PKAN pathogenesis and treatment

Hayflick, Susan J.; Jeong, Suh Young; Sibon, Ody C. M.

doi:10.1016/j.ymgme.2022.09.011

Cited by 13 publications

(11 citation statements)

References 82 publications

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“…The atypical form is less aggressive and is characterized by late onset (after 10 years of age) with psychiatric abnormalities being the most prominent feature but less cognitive decline and slower development of muscular symptoms. [10][11]. The literature has also reported cases of PKAN mimicking Tourette syndrome [12].…”

Section: Discussionmentioning

confidence: 99%

Treatment of Pantothenate-kinase neurodegeneration with baclofen, botulinum toxin, and deferiprone: A case report

Hameed¹,

Siddiqui²,

Khan

et al. 2023

Preprint

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Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder characterized by progressive motor symptoms such as dystonia and spasticity. Classical PKAN is the most common subtype of neurodegeneration with brain iron accumulation (NBIA). There is no current established treatment for PKAN. Baclofen and botulinum toxin have been reported to improve motor symptoms and ease care in these patients. Deferiprone is a well-tolerated iron chelator and has been shown effective in reducing the brain iron accumulation. We report a seven-year-old boy who presented to our ward with spastic gait and extrapyramidal signs. Brain MRI was performed which showed features of neurodegeneration secondary to brain iron accumulation with specific appearance of eye-of-the-tiger sign. Genetic testing was positive for a homozygous mutation in PKAN2 and the diagnosis of early stage classical PKAN was made. The case report highlights the potent efficacy of baclofen, botulinum toxin, and deferiprone in slowing down the disease progression at an early stage and improving the severity of symptoms.

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Section: Discussionmentioning

confidence: 99%

Treatment of Pantothenate-kinase neurodegeneration with baclofen, botulinum toxin, and deferiprone: A case report

Hameed¹,

Siddiqui²,

Khan

et al. 2023

Preprint

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“…Due to the ease of obtaining sufficient amounts of pantothenic acid from food sources (5 mg daily for adults [19]), deficiency is rare, and usually only present in individuals with severe general malnutrition. However, mutations in the pantothenate kinase 2 (PANK2) gene on chromosome 20 may result in pantothenic acid deficiency, with downstream CoA deficiency [20]. These mutations can result in a condition called pantothenate-kinase associated neurodegeneration (PKAN), a condition that arises in early life characterized by motor dysfunction that eventually leads to issues with falls, chewing, and swallowing [20].…”

Section: Pantothenic Acidmentioning

confidence: 99%

Localized Pantothenic Acid (Vitamin B5) Reductions Present Throughout the Dementia with Lewy Bodies Brain

Scholefield,

Church,

et al. 2024

Journal of Parkinson’s Disease

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Background: Localized pantothenic acid deficiencies have been observed in several neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease dementia (PDD), and Huntington’s disease (HD), indicating downstream energetic pathway perturbations. However, no studies have yet been performed to see whether such deficiencies occur across the dementia with Lewy bodies (DLB) brain, or what the pattern of such dysregulation may be. Objective: Firstly, this study aimed to quantify pantothenic acid levels across ten regions of the brain in order to determine the localization of any pantothenic acid dysregulation in DLB. Secondly, the localization of pantothenic acid alterations was compared to that previously in AD, PDD, and HD brains. Methods: Pantothenic acid levels were determined in 20 individuals with DLB and 19 controls by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC–MS/MS) across ten brain regions. Case–control differences were determined by nonparametric Mann–Whitney U test, with the calculation of S-values, risk ratios, E-values, and effect sizes. The results were compared with those previously obtained in DLB, AD, and HD. Results: Pantothenic acid levels were significantly decreased in six of the ten investigated brain regions: the pons, substantia nigra, motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. This level of pantothenic acid dysregulation is most similar to that of the AD brain, in which pantothenic acid is also decreased in the motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. DLB appears to differ from other neurodegenerative diseases in being the only of the four to not show pantothenic acid dysregulation in the cerebellum. Conclusions: Pantothenic acid deficiency appears to be a shared mechanism of several neurodegenerative diseases, although differences in the localization of this dysregulation may contribute to the differing clinical pathways observed in these conditions.

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“…This is supported by the metabolic profiles of PKAN plasma samples showing increased levels of mitochondrial dysfunction markers and decreased levels of different lipids [ 57 ]. However, CoA deficiency in human patients has not yet been proven [ 58 ].…”

Section: Inborn Errors Of Coa Biosynthesismentioning

confidence: 99%

Inherited Disorders of Coenzyme A Biosynthesis: Models, Mechanisms, and Treatments

Cavestro

Diodato

Tiranti

et al. 2023

IJMS

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Coenzyme A (CoA) is a vital and ubiquitous cofactor required in a vast number of enzymatic reactions and cellular processes. To date, four rare human inborn errors of CoA biosynthesis have been described. These disorders have distinct symptoms, although all stem from variants in genes that encode enzymes involved in the same metabolic process. The first and last enzymes catalyzing the CoA biosynthetic pathway are associated with two neurological conditions, namely pantothenate kinase-associated neurodegeneration (PKAN) and COASY protein-associated neurodegeneration (CoPAN), which belong to the heterogeneous group of neurodegenerations with brain iron accumulation (NBIA), while the second and third enzymes are linked to a rapidly fatal dilated cardiomyopathy. There is still limited information about the pathogenesis of these diseases, and the knowledge gaps need to be resolved in order to develop potential therapeutic approaches. This review aims to provide a summary of CoA metabolism and functions, and a comprehensive overview of what is currently known about disorders associated with its biosynthesis, including available preclinical models, proposed pathomechanisms, and potential therapeutic approaches.

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PKAN pathogenesis and treatment

Cited by 13 publications

References 82 publications

Treatment of Pantothenate-kinase neurodegeneration with baclofen, botulinum toxin, and deferiprone: A case report

Treatment of Pantothenate-kinase neurodegeneration with baclofen, botulinum toxin, and deferiprone: A case report

Localized Pantothenic Acid (Vitamin B5) Reductions Present Throughout the Dementia with Lewy Bodies Brain

Inherited Disorders of Coenzyme A Biosynthesis: Models, Mechanisms, and Treatments

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