Neurodegeneration with Brain Iron Accumulation Authors: Allison M. Gregory1, M.S. and Susan J. Hayflick1, M.D. Creation date: September 2004 Scientific Editor: Professor Alexis Brice 1Molecular and Medical Genetics, Pediatrics and Neurology, Oregon Health & Science University, L103a, 3181 SW Sam Jackson Park Rd., Portland, Oregon, United States. mailto:[email protected] Abstract Key-words Disease Name/Synonyms Definition/Diagnostic criteria Differential Diagnosis Etiology Diagnostic Methods Epidemiology Clinical Description Genetic Counseling Research opportunities for families Antenatal Diagnosis Management/Treatment Unresolved questions References Abstract Neurodegeneration with brain iron accumulation (NBIA, formerly Hallervorden-Spatz syndrome) encompasses a group of rare neurodegenerative disorders transmitted in an autosomal recessive fashion. An estimated prevalence of 1-3/1,000,000 has been suggested based on observed cases in a population. Since the recent discovery of the major genetic defect causing NBIA, this heterogeneous group of disorders can now be differentiated by clinical, radiographic, and molecular features. The hallmark features of NBIA include progressive extrapyramidal dysfunction (dystonia, rigidity, choreoathetosis) and iron accumulation in the brain, primarily in the basal ganglia. Brain MRI is standard in the diagnostic evaluation of all forms of NBIA. Approximately half of the patients given a clinical diagnosis of NBIA are found to have identifiable mutations in the PANK2 gene, which causes pantothenate kinase-associated neurodegeneration, or PKAN. 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. Key-words Dystonia, basal ganglia, pantothenate kinase-associated neurodegeneration, PKAN, Hallervorden-Spatz syndrome, neurodegeneration with brain iron accumulation, NBIA Disease Name/Synonyms NBIA encompasses a group of progressive • Neurodegeneration with brain iron extrapyramidal disorders characterized by accumulation (NBIA) radiographic evidence of iron accumulation in • Hallervorden-Spatz syndrome the brain, usually in the basal ganglia (Hayflick et • Pantothenate kinase-associated al., 2003). The term NBIA is already in use in neurodegeneration (PKAN) the medical literature (Arawaka et al., 1998; Bruscoli et al., 1998; Galvin et al., 2000; Gregory AM and Hayflick SJ. Neurodegeneration with Brain Iron Accumulation. Orphanet Encyclopedia. September 2004. http://www.orpha.net/data/patho/GB/uk-NBIA.pdf 1 Neumann et al., 2000; Swaiman 2001; Zhou et gene, Hayflick et al (Hayflick et al., 2003) al., 2001) and is sufficiently broad to cover the delineated two clinical forms of PKAN, the spectrum of disorders previously called classic form and an atypical form, based on age Hallervorden-Spatz syndrome and additional at onset and rate of disease progression. The disorders of high brain iron, including diagnostic criteria continue to evolve to reflect neuroferritinopathy and aceruloplasminemia. the distinctions between PKAN and other forms The major form of NBIA is pantothenate kinase- of NBIA. associated neurodegeneration, or PKAN, caused by mutations in the PANK2 gene (Zhou et al., Hallmark features of PKAN 2001). Extrapyramidal dysfunction, including one or The original eponym for this group of disorders more of the following: acknowledges the work of neuropathologists • Dystonia Julius Hallervorden and Hugo Spatz • Rigidity (Hallervorden et al., 1922). The new term NBIA • Choreoathetosis is now favored in light of the unethical activities of Hallervorden and Spatz before and during Onset World War II (Shevell 1992). • Classic form usually presents in first decade of life; Definition/Diagnostic criteria • Atypical form presents more commonly The category of NBIA consists of disorders in in the second or third decade of life. which there is progressive extrapyramidal disease with brain iron accumulation, usually in Loss of ambulation the basal ganglia. The subgroups of NBIA • Classic form: often occurring within 10- include PKAN, HARP syndrome, 15 years of onset aceruloplasminemia, neuroferritinopathy, and, by • Atypical form: often occurring within 15- exclusion, NBIA of unknown cause. This review 40 years of onset will mainly focus on PKAN, which accounts for the majority of NBIA cases. 