PANK2 – Neurodegeneration with Brain Iron Accumulation

Pantothenate kinase‐associated neurodegeneration (PKAN) is the most common form of neurodegeneration with brain iron accumulation (NBIA), characterized by progressive extrapyramidal dysfunction and the pathognomonic “eye‐of‐the‐tiger” sign on T2‐weighted MRI. The PANK2 gene (HGNC:15894) encodes a mitochondrial pantothenate kinase responsible for the rate‐limiting step in coenzyme A biosynthesis, and biallelic PANK2 variants cause autosomal recessive NBIA (MONDO:0018307).

1. Clinical Validity

Multiple independent cohorts have identified biallelic PANK2 mutations in at least 48 unrelated probands with NBIA (PMID:16437574) and in 34 affected individuals from 10 families demonstrating clear segregation of variants with disease (PMID:14743358). Functional studies consistently show loss of kinase activity and mitochondrial dysfunction in patient‐derived cells. Together, these data meet ClinGen criteria for a Definitive gene–disease association.

2. Genetic Evidence

Inheritance is autosomal recessive. Segregation of pathogenic variants has been documented in at least 10 families (PMID:14743358). Across case series, over 70 distinct PANK2 variants have been reported, including missense, nonsense, frameshift, splice, and large deletions. A recurrent homozygous missense variant c.882T>G (p.Asn294Lys) is described in late‐onset atypical PKAN (PMID:23634310).

3. Functional Evidence

Biochemical assays of PANK2 isoforms demonstrate mitochondrial localization of the mature enzyme and marked sensitivity to CoA feedback inhibition. The frequent G521R variant abolishes kinase activity and impairs folding, whereas other missense mutations yield variable residual activity correlating with age of onset (PMID:12554685; PMID:16272150). Zebrafish and yeast models expressing pathogenic alleles recapitulate key features of NBIA and are rescued by CoA pathway precursors, supporting a loss‐of‐function mechanism.

4. Phenotypic Spectrum

Patients present from infancy to late adulthood, with early‐onset cases exhibiting rapid dystonia, dysarthria, gait disturbance, optic atrophy, pigmentary retinopathy and cognitive impairment, while atypical or late‐onset cases often display focal dystonia, parkinsonism, blepharospasm, spasticity, torticollis, or psychiatric features before classic radiographic findings emerge (PMID:23634310; PMID:24655737). Disease prevalence is estimated at 1–3 per million, with carrier frequency enriched in specific populations.

5. Integration and Clinical Utility

The convergence of robust genetic, segregation, and functional data establishes PANK2 as a Definitive cause of autosomal recessive NBIA. Early recognition of the “eye‐of‐the‐tiger” sign should prompt targeted PANK2 sequencing, enabling accurate diagnosis, genetic counseling, and enrollment in emerging therapeutic trials (e.g., iron chelators, CoA‐augmenting compounds).

Key Take-home: Biallelic PANK2 mutations underlie a definitive, autosomal recessive NBIA phenotype, with characteristic MRI findings and loss‐of‐function biochemical defects, warranting early genetic testing to guide management and trial enrollment.

References

• Movement disorders • 2004 • Clinical heterogeneity of neurodegeneration with brain iron accumulation (Hallervorden‐Spatz syndrome) and pantothenate kinase‐associated neurodegeneration PMID:14743358
• Annals of neurology • 2006 • Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation PMID:16437574
• Case reports in neurological medicine • 2013 • Late onset atypical pantothenate‐kinase‐associated neurodegeneration PMID:23634310
• 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

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