Parkinsonism and Related Disorders 21 (2015) 658e660
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
Movement disorders and brain iron overload in a new subtype of aceruloplasminemia
Keywords: NBIA Chorea Dystonia Ceruloplasmin Tetrabenazine
Neurodegeneration with Brain Iron Accumulation (NBIA) syndromes are inherited disorders that lead to impaired iron metabolism with consequent cerebral and/or systemic metal overload. Pathological brain iron deposition usually results in neurological dysfunction characterized by movement disorders and cognitive impairment [1]. We report here a case of NBIA with aceruloplasminemia (ACP) and a novel mutation and clinical phenotype. A 51-year-old Caucasian woman was referred to our Neurology Unit with the subtle and progressive onset of involuntary movements, unsteady gait, cognitive deterioration and behavioral changes. Her previous medical history included microcytic anemia, type-1 diabetes and retinopathy. She was born to non-consanguineous parents and there was no family history of neurological diseases. The pattern of movement disturbances was compatible with acathisia, oro-facial dyskinesias, limb choreo-dystonia and cerebellar ataxia. Neuropsychological evaluation revealed executive dysfunctions. We performed an extensive work-up in order to rule out causes of secondary hyperkinetic disorder with dementia. Clinical biochemistry, autoimmune and hematological screenings were normal apart from microcytic anemia (hemoglobin 10.4 g/dL, mean cellular volume 67 fl) and changes in the serum metal indexes: copper (1.75 mmol/L) and iron (3.4 mmol/L) were below the reference range and ceruloplasmin (Cp) was undetectable as Cp concentration or as o-dianisidine Cp enzymatic activity [2]. Serum ferritin (85 ng/mL) and transferrin (2.6 g/dL) were within the normal range while transferrin saturation was very low (5%). A brain magnetic resonance imaging (MRI) was performed, and mineral sensitive sequences revealed a massive extrapallidal deposition of ferromagnetic substances (Fig. 1). Therefore, molecular tests were performed. Due to the absence of serum Cp and the presence of massive brain iron accumulation, we used polymerase chain reaction (PCR) based assays to look for coding regions and intron-exon boundaries of the CP gene on chromosome 3q coding for Cp. Amplifications of exon 12 gave no signal suggesting a homozygous deletion of the entire exon. No other mutation was observed by the CP sequencing. Huntington and Wilson's diseases were excluded by a PCR analysis for trinucleotide expansion http://dx.doi.org/10.1016/j.parkreldis.2015.03.014 1353-8020/© 2015 Elsevier Ltd. All rights reserved.
mutation of huntingtin gene on chromosome 4p and for mutations of ATP7B gene on chromosome 13q respectively. Finally, an ancillary MRI with metal sensitive sequences was performed to determine liver iron, but no signs of metal overload were observed. Hyperkinesias were successfully treated with tetrabenazine (12.5 mgs, t.i.d), with a concurrent mild improvement in behavioral symptoms. NBIA are heterogeneous neurological diseases characterized by young onset movement disorders and intellectual impairment. However a smaller subgroup of NBIA is characterized by adult onset symptoms (i.e. ACP and neuroferritinopathy). Apart from radiological and biochemical patterns, neuroferritinopathy can be distinguished from ACP by its dominant inheritance, lack of retinal degeneration and preserved cognition [1]. Our case did not have these features. On the other hand ACP is an autosomal recessive disorder caused by mutations in the gene coding for Cp. Cp is a copperenzyme, expressed either as a soluble secreted or as a membraneanchored isoform, depending on alternative splicing. The membrane-anchored isoform is mostly expressed in astrocytes in the brain, while the soluble isoform is mostly expressed in hepatocytes and released into the general circulation. Cp function allows iron trafficking in serum and tissues by supporting the cellular efflux, and its storage in ferritin [3]. A genetically determined absence or Cp malfunction leads to iron overload, especially in brain, retina, liver and pancreas. In adulthood (average age 50) ACP could present with the cerebellar