![Fig. 1: T2-weighted MRI showing bilateral iron deposition at the basal ganglia - "Eye-of-the-Tiger" sign [3].](https://neuropedia.net/wp-content/uploads/2025/02/PKAN-630x400.jpg)
Article Topic: Pantothenate Kinase-Associated Neurodegeneration (PKAN)
Author: Jana Warde
Editor: Odette El Ghawi, Joseph Akiki
Reviewer: Ethar Hazaimeh
Keywords: Pantothenate Kinase-Associated Neurodegeneration, Pantothenate Kinase 2, Eye-of-the-Tiger sign, globus pallidus, basal ganglia
Abbreviations: Pantothenate Kinase-Associated Neurodegeneration (PKAN), Neurodegeneration with Brain Iron Accumulation (NBIA), Magnetic Resonance Imaging (MRI), T2-weighted MRI (T2-MRI), Pantothenate Kinase 2 (PANK2), Deep Brain Stimulation (DBS)
Abstract
Background: Pantothenate Kinase-Associated Neurodegeneration (PKAN) is an autosomal recessive disorder caused by mutations in the PANK2 gene, leading to iron accumulation in the basal ganglia and progressive neurodegeneration.
Objective: This paper reviews current knowledge on PKAN, including its genetic basis, clinical manifestations, diagnosis, and treatment options.
Methods: A comprehensive literature review was conducted using Radiopaedia databases, focusing on case studies, neuroimaging reports, and genetic research related to PKAN.
Results: PKAN presents in two major forms: classic (early-onset, rapid progression) and atypical (later-onset, slower progression). The hallmark neuroimaging feature is the “eye-of-the-tiger” sign on T2-weighted MRI. Diagnosis is confirmed through genetic testing for PANK2 mutations. Currently, treatment is symptomatic, as no disease-modifying therapy is available, though deep brain stimulation (DBS) has shown potential benefits.
Conclusion: PKAN is a rare yet severe disorder characterized by progressive movement abnormalities due to basal ganglia dysfunction. Future research is needed to explore targeted therapies that could modify disease progression.
Introduction
Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a rare autosomal recessive disorder classified under Neurodegeneration with Brain Iron Accumulation (NBIA). This progressive neurodegenerative condition is characterized by involuntary spasticity and cognitive decline, distinguishing it within the broader NBIA spectrum. It results from mutations in the PANK2 gene, which encodes pantothenate kinase 2, an enzyme involved in coenzyme A biosynthesis. Impaired pantothenate metabolism leads to iron accumulation in the basal ganglia, particularly the globus pallidus, driving progressive neurodegeneration. PKAN presents with both motor and cognitive symptoms, making early recognition crucial for effective management.
Etiology and Pathogenesis
PKAN is caused by biallelic mutations in the PANK2 gene, located on chromosome 20p13. Pantothenate kinase 2 plays a key role in the biosynthesis of coenzyme A (CoA), which is essential for mitochondrial function.
Loss-of-function mutations in PANK2 result in CoA deficiency, leading to mitochondrial dysfunction and the accumulation of cysteine, which binds iron to form cytotoxic free radicals. Iron accumulation in the basal ganglia—particularly in the globus pallidus and substantia nigra—leads to oxidative stress, neuronal damage, and progressive motor dysfunction.
Clinical Presentation
Patients with pantothenate kinase-associated neurodegeneration (PKAN) typically present with a constellation of symptoms affecting multiple domains.
Motor manifestations include dystonia, rigidity, choreoathetosis, and gait disturbances [5]. Cognitively, patients often experience a progressive decline, particularly affecting executive functions. Ocular involvement is also common, with approximately 33% of cases exhibiting pigmentary retinopathy, and many patients developing optic atrophy [4]. Additionally, psychiatric symptoms such as depression, obsessive-compulsive behaviors, and emotional lability are frequently observed [3,5].
PKAN Subtypes
PKAN is clinically divided into two phenotypes: classic and atypical.
- Classic PKAN: Onset occurs before age 6, with rapid progression. Symptoms include severe dystonia (90% of cases), dysarthria, spasticity, and retinopathy. Intellectual decline is often severe, particularly in executive function [4].
