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Neuropediatrics 2021; 52(05): 377-382
DOI: 10.1055/s-0040-1722686
Original Article

Specific Cognitive Changes due to Hippocalcin Alterations? A Novel Familial Homozygous Hippocalcin Variant Associated with Inherited Dystonia and Altered Cognition

Sandy Siegert
1   Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria
,
Wolfgang M. Schmidt
2   Neuromuscular Research Department, Medical University of Vienna, Austria
,
Thomas Pletschko
1   Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria
,
Reginald E. Bittner
2   Neuromuscular Research Department, Medical University of Vienna, Austria
,
Sonja Gobara
3   Ambulatorium Sonnenschein, Sozialpädiatrisches Zentrum, St. Pölten, Austria
,
Michael Freilinger
1   Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria
› Author Affiliations Funding M.F. reports personal fees from Novartis outside the submitted work. T.P. reports grants from Austrian Childhood Cancer Organization, Austrian Childhood Cancer Organization-Parents' Initiative, Gemeinsame Gesundheitsziele aus dem Rahmen-Pharmavertrag, NF-Kinder, Occursus, and 42virtual outside the submitted work. W.M.S. reports personal fees from AveXis Inc. and PTC Therapeutics Inc. outside the submitted work.
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Abstract

Background Recent research suggested an hippocalcin (HPCA)-related form of DYT2-like autosomal recessive dystonia. Two reports highlight a broad spectrum of the clinical phenotype. Here, we describe a novel HPCA gene variant in a pediatric patient and two affected relatives.

Methods Whole exome sequencing was applied after a thorough clinical and neurological examination of the index patient and her family members. Results of neuropsychological testing were analyzed.

Results Whole exome sequencing revealed a novel homozygous missense variant in the HPCA gene [c.182C>T p.(Ala61Val)] in our pediatric patient and the two affected family members. Clinically, the cases presented with dystonia, dysarthria, and jerky movements. We observed a particular cognitive profile with executive dysfunctions in our patient, which corresponds to the cognitive deficits that have been observed in the patients previously described.

Conclusion We present a novel genetic variant of the HPCA gene associated with autosomal recessive dystonia in a child with childhood-onset dystonia supporting its clinical features. Furthermore, we propose specific HPCA-related cognitive changes in homozygous carriers, underlining the importance of undertaking a systematic assessment of cognition in HPCA-related dystonia.

