Pantothenate Kinase-Associated Neurodegeneration

Pantothenate kinase associated neurodegeneration (PKAN, neurodegeneration with brain iron accumulation type 1) is an autosomal recessive disorder due to biallelic variants in PANK2, with progressive dystonia, dysarthria and iron accumulation in the globus pallidus. Classic disease begins in early childhood, and atypical disease begins later with a slower course and psychiatric features.

Pathophysiology. PANK2 encodes the mitochondrial pantothenate kinase 2, the first enzyme in coenzyme A synthesis. Loss reduces coenzyme A, impairs mitochondrial function and phospholipid metabolism, and leads to cysteine accumulation and iron deposition in the globus pallidus.

Iron accumulation is a marker rather than the cause of neuronal damage.

Progressive dystonia drives most complications.

• Classic form (onset before 6 years): gait difficulty, falls, dystonia, rigidity, dysarthria and spasticity, with loss of ambulation within 10 to 15 years.
• Atypical form (onset after 10 years): speech difficulty, psychiatric symptoms (impulsivity, depression, personality change), and later dystonia, with slower progression.
• Pigmentary retinopathy in the classic form.
• Dysphagia, drooling and weight loss.
• Pyramidal signs, and tongue protrusion dystonia with self-injury.
• Acanthocytosis in some.
• Dystonic storms with severe, sustained dystonia, rhabdomyolysis and respiratory compromise.

• PANK2 sequencing with deletion and duplication analysis.
• Brain MRI: T2 hypointensity of the globus pallidus with a central hyperintense area ("eye of the tiger" sign), mainly in the classic form.
• Ophthalmology, with electroretinography for retinopathy.
• Blood film for acanthocytes.
• Swallow assessment, neuropsychology and psychiatric review.
• Creatine kinase and renal function during dystonic storms.

Differential diagnosis.

• Other neurodegeneration with brain iron accumulation disorders (PLA2G6-associated neurodegeneration, MPAN, BPAN, aceruloplasminaemia)
• Wilson disease
• Neuroacanthocytosis (chorea acanthocytosis, McLeod syndrome)
• Juvenile Huntington disease and other causes of childhood dystonia
• Leigh syndrome

• Dystonia and spasticity: baclofen 0.3 mg/kg daily in divided doses increasing weekly to 2 mg/kg daily (maximum 60 mg), trihexyphenidyl 1 mg daily increasing slowly by 1 to 2 mg weekly to the dose that is tolerated, and clonazepam 0.01 to 0.03 mg/kg daily in two or three divided doses. Botulinum toxin for focal dystonia.
• Dystonic storm: intensive care admission, intravenous midazolam 0.1 mg/kg bolus then infusion at 0.05 to 0.4 mg/kg/hour, deep sedation, hydration, treatment of rhabdomyolysis, and airway support.
• Deep brain stimulation: pallidal stimulation improves dystonia and speech in selected patients, though effect varies.
• Intrathecal baclofen for severe generalised dystonia or spasticity.
• Iron chelation: deferiprone 15 mg/kg twice daily has reduced pallidal iron, and a randomised study showed no clear clinical benefit, so it is not routinely given. Monitor neutrophils weekly if used.
• Feeding and nutrition: dietitian input and gastrostomy for dysphagia.
• Drooling: glycopyrronium bromide 15 microgram/kg orally three times daily, increasing every 7 days to a maximum of 100 microgram/kg daily (not over 6 mg daily), or botulinum toxin to salivary glands.
• Psychiatric symptoms: sertraline 25 to 50 mg daily increasing to a maximum of 200 mg daily for depression or anxiety.
• Tongue and lip self-injury: protective dental appliances, botulinum toxin, and extraction in severe cases.
• Eye and communication support: low vision aids, speech therapy with augmentative communication.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis available.

Special groups.

• Patients with sudden worsening of dystonia: look for infection, pain, constipation or drug withdrawal as triggers before attributing it to disease progression.

Monitoring. Dystonia severity, swallow and nutrition every 3 to 6 months. Eye review yearly, bone health, and psychiatric review at each visit.

Referral and escalation. Refer to clinical genetics, paediatric or adult neurology and functional neurosurgery. Emergency for dystonic storm, aspiration or respiratory failure.