ataxia (46%), dementia (42%), craniofacial dyskinesia (28%) and chorea (14%). In addition patients have undetectable Cp, low serum iron and transferrin saturation, increased serum ferritin, and their medical history includes microcytic anemia, diabetes and retinal degeneration that are hallmarks of the disease [1]. Here we present the first report of a patient with a deletion of exon 12 of the CP gene determining an ACP characterized by undetectable Cp but normal ferritin values in the absence of liver iron overload. The CP gene is composed of 19 exons and encodes a protein to an extent of 1046 amino acids. More than 40 mutations have been described, with no genotypeephenotype correlations [1,4]. Exon 12 encodes for an essential antioxidant 60 amino-acid domain in both Cp isoforms [3]; its deletion is likely to produce a defective Cp biosynthesis followed by a highly probable Cp denaturation in both liver and brain. However further analysis are needed to clarify why, in this particular case, there are no signs of liver and splanchnic iron overload in contrast to a massive brain iron deposition. The latter is possibly due to the defective iron efflux and mobilization caused by Cp deficiency, while there is no clear explanation for the absence of hepatic iron accumulation. It seems not to be directly related to the specific genetic abnormality, but could be due to a general iron deficiency or
Letter to the Editor / Parkinsonism and Related Disorders 21 (2015) 658e660
659
Fig. 1. Brain magnetic resonance imaging (MRI). Axial T2 FLAIR (fluid attenuated inversion recovery) (AeD) shows symmetric hypointensities of dentate nucleus (curved arrow), putamen (square), head (star) and tail (chevron) of caudate, and thalamus with pulvinar necrosis (thick arrow, hyperintensity among the hypointense lesion); GRE (gradient echoe) T2* (EeH) other than dentate, basal ganglia and thalamus shows cerebral cortex “blooming” hypointensity (thin arrow); finally SWI (susceptibility weighted imaging) (outlets IeK) depicts with higher sensitivity than GRE T2* the presence of ferromagnetic deposits in the dentate nucleus, the basal ganglia, the thalamus (triangle, empty arrow) and the cerebellar (ring) and cerebral gyri.
to variants of iron metabolism confined to the liver. The phenotypic features distinguish this ACP case from those previously described. Treatment with iron chelators could be considered in spite of the absence of liver iron overload and hyperferritinemia; in particular we considered a cautious use of low doses of chelators able to cross the bloodebrain barrier in order to avoid the worsening of anemia. Therefore Deferiprone 15 mg/kg po b.i.d. will be eventually offered only with careful hematological surveillance and brain MRI followup [5]. Finally, to our knowledge, we report here for the first time a successful symptomatic treatment of ACP-related hyperkinesias with low dose tetrabenazine. Conflict of interest/Financial disclosure None. Acknowledgments Matteo Paolucci, MD, for technical support on artwork. Carlo Liguori, MD, for radiological support on splanchnic imaging.
References [1] Schneider SA, Dusek P, Hardy J, Westenberger A, Jankovic J, Bhatia KP. Genetics and pathophysiology of neurodegeneration with brain iron accumulation (NBIA). Curr Neuroph 2013;11:59e79. [2] Siotto M, Pasqualetti P, Marano M, Squitti R. Automation of o-dianisidine assay for ceruloplasmin activity analyses: usefulness of investigation in Wilson's disease and in hepatic encephalopathy. J Neural Transm 2014;121:1281e6. [3] Bielli P, Calabrese L. Structure to function relationships in ceruloplasmin: a 'moonlighting' protein. Cell Mol Life Sci 2002;59:1413e27. [4] Meral Gunes A, Sezgin Evim M, Baytan B, Iwata A, Hida A, Avci R. Aceruloplasminemia in a Turkish adolescent with a novel mutation of ceruloplasmin
gene: the first diagnosed case from Turkey. J Pediatr Hematol Oncol 2014;36:e423e5. [5] Cossu G, Abbruzzese G, Matta G, Murgia D, Melis M, Ricchi V, et al. Efficacy and safety of deferiprone for the treatment of pantothenate kinase-associated neurodegeneration (PKAN) and neurodegeneration with brain iron accumulation (NBIA): results from a four years follow-up. Park Relat Disord 2014;20:651e4.
