Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

Abstract

Our understanding of the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) continues to grow considerably. In addition to the core syndromes of pantothenate kinase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2), several other genetic causes have been identified (including FA2H, C19orf12, ATP13A2, CP and FTL). In parallel, the clinical and pathological spectrum has broadened and new age-dependent presentations are being described. There is also growing recognition of overlap between the different NBIA disorders and other diseases including spastic paraplegias, leukodystrophies and neuronal ceroid lipofuscinosis which makes a diagnosis solely based on clinical findings challenging. Autopsy examination of genetically-confirmed cases demonstrates Lewy bodies, neurofibrillary tangles, and other hallmarks of apparently distinct neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease. Until we disentangle the various NBIA genes and their related pathways and move towards pathogenesis-targeted therapies, the treatment remains symptomatic. Our aim here is to provide an overview of historical developments of research into iron metabolism and its relevance in neurodegenerative disorders. We then focus on clinical features and investigational findings in NBIA and summarize therapeutic results reviewing reports of iron chelation therapy and deep brain stimulation. We also discuss genetic and molecular underpinnings of the NBIA syndromes.

Niemann-Pick’s disease type B and brain iron accumulation

“…[12] A shared feature of these diseases is brain iron accumulation that is likely secondary to abnormalities in lipid metabolism and autophagy. [3,4] Figure 2. Iron accumulation in the brain of the proband's mother but not of the father, who were both heterozygous carriers of the same c19orf12 gene deletion Figure 2A and B are T2 FFE (corresponding to T2*) weighted axial brain images taken by a 3 Tesla Philips scanner.…”

“…[1,2] New entities of neurodegeneration with brain iron accumulation (NBIA) have subsequently been identified along with mutations in the causative genes. [3,4] In the Hungarian population, the most frequent pathogenic NBIA-causing mutations have been detected in the c19orf12 gene underlying Mitochondrial Membrane Protein Associated Neurodegeneration (MPAN), followed by PANK2 and PLA2G6 mutations underlying PKAN and phospholipase A -related neurodegeneration (PLAN), respectively. [5] While most affected NBIA genes result in abnormalities in mitochondrial lipid metabolism, the question of how this biochemical pathway alterations relate to brain iron accumulation is still debated.…”

Iron chelation in the treatment of neurodegenerative diseases

“…Despite cerebral iron accumulation in aging and neurodegenerative disorders has been appreciated for a century, its mechanisms are still poorly understood [5]. In theory, several possible sources of increased brain iron deposits may be involved, (1) bleeding, (2) influx of iron-containing macrophages from the bloodstream or (3) dysregulation of iron transport across the blood-brain barrier (BBB).…”

“…This notion is witnessed by an increased brain iron content in aceruloplasminemia and neuroferritinopathy which are hereditary disorders caused by dysfunction of proteins involved in the transport and storage of iron, namely in ceruloplasmin [12] and ferritin light chain (FTL) [13]. Iron is essential for many cellular functions, including energy production, DNA synthesis and repair, phospholipid metabolism, myelination and neurotransmitter synthesis [5]. Impairment or upregulation of any of these functions in brain cells may thus increase the need for iron.…”

“…Pantothenate kinase-associated neurodegeneration (PKAN) caused by a mutation in the PANK2 gene is the most prevalent disorder from the NBIA group [5]. The affected gene codes for pantothenate kinase 2, a regulatory enzyme in coenzyme A synthesis, which is involved in cellular energy and lipid metabolism [65].…”