'Eye of the tiger' sign on T2-weighted magnetic resonance imaging (1.5 Tesla or greater). To PKAN date this has been observed in all patients with Suspicion of PKAN often arises when one or two PANK2 mutations (Hayflick et al., characteristic radiographic MRI changes are 2003) (Figure 1). demonstrated in a patient with suggestive clinical features. Following the discovery of the PANK2 Figure 1. Brain MRI of the globus pallidi: Left image shows the 'eye of the tiger' change characteristic of PKAN, whereas the image on the right shows only globus pallidus hypointensities, consistent with iron deposition and supporting a diagnosis of NBIA. Gregory AM and Hayflick SJ. Neurodegeneration with Brain Iron Accumulation. Orphanet Encyclopedia. September 2004. http://www.orpha.net/data/patho/GB/uk-NBIA.pdf 2 Corroborative features major component of this pigment (Hallervorden • Corticospinal tract involvement 1924). In PKAN, the accumulation of iron is o Spasticity specific to the globus pallidus and substantia o Extensor toe signs nigra. These areas contain approximately three times the normal amount of iron. Systemic iron • Retinal degeneration or optic atrophy. In metabolism is normal (Kornyey 1964; Volkl et al., early-onset, rapidly progressive (classic) 1972; Dooling et al., 1974; Vakili et al., 1977) PKAN, two-thirds of affected individuals and a global increase in brain iron is not seen demonstrate pigmentary retinopathy (Spatz 1922). In regions of iron accumulation, (Hayflick et al., 2003), a much higher spheroid bodies are also seen (Koeppen et al., fraction than was previously reported 2001). Axonal spheroids are thought to (Roth et al., 1971; Newell et al., 1979; represent swollen axons, possibly secondary to Luckenbach et al., 1983). Although this defects in axonal transport. They are not limited feature occurs early in disease, to those portions of brain in which iron retinopathy is not often recognized until accumulates. a full diagnostic evaluation, including electroretinogram (ERG) and visual field Differential Diagnosis testing, is performed. PKAN can be distinguished from the other cases • Red blood cell acanthocytosis. Red of NBIA by the changes on brain MRI. In most blood cell (RBC) acanthocytes have patients with non-PKAN NBIA, the globus been reported in a subset of individuals pallidus is uniformly hypodense on T2-weighted with PKAN (Roth et al., 1971; Swisher et images (see Figure 1). This change indicates al., 1972; Luckenbach et al., 1983; high iron content; however, it is distinct from the Higgins et al., 1992; Tripathi et al., 'eye of the tiger' sign and is not seen in 1992). Confirmation of erythrocyte association with PANK2 mutations. Iron morphology by scanning electron deposition in the red nucleus and dentate microscopy may be helpful if available. nucleus in conjunction with cerebellar atrophy • Low or absent plasma pre-beta are common in the non-PKAN NBIA group. lipoprotein fraction (see HARP Seizures are also more prominent in these syndrome). individuals but rarely occur in PKAN. Sea blue • Family history consistent with autosomal histiocytes in bone marrow, historically a feature recessive inheritance (may include of Hallervorden-Spatz syndrome, do not occur in consanguinity). PKAN, but may be observed in other forms of NBIA. NBIA Exclusionary features A distinct sub-group of individuals with non- PKAN NBIA have early developmental delay • Abnormalities of copper metabolism or with moderate-to-severe mental retardation other evidence of Wilson disease diagnosed in early childhood. They may have • Evidence of neuronal ceroid spasticity and often are diagnosed with cerebral lipofuscinosis by electron microscopy, palsy. Their disease is static until late childhood enzymatic assay or the presence of a or, more commonly, adolescence or early DNA mutation in any of the six genes adulthood. With no clear inciting event, these associated with this condition. individuals experience a sudden and rapid • Family history of Huntington disease or deterioration usually marked by prominent other dominantly inherited movement dystonia. At this later stage, brain MRI changes disorder associated with NBIA may be seen. The gene • Caudate atrophy causing this form of NBIA has not yet been • ß-hexosaminidase A deficiency or GM1- identified. galactosidase deficiency Patients with aceruloplasminemia have additional iron accumulation in the visceral NBIA Pathological Diagnosis organs and develop diabetes relatively early in Before the availability of MRI, NBIA was a post- disease progression. They have retinal mortem diagnosis. The neuropathologic degeneration with characteristic yellow opacities literature is limited by the heterogeneity of in the retinal pigment epithelium. conditions grouped under this diagnosis(Halliday Neuroferritinopathy typically presents with 1995). Hallervorden-Spatz syndrome was initially involuntary movements in the fourth to fifth characterized by the appearance of rust-brown decade of life and does not exhibit the marked pigmentation in the globus pallidus and the dysarthria observed in PKAN. reticular zone of the substantia