By Michael C. Kruer, MD and Susan J. Hayflick, MD
Portland, OR USA
Special to The Movement Disorder Society
Neurodegeneration with brain iron accumulation (NBIA) refers to a group of neurogenetic diseases that feature a movement disorder, intellectual decline, and a characteristic MRI appearance. NBIA disorders exhibit low signal in the globus pallidus and often the substantia nigra on T2-weighted imaging (along with an isointense appearance on T1) consistent with iron deposition. Interestingly, sporadic neurodegenerative disorders, including Alzheimer and Parkinson diseases, also feature brain iron deposition, although not to the degree seen in NBIA. The occurrence of Lewy bodies and neurofibrillary tangles in the brains of a subset of NBIA patients further supports a link to other neurodegenerative diseases, and suggests that common neurodegenerative pathways are involved. We highlight new developments in the field, which include both the identification and characterization of novel subtypes of NBIA, as well as progress that has been made in known forms of the disorder.
Pantothenate kinase-associated neurodegeneration (PKAN)
PKAN, formerly referred to as Hallervorden-Spatz disease, is caused by mutations in the PANK2 gene. Clinically, individuals with PKAN have a progressive pigmentary retinopathy, severe dystonia, and a variable degree of intellectual decline. Neuropsychiatric features and parkinsonism are prominent in those with later onset. Prominent oro-bucco-lingual dystonia is frequently seen in PKAN; this may manifest as a task-specific eating dystonia. Neuropathologically, neuroaxonal spheroids are observed.
Since the discovery almost a decade ago that mutations in PANK2 lead to PKAN, considerable progress has been made in understanding the pathogenesis of the disease and in developing targeted therapies. Driven by findings that use of the chelation agent deferiprone may reduce iron deposition in the CNS in Freidriech ataxia (Boddaert, et al. 2007) deferiprone clinical trials are currently underway for PKAN in Italy (Zorzi, et al. 2010; NCT00907283), and planned for the US (E. Vichinsky, personal communication). However, despite the progress that has been made in characterizing the pathogenesis of PKAN, a fundamental question remains in the field: is the iron deposition seen in NBIA pathogenic, or merely an epiphenomenon?
Although a mouse model that recapitulates the phenotype of iron deposition and neurodegeneration is lacking, a promising Drosophila model has been extensively studied (Wu, et al. 2009). Recently, work by Ody Sibon and colleagues has shown it is possible to rescue the fly neurodegenerative phenotype by bypassing the metabolic blockade in CoA synthesis by using pantethine, which restores CoA levels (Rana, et al. 2010). These findings have prompted further preclinical studies, with planning for subsequent clinical trials in PKAN in progress.
Neuroaxonal dystrophy (NAD)
NAD is caused by mutations in the calcium-independent phospholipase A2 gene, PLA2G6. Classically, NAD was recognized as a disease beginning in infancy (INAD), with affected children exhibiting a neurodevelopmental arrest and manifesting severe hypotonia, followed by ataxia, dystonia, optic atrophy, peripheral neuropathy, and a general intellectual and motor decline. Neuropathologically, affected individuals had prominent neuroaxonal spheroids detectable in skin or peripheral nerve biopsy and many had been shown to accumulate iron in the basal ganglia (Nardocci, et al. 1999).
With the identification of the causative gene, it was found that some individuals previously diagnosed with 'idiopathic NBIA,' with symptom onset later in childhood or even in adulthood, also harbored mutations in PLA2G6 (Gregory, et al. 2008; Kurian, et al. 2008). Further extending the phenotype, Paisan-Ruiz et al. (2009) found mutations in PLA2G6 in dystonia-parkinsonism without evidence of iron deposition, highlighting the remarkable variability seen in this class of diseases. Recent progress in NAD has included the generation of several additional mouse models (Malik, et al. 2008; Wada, et al. 2009; K. Seburn, personal communication) that will greatly facilitate efforts to develop rational therapies.
The only autosomal dominant form of NBIA, NFT is caused by mutations in the ferritin light chain gene, FTL. NFT leads to a complex neurological phenotype characterized by parkinsonism, choreoathetosis, dystonia, spasticity, ataxia, dementia, and autonomic features. Neuroaxonal spheroids are found in brain tissue from affected patients. In NFT, iron deposition may be observed in the caudate, putamen, globus pallidus, thalamus, and dentate in addition to a cavitation in the basal ganglia not seen in other forms of NBIA (McNeill, et al. 2008). A mouse model has recently been developed (Vidal, et al. 2008), which exhibits signs of increased oxidative stress and DNA damage, particularly in mitochondria (Deng, et al. 2010). This mouse model has ferritin inclusion bodies in the brain similar to those seen in human NFT (Barbeito, et al. 2009).
