Journal Article

Focus on Clinical and Genetic Aspects of PKAN Through the Description of New Patients

Borgione, Eugenia, Romano, Corrado, Giuliano, Marika, Santa Paola, Sandro, Di Blasi, Francesco Domenico, Scuderi, Carmela, Russo, Roberto, Lo Giudice, Mariangela, Elia, Maurizio, Vitello, Girolamo Aurelio

2025

Overview

Background/Objectives: The most prevalent form of neurodegeneration with brain iron accumulation (NBIA) is pantothenate kinase-associated neurodegeneration (PKAN), caused by mutations in the PANK2 gene. The hallmark of PKAN is the “eye-of-the-tiger” sign, which is characterized by a bilateral region of central hyperintense signal surrounded by a hypointense signal in the medial globus pallidus on T2-weighted brain magnetic resonance imaging (MRI). Methods: Whole-exome sequencing (WES) was performed in four patients who presented with dystonia, cognitive impairment and abnormalities of the globus pallidus. All patients underwent comprehensive clinical and instrumental evaluations. Results: Molecular analysis using WES revealed PANK2 variants in all four cases. Two patients were homozygous for the known pathogenic variant c.1169A > T (p.N390I). The remaining two patients displayed compound heterozygotes, each carrying the novel splicing variant c.906-1G > A on one allele, combined with a different second variant on the other allele: the new missense variant c.617G > A (p.G206D) in one case and the known pathogenic variant c.1231G > A (p.G411R) in the other. In one case, brain imaging documented the transition from initial hyperintensity of the globus pallidus to the development of the “eye-of-the-tiger” sign. In two cases, MRI findings clearly demonstrated the characteristic “eye-of-the-tiger” appearance. Ultimately, in one case, the imaging likely captured a later disease stage, in which the “eye-of-the-tiger” sign was no longer visible, and only the residual hypointensity remained. Conclusions: This study describes two novel likely pathogenic variants and documents the full MRI progression of globus pallidus involvement in PKAN. The sequence starts with early T2 hyperintensity, followed by the emergence of the typical “eye-of-the-tiger” sign, and culminates in marked hypointensity in advanced stages. Since the initial clinical presentation may mimic mitochondrial disorders or other neurometabolic conditions, these imaging features are crucial for guiding differential diagnosis and enabling accurate disease identification.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Age / Alleles / Care and treatment / Child development / Development and progression / Differential diagnosis / Disease / Dystonia / Electromyography / Exome Sequencing / Gait / Genes / Genetic aspects / Genomes / Genomics / Globus pallidus / Globus Pallidus - diagnostic imaging / Globus Pallidus - pathology / Heterozygotes / Humans / Kinases / Magnetic Resonance Imaging / Mutation / Neurodegeneration / Neuroimaging / Pantothenate kinase / Pantothenate kinase-associated neurodegeneration / Pantothenate Kinase-Associated Neurodegeneration - diagnostic imaging / Pantothenate Kinase-Associated Neurodegeneration - genetics / Pantothenate Kinase-Associated Neurodegeneration - pathology / Patients / Phosphotransferases (Alcohol Group Acceptor) - genetics / Physiological aspects / Physiology / Pregnancy / Proteins / Software / Spasticity / Whole genome sequencing