.
5.
6.
Yuan Y, Zhou X, Ding F, Liu Y, Tu J (2010) Molecular genetic analysis of a new form of spinocerebellar ataxia in a Chinese Han family. Neurosci Lett 479(3):321–326PubMedCrossRef
7.
Urbanek MO, Krzyzosiak WJ (2016) RNA FISH for detecting expanded repeats in human diseases. Methods 98:115–123PubMedCrossRef
8.
Johnson JO, Stevanin G, van de Leemput J, Hernandez DG, Arepalli S, Forlani S et al (2015) A 7.5-Mb duplication at chromosome 11q21–11q22.3 is associated with a novel spastic ataxia syndrome. Mov Disord 30(2):262–266PubMedCrossRef
9.
Trott A, Houenou LJ (2012) Mini-review: spinocerebellar ataxias: an update of SCA genes. Recent Pat DNA Gene Seq 6(2):115–121PubMedCrossRef
10.
Verbeek DS, van de Warrenburg BP, Wesseling P, Pearson PL, Kremer HP, Sinke RJ (2004) Mapping of the SCA23 locus involved in autosomal dominant cerebellar ataxia to chromosome region 20p13–12.3. Brain 127(Pt 11):2551–2557PubMedCrossRef
11.
Bakalkin G, Watanabe H, Jezierska J, Depoorter C, Verschuuren-Bemelmans C, Bazov I et al (2010) Prodynorphin mutations cause the neurodegenerative disorder spinocerebellar ataxia type 23. Am J Hum Genet 87(5):593–603PubMedPubMedCentralCrossRef
12.
Fawcett K, Mehrabian M, Liu YT, Hamed S, Elahi E, Revesz T et al (2013) The frequency of spinocerebellar ataxia type 23 in a UK population. J Neurol 260(3):856–859PubMedCrossRef
13.
Liu YT, Tang BS, Wang JL, Guan WJ, Shen L, Shi YT et al (2012) Spinocerebellar ataxia type 23 is an uncommon SCA subtype in the Chinese Han population. Neurosci Lett 528(1):51–54PubMedCrossRef
14.
Jezierska J, Stevanin G, Watanabe H, Fokkens MR, Zagnoli F, Kok J et al (2013) Identification and characterization of novel PDYN mutations in dominant cerebellar ataxia cases. J Neurol 260(7):1807–1812PubMedCrossRef
15.
Mascalchi M, Vella A (2018) Neuroimaging applications in chronic ataxias. Int Rev Neurobiol 143:109–162PubMedCrossRef
16.
Ito K, Ohtsuka C, Yoshioka K, Maeda T, Yokosawa S, Mori F et al (2019) Differentiation between multiple system atrophy and other spinocerebellar degenerations using diffusion kurtosis imaging. Acad Radiol 26(11):e333–e339PubMedCrossRef
17.
Kim M, Ahn JH, Cho Y, Kim JS, Youn J, Cho JW (2019) Differential value of brain magnetic resonance imaging in multiple system atrophy cerebellar phenotype and spinocerebellar ataxias. Sci Rep 9(1):17329PubMedPubMedCentralCrossRef
18.
Xue Y, Ankala A, Wilcox WR, Hegde MR (2015) Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet Med 17(6):444–451PubMedCrossRef
19.
Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR et al (2008) ACMG recommendations for standards for interpretation and reporting of sequence variations: revisions 2007. Genet Med 10(4):294–300PubMedCrossRef
20.
Whaley NR, Fujioka S, Wszolek ZK (2011) Autosomal dominant cerebellar ataxia type I: a review of the phenotypic and genotypic characteristics. Orphanet J Rare Dis 6:33PubMedPubMedCentralCrossRef
21.
22.
van Gaalen J, Kerstens FG, Maas RP, Härmark L, van de Warrenburg BP (2014) Drug-induced cerebellar ataxia: a systematic review. CNS Drugs 28(12):1139–1153PubMedCrossRef
23.
Pedroso JL, Vale TC, Braga-Neto P, Dutra LA, França MC, Jr., Teive H A G, et al (2019) Acute cerebellar ataxia: differential diagnosis and clinical approach. Arq Neuropsiquiatr 77(3):184–193PubMedCrossRef
24.
