Neurodegeneration With Brain Iron Accumulation
Neurodegeneration with brain iron accumulation is a heterogenous group of inherited neurological disorders, still under research, in which iron accumulates in the basal ganglia, either resulting in progressive dystonia, Parkinsonism, spasticity, optic atrophy, retinal degeneration, neuropsychiatric, or diverse neurologic abnormalities. Some of the NBIA disorders have also been associated with several genes in synapse and lipid metabolism related pathways. NBIA is not one disease but an entire group of disorders, characterized by an accumulation of brain iron, sometimes in the presence of axonal spheroids in the central nervous system. Iron accumulation can occur anywhere in the brain, with accumulation typically occurring in globus pallidus, substantia nigra, pars reticula, striatum and cerebellar dentate nuclei. Symptoms can include various movement disorders, neuropsychiatric issues, seizures, visual disturbances, and cognitive decline, usually in different combinations. The cause of NBIA disorders are a multitude of possible mutations in genes directly involved in iron metabolism, and/or impaired phospholipid, and/or ceramide metabolism, and/or lysosomal disorders, as well as mutations in genes with unknown functions. Onset can occur at different ages, from early childhood to late adulthood.
Variants
| NBIA variant | Gene | Inheritance | MRI diagnosis | Symptoms |
|---|---|---|---|---|
| Pantothenate kinase-associated neurodegeneration (PKAN) | PANK2 | autosomal recessive | ||
| PLA2G6-associated neurodegeneration (PLAN) | PLA2G6 | autosomal recessive | ||
| Mitochondrial membrane protein-associated neurodegeneration (MPAN) | C19orf12 | autosomal recessive | ||
| Beta-propeller protein-associated neurodegeneration (BPAN) | WDR45 | X-linked dominant (mostly de novo mutations) | ||
| Fatty acid hydroxylase-associated neurodegeneration (FAHN) | FA2H | autosomal recessive | ||
| Kufor–Rakeb syndrome | ATP13A2 | autosomal recessive | ||
| Neuroferritinopathy | FTL | autosomal dominant | ||
| Aceruloplasminemia | CP | autosomal recessive | ||
| Woodhouse–Sakati syndrome | DCAF17 | autosomal recessive | ||
| COASY protein-associated neurodegeneration (CoPAN) | COASY | autosomal recessive | ||
| NBIA7 | REPS1 | autosomal recessive | ||
| NBIA8 | CRAT | autosomal recessive |
Other variants
There are a number of idiopathic NBIA variants for which details are still rare or missing. They all have in common that a disturbed iron metabolism causes havoc in the brain, especially the basal ganglia.
Diagnosis
DAT-Scans, TC(D)-Sonography, PET-Scans and in some cases Magnetic resonance imaging (MRI) (type of scans depending on the symptoms) are used to distinguish between the different forms of NBIA due to the accumulation of iron in different areas of the brain. Patients typically fall into two different categories: (1) early onset, rapid progression or (2) late onset, slow progression. The first type is considered to be the classic presentation, while the second type is thought to be a more atypical presentation. Phenotypes of the different disorders appear to be dependent on age, i.e. amount of iron accumulation and cognitive abilities.
Treatments
An effective treatment has yet to be found. In many cases electrical stimulation of the globus pallidus has been shown to produce improvement of dystonia severity, however it has not been shown to delay neurodegeneration. There is often overlap in the phenotypes of the symptoms both between different NBIA disorders and between NBIA and other disorders, leading to misdiagnoses. Treatments typically treat or ameliorate the symptoms and do not address the accumulation of iron. Psychopharmacology, such as with dopaminergic drugs, anticholinergics, tetrabenazine, is often used to treat the symptoms but does not improve the long term outcome of the patient.