Acanthocytosis and the c.680 A&gt;G Mutation in the PANK2 Gene: A Study Enrolling a Cohort of PKAN Patients from the Dominican Republic

Schiessl-Weyer, Jasmin; Roa, P. D.; Laccone, Franco; Kluge, Britta; Tichy, Alexander; Ribeiro, Euripedes de Almeida; Prohaska, Rainer; Stoeter, P.; Siegl, Claudia; Salzer, Ulrich

doi:10.1371/journal.pone.0125861

Cited by 18 publications

(11 citation statements)

References 24 publications

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“…While these acanthocytes are clinically irrelevant (e.g., not associated with anemia), they constitute an interesting cellular model system to study molecular mechanisms of the disease. [4][5][6][7][8][9] PANK2 encoded by the PANK2 gene is one of four isoforms of pantothenate kinases (PANK1-4) catalyzing the rate-limiting step in coenzyme A (CoA) biosynthesis. PANK2 has a mitochondrial targeting sequence and in neurons is localized to mitochondria.…”

Section: Introductionmentioning

confidence: 99%

PKAN neurodegeneration and residual PANK2 activities in patient erythrocytes

Werning

Müllner

Mlynek

et al. 2020

Ann Clin Transl Neurol

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Objective Pantothenate 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. Methods Residual 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. Results Erythrocytes 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. Interpretation Residual 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.

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Section: Introductionmentioning

confidence: 99%

PKAN neurodegeneration and residual PANK2 activities in patient erythrocytes

Werning

Müllner

Mlynek

et al. 2020

Ann Clin Transl Neurol

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“…In our group, homozygotes for missense mutation c.1583C>T showed a markedly later onset of disease than compound heterozygotes with frameshift deletion on the other allele. As expected, the PANK2 mutation spectrum differs in other world populations [10][11][12][13][14]. A genotype-phenotype correlation is not always clear because of the number of PANK2 rare variants in homozygous or compound heterozygous states.…”

Section: Discussionmentioning

confidence: 74%

Phenotypic expression and founder effect of PANK2 c.1583C>T (p.T528M) mutation in Serbian pantothenate kinase-associated neurodegeneration patients

Svetel

Hartig²,

Cvetković

et al. 2019

ARCH BIOL SCI BELGRA

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Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder characterized by dystonia, parkinsonism, cognitive and visual impairment, and iron accumulation in the brain. Many cases of PKAN result from mutations in the PANK2 gene that encodes pantothenate kinase 2, a key regulatory enzyme in the biosynthesis of coenzyme A. We previously detected six Serbian patients with clinically suggestive PKAN, all of whom had PANK2 c.1583C>T (p.T528M) mutation either in the homozygous or in the heterozygous state. In this study we explored the phenotypic expression and a possible founder effect of this substitution. We performed the analysis of linkage disequilibrium (LD) and organization in haplotypes of 23 single nucleotide polymorphisms (SNPs) adjacent to the PANK2 gene in all of the six patients and their parents, as well as in control healthy child-parents trios. The age of PANK2 c.1583C>T mutation was determined using the r 2 degeneration method. Clinical findings in our patients were markedly similar. Different LD structures between patients and controls is revealed, and PANK2 c.1583T allele was significantly associated with a particular haplotype. The age of PANK2 c.1583C>T mutation was estimated to be about 15 generations. Our results suggest that PANK2 c.1583C>T in Serbian PKAN patients represents a founder mutation descended from one common ancestor.

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“…By examination of functional connectivity between various sub-components of this network, we expect to see differences between dystonic patients and controls that possibly mirror their movement disorder. Our functional Magnetic Resonance Imaging (MRI) Region-of-interest (ROI) based study is the first one to look into connectivity within the motor network in PKAN dystonia by analyzing resting state activity in motor-related areas in a group of genetically confirmed patients living in the Dominican Republic [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Functional connectivity of the motor system in dystonia due to PKAN

et al. 2021

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Purpose To demonstrate deviations of functional connectivity within the motor system in dystonic patients suffering from Pantothenate Kinase Associated Neurodegeneration, a genetic and metabolic disease, which is characterized by a primary lesion in the globus pallidus. Material and methods Functional Magnetic Resonance Imaging data were measured during resting state in 12 patients suffering from a confirmed mutation of the PANK2 gene. In this region-of-interest based analysis, data were evaluated in respect to correlation of signal time course between basal ganglia, motor-related cortical regions and cerebellum, were related to clinical data and were compared to a control group of 20 healthy volunteers. Results During resting state, correlation coefficients within the motor system were significantly lower in patients than in controls (0.025 vs. 0.133, p < 0.05). Network analysis by Network Based Statistics showed that these differences mainly affected the connectivity between a sub-network consisting of the basal ganglia and another one, the motor system-related cortical areas ( p < 0.05). 6 out of 12 connections, which correlated significantly to duration of disease, were connections between both sub-networks. Conclusion The finding of a reduced functional connectivity within the motor network, between the basal ganglia and cortical motor-related areas, fits well into the concept of a general functional disturbance of the motor system in PKAN.

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Acanthocytosis and the c.680 A>G Mutation in the PANK2 Gene: A Study Enrolling a Cohort of PKAN Patients from the Dominican Republic

Cited by 18 publications

References 24 publications

PKAN neurodegeneration and residual PANK2 activities in patient erythrocytes

PKAN neurodegeneration and residual PANK2 activities in patient erythrocytes

Phenotypic expression and founder effect of PANK2 c.1583C>T (p.T528M) mutation in Serbian pantothenate kinase-associated neurodegeneration patients

Functional connectivity of the motor system in dystonia due to PKAN

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