Keywords

hippocalcin - inherited dystonia - cognition


Publication History

Received: 08 July 2020

Accepted: 23 October 2020

Article published online:
28 January 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Albanese A, Bhatia K, Bressman SB. et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord 2013; 28 (07) 863-873
    CrossrefPubMedGoogle Scholar
  • 2 Klein C, Lohmann K, Marras C. et al. Hereditary Dystonia Overview. In: Adam MP, Ardinger HH, Pagon RA. et al., eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2020 ; 2003
    Google Scholar
  • 3 Charlesworth G, Angelova PR, Bartolomé-Robledo F. et al. Mutations in HPCA cause autosomal-recessive primary isolated dystonia. Am J Hum Genet 2015; 96 (04) 657-665
    CrossrefPubMedGoogle Scholar
  • 4 Mercer EA, Korhonen L, Skoglösa Y, Olsson PA, Kukkonen JP, Lindholm D. NAIP interacts with hippocalcin and protects neurons against calcium-induced cell death through caspase-3-dependent and -independent pathways. EMBO J 2000; 19 (14) 3597-3607
    CrossrefPubMedGoogle Scholar
  • 5 Paterlini M, Revilla V, Grant AL, Wisden W. Expression of the neuronal calcium sensor protein family in the rat brain. Neuroscience 2000; 99 (02) 205-216
    CrossrefPubMedGoogle Scholar
  • 6 Burgoyne RD, O'Callaghan DW, Hasdemir B, Haynes LP, Tepikin AV. Neuronal Ca2+-sensor proteins: multitalented regulators of neuronal function. Trends Neurosci 2004; 27 (04) 203-209
    CrossrefPubMedGoogle Scholar
  • 7 Burgoyne RD. Neuronal calcium sensor proteins: generating diversity in neuronal Ca2+ signalling. Nat Rev Neurosci 2007; 8 (03) 182-193
    CrossrefPubMedGoogle Scholar
  • 8 Helassa N, Antonyuk SV, Lian LY, Haynes LP, Burgoyne RD. Biophysical and functional characterization of hippocalcin mutants responsible for human dystonia. Hum Mol Genet 2017; 26 (13) 2426-2435
    CrossrefPubMedGoogle Scholar
  • 9 Palmer CL, Lim W, Hastie PG. et al. Hippocalcin functions as a calcium sensor in hippocampal LTD. Neuron 2005; 47 (04) 487-494
    CrossrefPubMedGoogle Scholar
  • 10 Atasu B, Hanagasi H, Bilgic B. et al. HPCA confirmed as a genetic cause of DYT2-like dystonia phenotype. Mov Disord 2018; 33 (08) 1354-1358
    CrossrefPubMedGoogle Scholar
  • 11 Balint B, Charlesworth G, Erro R, Wood NW, Bhatia KP. Delineating the phenotype of autosomal-recessive HPCA mutations: not only isolated dystonia!. Mov Disord 2019; 34 (04) 589-592
    CrossrefPubMedGoogle Scholar
  • 12 Kobayashi M, Masaki T, Hori K. et al. Hippocalcin-deficient mice display a defect in cAMP response element-binding protein activation associated with impaired spatial and associative memory. Neuroscience 2005; 133 (02) 471-484
    CrossrefPubMedGoogle Scholar
  • 13 Petermann F. Wechsler Adult Intelligence Scale. 4th edition.. (WAIS-IV). German adaptation of the WAIS-IV by D. Wechsler. Frankfurt, Germany: Pearson Assessment; 2012
    Google Scholar
  • 14 Schuhfried G. Vienna Test System: Psychological Assessment. Moedling, Austria: Schuhfried; 2013
    Google Scholar
  • 15 Kongs SK, Thompson LL, Iverson GL, Heaton RK. The Wisconsin Card Sorting Test - 64 Card Version. Lutz FL: Psychological Assessment Resources; 2000
    Google Scholar
  • 16 Aschenbrenner S, Tucha O, Lange KW. Regensburger Wortflüssigkeits-Test (RWT). Göttingen: Hogrefe Verlag für Psychologie; 2000
    Google Scholar
  • 17 Zimmermann P, Fimm B. TAP 2.3.1. Testbatterie zur Aufmerksamkeits-prüfung Version 2.3.1. Herzogenrath: Vera Fimm, Psychologische Testsysteme; 2017
    Google Scholar
  • 18 Helmstaedter C, Lendt M, Lux S. Verbaler Lern- und Merkfähigkeitstest: VLMT, Manual. Weinheim: Beltz-Test; 2001
    Google Scholar
  • 19 Stiensmeier-Pelster J, Schürmann M, Duda K. Depressions-Inventar für Kinder und Jugendliche (DIKJ). Handanweisung (2., überarb. u. neunorm. Aufl.). Göttingen: Hogrefe; 2000
    Google Scholar
  • 20 Döpfner M, Goertz-Dorten A. DISYPS-III: Diagnostik-System für psychische Störungen im Kindes- und Jugendalter nach ICD-10 und DSM 5 [DISYPS-III: Diagnostic system for psychiatric disorders in children and adolescents]. Göttingen, Germany: Hogrefe; 2017
    Google Scholar
  • 21 Rosenstein L. Research Design and Analysis: A Primer for the Non-Statistician. 2019: 94
    CrossrefGoogle Scholar
  • 22 Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 2014; 11 (04) 361-362
    CrossrefPubMedGoogle Scholar
  • 23 Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 2014; 46 (03) 310-315
    CrossrefPubMedGoogle Scholar
  • 24 Grogan A, Green DW, Ali N, Crinion JT, Price CJ. Structural correlates of semantic and phonemic fluency ability in first and second languages. Cereb Cortex 2009; 19 (11) 2690-2698
    CrossrefPubMedGoogle Scholar
  • 25 Sheldon S, Moscovitch M. The nature and time-course of medial temporal lobe contributions to semantic retrieval: an fMRI study on verbal fluency. Hippocampus 2012; 22 (06) 1451-1466
    CrossrefPubMedGoogle Scholar
  • 26 Whitney C, Weis S, Krings T, Huber W, Grossman M, Kircher T. Task-dependent modulations of prefrontal and hippocampal activity during intrinsic word production. J Cogn Neurosci 2009; 21 (04) 697-712
    CrossrefPubMedGoogle Scholar
  • 27 Jahanshahi M, Torkamani M. The cognitive features of idiopathic and DYT1 dystonia. Mov Disord 2017; 32 (10) 1348-1355
    CrossrefPubMedGoogle Scholar
  • 28 Holtzer R, Goldin Y, Donovick PJ. Extending the administration time of the letter fluency test increases sensitivity to cognitive status in aging. Exp Aging Res 2009; 35 (03) 317-326
    CrossrefPubMedGoogle Scholar
  • 29 Fischer-Baum S, Miozzo M, Laiacona M, Capitani E. Perseveration during verbal fluency in traumatic brain injury reflects impairments in working memory. Neuropsychology 2016; 30 (07) 791-799
    CrossrefPubMedGoogle Scholar
  • 30 Marsh JE, Hansson P, Sörman DE, Ljungberg JK. Executive processes underpin the bilingual advantage on phonemic fluency: evidence from analyses of switching and clustering. Front Psychol 2019; 10: 1355
    CrossrefPubMedGoogle Scholar
  • 31 Schwering SC, MacDonald MC. Verbal working memory as emergent from language comprehension and production. Front Hum Neurosci 2020; 14: 68
    CrossrefPubMedGoogle Scholar