Development of a Genetic Testing and Counseling for Pantothenate Kinase Associated Neurodegeneration in the Dominican Republic - PROJECT SUMMARY. Pantothenate kinase-associated neurodegeneration (PKAN) is a rare, autosomal recessive neurological disorder characterized by the progressive degeneration of the central nervous system. PKAN is the most common form of neurodegeneration associated with brain iron accumulation, a group of clinical disorders characterized by abnormal involuntary movements, alterations in muscle tone, and extrapyramidal signs. It is an invariably a fatal disease. Classical PKAN begins in early childhood and worsens gradually such that within the first five years of life dystonia of the musculature of the mouth, throat and tongue results progressive dysarthria, dysphagia and eventually loss of speech and impaired swallowing. Most individuals are unable to walk without assistance by age 10 to 15 years. Atypical PKAN, progresses more slowly, and appears later in childhood or early adolescence, usually after the age of 10 years. Multiple rare, completely penetrant variants in the PANK2 gene cause PKAN and are believed to alter the function of mitochondrial pantothenate kinase 2 reducing coenzyme A (CoA) primarily in the basal ganglia, especially in the globus pallidus. In 2022, physician colleagues in the Dominican Republic told us about multiple individuals and families with PKAN in an isolated region in Barahona Province and knew of more affected individuals scattered throughout the country. If confirmed, this would indicate that the frequency of heterozygous carriers of PANK2 causal variants was likely to be highly elevated. Currently there is no process for genetic testing available and there is limited genetic counseling in the country. Carrier testing for individuals at risk and their relatives, and prenatal testing for pregnancies, would be possible if all the pathogenic variants were identified. Our colleagues asked whether we could assist them in developing capacity for a clinical and research program for individuals putatively diagnosed with PKAN and for genetic testing and for prenatal diagnosis for couples at or before marriage, preconception or early in pregnancy with intensive programs of genetic counseling. The overarching goal of this project is to identify all PANK2 variants among individuals with PKAN in the Cabral- Barahona region, the surrounding villages, and in other parts of the country. We previously obtained blood for DNA extraction in affected individuals with clinically diagnosed PKAN and confirmed PANK2 variants by whole genome sequencing and sequenced their first-degree relatives to identify heterozygous carriers. Working with our colleagues, we intend to establish genotype-phenotype correlations, identify possible modifiers influencing the age-at-onset and disease type, establish a PCR-based molecular testing program in the capital in Santo Domingo, develop a community health worker-facilitated genetic counseling program, and establish the capacity for a sustainable testing and counseling program to manage PKAN and facilitate research.
