Therapeutic Advances in Neurodegeneration With Brain Iron Accumulation

Therapeutic Advances in Neurodegeneration With Brain Iron Accumulation Giovanna Zorzi, MD,* Federica Zibordi, MD,* Luisa Chiapparini, MD,† and Nardo Nardocci, MD* Neurodegeneration with brain iron accumulation (NBIA) includes a heterogeneous group of genetically defined disorders characterized by progressive extrapyramidal deterioration and iron accumulation in the basal ganglia. Current medical options for these disorders remain largely unsatisfactory and do not prevent the disease from progressing to a severe and disabling state. In select cases, surgical techniques, such as deep brain stimulation, may be effective in ameliorating some of the symptoms of the disease. The availability of chelating agents with specific properties that have been demonstrated to be effective in other disorders with regional iron accumulation as well as magnetic resonance imaging techniques that allow for quantitative assessment of iron have stimulated interest in the use of chelating agents in NBIA. This review aims to describe the role of surgical therapies in NBIA, discuss the use of chelating agents in NBIA, and presents new therapeutic approaches under consideration. Semin Pediatr Neurol 19:82-86 © 2012 Elsevier Inc. All rights reserved.

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eurodegeneration with brain iron accumulation (NBIA) includes a heterogeneous group of genetically defined disorders characterized by progressive extrapyramidal deterioration and by iron accumulation in the basal ganglia.1 In recent years, there has been an extraordinary increasing knowledge about these conditions that has led to the identification of new genes, new phenotypes, and, at the same time, to new therapeutic strategies. Up to now, 7 genes have been associated with specific forms of NBIA. Neuroferritinopathy (MIM#606159) due to FTL mutation is an adult-onset, autosomal, dominant rare disease with a well-defined phenotype. Recessive NBIA syndromes may be due to mutations in the PANK2, PLA2G6, FA2H, ATP13A2, C19orf12, or CP genes, but still in a large proportion of patients, no genetic alteration can be found (idiopathic NBIA). Patients with recessive NBIA may overlap in clinical phenotype, showing a variable combination of dystonia, parkinsonism, spasticity, ataxia, cognitive deficit, and psychiatric symptoms, but significant progress has been made in differentiating types of NBIA on the basis of clinical and radiological findings.2 Form the *Department of Child Neurology, Fondazione IRCCS Istituto Neurologico “Carlo Besta,” Milan, Italy. †Department of Neuroradiology, Fondazione IRCCS Istituto Neurologico “Carlo Besta,” Milan, Italy. Address reprint requests to Nardo Nardocci, MD, Department of Child Neurology, Fondazione IRCCS Istituto Neurologico “Carlo Besta,” Via Celoria 11, 20133 Milan, Italy. E-mail: [email protected]

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The most common form, accounting for approximately 50% of NBIA cases, is pantothenate kinase–associated neurodegeneration (PKAN, MIM#234200) caused by mutations in the pantothenate kinase 2 gene (PANK2). Classic PKAN is an early-onset rapidly progressive disorder with dystonia, spasticity, cognitive decline, and retinopathy. Patients with atypical PKAN have usually a later onset and milder disease course, and psychiatric symptoms may be predominant.3,4 Phospholipase-associated neurodegeneration (PLAN, MIM # 256600) is caused by mutations in the PLA2G6 gene.5 Earlyonset PLAN displays the relatively uniform phenotype of infantile neuroaxonal dystrophy.6-8 The clinical spectrum of late-onset PLAN is not as well characterized and includes progressive dystonia, spastic ataxia, and parkinsonism.9-11 NBIA due to mutations in the fatty acid hydroxylase gene (fatty acid hydroxylase-associated neurodegeneration) was recently described in 2 families.12 Onset was during early childhood with progressive ataxia, spasticity, optic atrophy, and abnormal eye movements. Mutations in the same gene were previously found in cases of familial leukodystrophy13 and of hereditary spastic paraplegia.14 Most recently, a new gene for NBIA, C19orf12, has been identified in Polish and German cohorts, where it seems to be the most frequent NBIA disorder after PKAN. Mean age at onset is 9 years, and the clinical phenotype is characterized by progressive spasticity, dystonia, optic atrophy, motor axonal neuropathy, and psychiatric signs.15

