Imagine your body as a finely-tuned machine, with every part working together seamlessly. But what happens when there’s a glitch in the system? That’s what researchers have been studying in the case of pantothenate kinase-associated neurodegeneration (PKAN), a rare genetic disorder caused by mutations in the PANK2 gene. In a recent study, scientists identified three new mutations in patients with PKAN, shedding light on the link between these mutations and disease severity. By analyzing different types of mutations, the researchers found that patients with loss-of-function mutations experienced more severe symptoms and an earlier onset of the disease. On the other hand, patients with missense mutations in the mitochondrial trafficking domain showed the earliest onset age. This research not only expands our understanding of PKAN but also highlights the importance of evaluating mitochondrial dysfunction in patients to determine their clinical prognosis. To delve into the fascinating details of this study, check out the full article!

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare genetic disorder caused by mutations in the mitochondrial pantothenate kinase 2 (PANK2) gene and displays an inherited autosomal recessive pattern. In this study, we identified eight PANK2 mutations, including three novel mutations (c.1103A > G/p.D368G, c.1696C > G/p.L566V, and c.1470delC/p.R490fs494X), in seven unrelated families with PKAN. All the patients showed an eye-of-the-tiger sign on the MRI, six of seven patients had dystonia, and two of seven patients had Parkinsonism. Biallelic mutations of PANK2 decreased PANK2 protein expression and reduced mitochondrial membrane potential in human embryonic kidney (HEK) 293T cells. The biallelic mutations from patients with early-onset PKAN, a severity phenotype, showed decreased mitochondrial membrane potential more than that from late-onset patients. We systematically reviewed all the reported patients with PKAN with PANK2 mutations. The results indicated that the early-onset patients carried a significantly higher frequency of biallelic loss-of-function (LoF) mutations compared to late-onset patients. In general, patients with LoF mutations showed more severe phenotypes, including earlier onset age and loss of gait. Although there was no significant difference in the frequency of biallelic missense mutations between the early-onset and late-onset patients, we found that patients with missense mutations in the mitochondrial trafficking domain (transit peptide/mitochondrial domain) of PANK2 exhibited the earliest onset age when compared to patients with mutations in the other two domains. Taken together, this study reports three novel mutations and indicates a correlation between the phenotype and mitochondrial dysfunction. This provides new insight for evaluating the clinical severity of patients based on the degree of mitochondrial dysfunction and suggests genetic counseling not just generalized identification of mutated PANK2 in clinics.

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