Kotwal SK, Kotwal S, Gupta R, Singh JB, Mahajan A (2016) Cerebellar ataxia as a presenting feature of hypothyroidism. Acta Endocrinol (Buchar) 12(1):77–79CrossRef
25.
Elhadd TA, Linton K, McCoy C, Saha S, Holden R (2014) A hitherto undescribed case of cerebellar ataxia as the sole presentation of thyrotoxicosis in a young man: a plausible association. Ann Saudi Med 34(5):440–443PubMedPubMedCentralCrossRef
26.
27.
Rd S, Dr C, H S, (2020) Invited review: epigenetics in neurodevelopment. Neuropathol Appl Neurobiol 46(1):6–27CrossRef
28.
Harvey ZH, Chen Y, Jarosz DF (2018) Protein-based inheritance: epigenetics beyond the chromosome. Mol Cell 69(2):195–202PubMedCrossRef
29.
30.
31.
Biemont C (2010) From genotype to phenotype. What do epigenetics and epigenomics tell us? Heredity (Edinb) 105(1):1–3CrossRef
32.
Bazov I, Sarkisyan D, Kononenko O, Watanabe H, Taqi MM, Stalhandske L et al (2018) Neuronal expression of opioid gene is controlled by dual epigenetic and transcriptional mechanism in human brain. Cereb Cortex 28(9):3129–3142PubMedCrossRef
33.
34.
Esteller M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8(4):286–298PubMedCrossRef
35.
36.
Safi-Stibler S, Gabory A (2020) Epigenetics and the developmental origins of health and disease: parental environment signalling to the epigenome, critical time windows and sculpting the adult phenotype. Semin Cell Dev Biol 97:172–180PubMedCrossRef
37.
Cavalli G, Heard E (2019) Advances in epigenetics link genetics to the environment and disease. Nature 571(7766):489–499PubMedCrossRef
38.
39.
40.
Bert SA, Robinson MD, Strbenac D, Statham AL, Song JZ, Hulf T et al (2013) Regional activation of the cancer genome by long-range epigenetic remodeling. Cancer Cell 23(1):9–22PubMedCrossRef
41.
Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P et al (2002) Role of histone H3 lysine 27 methylation in polycomb-group silencing. Science 298(5595):1039–1043PubMedCrossRef
42.
Satoh S, Kondo Y, Ohara S, Yamaguchi T, Nakamura K, Yoshida K (2020) Intrafamilial phenotypic variation in spinocerebellar ataxia type 23. Cerebellum Ataxias 7:7PubMedPubMedCentralCrossRef
43.
Ruano L, Melo C, Silva MC, Coutinho P (2014) The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology 42(3):174–183PubMedCrossRef
44.
Schicks J, Synofzik M, Beetz C, Schiele F, Schöls L (2011) Mutations in the PDYN gene (SCA23) are not a frequent cause of dominant ataxia in Central Europe. Clin Genet 80(5):503–504PubMedCrossRef
45.
Fogel BL, Lee JY, Lane J, Wahnich A, Chan S, Huang A et al (2012) Mutations in rare ataxia genes are uncommon causes of sporadic cerebellar ataxia. Mov Disord 27(3):442–446PubMedPubMedCentralCrossRef
46.
Saigoh K, Mitsui J, Hirano M, Shioyama M, Samukawa M, Ichikawa Y et al (2015) The first Japanese familial case of spinocerebellar ataxia 23 with a novel mutation in the PDYN gene. Parkinsonism Relat Disord 21(3):332–334PubMedCrossRef
47.
Hauser KF, Aldrich JV, Anderson KJ, Bakalkin G, Christie MJ, Hall ED et al (2005) Pathobiology of dynorphins in trauma and disease. Front Biosci 10:216–235PubMedPubMedCentralCrossRef
48.
Ludwig M, Leng G (2006) Dendritic peptide release and peptide-dependent behaviours. Nat Rev Neurosci 7(2):126–136PubMedCrossRef
49.
