Basal ganglia calcification and novel compound heterozygous mutations in the PANK2 gene in a Chinese boy with classic Pantothenate kinase-associated neurodegeneration

Shi, Xulai; Zheng, Fang; Ye, Xiuyun; Li, Xiucui; Zhao, Qianlei; Lin, Zhongdong; Hu, Ying; Wang, Jiwen

doi:10.1097/md.0000000000010316

Cited by 10 publications

(6 citation statements)

References 9 publications

(15 reference statements)

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“…A recent study found calcium phosphate aggregates in the mitochondria of glutamatergic neurons from PKAN patients, together with signs of altered calcium homeostasis [86]. Calcification in the basal ganglia was previously described [87][88][89] in some PKAN patients and confirmed in about 50% of the cases analysed in this recent work [86], thus indicating a potential harmful association among iron, calcium and defective PANK2. Several informative hints about the biochemical processes perturbed by limited CoA availability came also from the analysis of Drosophila Schneider's S2 cells.…”

Section: Pkansupporting

confidence: 69%

Coenzyme a Biochemistry: From Neurodevelopment to Neurodegeneration

et al. 2021

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Coenzyme A (CoA) is an essential cofactor in all living organisms. It is involved in a large number of biochemical processes functioning either as an activator of molecules with carbonyl groups or as a carrier of acyl moieties. Together with its thioester derivatives, it plays a central role in cell metabolism, post-translational modification, and gene expression. Furthermore, recent studies revealed a role for CoA in the redox regulation by the S-thiolation of cysteine residues in cellular proteins. The intracellular concentration and distribution in different cellular compartments of CoA and its derivatives are controlled by several extracellular stimuli such as nutrients, hormones, metabolites, and cellular stresses. Perturbations of the biosynthesis and homeostasis of CoA and/or acyl-CoA are connected with several pathological conditions, including cancer, myopathies, and cardiomyopathies. In the most recent years, defects in genes involved in CoA production and distribution have been found in patients affected by rare forms of neurodegenerative and neurodevelopmental disorders. In this review, we will summarize the most relevant aspects of CoA cellular metabolism, their role in the pathogenesis of selected neurodevelopmental and neurodegenerative disorders, and recent advancements in the search for therapeutic approaches for such diseases.

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Section: Pkansupporting

confidence: 69%

Coenzyme a Biochemistry: From Neurodevelopment to Neurodegeneration

et al. 2021

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“…These data prompted us to investigate if not only in vitro but also in PKAN patients in vivo, calcium accumulation was detectable. Recently, a case report showed basal ganglia calcifications in a patient affected by PKAN [27]. A survey of a cohort of 15 genetically defined PKAN patients who underwent CT scan demonstrated calcium accumulation in 47% of the cases.…”

Section: Discussionmentioning

confidence: 99%

Harmful Iron-Calcium Relationship in Pantothenate kinase Associated Neurodegeneration

Santambrogio

Ripamonti

Paolizzi

et al. 2020

IJMS

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Pantothenate Kinase-associated Neurodegeneration (PKAN) belongs to a wide spectrum of diseases characterized by brain iron accumulation and extrapyramidal motor signs. PKAN is caused by mutations in PANK2, encoding the mitochondrial pantothenate kinase 2, which is the first enzyme of the biosynthesis of Coenzyme A. We established and characterized glutamatergic neurons starting from previously developed PKAN Induced Pluripotent Stem Cells (iPSCs). Results obtained by inductively coupled plasma mass spectrometry indicated a higher amount of total cellular iron in PKAN glutamatergic neurons with respect to controls. PKAN glutamatergic neurons, analyzed by electron microscopy, exhibited electron dense aggregates in mitochondria that were identified as granules containing calcium phosphate. Calcium homeostasis resulted compromised in neurons, as verified by monitoring the activity of calcium-dependent enzyme calpain1, calcium imaging and voltage dependent calcium currents. Notably, the presence of calcification in the internal globus pallidus was confirmed in seven out of 15 genetically defined PKAN patients for whom brain CT scan was available. Moreover, we observed a higher prevalence of brain calcification in females. Our data prove that high amount of iron coexists with an impairment of cytosolic calcium in PKAN glutamatergic neurons, indicating both, iron and calcium dys-homeostasis, as actors in pathogenesis of the disease.

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“…We searched for literatures about PKAN on the Chinese Biological Medicine (CBM) Database (http://www.sinomed.ac.cn/zh/) and PubMed. We excluded the literatures lack of genetic analysis or complete data by reading the full text and finally 9 studies [4–12] were included in the review. The genetic and clinical features of PKAN in China were summarized.…”

Section: Methodsmentioning

confidence: 99%

Novel PANK2 mutation in a Chinese boy with PANK2-associated neurodegeneration

2019

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Rationale:Pantothenate kinase-associated neurodegeneration (PKAN), also called Hallervorden–Spatz Syndrome (HSS), is a rare neurodegeneration with brain iron accumulation from pantothenate kinase 2 gene (PANK2) mutation characterized as extrapyramidal symptoms. However, few studies involving PKAN patients were reported in China. This study was conducted to identify the genetic mutations in a Chinese boy with PKAN, and to review all PANK2 mutations reported in Chinese cases with PKAN.Patient concern:We reported a 23-year-old Chinese boy with PKAN, exhibiting difficulty in writing and manipulation using right hand with slow progression for 12 years. He spoke with a severe stutter when he was 15 years old.Diagnosis:Considering results of magnetic resonance images, brain computed tomography and medical history, the case was suspected to be related to genetic factors.Interventions:Whole exome sequencing was arranged, and the mutations were identified in his parents’ genome.Outcomes:In the present study, whole exome sequencing revealed 2 novel mutations (c.1696C > G in exon 7 and c.1160_c.1161insG in exon3) of the PANK2 gene in the proband. c.1696C > G and c.1160_c.1161insG, respectively, were confirmed in his father and mother. We also reviewed 14 different PANK2 mutations, most of which were missense type in Chinese cases. Those mutations did not show apparent hotspots, but exon 3 and 4 were frequently involved.Lessons:Two novel compound heterozygous mutations were identified and considered to be pathogenic in PKAN patients. This review of the reports indicated that atypical PKAN is the more common phenotype in China and no apparent genotype-phenotype correlation was found.

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Basal ganglia calcification and novel compound heterozygous mutations in the PANK2 gene in a Chinese boy with classic Pantothenate kinase-associated neurodegeneration

Cited by 10 publications

References 9 publications

Coenzyme a Biochemistry: From Neurodevelopment to Neurodegeneration

Coenzyme a Biochemistry: From Neurodevelopment to Neurodegeneration

Harmful Iron-Calcium Relationship in Pantothenate kinase Associated Neurodegeneration

Novel PANK2 mutation in a Chinese boy with PANK2-associated neurodegeneration

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