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When a family first receives a diagnosis of neurodegeneration with brain iron accumulation, or NBIA, they soon realize that part of the challenge of learning more about this group of disorders is simply understanding all the names and related acronyms.  This may be a challenge that their physicians take on as well, since historically NBIA was called Hallervorden-Spatz syndrome and this is still a name that appears in many medical texts and journal articles.  

As we learn more about the group of disorders that involve neurodegeneration and accumulation of iron in the brain region called the basal ganglia, the related language has also evolved to reflect our new understanding.  Identification of genes causing different types of NBIA has also helped us to better categorize the different disorders falling under this umbrella. The term NBIA is general enough to cover all conditions previously categorized as Hallervorden-Spatz syndrome plus other conditions found to fit in this group. 

The diagram below shows the different forms of NBIA and, when known, the genes that cause them.  Although NBIA is generally divided into early onset and late onset forms, there are always exceptions to this rule and some cases will fall between these two categories. 

Most recently, we have proposed to add classic infantile neuroaxonal dystrophy (INAD) and atypical neuroaxonal dystrophy (NAD) to the NBIA umbrella. These are both caused by changes in the PLA2G6 gene.  The Hayflick research group initially started studying INAD because several physicians worldwide sent us examples of patients with this diagnosis who had brain iron accumulation identical to that seen in NBIA.  At first, we thought these cases were rare, but we have since found that several individuals with INAD also have high brain iron in a similar pattern to other NBIA. 

In addition, individuals with this diagnosis have axonal spheroids like those seen in NBIA, although in INAD they are not limited to just the brain but can also be found in other tissues like skin or muscle.  We also found that some individuals who we never suspected to have INAD have mutations in the PLA2G6 gene.  Unlike classic INAD, which usually involves floppiness (hypotonia) in infancy, followed by spasticity (stiffness), these atypical individuals have later onset with dystonia as a main symptom.  For this reason, we created a separate category called atypical NAD. 

Two other rare disorders are also considered to be part of NBIA, although to date they haven’t received much attention within our NBIA community.  This is primarily because they affect small, discreet groups of people and appear to be even more rare than PKAN or other types of NBIA that many of us know well.

Aceruloplasminemia has mainly been studied in Japan, where it affects about 1 in 2 million adults.  It is unclear how often it occurs outside the Japanese population, but is even more rare.  Aceruloplasminemia has three main symptoms:  retinal degeneration, diabetes, and neurologic disease.  These are caused by iron accumulation in the brain and visceral organs.  This is a disorder of adulthood that usually begins during the third to fifth decade of life.  Like most NBIA, it is inherited in an autosomal recessive fashion. 

Neuroferritinopathy typically starts in adulthood with dystonia, jerky movements (chorea), and mild changes in thinking (cognitive effects).  The prevalence is unknown, but fewer than 50 cases have been described in the literature and most of these individuals have the same gene change, suggesting a common ancestor. Brain MRI shows abnormal iron accumulation in the basal ganglia during early disease; later, cysts develop in these regions.  So far, neuroferritinopathy is the only type of NBIA known to be passed through the family in a dominant pattern, meaning that an affected individual has a 50% chance of passing it to each of his/her children. 

Of all cases of NBIA, about one-half to two-thirds are accounted for by one of the conditions described above, with PKAN being the most common. The remaining individuals are said to have “idiopathic NBIA,” meaning that the underlying cause is not yet known.  For many of these families, the person diagnosed with NBIA is the first and only affected individual, so it is difficult to know whether there is a specific pattern of inheritance. 

It is thought that most of these cases are probably recessive because (a) there are some families with more than one affected child and (b) idiopathic NBIA is more common in families where the parents are related, such as distant cousins (this makes it more likely that they share a common recessive gene).  The symptoms in this group are more varied because there are probably several different causes of neurodegeneration in this group. As with other forms of NBIA, there are both early-onset and late-onset types. 

As we and other researchers continue to identify genes that cause NBIA, it is likely that definitions will continue to change.  We hope that expanding this NBIA umbrella and trying to understand the underlying processes that are common among people with different forms of NBIA will lead us to new treatments and a better understanding of this disease. 

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