Jean-Marc Melgari*,1 Campus Bio-Medico, Rome, Italy Neurology Unit, Universita Neurology Unit, Treviglio Hospital, Treviglio, Bergamo, Italy Massimo Marano1 Neurology Unit, Universita Campus Bio-Medico, Rome, Italy Carlo Cosimo Quattrocchi Campus Bio-Medico, Rome, Italy Radiology Unit, Universita Alberto Piperno Human Molecular Genetics Consortium, Monza, Italy University of Milano-Bicocca, Department of Health Sciences, Monza, Italy Cristina Arosio Human Molecular Genetics Consortium, Monza, Italy Marina Frontali CNR Institute of Translational Pharmacology, Rome, Italy Medical Genetics Unit, Policlinico Tor Vergata, Rome, Italy Sara Nuovo Medical Genetics Unit, Policlinico Tor Vergata, Rome, Italy Mariacristina Siotto Don Carlo Gnocchi Foundation ONLUS, Milan, Italy
660
Letter to the Editor / Parkinsonism and Related Disorders 21 (2015) 658e660
Gaetano Salomone, Riccardo Altavilla, Lazzaro di Biase Campus Bio-Medico, Rome, Italy Neurology Unit, Universita Federica Scrascia Neurology Unit, Treviglio Hospital, Treviglio, Bergamo, Italy Rosanna Squitti Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome, Italy
Fabrizio Vernieri Campus Bio-Medico, Rome, Italy Neurology Unit, Universita * Corresponding author. Neurology Unit, Campus Bio-Medico of Rome University, Via Alvaro del Portillo 200, 00128 Rome, Italy. Tel.: þ39 06 225411220. E-mail address: [email protected] (J.-M. Melgari).
16 December 2014
1
Both authors contributed equally to this work.
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
Movement disorders and brain iron overload in a new subtype of aceruloplasminemia
Keywords: NBIA Chorea Dystonia Ceruloplasmin Tetrabenazine
Neurodegeneration with Brain Iron Accumulation (NBIA) syndromes are inherited disorders that lead to impaired iron metabolism with consequent cerebral and/or systemic metal overload. Pathological brain iron deposition usually results in neurological dysfunction characterized by movement disorders and cognitive impairment [1]. We report here a case of NBIA with aceruloplasminemia (ACP) and a novel mutation and clinical phenotype. A 51-year-old Caucasian woman was referred to our Neurology Unit with the subtle and progressive onset of involuntary movements, unsteady gait, cognitive deterioration and behavioral changes. Her previous medical history included microcytic anemia, type-1 diabetes and retinopathy. She was born to non-consanguineous parents and there was no family history of neurological diseases. The pattern of movement disturbances was compatible with acathisia, oro-facial dyskinesias, limb choreo-dystonia and cerebellar ataxia. Neuropsychological evaluation revealed executive dysfunctions. We performed an extensive work-up in order to rule out causes of secondary hyperkinetic disorder with dementia. Clinical biochemistry, autoimmune and hematological screenings were normal apart from microcytic anemia (hemoglobin 10.4 g/dL, mean cellular volume 67 fl) and changes in the serum metal indexes: copper (1.75 mmol/L) and iron (3.4 mmol/L) were below the reference range and ceruloplasmin (Cp) was undetectable as Cp concentration or as o-dianisidine Cp enzymatic activity [2]. Serum ferritin (85 ng/mL) and transferrin (2.6 g/dL) were within the normal range while transferrin saturation was very low (5%). A brain magnetic resonance imaging (MRI) was performed, and mineral sensitive sequences revealed a massive extrapallidal deposition of ferromagnetic substances (Fig. 1). Therefore, molecular tests were performed. Due to the absence of serum Cp and the presence of massive brain iron accumulation, we used polymerase chain reaction (PCR) based assays to look for coding regions and intron-exon boundaries of the CP gene on chromosome 3q coding for Cp. Amplifications of exon 12 gave no signal suggesting a homozygous deletion of the entire exon. No other mutation was observed by the CP sequencing. Huntington and Wilson's diseases were excluded by a PCR analysis for trinucleotide expansion http://dx.doi.org/10.1016/j.parkreldis.2015.03.014 1353-8020/© 2015 Elsevier Ltd. All rights reserved.
