Reply: Safe and effective deep brain stimulation for Parkinson's disease in the context of HIV

I read with interest the fascinating article by Schneider et al describing evidence of brain iron deposition on MRI scans from a case of Kufor-Rakeb disease (KRD). Schneider et al suggest that KRD should be classified as a member of the Neurodegenerative disorders with Brain Iron Accumulation group (NBIA). Here I provide a comparison between the clinical and radiological phenotype of KRD and the other genetic subtypes of NBIA. The pattern of brain iron deposition on MRI can distinguish between the four genetically defined subtypes of NBIA. The imaging features of neuroferritinopathy (dominant, ferritin light chain mutations) are complex. In early disease there is T2* hypointensity (suggestive of iron) in the putamen, caudate, and globus pallidus. As disease advances T2* hypointesity spreads to involve the substantia nigra, dentate nucleus, and cerebral cortex. Cavitation of the lentiform nucleus and caudates occurs in end stage disease. In aceruloplasminemia (recessive, ceruloplasmin mutations) there is diffuse iron deposition in all basal ganglia nuclei, substantia nigra, and cerebral and cerebellar cortex. The iron deposition in the paediatric recessive NBIA disorders Pantothenate Kinase Associated Neurodegeneration (PKAN, pantothenate kinase-2 mutations) and Infantile Neuroaxonal Dystrophy (INAD, PLA2G6 mutations) is restricted to the globus pallidus and substantia nigra, with an ‘‘eye-of-the-tiger’’ sign in PKAN and cerebellar atrophy and gliosis in INAD. Schneider et al report T2* hypointensities, suggestive of iron deposition, in the putamen and caudate nucleus of KRD. This pattern is distinct from that observed in the other NBIA subtypes, though does overlap with putamen and caudate involvement in early neuroferritinopathy. T2* MRI may thus provide a noninvasive method of distinguishing KRD from other causes of NBIA, but further imaging studies of KRD are required to validate this. The clinical phenotype of KRD overlaps with the paediatric NBIA disorders. Both PKAN and INAD have dystonia and pyramidal signs as major features, but retinitis pigmentosa is seen in PKAN not KRD and cerebellar signs are present in INAD but not KRD. KRD is distinct from neuroferritinopathy, which presents in adulthood with chorea or dystonia and preserved cognition, and aceruloplasminemia, which presents with combinations of chorea, ataxia, and dementia. Parkinsonism in these NBIA disorders is not levodopa responsive. There are clinical and pathological links between NBIA and Parkinson’s disease (PD). Parkinsonism has been reported in patients with neuroferritinopathy, INAD, PKAN, aceruloplasminemia, and KRD. Pathological and radiological evidence of nigral iron accumulation is reported in both PD and NBIA, whereas a case of INAD had classic nigral Lewy bodies at autopsy. Mitochondrial dysfunction had been reported in sporadic PD and neuroferritinopathy, and PANK2 and PLA2G6 genes may play a role in mitochondrial function. Thus, a common cellular mechanism linking these diverse disorders and explaining their similarities may be mitochondrial dysfunction. This hypothesis might be further examined by investigating a role for ATP13A2 in mitochondrial function.