Disease relevance of PANK2

• A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome [1].
• Mutations in the pantothenate kinase gene PANK2 are not associated with Parkinson disease [2].
• The presence of mutation in the PANK2 gene is associated with younger age at onset and a higher frequency of dystonia, dysarthria, intellectual impairment, and gait disturbance [3].
• RECENT FINDINGS: Disease caused by mutations in the gene encoding pantothenate kinase 2 (PANK2) is characterized by dystonia and pigmentary retinopathy in children or speech and neuropsychiatric defects in adults, in concert with a specific pattern on MRI of the brain [4].
• We describe a 24-year-old Japanese woman with pantothenate kinase-associated neurodegeneration (PKAN) whose only early symptom was postural tremor in the right hand at around 18 years of age, leading to a diagnosis of essential tremor at age 21 [5].

Psychiatry related information on PANK2

• These findings give further evidence that accumulation of alpha-synuclein is generally associated with LB formation, i.e., in Parkinson's disease, dementia with Lewy bodies and NBIA-1 [6].
• The present investigation examined the psychometric properties of the Wisconsin HSS Quality of Life Inventory (WI HSS QOL) when used in the study of traumatic brain injury (TBI) [7].

High impact information on PANK2

• We have identified nonsense mutations in the gene CDSN (encoding corneodesmosin) in three families suffering from hypotrichosis simplex of the scalp (HSS; OMIM 146520) [8].
• Pantothenate kinase-associated neurodegeneration (PKAN, formerly known as Hallervorden-Spatz syndrome) is a rare but devastating neurodegenerative disorder, resulting from an inherited defect in coenzyme A biosynthesis [9].
• Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia [9].
• Pank2 mice are 20% decreased in weight when compared with their wild-type littermates; however, dysphagia was not apparent [9].
• We have determined the exon-intron structure of the hPANK2 gene and identified two alternatively used first exons [10].

Chemical compound and disease context of PANK2

• Bezafibrate (BF), a hypolipidemic drug and a peroxisome proliferator activator receptor-alpha (PPARalpha) agonist, specifically increased hPANK1alpha mRNA expression in human hepatoblastoma (HepG2) cells as a function of time and dose of the drug, compared with hPANK1beta, hPANK2, and hPANK3, which did not significantly increase [11].
• To determine sensitivity and specificity for detection of haemodynamically significant stenoses (HSS; >50% reduction of luminal diameter) MR angiograms were compared with intra-arterial digital subtraction angiography (IA DSA), which was considered the standard of reference [12].
• Chickens in the MSS environment, compared with those on the HSS and LSS environments, had greater weight gains, superior feed efficiencies, medium plasma corticosterone levels, a better negative correlation between antibody responsiveness and RBC antigens, and better resistance to Mycoplasma gallisepticum challenge [13].

Biological context of PANK2

• Magnetic resonance showed the typical "eye of the tiger" sign, and genetic screening disclosed that both siblings were compound heterozygotes with two missense mutations in the PANK2 gene 734A-->G and 1172T-->C [14].
• Direct sequencing of the patient's genomic DNA revealed homozygous base substitutions in the pantothenate kinase gene (PANK2): the A764-->G substitution (N245S) due to consanguinity of her parents [5].
• Once the responsible gene PANK2 had been discovered on chromosome 20 it was found that this encoded for pantothenate kinase which is essential for the synthesis of coenzyme A from pantothenate; and this is integral to fatty acid synthesis and energy metabolism [15].
• The entire coding region of the PANK2 gene (20p12.3) was investigated for point mutations and deletions [16].
• The defect in PANK2 is predicted to cause the accumulation of cysteine, which binds iron and causes oxidative stress in the iron-rich globus pallidus [17].

Anatomical context of PANK2

• Pantothenate kinase is essential to coenzyme A biosynthesis, and PANK2 is targeted to mitochondria, a feature that distinguishes it from the three other human pantothenate kinase homologs [4].
• Radiographic evidence for iron deposition in the substantia nigra was absent early in disease associated with PANK2 mutations [18].
• Hypotheses of PKAN pathogenesis are based on the predictions of tissue-specific coenzyme A deficiency and the accumulation of cysteine-containing enzyme substrates, which may chelate iron and lead to the cardinal disease feature of basal ganglia iron accumulation [4].
• This patient had a 10-year history of PKAN characterized by a slight tremor of the right hand when writing at onset and a slow progressive rigidity of the neck and the right arm and resting tremor in upper extremities [19].
• The hallmark pathological lesions of NBIA 1 are axonal spheroids, but Lewy body (LB)-like intraneuronal inclusions, glial inclusions, and rare neurofibrillary tangles also occur [20].

Associations of PANK2 with chemical compounds

• Moreover, sequencing in seven INAD families revealed no mutations in PANK2 or in other genes of CoA biogenesis [21].
• We report on a patient with late-onset, pantothenate kinase-associated neurodegeneration (PKAN) who revealed two new heterozygous mutations at gene testing and showed asymmetric moderately reduced striatal dopamine transporter binding with single photon emission computed tomography, possibly due to prolonged neuroleptic treatment [22].
• In the second family with atypical PKAN, we identified a novel homozygous C-to-T transition at nucleotide 1069 of the PANK2 gene, which resulted in an arginine to tryptophane substitution at codon 357 [23].
• The effects of hHSS in reversing the lethality of D-galactosamine (1.6 gm/kg body weight)-induced hepatic necrosis in rats were further evaluated [24].
• Western blot analysis demonstrated high-molecular weight alphaS aggregates in the high-salt-soluble and Triton X-100-insoluble/sodium dodecyl sulfate-soluble fraction of the NBIA 1 brain [20].

Other interactions of PANK2

• To date, 2 genetic forms have been associated with mutations in PANK2 and PLA2G6, both of which encode proteins that are critical to membrane integrity [25].
• The authors describe a patient with hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP) who has two compound heterozygote mutations of the PANK2 gene [26].
• These results suggest that NBIA is caused by altered neuronal mitochondrial lipid metabolism caused by mutations disrupting PanK2 protein levels and catalytic activity [27].
• Here we show that there is an accumulation of alpha-synuclein (alphaS) in LB-like inclusions, glial inclusions, and spheroids in the brains of three NBIA 1 patients [20].

Analytical, diagnostic and therapeutic context of PANK2

• The newly described defect of the pantothenate kinase enzyme enables a novel therapeutic approach to be considered, based on the mutation analyses of the PANK2 gene, as well as the prenatal diagnosis of this disorder [28].
• Identification of the genetic basis for the major form of NBIA has allowed more accurate clinical delineation of the specific diseases that compose this group, a new molecular diagnostic test for PKAN, and hypotheses for treatment of this neurodegenerative disorder [4].
• [123I]FP-CIT SPECT findings in two patients with Hallervorden-Spatz disease with homozygous mutation in PANK2 gene [29].
• In this paper, we present our first results and experience in the diagnosis of PKAN in the Czech Republic and discuss questions related to differential diagnosis [30].
• Clinical examination was rated using HSS, Knee Society, and patellar scores and a visual analogue scale for pain [31].

References