Advances in NBIA

General Principles of Treatment in NBIA Treating NBIA disorders is a challenging issue that requires expertise and a comprehensive approach to the patient. It is primarily symptomatic, aimed at reducing abnormal movements and spasticity. Dystonia often represents the most disabling symptom, with status dystonicus a particularly severe and potentially life-threatening issue that may require continuous infusions. Several drugs may be efficacious, including benzodiazepines, anticholinergics, baclofen, typical and atypical neuroleptics, and L-dopa (particularly if parkinsonian features are prominent). In some cases, botulinum toxin injection or intrathecal baclofen may be of benefit.4 Psychiatric symptoms and behavioral disturbances may require specific interventions. Deep brain stimulation (DBS) of the internal globus pallidus has recently emerged as an effective treatment, in particular, in patients with PKAN.16-19 However, results with current therapies remain largely unsatisfactory and do not prevent the disease from progressing to a severe and disabling condition for most patients. Recently, new therapeutic chelating agents with the potential to cross the blood– brain barrier have been developed. These advances, coupled with progress in radiological techniques that allow for the quantitative assessment of iron by magnetic resonance imaging (MRI), as well as promising preliminary results in patients with Friedreich ataxia (which itself features iron accumulation in the dentate nuclei), has stimulated interest in the possible efficacy of chelating agents in NBIA.

Brain Iron Iron is essential for normal neuroembryogenesis and physiology and participates in a spectrum of cellular function, including myelination, antioxidant enzyme activity, and biogenic amine metabolism. Iron homeostasis in peripheral and neural tissues is regulated by a number of proteins controlling absorption, transport, cellular flux, and intracellular storage.20,21 The central nervous system (CNS) maintains autonomous control and the blood– brain barrier precludes free flux of transferrin, ferritin, ceruloplasmin, and other ironregulating proteins from the systemic circulation to the CNS. Iron progressively accumulates in the CNS in the brain parenchyma and cerebrospinal fluid as part of the normal aging process, and iron preferentially accumulates in the basal ganglia, hippocampus, and cerebellar nuclei. Various biochemical and physiological characteristics of the CNS make it vulnerable to iron-related damage, such as the flux of molecular oxygen in neural tissues, the generation of reactive oxygen species, the susceptibility of the CNS to lipid peroxidation due to high cholesterol and unsaturated fat, and the abundance of potentially excitotoxic neurotransmitters. In the diseases characterized by abnormal brain accumulation, iron-derived reactive oxygen species may facilitate protoxin activation, abnormal cell signaling, energetic failure, protein aggregation and inclusion formation, synaptoly-

83 sis, apoptosis, and necrosis.22 Not only NBIA syndromes, but Parkinson disease, Alzheimer disease, and multiple sclerosis are associated with increased iron levels in the brain.23 Thus, iron deposition, in addition to serving as a valuable diagnostic marker, may potentially constitute an important therapeutic target. A radiological and clinical improvement with iron-chelating treatment in patients affected by Friedreich ataxia has been demonstrated. Friedreich patients accumulate iron in the heart, spinocerebellar tract, and spinal cord.24,25 However, the clinical relevance of iron deposition and its relationship with disease pathology remain uncertain. In fact, despite the evidence that labile iron may damage tissue, iron deposition may represent a secondary downstream consequence not related to the primary mechanisms that drive neurodegeneration.

Regional Brain Iron and MRI High-field strength MRI can demonstrate iron in the brain. Iron-related paramagnetic signal is thought to arise primarily from ferritin and hemosiderin accumulation.26 Iron causes a shortening of T2 relaxation time. The areas where iron accumulates thereby present low-signal intensity on T2-weighted images, which becomes more evident on T2*-weighted gradient echo images. The T2 shortening is attributed to the dephasing of water protons by iron-loaded molecules that create microscopic field inhomogeneities. T2 shortening is proportional to the square of the field strength of the magnet applied. This leads to an increased degree of hypointensity with higher Tesla strength magnets.26-28 Brain iron content varies with age; it is not present at birth, but accumulates during life with an uneven distribution. Iron is present at a high concentration in the basal ganglia, particularly in the pallidum and the substantia nigra, red nucleus, and dentate nucleus. In the pallidum and substantia nigra, it rapidly increases from birth until about 20 years of age. In other structures, such as the putamen, iron deposits increase more slowly, reaching a plateau in the middle age but may show a pathologic accumulation in some atypical forms of parkinsonism.29 In NBIA, the deposition of iron prevails in the pallidum. Iron in the brain can be detected and quantified using MRI techniques that are continuously being refined. The 3 primary relaxometry metrics used to detect brain iron are the transverse relaxation rates (R2, R2*, R2’), or the reciprocals of the transverse relaxation time (1/T2), (1/T2*), or (1/T2’) (5). R2’ has the highest iron-related specificity, but it is hampered by artefacts related to field inhomogeneities, especially in high-field studies (3t).30 There is a considerable debate and controversy as to which MRI technique most closely estimates iron deposition with acceptable sensitivity and specificity. Many studies focused on the correlation of R2 and R2’ at high-field strength.31-33 Among the common MR sequences, susceptibility-weighted imaging is becoming more and more popular with the increased use of 3T units.34 A cumbersome technique that requires the use of 2 MR machines of different field strength is the field-dependent R2

