Neurodegeneration with brain iron accumulation

Abstract

Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders affecting children and adults. These rare disorders are often first suspected when increased basal ganglia iron is observed on brain magnetic resonance imaging. For the majority of NBIA disorders the genetic basis has been delineated, and clinical testing is available. The four most common NBIA disorders include pantothenate kinase-associated neurodegeneration (PKAN) due to mutations in PANK2, phospholipase A₂-associated neurodegeneration caused by mutation in PLA2G6, mitochondrial membrane protein-associated neurodegeneration from mutations in C19orf12, and beta-propeller protein-associated neurodegeneration due to mutations in WDR45. The ultrarare NBIA disorders are caused by mutations in CoASY, ATP13A2, and FA2H (causing CoA synthase protein-associated neurodegeneration, Kufor-Rakeb disease, and fatty acid hydroxylase-associated neurodegeneration, respectively). Together, these genes account for disease in approximately 85% of patients diagnosed with an NBIA disorder. New NBIA genes are being recognized with increasing frequency as a result of whole-exome sequencing, which is also facilitating early ascertainment of patients whose phenotype is often nonspecific.

Keywords: BPAN; INAD; MPAN; NBIA; PKAN; PLAN; infantile neuroaxonal dystrophy; neurodegeneration with brain iron accumulation; pantothenate kinase.

Fig. 19.1.

Magnetic resonance imaging of globus pallidus and substantia nigra in four main forms of neurodegeneration with brain iron accumulation. Axial T2-weighted imaging of globus pallidus (top series) and substantia nigra (bottom series) in (A) pantothenate kinase-associated neurodegeneration; (B) phospholipase A₂-associated neurodegeneration (inset shows cerebellar atrophy); (C) mitochondrial membrane protein-associated neurodegeneration; and (D) beta-propeller protein-associated neurodegeneration (inset shows T1 hyperintense “halo” in cerebellar peduncles).

Fig. 19.2.

Overview of genes and pathways involved in neurodegeneration with brain iron accumulation (NBIA). Schematic representation of a cell indicating the pathophysiologic mechanisms postulated for NBIA. Nine reported NBIA genes (white box, red outline) and their associated cellular processes are shown. Ceruloplasmin (CP) and ferritin light polypeptide (FTL) are important regulators of cellular iron homeostasis. Phospholipase A2 (PLA2G6) and fatty acid 2-hydroxylase (FA2H) are involved in lipid metabolism and membrane remodeling. Pantothenate kinase 2 (PANK2) and CoA synthase (COASY) are key enzymes in the biosynthesis of coenzyme A (CoA) utilized in a multitude of cellular processes, including the synthesis of fatty acids. WD repeat domain 45 (WDR45) and ATPase type13A2 (ATP13A2) play a role in the degradation process of autophagy. The function of the mitochondrial membrane protein C19orf12 is still unknown, but it is postulated to be associated with fatty acid biogenesis. (Reproduced from Meyer E, Kurian MA, Hayflick SJ (2015) Neurodegeneration with brain iron accumulation: genetic diversity and pathophysiological mechanisms. Annu Rev Genomics Hum Genet 16: 8.1–8.23, with permission.)