- Atypical PKAN: Onset occurs in late childhood or adolescence, with slower disease progression. Symptoms include gait abnormalities, psychiatric disturbances (e.g., impulsivity), and milder parkinsonism. Cognitive decline is variable.
Table 1 summarizes the differences between classic and atypical PKAN in terms of age of onset, disease progression, clinical symptoms, and cognitive decline.
| Feature | Classic PKAN | Atypical PKAN |
| Onset Age | Childhood (before age 10) | Late childhood to adulthood |
| Progression | Rapid (wheelchair-bound within 10 years) | Slower (longer disease course) |
| Symptoms | Dystonia, rigidity, spasticity, speech impairment, retinal degeneration | Gait abnormalities, psychiatric symptoms, speech difficulties |
| Cognitive Decline | Frequent | Variable |
Table 1: Key differences between classic and atypical PKAN.
Diagnosis
Diagnosis of PKAN involves a combination of clinical evaluation, neuroimaging, and genetic testing.
Neuroimaging
Neuroimaging is central to the diagnosis and management of PKAN. On T2-weighted MRI, the most striking feature is the “eye-of-the-tiger” sign—a pattern that is both distinctive and highly suggestive of the disease. This sign is seen in the globus pallidus, where a central area of hyperintensity is surrounded by a rim of hypointensity. The central hyperintensity is thought to reflect gliosis, tissue necrosis, or edema, while the peripheral hypointensity corresponds to iron deposition, which creates a magnetic susceptibility effect. This contrast provides a clear, almost pathognomonic image for PKAN, setting it apart from other neurodegenerative disorders.
Figure 1 shows the eye-of-the-tiger sign in the globus pallidus of a patient diagnosed with PKAN [3].
![Fig. 1: T2-weighted MRI showing bilateral iron deposition at the basal ganglia - "Eye-of-the-Tiger" sign [3].](https://neuropedia.net/wp-content/uploads/2025/02/PKAN-300x300.jpg)
Figure 1: T2-weighted MRI showing bilateral iron deposition at the basal ganglia – “Eye-of-the-Tiger” sign [3].
By combining these imaging modalities, clinicians can obtain a comprehensive view of both the structural changes and the biochemical environment within the basal ganglia, which is critical for accurate diagnosis and ongoing management of PKAN.
Genetic testing
Genetic testing for pantothenate kinase-associated neurodegeneration (PKAN) detects biallelic pathogenic mutations in the PANK2 gene, confirming the diagnosis [2,6]. This test is definitive, providing clear evidence of the disorder’s underlying cause and is considered the gold standard for diagnosis. The process typically begins with a blood draw to extract genomic DNA, followed by PCR amplification of the gene’s exons and flanking regions. Sanger sequencing identifies point mutations and small insertions or deletions.
For broader analysis, next-generation sequencing (NGS) can cover the entire coding region and related genes, while multiplex ligation-dependent probe amplification (MLPA) helps detect larger deletions or duplications.
The identification of homozygous or compound heterozygous mutations confirms the diagnosis of PKAN and aids in genetic counseling and management decisions.
Management and Treatment
Currently, there is no cure for PKAN, and the management strategy is primarily focused on symptomatic relief and improving the patient’s quality of life.
Symptomatic treatments include the use of botulinum toxin for focal dystonia, trihexyphenidyl for generalized dystonia, and levodopa-carbidopa for parkinsonism-like symptoms. Regular physical therapy is an essential component of care, as it helps maintain mobility, prevent contractures, and improve gait. In cases of severe dystonia, deep brain stimulation (DBS) has been shown to improve motor symptoms significantly.
Emerging therapeutic approaches are also under investigation; iron chelation with deferiprone has demonstrated some benefit in reducing brain iron accumulation, although its clinical impact varies among patients.
Additionally, ongoing research into gene therapy aims to restore PANK2 function, while neuroprotective strategies—such as the use of antioxidant therapies—are being explored to mitigate neuronal damage and slow disease progression.
Conclusion
PKAN is a devastating neurodegenerative disorder characterized by iron accumulation in the basal ganglia and progressive motor and cognitive impairment. While no disease-modifying treatments exist, symptomatic therapies, including DBS and physical therapy, can offer some relief. Genetic testing and neuroimaging have advanced the diagnosis, allowing for earlier detection. Future research should focus on targeted gene therapies and neuroprotective strategies to halt or slow disease progression.
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