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84 increase, described by Bartzokis et al35. In clinical practice, a voxel-based analysis of the decay rate of R2* (R2* map) and R2 seems to be a rapid, reproducible, and sensitive analysis to quantify brain iron.28 The constantly improving ability to assess regional brain iron quantitatively has the potential to not only facilitate better diagnosis but may ultimately allow investigators to track iron deposition as a measure of disease progression treatment response.

Deferiprone as an Iron-Chelating Agent Deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one, DFP) is a chelating agent that may facilitate iron relocation. Advocates have thus suggested that DFP is a promising agent for treating conditions characterized by regional iron deposition.24 It has the ability to donate iron to physiological acceptors, which means that it can transfer iron from cellular pools to circulating transferrin. It has a high permeability across cell membranes, can gain access to mitochondria, and reduces the formation of iron free radicals. Moreover, it has been shown to cross the blood– brain barrier with obvious therapeutic implications for neurodegenerative disorders.25

Chelating Treatment in NBIA In the initial study, 3 adults patients with neuroferritinopathy were given chelation therapy (2 patients were treated with intravenous desferrioxamine, 4 g weekly for 14 months and 1 with oral DFP 2 g 3 times daily for 2 months), and the response to therapy was documented by clinical observation and videotaping. In 1 case dystonia remarkably worsened, whereas the remaining 2 patients did not experience any benefit.36 In 2008, Forni et al reported the result of iron chelation therapy in a 61-year-old woman affected by adult-onset idiopathic NBIA. She was treated with DFP 15/mg/kg/d for 6 months; there was a marked improvement after 6 months of therapy without side effects. MR images at 7 months demonstrated a reduction of iron deposits in the basal ganglia. Notably, both clinical status and MRI changes were assessed qualitatively.37 Another recent study describes the long-term improvement under DFP (30 mg/kg/d) in a case of idiopathic NBIA with onset at 47 years presenting with cerebellar ataxia and parkinsonism. The patient’s clinical status was assessed by standardized scales (motor Unified Parkinson’s Disease Rating Scale, International Cooperative Ataxia rating Scale, and Scale for the Assessment and Rating of Ataxia); after 6 months, there was 30% improvement in ataxia, 35% in dysarthria, and 45% in orofacial dystonia. After the first year of treatment, there was a slight progression of symptoms, but at the end of the follow-up (32 months), the clinical status was overall better than the pretreatment phase. Quantitative analysis of T2* MRI changes revealed a marked but transient decrease of iron concentration in the dentate nuclei, sustained decrease in the substantia nigra to a lesser extent, and

no changes in the red nuclei.38 As in the patient reported by Forni et al, DFP caused no neurological or hematological side effects. In addition to these reports of single cases, 2 studies on larger series of patients have more recently been published. Zorzi et al reported the results of the first phase II pilot open trial in PKAN, assessing the clinical and radiological effects of DFP at a dose of 25 mg/kg/d during a 6-month period. Among the 9 patients who completed the study, 6 had classic disease and 3 had atypical disease. At enrollment, median age was 26 years (range, 7-39 years), and median disease duration was 11 years. DFP was well tolerated overall; side effects included nausea and gastralgia (44%), but no serious adverse events occurred. The authors observed a significant (median, 30%) reduction in globus pallidus iron content, ranging from 15% to 61% in individual patients. However, there was no demonstrable clinical benefit, as rated on the Burke-FahnMarsden Dystonia Rating Scale and 36-item short-form health survey. The authors suggested that the discrepancy between radiological and clinical data may have multiple different explanations: the relatively short treatment duration, long disease duration, or neuronal damage too advanced to allow a rescue of function.39 A similar study was conducted for a longer period on a series of 6 patients with different forms of NBIA (4 PKAN and 2 with idiopathic NBIA) treated with DFP (15/mg/kg/d) and assessed in follow-up at 6 and 12 months. Mean age at enrollment was 36.5, and mean disease duration was 7.5 (range: 3-13). Clinical rating scales (Unified Parkinson Disease Rating Scale-III, International Cooperative Ataxia Rating Scale, and Unified Dystonia Rating Scale), and blinded video rating documented a slight improvement in 3 cases (2 PKAN and 1 NBIA) and no change in the remaining 3 cases. The improvement was observed after 6 months of treatment and persisted at 12 months. Quantitative analysis of brain iron through T2* relaxometry was possible only in 3 patients and demonstrated a reduction of iron content in the globus pallidus. According to previous reports, DFP was safe and well tolerated.40

