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Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Pantothenate kinase–associated neurodegeneration (PKAN) is one of a growing family of disorders of NBIA. PKAN is an autosomal recessive disorder caused by mutations in the PANK2 gene. PANK2 codes for pantothenate kinase 2, which participates in the synthesis of coenzyme A and in the phosphorylation of pantothenate (vitamin B5), N-pantothenoyl-cysteine, and pantetheine. Without pantothenate kinase 2, cysteine and cysteine-containing compounds collect in the basal ganglia, causing chelation of iron in the globus pallidus, and oxidative cell death. Males and females are equally affected.
Associated disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
In this rare disorder there is a progressive degeneration of the nervous system, frequently associated with an accumulation of iron in certain areas of the brain. There are two forms of the disorder – a classical form and an atypical form. In the classical form there is a deficiency or an absence of the enzyme pantothenate kinase, due to mutations in the PANK2 gene.
Neurogenetics
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
Sonia Gandhi, Sarah Tabrizi, Nicholas Wood
Neurodegeneration with brain iron accumulation may present with a mixed movement disorder. Pantothenate kinase associated neurodegeneration (PKAN) is due to mutations in the PANK2 gene, which encodes pantothenate kinase, which is key in regulating coenzyme A synthesis. The condition typically presents in the first decade of life with progressive and severe extrapyramidal features, corticospinal signs and cognitive decline. An atypical form is seen that presents in early adulthood with parkinsonism and slow progression. Iron accumulation in the basal ganglia results in the classic radiological feature of bilateral hypointensity in the median globus pallidus with a central area of hyperintensity (the eye of the tiger sign) on T2-weighted magnetic resonance imaging (MRI).
Malaria transmission blocking compounds: a patent review
Published in Expert Opinion on Therapeutic Patents, 2022
Sara Consalvi, Chiara Tammaro, Federico Appetecchia, Mariangela Biava, Giovanna Poce
Panthotenamides are a class of compounds able to modulate the CoA biosynthetic pathway by acting as substrate or inhibitors of pantothenate kinase (PanK) and were first identified as broad inhibitors of numerous target organisms, such as bacteria, fungi, and protozoa. The low stability of pantothenic acid derivatives in body fluids, due to the pantetheinase hydrolytic activity, seriously limit their use. In 2016, Hermkens et al. patented a series of pantothenamide analogues resistant to pantetheinase, which yielded a series of antiplasmodial agents able to strongly reduce parasitemia in a in vivo model. Studies about the mechanism of action of these compounds revealed that their IC50 increase when pantothenate is added to the culture medium and that they act with a noncompetitive mode of action. Two selected compounds of this series (compound 15 (CXP 0.17) and 16 (CXP 0.26), Table 5) and their improved analogs 17–20 [64,65] reduced gametocidal viability with a dose-dependent effect, with IC50 in the sub-micromolar range (Table 5). Both CXP 0.17 and 0.26 potently inhibited the female gametogenesis capacity with an IC50 of 36 and 13 nM, respectively (Table 5). Their effects of gametocyte inhibition on transmission were confirmed through a SMFA, using a transgenic P. falciparum NF54 strain expressing a luciferase reporter gene. The obtained results supported a gametocidal action and revealed that both compounds reduced oocysts intensity and prevalence with IC50 in the submicromolar range, confirming their potential as multiactive antimalarial agents.
Novel compound heterozygous PANK2 gene mutations in a Chinese patient with atypical pantothenate kinase-associated neurodegeneration
Published in International Journal of Neuroscience, 2018
Yuan Cheng, Yu-tao Liu, Zhi-hua Yang, Jing Yang, Chang-he Shi, Yu-ming Xu
PANK2 is a human gene that encodes pantothenate kinase, which is a key regulatory enzyme in the biosynthesis of coenzyme A (CoA). The exact pathogenesis of this disease is unclear. It is currently believed that the PANK2 gene mutation may generate structural changes and functional damage in pantothenic kinase 2, resulting in a lack of CoA and cysteine accumulation. Cysteine can be chelated with iron, and leads to the increase of free radicals. It further gives rise to energy metabolism disorders and has a toxic effect on cells, which can eventually result in central nervous system dysfunction [3].
Concurrent PANK2 and OCA2 variants in a patient with retinal dystrophy, hypopigmented irides and neurodegeneration
Published in Ophthalmic Genetics, 2023
Eva Wai Nam Wong, Shirley S.W. Cheng, Tiffany T.Y. Woo, Robert F. Lam, Frank H.P. Lai
In view of the finding of PANK2 variant, magnetic resonance imaging (MRI) of the brain with contrast was arranged. The scan revealed symmetrical low T2 signal in globus pallidi with central T2 hyperintensity, consistent with the “eye of the tiger” sign. (Figure 3a). Similar bilateral T2-hypointensity was also observed in the pars reticulata of the substantia nigra (Figure 3b). No caudate atrophy was seen. The MRI findings were consistent with features of pantothenate kinase-associated neurodegeneration (PKAN).