Clinical and genetic delineation of neurodegeneration with brain iron accumulation

Abstract

Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive neurodegenerative disorders characterised by high brain iron and the presence of axonal spheroids, usually limited to the central nervous system. Mutations in the PANK2 gene account for the majority of NBIA cases and cause an autosomal recessive inborn error of coenzyme A metabolism called pantothenate kinase associated neurodegeneration (PKAN). More recently, it was found that mutations in the PLA2G6 gene cause both infantile neuroaxonal dystrophy (INAD) and, more rarely, an atypical neuroaxonal dystrophy that overlaps clinically with other forms of NBIA. High brain iron is also present in a portion of these cases. Clinical assessment, neuroimaging, and molecular genetic testing all play a role in guiding the diagnostic evaluation and treatment of NBIA.

Figure 1

Categorisation of neurodegeneration with brain iron accumulation (NBIA) subtypes and causative genes. INAD, infantile neuroaxonal dystrophy; NAD, neuroaxonal dystrophy; PKAN, pantothenate kinase associated neurodegeneration.

Figure 2

Patterns of iron accumulation on T2 weighted magnetic resonance imaging (MRI) of the brain. The image on the left is from a normal patient. The centre image from a patient with idiopathic neurodegeneration with brain iron accumulation (NBIA) (PANK2 mutation negative) has a region of hypointensity (arrow) seen in the medial globus pallidus. The right image from a patient with mutation positive pantothenate kinase associated neurodegeneration (PKAN) shows an eye-of-the-tiger sign with hypointensity (thick arrow) with a central region of hyperintensity (thin arrow) in the medial globus pallidus.

Figure 3

Magnetic resonance imaging (MRI) findings associated with infantile and atypical neuroaxonal dystrophy. The image on the left shows a region of hypointensity (arrow) in the medial globus pallidus from a patient with PLA2G6 mutation positive infantile neuroaxonal dystrophy. The image on the right shows cerebellar atrophy (arrow) in the same patient. These findings appear similarly in patients with the infantile and atypical forms of disease.

Figure 4

Diagnostic pathway for infantile neuroaxonal dystrophy (INAD). MRI, magnetic resonance imaging.

Figure 5

Diagnostic pathway for neurodegeneration with brain iron accumulation (NBIA). MRI, magnetic resonance imaging; NAD, neuroaxonal dystrophy; PKAN, pantothenate kinase associated neurodegeneration.