Classic pantothenate kinase-associated neurodegeneration

Classic pantothenate kinase-associated neurodegeneration (PKAN), formerly known as Hallervorden-Spatz syndrome or neurodegeneration with brain iron accumulation type 1 (NBIA1), is a rare inherited neurodegenerative disorder caused by mutations in the PANK2 gene located on chromosome 20p13. This gene encodes the enzyme pantothenate kinase 2, which plays a critical role in coenzyme A biosynthesis. Deficiency of this enzyme leads to progressive iron accumulation in the basal ganglia, particularly the globus pallidus, resulting in characteristic neurological deterioration. The classic form accounts for approximately 75% of all PKAN cases and is distinguished from the atypical form by its earlier onset and more rapid progression. The classic form typically presents in early childhood, usually before age 6 years. Key clinical features include progressive dystonia (the most prominent symptom), spasticity, rigidity, choreoathetosis, and gait disturbance that often leads to loss of independent ambulation within 10-15 years of onset. Dysarthria and dysphagia develop as the disease progresses. Pigmentary retinopathy (retinitis pigmentosa) is a distinguishing feature seen in many patients with classic PKAN. Cognitive decline occurs but is variable. Brain MRI characteristically shows the "eye-of-the-tiger" sign — a central hyperintensity surrounded by a region of hypointensity in the globus pallidus on T2-weighted imaging — which is highly suggestive of the diagnosis. There is currently no cure or disease-modifying treatment for classic PKAN. Management is symptomatic and supportive. Dystonia may be partially managed with oral medications such as baclofen, trihexyphenidyl, or benzodiazepines, and in severe cases, intrathecal baclofen or deep brain stimulation (DBS) of the globus pallidus internus may provide some relief. Botulinum toxin injections can help with focal dystonia. Physical therapy, occupational therapy, speech therapy, and nutritional support are important components of multidisciplinary care. Iron chelation therapy with deferiprone has been investigated in clinical trials, though definitive evidence of clinical benefit remains under evaluation.

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