Neurodegeneration with brain iron accumulation (NBIA, formerly Hallervorden-Spatz syndrome) encompasses a group of rare neurodegenerative disorders characterized by progressive extrapyramidal dysfunction (dystonia, rigidity, choreoathetosis), iron accumulation in the brain and the presence of axonal spheroids, usually limited to the central nervous system.
An estimated prevalence of 1-3/1,000,000 has been suggested based on observed cases in a population. The most common form of NBIA is pantothenate kinase-associated neurodegeneration (PKAN; see this term), which accounts for approximately 50% of cases.
NBIA can present as early onset with rapid progression: classic pantothenate kinase-associated neurodegeneration (PKAN), infantile neuroaxonal dystrophy (INAD) and atypical neuroaxonal dystrophy (atypical NAD) (see these terms); or later onset with slower progression: atypical PKAN, neuroferritinopathy and aceruloplasminemia (see these terms). Idiopathic NBIA can have either type of onset and progression.
Classic and atypical PKAN are caused by mutations in the PANK2 gene (20p13-p12.3), infantile and atypical neuroaxonal dystrophy are caused by mutation in the PLA2G6 gene (22q13.1), aceruloplasminemia is caused by mutation of the ceruloplasmin (CP) gene (3q23-q24) and neuroferritinopathy is caused by mutations in the ferritin light chain (FTL1) gene (19q13.3-q13.4). Idiopathic NBIA is likely caused by several additional, as yet undiscovered genes.
This heterogeneous group of disorders can be differentiated by clinical, radiographic, and molecular features. Brain MRI is standard in the diagnostic evaluation of all forms of NBIA. Individuals with PKAN and HARP syndrome, which is considered part of the PKAN disease spectrum, show a characteristic "eye of the tiger''sign on MRI, a central region of hyperintensity surrounded by a rim of hypointensity on coronal or transverse T2-weighted images of the globus pallidus. Infantile and atypical NAD have characteristic axonal swellings throughout the central and peripheral nervous system. Diagnosis of aceruloplasminemia is based on the absence of serum ceruloplasmin in combination with MRI findings of iron accumulation.
The majority of NBIA types are transmitted in an autosomal recessive manner, except neuroferritinopathy which is transmitted in an autosomal dominant manner with high penetrance.
At this time most treatments for NBIA are palliative. Research is currently underway to identify additional NBIA genes and improve treatment possibilities by characterizing the underlying causes of these disorders.
Last update: March 2010
- Dr Allison GREGORY
- Pr Susan HAYFLICK