Pantothenate kinase-associated neurodegeneration

Overview

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare, inherited neurodegenerative disorder and the most common form of a group of conditions known as neurodegeneration with brain iron accumulation (NBIA). PKAN primarily affects the basal ganglia, a region of the brain responsible for movement control, leading to progressive dystonia, spasticity, and other motor and cognitive impairments. It is characterized by the excessive accumulation of iron in the brain, particularly in the globus pallidus, as well as by the presence of a distinctive MRI finding known as the “eye of the tiger” sign. The condition typically presents in childhood but may also appear later in adolescence or early adulthood.

Causes

PKAN is caused by mutations in the PANK2 gene, which is located on chromosome 20 and provides instructions for making the enzyme pantothenate kinase 2. This enzyme plays a critical role in the biosynthesis of coenzyme A, which is vital for cellular energy metabolism. When the PANK2 gene is mutated, the resulting enzyme is either dysfunctional or absent, leading to metabolic disturbances and the accumulation of potentially toxic compounds. This metabolic dysfunction contributes to neuronal damage and abnormal iron accumulation in the brain. PKAN is inherited in an autosomal recessive manner, meaning an individual must inherit two copies of the faulty gene—one from each parent—to develop the disease.

Symptoms

The clinical presentation of PKAN can vary significantly based on the age of onset and disease progression. It is broadly categorized into two types: classic and atypical.

Classic PKAN (early-onset)

• Onset: Usually occurs before age 6.

• Dystonia: Involuntary muscle contractions causing twisting, repetitive movements, or abnormal postures, often starting in the legs and spreading to the trunk and arms.

• Spasticity: Muscle stiffness and tightness, leading to difficulty with movement and walking.

• Choreoathetosis: Irregular, involuntary movements that combine chorea and athetosis.

• Rigidity and bradykinesia: Features similar to Parkinsonism may be present.

• Speech difficulties: Dysarthria (slurred speech) and progressive loss of speech capabilities.

• Cognitive decline: Progressive intellectual disability in some patients.

• Visual disturbances: Retinal degeneration may occur in some cases.

Atypical PKAN (late-onset)

• Onset: Later in childhood, adolescence, or even early adulthood.

• Slower progression: Symptoms develop more gradually and may include mild dystonia, parkinsonism, or psychiatric features such as depression or obsessive-compulsive behaviors.

• Cognitive abilities: May remain relatively preserved in the earlier stages.

Diagnosis

Diagnosing PKAN involves a combination of clinical evaluation, neuroimaging, and genetic testing:

• Clinical assessment: Neurological examination focuses on movement abnormalities, cognitive function, and visual changes.

• MRI of the brain: Reveals the characteristic “eye of the tiger” sign—a central area of hyperintensity surrounded by a hypointense region in the globus pallidus on T2-weighted images due to iron deposition.

• Genetic testing: Confirms the diagnosis by identifying mutations in the PANK2 gene.

• Laboratory tests: Rule out other causes of neurodegeneration or metabolic disease.

Treatment

There is currently no cure for PKAN. Treatment is supportive and symptomatic, aimed at improving quality of life and managing complications. A multidisciplinary team is often involved in care:

• Medications:

  • Anticholinergics: May help reduce dystonia and muscle rigidity.

  • Baclofen and benzodiazepines: Used to control spasticity and muscle spasms.

  • Levodopa: May be trialed for Parkinsonian symptoms but with variable results.

  • Iron chelation therapy: Deferiprone has been studied to reduce brain iron, though long-term benefits are uncertain.

• Deep brain stimulation (DBS): An option for severe dystonia, targeting the globus pallidus internus to improve motor function.

• Physical and occupational therapy: Helps maintain mobility, prevent contractures, and support daily activities.

• Speech and feeding therapy: Useful for addressing dysarthria and swallowing difficulties.

• Psychological support: Counseling and psychiatric care may be needed for mood or behavioral issues, especially in atypical PKAN.

Prognosis

The prognosis for individuals with PKAN varies depending on the form of the disease and the age at onset. Classic PKAN tends to progress rapidly, with many patients becoming wheelchair-dependent within a decade of symptom onset. Life expectancy may be shortened due to complications such as respiratory infections, aspiration pneumonia, or severe contractures. Atypical PKAN progresses more slowly and is associated with a better overall prognosis and longer survival. Although the condition remains incurable, ongoing research is exploring gene therapy, targeted molecular treatments, and advanced neuroprotective strategies to improve outcomes in the future.