PANK2 – Pantothenate Kinase-Associated Neurodegeneration

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive neurodegenerative disorder caused by biallelic mutations in the pantothenate kinase-2 gene (PANK2). Clinically, PKAN presents with early‐onset dystonia, parkinsonism, choreoathetosis, dysarthria, cognitive impairment, pigmentary retinopathy and the pathognomonic “eye-of-the-tiger” sign on T2 MRI of the globus pallidus.

Genetic evidence for PANK2 involvement is definitive. In a cohort of 123 unrelated probands from 98 families, all classic PKAN cases and one-third of atypical cases harbored biallelic PANK2 mutations, with genotype correlating to disease severity and MRI pattern ([PMID:12510040]). Segregation across multiple consanguineous and nonconsanguineous families further supports causality.

The variant spectrum includes missense, truncating, splice-site and frameshift alleles. For example, a homozygous nonsense mutation c.1111C>T (p.Arg371Ter) in exon 5 abolishes enzymatic function and was first described in the original HARP patient ([PMID:12058097]). Founder alleles have been reported, such as the Dutch 1142_1144delGAG (p.Glu381_Ala382delinsThr) ([PMID:16240131]) and the Korean c.1319G>C (p.Arg440Pro) ([PMID:22103354]).

Functional studies demonstrate that PANK2 encodes a mitochondrial enzyme catalyzing the rate-limiting step in coenzyme A biosynthesis. One isoform localizes to mitochondria via an N-terminal targeting peptide, and disease‐associated mutants lack activity or proper folding ([PMID:12554685]). Biochemical assays reveal that certain missense mutants retain catalytic activity but are hypersensitive to feedback inhibition, whereas truncating and other missense alleles abolish function ([PMID:16272150]).

The pathogenic mechanism is loss of PANK2 activity leading to intramitochondrial CoA deficiency, iron accumulation and neuronal degeneration. Animal and cell models recapitulate neurodegeneration, supporting a haploinsufficiency or null mechanism. Deep brain stimulation, preimplantation genetic diagnosis and emerging CoA-precursor supplementation strategies have shown clinical benefit.

Key Take-Home: Genetic testing for PANK2 variants in patients with characteristic MRI findings enables definitive diagnosis, informs genetic counseling, and guides emerging targeted therapies.

References

• Neurology • 2002 • HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration. PMID:12058097
• The New England Journal of Medicine • 2003 • Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. PMID:12510040
• Human Molecular Genetics • 2003 • An isoform of hPANK2, deficient in pantothenate kinase-associated neurodegeneration, localizes to mitochondria. PMID:12554685
• The Journal of Biological Chemistry • 2006 • Biochemical properties of human pantothenate kinase 2 isoforms and mutations linked to pantothenate kinase-associated neurodegeneration. PMID:16272150

Evidence Based Scoring (AI generated)