Greek Case Study on Atypical PKAN with PANK2 Mutations
This case study presents the first Greek case of atypical Pantothenate Kinase-Associated Neurodegeneration (PKAN) confirmed by molecular analysis. A 25-year-old Greek male with focal orobucal dystonia and dysarthria was found to have two trans-acting mutations in PANK2, with one mutation also identified in his mother. The patient's brain MRI showed the characteristic "eye-of-the-tiger" sign. These findings emphasize the role of rare variants in disease risk and variable clinical phenotypes.
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Presentation Transcript
Background/aims: Pantothenate kinase-associated neurodegeneration (PKAN) is the most common autosomal recessive form of neurodegeneration with brain iron accumulation (NBIA). Less than ten mutations in PANK2 gene (20p13) are responsible for classic and atypical cases. We report here the first Greek case of atypical PKAN, confirmed by molecular analysis that revealed two trans-acting mutations.
Material and Methods: We present a 25-year-old Greek male with a 3-year history of focal orobucal dystonia and dysarthria, who was diagnosed with atypical PKAN according the NBIA criteria of Dooling and Swaiman. His brain MRI scan revealed the characteristic "eye-of-the-tiger" sign, but cognitive and laboratory evaluation were normal. There was no positive family history and patient s parents originate from different parts of Greece. In patient s blood DNA sample the seven exons of PANK2, including the exon/ intron boundaries, were sequenced. The detected mutations were verified by combination of PCR and rectriction enzyme analysis in the patient and were also investigated in blood DNA samples of the patient s mother and of 100 healthy Greeks.
Results: The patient had two mutations in combined heterozygosity (1424T>C, c.1583T>C), in exons 5 and 6 of PANK2, respectively. His mother was a carrier of one mutation only (c.1583T>C) previously reported in PKAN patients. Both mutations were absent in the database of single nucleotide polymorphisms of 1,000 genomes, and were not observed by restriction digestion analysis in the DNA samples of 100 healthy controls.
Figure 1. Agarose gel electrophoresis of DNA samples after restriction cleavage of PCR fragments. M: 100bp ladder as size marker; (1-3) c.1583T>C alleles after incubation with PvuI; 1: healthy control TT, 2: patient T/C, 3: patient's mother T/C; (4-6): c.1424T>C alleles after incubation with NlaIII; 4: patient's mother T/T, 5: patient T/C, 6: healthy control T/T. Figure heterozygous PANK2 gene mutations. Proband with PKAN is indicated with an arrow. Square, male; circle, female; filled symbol: affected, semifilled symbol: carrier. Proband s mother as carrier of 1583T>C PANK2 mutation is indicated below the symbol. Figure 2. 2. Family with compound
Figure 3. T2-weighted brain MRI showing the eye-of- the-tiger sign (arrows) Conclusion: Our findings highlight the possible role of rare variants contributing to disease risk and possibly to variable clinical phenotype.
