Neurodegeneration with brain iron accumulation: diagnosis and management

Abstract

Neurodegeneration with brain iron accumulation (NBIA) encompasses a group of inherited disorders that share the clinical features of an extrapyramidal movement disorder accompanied by varying degrees of intellectual disability and abnormal iron deposition in the basal ganglia. The genetic basis of ten forms of NBIA is now known. The clinical features of NBIA range from rapid global neurodevelopmental regression in infancy to mild parkinsonism with minimal cognitive impairment in adulthood, with wide variation seen between and within the specific NBIA sub-type. This review describes the clinical presentations, imaging findings, pathologic features, and treatment considerations for this heterogeneous group of disorders.

Keywords: Brain diseases; Iron; Iron metabolism disorders; Neuroaxonal dystrophies; Neurodegenerative diseases; Pantothenate kinase associated neurodegeneration; inborn; metabolic.

Figure 1

Distribution of NBIA subtypes in the North American database. NBIA: neurodegeneration with brain iron accumulation, PKAN: pantothenate kinase-associated neurodegeneration, PLAN: phospholipase A2-associated neurodegeneration, INAD: infantile neuroaxonal dystrophy, MPAN: mitochondrial membrane protein-associated neurodegeneration, BPAN: beta-propeller protein-associated neurodegeneration, FAHN: fatty acid hydroxylase-associated neurodegeneration, CoPAN: Coenzyme A synthase protein-associated neurodegeneration, NF: neuroferritinopathy, KRS: Kufor-Rakeb syndrome, ACP: aceruloplasminemia.

Figure 2

Imaging characteristics of the four major subtypes of NBIA. All images performed on 3.0T magnet except (G) and (H) which were performed on 1.5T. A: T2-weighted imaging in PKAN shows GP hypointensity indicating iron accumulation with an anteromedially-located area of hyperintensity, the so-called “eye of the tiger”. B: SN in same patient showing hypointensity in medial aspect of nucleus. C: T2-weighted sequence in a patient with MPAN showing pallidal hypointensity with hyperintense streaking in the region of the medial medullary lamina. Depending on the cut, this may be mistaken for an “eye of the tiger” characteristic of PKAN. D: The SN in the same patient also demonstrates iron accumulation. E: T2 sequence of GP and (F) SN in a 9 yo child with PLAN showing evidence of iron accumulation. Imaging performed earlier in the disease course had shown no signal changes. Inset in (F) showing cerebellar atrophy in the same child. G: T2 imaging showing the GP in a young adult with BPAN, after the onset of parkinsonian symptoms. In (H) note the marked hypointensity in the SN, and, in the inset in (H), the same region on T1 weighted sequence showing the characteristic hyperintense “halo” thought to represent neuromelanin release from degenerating neurons. PKAN: pantothenate kinase associated neurodegeneration, MPAN: mitochondrial membrane protein-associated neurodegeneration, BPAN: beta-propeller protein-associated neurodegeneration, PLAN: phospholipase A2-associated neurodegeneration, GP: globus pallidus, SN: substantia nigra, NBIA: neurodegeneration with brain iron accumulation.