Efficacy and safety of iron chelating agent Deferiprone in patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN)

1Neuroradiology, 2Unit of Child Neurology, 3Neuroepidemiology, 4Neurogenetics, Fondazione IRCCS Istituto Neurologico “Carlo Besta”; 5 Unit of Pediatrics, Department of Clinical and Biological Sciences, University of Torino; 6Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Ospedale Bambino Gesù, Roma

1Luisa Chiapparini, 1Domenico Aquino, 2Giovanna Zorzi, 3Alessandra Solari, 4Barbara Garavaglia, 5Antonio Piga, 6Enrico Bertini, 2Federica Zibordi, 1Mario Savoiardo, 1Maria Grazia Bruzzone, 2Nardo Nardocci

Iron is an indispensable enzymatic cofactor for several proteins and various neurodegenerative diseases are associated with increased iron levels.

The role of iron accumulation as causative factor

in neuronal oxidative damage in these diseases is not yet fully understood.

INTRODUCTION

However, recent data demonstrated a radiological

and clinical improvement with iron-chelating treatment in patients affected by Friedreich ataxia, histopathologically characterized by iron accumulation in spinal cord and dentate nuclei, and in a case of idiopathic NBIA.

Chelation of labile iron, therefore, could be

considered a possible treatment for PKAN and other neurodegenerative disorders characterized by brain iron accumulation.

Deferiprone is an iron chelating agent effective in

preventing the progression of iron accumulation and in promoting iron excretion.

INTRODUCTION

INTRODUCTION Pantothenate Kinase-Associated Neurodegeneration (PKAN) is

a rare autosomal recessive disorder associated with brain iron accumulation. PKAN is caused by a defect in the pantothenate kinase 2 gene (PANK2).

The classical form of the disease has onset in early childhood with dystonia as predominant feature, associated with retinopathy, parkinsonism, ataxia and spasticity.

The disease rapidly progresses with inability to walk usually in the second decade of life.

Brain magnetic resonance imaging (MRI) changes, virtually pathognomonic of PKAN, are seen on T2-weighted images: a central hyperintense signal in the medial globus pallidus, surrounded by hypointensity, related to iron accumulation called the “eye of the tiger sign”.

At present, no treatment is available.

Pantothenate kinase-associated neurodegenerationHayflick SJ et al.: NEJM 2003,348:33-40

PKANNormal iron distribution(Pearl’ stain)

Savoiardo M, Halliday WC, Nardocci N et al. AJNR 1993

In this phase II two-center clinical trial in patients with PKAN, we investigated with brain MRI the efficacy and safety of 6-month treatment with Deferiprone in reducing iron concentration in the globus pallidus.

We also evaluated changes in the Burke-Fahn

and Marsden Dystonia Rating Scale (BFMDRS) scores and in health-related quality of life scale scores (SF-36)

INTRODUCTION

10 patients with PKAN

Eligible patients had: clinical diagnosis of NBIA “eye of the tiger” sign on MRI genetical confirmation (mutations in the PANK2 gene)

Exclusion when: contraindication to Deferiprone (episodes of neutropenia, agranulocytosis) other neurological disorders or major co-morbidities (e.g. psychiatric disease other than OCD, overt heart, kidney or lung failure, overt malignancy, HIV infection)

METHODS

Treatment plan Enrolled patients received Deferiprone

(Ferriprox®) 25 mg/kg/day administered orally for six months.

Clinical protocol Patients were examined at baseline, and after two,

four and six months. The clinical protocol included neurological

examination, administration of Burke-Fahn and Marsden Dystonia Rating scales (BFMDRS) of health-related quality of life scale scores (SF-36) and standardized video-recordings.

METHODS

Neuroradiological protocol PKAN patients were imaged on a Siemens Magnetom Avanto 1.5 T

system at baseline and after six months. Basic imaging included axial T2 and proton density–weighted

sequences and axial T2 Gradient Echo sequences. Morphological imaging was acquired by means of volumetric

gradient-echo (Flash) and T1 3D MPRAGE sagittal sequences. In order to detect iron deposition in the globus pallidus, T2*

Relaxometry was performed with a multi-echo gradient echo sequence composed by 12 echo times 5/55 milliseconds (t = 5msec).