Surgical Approaches A large series of patients with PKAN or idiopathic forms of NBIA treated with DBS targeting the globus pallidus was recently published.41 This multinational study reported outcomes of 23 patients with NBIA treated with pallidal DBS. The primary outcome measured dystonia severity using the Burke-Fahn-Marsden and Barry-Albright dystonia scales. A mean improvement of 28.5% in dystonia severity was seen at 2-6 months and 25.7% improvement was seen at 9-15 months. Two-thirds of the patients treated experienced an improvement in their dystonia of 20% or more. Although overall improvements were modest, global quality of life ratings showed a median improvement of 83.3% at 9-15 months, suggesting that even this relatively small effect led to clinically meaningful improvements. In addition, a case series recently described the use of intraventricular baclofen in patients with treatment-refrac-

Advances in NBIA tory dystonia.42 Included among them was a patient with PKAN. This patient’s dystonia improved significantly with intraventricular baclofen administration.

Other Therapeutic Avenues In the decade since the gene defect for NBIA1 was identified as pantothenate kinase–associated neurodegeneration, and the disorder was renamed accordingly (PKAN), there have been significant insights into NBIA disease biology. Notably among them is the identification of a vitamin B5 analog, pantethine, that has the ability to potentially circumvent the enzymatic defect in PKAN and restore the ability to synthesize adequate quantities of coenzyme A. Pantethine was administered to drosophila fumble mutants, which feature mutation of dPANK, the drosophila homolog of human PANK enzymes, with resulting rescue of the phenotype.43 Although this therapy has significant potential as a rational therapeutic, several limitations exist. This includes incomplete data regarding the bioavailability, pharmacokinetics, and ability of this compound to cross the blood– brain barrier in humans. Furthermore, there are important differences between drosophila and human physiology, including a single PANK in drosophila but 4 distinct isoforms in humans, with PANK2 being specifically targeted to mitochondria. Despite these limitations, the identification of pantethine as a potential therapeutic agent has generated much interest within the NBIA community.

Conclusions The role of surgical treatments for NBIA continue to evolve, with modest improvements seen in dystonia severity, but more significant improvements seen in quality of life scores. The potential utility of pantethine in PKAN can only be speculated on. Although the rationale for the use of this compound appears sound, further studies will be crucial to determine whether this agent holds therapeutic promise. No conclusive statements can be made regarding the role of chelating treatment in NBIA at the current time. The number of patients treated to date is too small (11 patients with PKAN, 4 patients with idiopathic NBIA, and 1 case with neuroferritinopathy) to draw firm conclusions. Nevertheless, some considerations can be outlined. DFP is well tolerated, causing no serious neurological or hematological side effects. The available data suggest that DFP may lead to a decreased iron burden in several brain regions as quantified by serial MRI. This reduction can be observed as early as 3 month after chelating treatment begins and seems to remain stable over time. Dose–response relationships remain to be determined. The changes in the clinical status of patients are variable, and differences between studies are difficult to compare and should be verified in larger series. As the age range of treated patients is wide, so is the disease duration. The clinical assessment of NBIA patients is complex, with a mixed movement disorder being typical, complicating clinical assessment

85 using rating scales. In addition, none of the studies to date have investigated cognitive or psychiatric aspects of the condition, which can be the most prominent symptoms. However, a clinical benefit was reported in almost half of the patients, and it is therefore imperative that larger follow-up controlled studies be performed to determine whether chelation is a valuable therapeutic option for these severe and relentlessly progressive disorders.

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