Riters LV, Cordes MA, Stevenson SA (2017) Prodynorphin and kappa opioid receptor mRNA expression in the brain relates to social status and behavior in male European starlings. Behav Brain Res 320:37–47PubMedCrossRef
50.
51.
52.
Bazov I, Sarkisyan D, Kononenko O, Watanabe H, Taqi MM, Stålhandske L et al (2018) Neuronal expression of opioid gene is controlled by dual epigenetic and transcriptional mechanism in human brain. Cereb Cortex 28(9):3129–3142PubMedCrossRef
53.
Kuzmin A, Madjid N, Terenius L, Ogren SO, Bakalkin G (2006) Big dynorphin, a prodynorphin-derived peptide produces NMDA receptor-mediated effects on memory, anxiolytic-like and locomotor behavior in mice. Neuropsychopharmacology 31(9):1928–1937PubMedCrossRef
54.
Kreek MJ, Bart G, Lilly C, LaForge KS, Nielsen DA (2005) Pharmacogenetics and human molecular genetics of opiate and cocaine addictions and their treatments. Pharmacol Rev 57(1):1–26PubMedCrossRef
55.
Trezza V, Damsteegt R, Achterberg EJ, Vanderschuren LJ (2011) Nucleus accumbens μ-opioid receptors mediate social reward. J Neurosci 31(17):6362–6370PubMedPubMedCentralCrossRef
56.
57.
Silvia RC, Slizgi GR, Ludens JH, Tang AH (1987) Protection from ischemia-induced cerebral edema in the rat by U-50488H, a kappa opioid receptor agonist. Brain Res 403(1):52–57PubMedCrossRef
58.
Baskin DS, Hosobuchi Y, Loh HH, Lee NM (1984) Dynorphin(1–13) improves survival in cats with focal cerebral ischaemia. Nature 312(5994):551–552PubMedCrossRef
59.
Macdonald RL, Werz MA (1986) Dynorphin A decreases voltage-dependent calcium conductance of mouse dorsal root ganglion neurones. J Physiol 377:237–249PubMedPubMedCentralCrossRef
60.
Rusin KI, Giovannucci DR, Stuenkel EL, Moises HC (1997) Kappa-opioid receptor activation modulates Ca2+ currents and secretion in isolated neuroendocrine nerve terminals. J Neurosci 17(17):6565–6574PubMedPubMedCentralCrossRef
61.
Hauser KF, Mangoura D (1998) Diversity of the endogenous opioid system in development. Novel signal transduction translates multiple extracellular signals into neural cell growth and differentiation. Perspect Dev Neurobiol 5(4):437–449PubMed
62.
Knapp PE, Itkis OS, Zhang L, Spruce BA, Bakalkin G, Hauser KF (2001) Endogenous opioids and oligodendroglial function: possible autocrine/paracrine effects on cell survival and development. Glia 35(2):156–165PubMedCrossRef
63.
Caudle RM, Dubner R (1998) Ifenprodil blocks the excitatory effects of the opioid peptide dynorphin 1–17 on NMDA receptor-mediated currents in the CA3 region of the guinea pig hippocampus. Neuropeptides 32(1):87–95PubMedCrossRef
64.
Lai SL, Gu Y, Huang LY (1998) Dynorphin uses a non-opioid mechanism to potentiate N-methyl-d-aspartate currents in single rat periaqueductal gray neurons. Neurosci Lett 247(2–3):115–118PubMedCrossRef
65.
Chen L, Gu Y, Huang LY (1995) The mechanism of action for the block of NMDA receptor channels by the opioid peptide dynorphin. J Neurosci 15(6):4602–4611PubMedPubMedCentralCrossRef
66.
Tang Q, Gandhoke R, Burritt A, Hruby VJ, Porreca F, Lai J (1999) High-affinity interaction of (des-Tyrosyl)dynorphin A(2–17) with NMDA receptors. J Pharmacol Exp Ther 291(2):760–765PubMed
67.
Tan-No K, Esashi A, Nakagawasai O, Niijima F, Tadano T, Sakurada C et al (2002) Intrathecally administered big dynorphin, a prodynorphin-derived peptide, produces nociceptive behavior through an N-methyl-d-aspartate receptor mechanism. Brain Res 952(1):7–14PubMedCrossRef
