Case reportPallidal Stimulation for Dystonia in Pantothenate Kinase-associated Neurodegeneration
Introduction
Neurodegeneration with brain iron accumulation encompasses a cluster of progressive extrapyramidal disorders such as aceruloplasminemia (resulting from mutations in the ceruloplasmin gene), neuroferritinopathy (mutations in the ferritin light chain), and Hallervorden-Spatz disease. These disorders are characterized by radiographic evidence of iron accumulation in the brain, often in the basal ganglia. The latter disorder was first described by Julius Hallervorden and Hugo Spatz in 1922 [1]. In 2001, mutations in the pantothenate kinase 2 gene were mapped to chromosome 20p13 [2], [3]. This autosomal-recessive Hallervorden-Spatz disease subtype, which comprises 50-70% of neurodegeneration with brain iron accumulation cases, became known as pantothenate kinase-associated neurodegeneration [4]. Unlike the atypical form of this disease, which often presents with a later onset and slower progression, the classic presentation is more homogeneous, with rapid progression and a usual onset before 6 years of age [4]. These children often develop rigidity, dystonia, dysarthria, and spasticity. In this poorly understood condition, patients with classic pantothenate kinase-associated neurodegeneration may demonstrate periods of precipitous decline for several months, followed by prolonged episodes of slower progression. They are usually unable to ambulate 10-15 years after the onset of symptoms.
These findings in patients with pantothenate kinase-associated neurodegeneration are presumably related to abnormal iron accumulation in the globus pallidus and substantia nigra reticular zone regions (areas with typically higher iron concentrations in the normal brain). Metal deposition is largely observed in macrophages and microglia, although iron has also been detected in neurons and extracellular spaces adjacent to blood vessels. Up to three times the normal levels are described in these structures, whereas other regions of the brain are not affected [5]. Iron-laden axonal spheroid bodies, possibly due to axonal transport defects, are commonly found in these areas [6]. Gliosis, demyelination, and neuronal loss are also common. These effects may be explicable insofar as pantothenate kinase is a critical regulatory enzyme in the production of coenzyme A [7]. Coenzyme A is involved in fatty-acid synthesis, neurotransmitter synthesis, and mitochondrial energy metabolism. The basal ganglia are particularly sensitive to oxidative stress, and thus pallidal lesions in these patients may be due to lipid metabolism defects or oxidative damage.
Traditional therapies for this disorder consist of medical palliation. Baclofen and trihexyphenidyl are commonly used to treat dystonic signs, although patients with pantothenate kinase-associated neurodegeneration typically do not respond well to l-DOPA [7]. We describe a patient with intractable dystonia, secondary to pantothenate kinase-associated neurodegeneration, who underwent placement of pallidal deep-brain stimulators.
Section snippets
Case Report
The 18-year-old male described here is the oldest of four children. The second oldest also presents with pantothenate kinase-associated neurodegeneration. The third child is a carrier, whereas the youngest does not carry a copy of the mutation. The patient demonstrated normal neurologic development until approximately age 9 years, when he began to develop dystonia in his hands. His dystonia subsequently progressed, with choreoathetoid movements of the tongue and the truncal muscles, resulting
Discussion
Generalized dystonia was traditionally linked to pathologic neuronal firing patterns in the basal ganglia [8]. Thus, stereotactic approaches to deep-brain structures have been attempted since the 1970s. Initially, thalamic targets were favored, but improved dystonic symptoms in Parkinsonian patients after pallidotomies also led to an interest in this target for patients with medically refractory dystonia. Bilateral pallidotomies were associated with severe side effects and subsequent reduction
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