mutation of huntingtin gene on chromosome 4p and for mutations of ATP7B gene on chromosome 13q respectively. Finally, an ancillary MRI with metal sensitive sequences was performed to determine liver iron, but no signs of metal overload were observed. Hyperkinesias were successfully treated with tetrabenazine (12.5 mgs, t.i.d), with a concurrent mild improvement in behavioral symptoms. NBIA are heterogeneous neurological diseases characterized by young onset movement disorders and intellectual impairment. However a smaller subgroup of NBIA is characterized by adult onset symptoms (i.e. ACP and neuroferritinopathy). Apart from radiological and biochemical patterns, neuroferritinopathy can be distinguished from ACP by its dominant inheritance, lack of retinal degeneration and preserved cognition [1]. Our case did not have these features. On the other hand ACP is an autosomal recessive disorder caused by mutations in the gene coding for Cp. Cp is a copperenzyme, expressed either as a soluble secreted or as a membraneanchored isoform, depending on alternative splicing. The membrane-anchored isoform is mostly expressed in astrocytes in the brain, while the soluble isoform is mostly expressed in hepatocytes and released into the general circulation. Cp function allows iron trafficking in serum and tissues by supporting the cellular efflux, and its storage in ferritin [3]. A genetically determined absence or Cp malfunction leads to iron overload, especially in brain, retina, liver and pancreas. In adulthood (average age 50) ACP could present with the cerebellar ataxia (46%), dementia (42%), craniofacial dyskinesia (28%) and chorea (14%). In addition patients have undetectable Cp, low serum iron and transferrin saturation, increased serum ferritin, and their medical history includes microcytic anemia, diabetes and retinal degeneration that are hallmarks of the disease [1]. Here we present the first report of a patient with a deletion of exon 12 of the CP gene determining an ACP characterized by undetectable Cp but normal ferritin values in the absence of liver iron overload. The CP gene is composed of 19 exons and encodes a protein to an extent of 1046 amino acids. More than 40 mutations have been described, with no genotypeephenotype correlations [1,4]. Exon 12 encodes for an essential antioxidant 60 amino-acid domain in both Cp isoforms [3]; its deletion is likely to produce a defective Cp biosynthesis followed by a highly probable Cp denaturation in both liver and brain. However further analysis are needed to clarify why, in this particular case, there are no signs of liver and splanchnic iron overload in contrast to a massive brain iron deposition. The latter is possibly due to the defective iron efflux and mobilization caused by Cp deficiency, while there is no clear explanation for the absence of hepatic iron accumulation. It seems not to be directly related to the specific genetic abnormality, but could be due to a general iron deficiency or
Letter to the Editor / Parkinsonism and Related Disorders 21 (2015) 658e660
659
Fig. 1. Brain magnetic resonance imaging (MRI). Axial T2 FLAIR (fluid attenuated inversion recovery) (AeD) shows symmetric hypointensities of dentate nucleus (curved arrow), putamen (square), head (star) and tail (chevron) of caudate, and thalamus with pulvinar necrosis (thick arrow, hyperintensity among the hypointense lesion); GRE (gradient echoe) T2* (EeH) other than dentate, basal ganglia and thalamus shows cerebral cortex “blooming” hypointensity (thin arrow); finally SWI (susceptibility weighted imaging) (outlets IeK) depicts with higher sensitivity than GRE T2* the presence of ferromagnetic deposits in the dentate nucleus, the basal ganglia, the thalamus (triangle, empty arrow) and the cerebellar (ring) and cerebral gyri.