68.
Watanabe H, Mizoguchi H, Verbeek DS, Kuzmin A, Nyberg F, Krishtal O et al (2012) Non-opioid nociceptive activity of human dynorphin mutants that cause neurodegenerative disorder spinocerebellar ataxia type 23. Peptides 35(2):306–310PubMedCrossRef
69.
Yakovleva T, Marinova Z, Kuzmin A, Seidah NG, Haroutunian V, Terenius L et al (2007) Dysregulation of dynorphins in Alzheimer disease. Neurobiol Aging 28(11):1700–1708PubMedCrossRef
70.
Hauser KF, Knapp PE, Turbek CS (2001) Structure-activity analysis of dynorphin A toxicity in spinal cord neurons: intrinsic neurotoxicity of dynorphin A and its carboxyl-terminal, nonopioid metabolites. Exp Neurol 168(1):78–87PubMedCrossRef
71.
Sherwood TW, Askwith CC (2009) Dynorphin opioid peptides enhance acid-sensing ion channel 1a activity and acidosis-induced neuronal death. J Neurosci 29(45):14371–14380PubMedPubMedCentralCrossRef
72.
Hugonin L, Vukojević V, Bakalkin G, Gräslund A (2006) Membrane leakage induced by dynorphins. FEBS Lett 580(13):3201–3205PubMedCrossRef
73.
Madani F, Taqi MM, Wärmländer SK, Verbeek DS, Bakalkin G, Gräslund A (2011) Perturbations of model membranes induced by pathogenic dynorphin A mutants causing neurodegeneration in human brain. Biochem Biophys Res Commun 411(1):111–114PubMedCrossRef
74.
Marinova Z, Vukojevic V, Surcheva S, Yakovleva T, Cebers G, Pasikova N et al (2005) Translocation of dynorphin neuropeptides across the plasma membrane. A putative mechanism of signal transmission. J Biol Chem 280(28):26360–26370PubMedCrossRef
75.
Hugonin L, Vukojević V, Bakalkin G, Gräslund A (2008) Calcium influx into phospholipid vesicles caused by dynorphin neuropeptides. Biochim Biophys Acta 1778(5):1267–1273PubMedCrossRef
76.
Smeets CJ, Zmorzyńska J, Melo MN, Stargardt A, Dooley C, Bakalkin G et al (2016) Altered secondary structure of Dynorphin A associates with loss of opioid signalling and NMDA-mediated excitotoxicity in SCA23. Hum Mol Genet 25(13):2728–2737PubMed
77.
Watanave M, Hoshino C, Konno A, Fukuzaki Y, Matsuzaki Y, Ishitani T et al (2019) Pharmacological enhancement of retinoid-related orphan receptor α function mitigates spinocerebellar ataxia type 3 pathology. Neurobiol Dis 121:263–273PubMedCrossRef
78.
Huang M, Verbeek DS (2019) Why do so many genetic insults lead to Purkinje cell degeneration and spinocerebellar ataxia? Neurosci Lett 688:49–57PubMedCrossRef
79.
Shimobayashi E, Kapfhammer JP (2018) Calcium signaling, PKC gamma, IP3R1 and CAR8 link spinocerebellar Ataxias and Purkinje cell dendritic development. Curr Neuropharmacol 16(2):151–159PubMedPubMedCentralCrossRef
80.
Nibbeling EAR, Duarri A, Verschuuren-Bemelmans CC, Fokkens MR, Karjalainen JM, Smeets C et al (2017) Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia. Brain 140(11):2860–2878PubMedCrossRef
81.
82.
Schmitz-Hübsch T, Coudert M, Tezenas du Montcel S, Giunti P, Labrum R, Dürr A et al (2011) Depression comorbidity in spinocerebellar ataxia. Mov Disord 26(5):870–876PubMedCrossRef
83.
Bushart DD, Murphy GG, Shakkottai VG (2016) Precision medicine in spinocerebellar ataxias: treatment based on common mechanisms of disease. Ann Transl Med 4(2):25PubMedPubMedCentral
84.
Scoles DR, Pulst SM (2019) Antisense therapies for movement disorders. Mov Disord 34(8):1112–1119PubMedCrossRef
85.
86.
87.