ACP is caused by mutations in the CP gene. Clinical symptoms may include ataxia, chorea, parkinsonism, dysarthria, and progressive dementia, as well as a retinopathy. Neuroimaging typically demonstrates widespread iron deposition in basal ganglia nuclei. Also, iron deposition may be detectable in the liver, pancreas, and other viscera, with concurrent diabetes mellitus observed in some patients. Recent efforts in ACP have focused on the intersection of iron deposition and oxidative stress, as evidenced by the finding that ceruloplasmin-deficient mice demonstrate increased deposition of oxidative by-products (Kaneko, et al. 2008). Other studies indicate that in conditions of increased oxidative stress, mRNA decay leads to a decrease in ACP transcript abundance (Tapryal, et al. 2009). This finding links iron deposition with copper metabolism, as most ACP mutants demonstrate a loss of copper binding ability, an essential function for the enzyme to maintain the function of the iron exporter ferroportin (di Patti, et al. 2009).
Fatty Acid Hydroxylase-associated Neurodegeneration (FAHN)
A newly described subtype of NBIA (Kruer, et al. 2010a), FAHN is caused by mutations in the fatty acid-2 hydroxylase FA2H. Clinically, symptoms in affected patients typically begin with childhood-onset focal dystonia of the lower limbs. Patients with FAHN then develop progressive ataxia and dysmetria. A spastic quadriparesis then ensues, as well as optic atrophy. FAHN patients may develop epilepsy later in the course of the disease. Phenotypically, FAHN resembles NAD, although peripheral neuropathy is notably absent. Several mouse models of FA2H disruption are available (Zoller, et al. 2008; J. Sundberg, personal communication; H. Hama, personal communication), which will facilitate further study of this subtype of NBIA.
Kufor Rakeb Syndrome (KRS)
Originally described as a rare, autosomal recessive form of parkinsonism caused by mutations in the ATP13A2 gene, KRS was recently recognized as a form of NBIA, with significant iron accumulation in the globus pallidus (Schneider, et al. 2010). Clinically, KRS features parkinsonism, dystonia, dysarthria, and spastic paraparesis. A progressive intellectual decline is typical, and neuropsychiatric features may include aggression and psychosis. Distinctive features include supranuclear gaze palsy, oculogyric crises, and facial-faucio-finger (FFF) mini-myoclonus.
Woodhouse-Sakati Syndrome (WSS)
An unusual NBIA subtype, WSS is caused by mutations in the c2orf37 gene, a nucleolar protein (Alazami, et al. 2008). WSS is phenotypically distinct, with affected individuals demonstrating alopecia, a dysmorphic facial appearance, hypogonadism, and diabetes mellitus, as well as EKG abnormalities (Schneider & Bhatia, 2008). However, WSS individuals feature marked hypointensity of the globus pallidus on T2-weighted MRI, and choreoathetosis, dystonia, and dementia, consistent with classification as an NBIA syndrome. A mouse model has recently been established (F. Alkuraya, personal communication) enabling further study of this disorder.
Static Encephalopathy with NeuroDegeneration in Adulthood (SENDA)
Challenging notions of static versus progressive encephalopathies, patients with this newly-recognized NBIA phenotype are diagnosed with mental retardation during the preschool years. Many exhibit concurrent neuromotor impairment that leads to a diagnosis of spastic cerebral palsy. However, affected patients subsequently gain skills for one or more decades without progression of symptoms before a neurodegenerative course emerges in adulthood. At this time, brain imaging shows the characteristic pattern of iron deposition common to NBIA, along with additional MRI features which distinguish SENDA. Clinically, affected patients develop mixed parkinsonism-dystonia, worsening spastic quadriparesis, and intellectual decline. A manuscript describing the SENDA phenotype in detail has been submitted (Kruer, et al. 2010b). No causative gene has been identified for this disease thus far.
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About Dr. Michael C. Kruer, MD
Dr. Michael C. Kruer is a fellow in Pediatric Neurology and Developmental Pediatrics at Oregon Health & Science University and a postdoctoral fellow in the laboratory of Dr. Susan Hayflick. Dr. Kruer is a Clinical Neurology Research Fellow of the American Academy of Neurology (AAN). He completed his MD degree with distinction in research from the University of Arizona (2004). He received postdoctoral training in neurogenetics at the Translational Genomics Research Institute (Phoenix, AZ) where he studied the role of genomic copy number variants in neurologic disease. His pediatric residency training was at Maricopa Medical Center/Phoenix Children's Hospital. Dr. Kruer's research focuses on the characterization of novel forms of NBIA, and the mechanisms that connect subtypes of NBIA and other neurodegenerative diseases. Dr. Kruer is supported by the NBIA Disorders Association, the Medical Research Foundation of Oregon, the AAN, the American Philosophical Society, the Oregon Clinical and Translational Research Institute (OHSU's Clinical & Translational Science Award Institution) and the National Institutes of Health. Dr. Kruer can be reached at firstname.lastname@example.org.
About Prof. Susan J. Hayflick, MD
Dr. Susan J. Hayflick is Professor and Interim Chair of Molecular & Medical Genetics and is Professor of Pediatrics and Neurology at Oregon Health & Science University in Portland, Oregon. Dr. Hayflick can be reached at email@example.com.