to variants of iron metabolism confined to the liver. The phenotypic features distinguish this ACP case from those previously described. Treatment with iron chelators could be considered in spite of the absence of liver iron overload and hyperferritinemia; in particular we considered a cautious use of low doses of chelators able to cross the bloodebrain barrier in order to avoid the worsening of anemia. Therefore Deferiprone 15 mg/kg po b.i.d. will be eventually offered only with careful hematological surveillance and brain MRI followup [5]. Finally, to our knowledge, we report here for the first time a successful symptomatic treatment of ACP-related hyperkinesias with low dose tetrabenazine. Conflict of interest/Financial disclosure None. Acknowledgments Matteo Paolucci, MD, for technical support on artwork. Carlo Liguori, MD, for radiological support on splanchnic imaging.
References [1] Schneider SA, Dusek P, Hardy J, Westenberger A, Jankovic J, Bhatia KP. Genetics and pathophysiology of neurodegeneration with brain iron accumulation (NBIA). Curr Neuroph 2013;11:59e79. [2] Siotto M, Pasqualetti P, Marano M, Squitti R. Automation of o-dianisidine assay for ceruloplasmin activity analyses: usefulness of investigation in Wilson's disease and in hepatic encephalopathy. J Neural Transm 2014;121:1281e6. [3] Bielli P, Calabrese L. Structure to function relationships in ceruloplasmin: a 'moonlighting' protein. Cell Mol Life Sci 2002;59:1413e27. [4] Meral Gunes A, Sezgin Evim M, Baytan B, Iwata A, Hida A, Avci R. Aceruloplasminemia in a Turkish adolescent with a novel mutation of ceruloplasmin
gene: the first diagnosed case from Turkey. J Pediatr Hematol Oncol 2014;36:e423e5. [5] Cossu G, Abbruzzese G, Matta G, Murgia D, Melis M, Ricchi V, et al. Efficacy and safety of deferiprone for the treatment of pantothenate kinase-associated neurodegeneration (PKAN) and neurodegeneration with brain iron accumulation (NBIA): results from a four years follow-up. Park Relat Disord 2014;20:651e4.
Jean-Marc Melgari*,1 Campus Bio-Medico, Rome, Italy Neurology Unit, Universita Neurology Unit, Treviglio Hospital, Treviglio, Bergamo, Italy Massimo Marano1 Neurology Unit, Universita Campus Bio-Medico, Rome, Italy Carlo Cosimo Quattrocchi Campus Bio-Medico, Rome, Italy Radiology Unit, Universita Alberto Piperno Human Molecular Genetics Consortium, Monza, Italy University of Milano-Bicocca, Department of Health Sciences, Monza, Italy Cristina Arosio Human Molecular Genetics Consortium, Monza, Italy Marina Frontali CNR Institute of Translational Pharmacology, Rome, Italy Medical Genetics Unit, Policlinico Tor Vergata, Rome, Italy Sara Nuovo Medical Genetics Unit, Policlinico Tor Vergata, Rome, Italy Mariacristina Siotto Don Carlo Gnocchi Foundation ONLUS, Milan, Italy
660
Letter to the Editor / Parkinsonism and Related Disorders 21 (2015) 658e660
Gaetano Salomone, Riccardo Altavilla, Lazzaro di Biase Campus Bio-Medico, Rome, Italy Neurology Unit, Universita Federica Scrascia Neurology Unit, Treviglio Hospital, Treviglio, Bergamo, Italy Rosanna Squitti Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome, Italy
Fabrizio Vernieri Campus Bio-Medico, Rome, Italy Neurology Unit, Universita * Corresponding author. Neurology Unit, Campus Bio-Medico of Rome University, Via Alvaro del Portillo 200, 00128 Rome, Italy. Tel.: þ39 06 225411220. E-mail address: [email protected] (J.-M. Melgari).
16 December 2014
1
Both authors contributed equally to this work.