Kampinga HH, Bergink S (2016) Heat shock proteins as potential targets for protective strategies in neurodegeneration. Lancet Neurol 15(7):748–759PubMedCrossRef
88.
89.
Shuvaev AN, Hosoi N, Sato Y, Yanagihara D, Hirai H (2017) Progressive impairment of cerebellar mGluR signalling and its therapeutic potential for cerebellar ataxia in spinocerebellar ataxia type 1 model mice. J Physiol 595(1):141–164PubMedCrossRef
90.
Nishizawa M, Onodera O, Hirakawa A, Shimizu Y, Yamada M (2020) Effect of rovatirelin in patients with cerebellar ataxia: two randomised double-blind placebo-controlled phase 3 trials. J Neurol Neurosurg Psychiatry 91(3):254–262PubMedCrossRef
91.
Rodríguez-Labrada R, Velázquez-Pérez L, Ziemann U (2018) Transcranial magnetic stimulation in hereditary ataxias: diagnostic utility, pathophysiological insight and treatment. Clin Neurophysiol 129(8):1688–1698PubMedCrossRef
92.
Tsai YA, Liu RS, Lirng JF, Yang BH, Chang CH, Wang YC et al (2017) Treatment of spinocerebellar Ataxia with mesenchymal stem cells: a phase I/IIa clinical study. Cell Transplant 26(3):503–512PubMedPubMedCentralCrossRef
93.
Orozco-Gutiérrez MH, Cervantes-Aragón I, García-Cruz D (2017) Ethical considerations in presymptomatic diagnosis of autosomal dominant spinocerebellar ataxias. Neurologia 32(7):469–475PubMedCrossRef
94.
do Nascimento-Marinho AS, de Faria-Domingues-de-Lima MA, Vargas FR (2015) Analysis of pre-test interviews in a cohort of Brazilian patients with movement disorders. J Community Genet 6(3):259–264PubMedPubMedCentralCrossRef
95.
Diallo A, Jacobi H, Cook A, Giunti P, Parkinson MH, Labrum R et al (2019) Prediction of survival with long-term disease progression in most common Spinocerebellar ataxia. Mov Disord 34(8):1220–1227PubMedCrossRef
96.
Sarro L, Nanetti L, Castaldo A, Mariotti C (2017) Monitoring disease progression in spinocerebellar ataxias: implications for treatment and clinical research. Expert Rev Neurother 17(9):919–931PubMedCrossRef
97.
Maas RP, van Gaalen J, Klockgether T, van de Warrenburg BP (2015) The preclinical stage of spinocerebellar ataxias. Neurology 85(1):96–103PubMedCrossRef
Metadata
Title
Spinocerebellar ataxia type 23 (SCA23): a review
Authors
Fan Wu
Xu Wang
Xiaohan Li
Huidi Teng
Tao Tian
Jing Bai
Publication date
01-12-2021
Publisher
Springer Berlin Heidelberg
Published in
Journal of Neurology / Issue 12/2021
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI
https://doi.org/10.1007/s00415-020-10297-5

Other articles of this Issue 12/2021

Journal of Neurology 12/2021 Go to the issue

Pioneers in Neurology

Theodor Schwann (1810–1882)

Original Communication

Iron-sensitive magnetic resonance imaging in Parkinson’s disease: a systematic review and meta-analysis

Original Communication

The socioeconomic burden of facioscapulohumeral muscular dystrophy

Review

Therapeutic plasma exchange vs conventional treatment with intravenous high dose steroid for neuromyelitis optica spectrum disorders (NMOSD): a systematic review and meta-analysis

Original Communication

Memory enhancement by multidomain group cognitive training in patients with Parkinson’s disease and mild cognitive impairment: long-term effects of a multicenter randomized controlled trial

Letter to the Editors

Elderly onset neuromyelitis optica spectrum disorder: a case report