Objective: Propose a new systems approach model for PKAN, investigate treatment, and establish biologic and genetic markers.

Background: PKAN is a recessive, rare, inborn error with an incidence of 1-3 per million, basal ganglia iron accumulation and a defect in PANK2 gene, the rate-limiting enzyme in coenzyme A synthesis.  Many genes exist for PKAN, but RNA sequencing has not been systematically examined. A large PKAN cohort (70 patients, c.680 A>G mutation) in the Dominican Republic (DR) shows prevalence 1,000 times higher than normal; 1-2 patients/1000, and a carrier rate of 15%.The traditional view of the CoA pathway in PKAN (fig 1) fails to explain complex pathways involved in PANK2 gene function and the body systems involved. Our model incorporates cysteine, cysteamine, ADO, and CDO (fig 2). Clinical symptoms involve hepatic, brain, muscle, blood, and eye systems in this disorder (fig 3). Altered hepatic function reduces bile salt conjugation and changes lipid metabolism; changes in lipid metabolism alter red cell membranes with formation of acanthocytes. Brain pathology includes iron accumulation and cell death. Muscle involvement include wasting and pathologic features, and eye changes include retinopathy. Our model includes pantetheine and pantetheine kinase as a therapeutic entry point into the cycle (fig 2). Clinically, two DR patients receiving pantethine had significant improvement (18); 6 additional patients show improvement and treatment is ongoing. Pantethine rapidly converts to pantetheine, a substrate of pantetheine kinase. Pantetheine hydrolyzes into cysteamine and pantothenate; cysteamine enters the cycle via ADO (fig 2).

Method: We will treat 20 genetically confirmed patients using oral pantethine.  Evaluation of pre- and post-treatment include BMI, BMR, fat and muscle mass, video scoring, MRI, blood lipids, bile salts, and acanthocytes, retinal exams, and RNA sequencing.

Results: Treatment effects will be measured as quantifiable changes in symptoms, metabolism, and genetic markers that occur in our PKAN patients. The detailed protocol will be presented.

Conclusion: Our systems approach model for PKAN helps to explain complexity of the metabolic pathways involved in PANK2 gene function, the myriad of body systems involved, and supports the use of pantethine in the treatment of PKAN.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-systems-approach-model-for-pantothenate-kinase-associated-neurodegeneration-pkan-assessment-and-treatment/