METHODS

R2* at baseline= 38.31 sec-1

R2* MAPTEMPLATE

Relaxometry analysis: R2* maps were calculated for each subject fitting voxel by voxel the signal samples of the GE sequence; for all basal ganglia R2* versus age curves were obtained tracing fine 3D ROIs on the MPRAGE sequence, and reporting them on the R2* maps

Radiology 2009

Dec./R2* Globus Pallidus Putamen Sub.Nigra Caudate Nuclei FWM

1-9 22.38 ± 2.98 20.83 ± 1.68 25.80 ± 4.50 18.26 ± 1.20 21.37 ± 1.11

10-19 25.22 ± 0.48 21.61 ± 0.82 28.13 ± 0.55 19.98 ± 0.94 22.8 ± 0.386

20-29 27.01 ± 0.95 22.63 ± 0.84 29.72 ± 1.90 19.87 ± 0.43 22.86 ± 0.37

30-39 28.21 ± 1.91 23.63 ± 0.71 30.82 ± 1.70 19.28 ± 1.27 22.77 ± 0.72

40-49 28.12 ± 1.54 24.09 ± 1.21 30.42 ± 1.55 20.52 ± 0.94 23.02 ± 0.89

50-59 26.96 ± 0.85 22.07 ± 0.98 27.79 ± 3.48 18.66 ± 0.41 21.75 ± 1.63

60-69 30.93 ± 1.07 26.20 ± 1.52 30.64 ± 1.42 20.53 ± 2.10 22.53 ± 1.42

70-79 29.58 ± 2.31 25.18 ± 1.17 30.17 ± 1.98 18.91 ± 1.07 23.16 ± 0.90

R2* values (sec -1 ) x decade (average±DS)

Radiology 2009

9 patients completed the study

Deferiprone was overall well tolerated

R2* values of PKAN patients after treatment were reduced in all cases.

None of the patients reported a subjective improvement or modification of the neurological picture. There were no changes in the scores obtained at BFMDRS and SF-36 before, during and after treatment.

RESULTS

Box plots of iron content in the globus pallidus at baseline (t0) and at study end (t1) in the nine PKAN patients.

2040

6080

100

t0 t1

Patient no.

Age (years) Baseline

End of study

Change (%)

1 22 85.83 48.61 -43.4

2 39 67.72 47.16 -30.3

3 7 38.31 35.55 -7.20

4 10 33.74 30.66 -9.11

5 28 61.86 40.90 -33.9

6 26 80.50 51.92 -35.5

7 13 44.46 31.81 -28.4

8 36 36.75 31.47 -14.3

9 27 66.34 25.50 -61.5

Age, R2* values at baseline and at study end, and percent changes in the nine PKAN patients

R2*= 65 sec^-1 R2* = 33 sec^-1

Pre-treatment Post-treatment

PKAN and Deferiprone

Comparison between PKAN at baseline and PKAN after six months of chelating therapy demonstrated that chelation was effective in removing iron from the globus pallidus.

However, in spite of the demonstrated efficacy of treatment in reducing iron accumulation in the globus pallidus, the clinical status of the PKAN patients did not improve.

DISCUSSION

The reasons for this discrepancy can be various: 1) the damage to neurons in the nuclei was far

advanced to allow a rescue of function with removal of iron

2) even if iron is removed and function of residual neurons is improved, the damage to connections and circuits involved is not reversible

3) accumulation of iron may only be an epiphenomenon of the disease process but not the primary cause.

DISCUSSION

CONCLUSION

Considering the efficacy of iron removal butthe lack of clinical improvement, different strategies can be proposed: 1) to prolong the time of administration of the chelating agent 2) to select patients at an earlier stage of the disease Considering that PKAN can be detected genetically,the treatment could be even started in the pre-symptomatic stage.

Thank you for your attention

1. Hayflick SJ, et al; N Engl J Med 2003 348: 33-40

2. Hartig MB et al, Ann Neurol. 2006; 59:2483. Sethi KD et al Ann Neurol 1988 24: 692-6944. Angelini et al, J Neurol 1992; 239:417-4255. Boddaert N, et al, Blood 2007 110: 401-86. Forni L et al, . Mov Dis 2008 23,6 904-9077. Aquino D, et al. Radiology. 2009; 252:165-72.

REFERENCES

Iron Iron is not present at birth. It deposits greatly during the first two decades of life

and maximum concentration of iron in normal adults is found in the globus pallidus, red nucleus and pars reticulata of the substantia nigra.

Iron and MRBrain iron can be detected by MRI and is better visible on SE T2-weighted and GE T2* images as hypointensity due to field inhomogeneity and magnetic susceptibility effects.Quantitative MR techniques: R2, R2*, R2’

PKAN – 10 years Healthy subject – 10 years

R2*=33.7362

A

R2*=16.2398

B

Iron and MR

Brain iron can be detected by MRI and is better visible on SE T2-weighted and GE T2* images as hypointensity due to field inhomogeneity and magnetic susceptibility effects.Quantitative MR techniques: R2, R2*, R2’

Iron is an indispensable enzymatic cofactor for several proteins and various neurodegenerative diseases are associated with increased iron levels. Organ iron overload may be responsible for the oxidative damage observed in these disorders.

However, the relationship between iron accumulation and disease pathology is still unclear and require elucidation.

CONCLUSION