Journal Article

DZNE-2020-01270

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png PKAN neurodegeneration and residual PANK2 activities in patient erythrocytes

Werning, M. ; Müllner, E. W. ; Mlynek, G. ; Dobretzberger, V. ; Djinovic‐Carugo, K. ; Baron, D. M. ; Prokisch, H. ; Büchner, B. ; Klopstock, T.DZNE* ; Salzer, U. (Corresponding author)

2020
Wiley Chichester [u.a.]

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Please use a persistent id in citations: doi:10.1002/acn3.51127

Abstract: ObjectivePantothenate kinase 2‐associated neurodegeneration (PKAN) is a rare neurodegenerative disease caused by mutations in the pantothenate kinase 2 (PANK2) gene. PKAN is associated with iron deposition in the basal ganglia and, occasionally, with the occurrence of misshaped erythrocytes (acanthocytes). The aim of this study was to assess residual activity of PANK2 in erythrocytes of PKAN patients and to correlate these data with the type of PANK2 mutations and the progression of neurodegeneration.MethodsResidual PANK2 activities in erythrocytes of 14 PKAN patients and 14 related carriers were assessed by a radiometric assay. Clinical data on neurodegeneration included the Barry–Albright Dystonia Scale (BAD‐Scale) besides further general patient features. A molecular visualization and analysis program was used to rationalize the influence of the PKAN causing mutations on a molecular level.ResultsErythrocytes of PKAN patients had markedly reduced or no PANK2 activity. However, patients with at least one allele of the c.1583C > T (T528M) or the c.833G > T (R278L) variant exhibited 12–56% of residual PANK2 activity. In line, molecular modeling indicated only minor effects on enzyme structure for these point mutations. On average, these patients with c.1583C > T or c.833G > T variant had lower BAD scores corresponding to lower symptom severity than patients with other PANK2 point mutations.InterpretationResidual erythrocyte PANK2 activity could be a predictor for the progression of neurodegeneration in PKAN patients. Erythrocytes are an interesting patient‐derived cell system with still underestimated diagnostic potential.

Keyword(s): Adolescent (MeSH) ; Adult (MeSH) ; Biological Specimen Banks (MeSH) ; Disease Progression (MeSH) ; Erythrocytes: metabolism (MeSH) ; Female (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Pantothenate Kinase-Associated Neurodegeneration: blood (MeSH) ; Pantothenate Kinase-Associated Neurodegeneration: diagnosis (MeSH) ; Pantothenate Kinase-Associated Neurodegeneration: genetics (MeSH) ; Pantothenate Kinase-Associated Neurodegeneration: pathology (MeSH) ; Phosphotransferases (Alcohol Group Acceptor): genetics (MeSH) ; Phosphotransferases (Alcohol Group Acceptor): metabolism (MeSH) ; Prognosis (MeSH) ; Registries (MeSH) ; Young Adult (MeSH)

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Contributing Institute(s):

1. Clinical Neurodegeneration (AG Levin)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2020

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