Neurol Sci (2015) 36:341–343 DOI 10.1007/s10072-014-1898-y
LETTER TO THE EDITOR
PARK2 presenting as a disabling peripheral axonal neuropathy Joana Domingos • Teresa Coelho • Ricardo Taipa Jorge P. Basto • Manuel Melo-Pires • Marina J. Magalha˜es
•
Received: 23 April 2014 / Accepted: 16 July 2014 / Published online: 25 July 2014 Ó Springer-Verlag Italia 2014
Dear Sirs, Mutations in parkin gene (PARK2) have been associated with autosomal recessive early-onset Parkinson’s disease (PD), characterized by early onset and marked response to levodopa but with rapid onset of dyskinesia. A 49-year-old male patient, with non-consanguineous parents, presented at the age of 37 with progressive gait difficulties. He complained that the tip of his right foot started to beat on the floor when he walked for an extended period. When first observed at the age of 38, the neurological examination, blood analysis and electromyography were all normal. He has six siblings, all healthy. There is no family history of neuropathy or parkinsonism.
Electronic supplementary material The online version of this article (doi:10.1007/s10072-014-1898-y) contains supplementary material, which is available to authorized users. J. Domingos (&) M. J. Magalha˜es Department of Neurology, Centro Hospitalar do Porto, Hospital de Santo Anto´nio, Largo Prof. Abel Salazar, 4099-001 Porto, Portugal e-mail: [email protected] T. Coelho Department of Neurophysiology, Centro Hospitalar do Porto, Hospital de Santo Anto´nio, Largo Prof. Abel Salazar, 4099-001 Porto, Portugal R. Taipa M. Melo-Pires Neuropathology Unit, Centro Hospitalar do Porto, Hospital de Santo Anto´nio, Largo Prof. Abel Salazar, 4099-001 Porto, Portugal J. P. Basto Instituto de Biologia Molecular e Celular, Rua do Campo Alegre 823, Porto, Portugal
At the age of 40, his walking difficulties increased, with sensation of foot drop after a few meters of walking. Neurological examination remained normal. Electroneuromyography showed a chronic axonal sensory and motor polyneuropathy. The sensory nerve action potential amplitude was reduced in the ulnaris (13 lV), peroneus superficialis (2.8 lV) and suralis (6.8 lV) nerves with normal conduction velocities. The compound muscle action potential of ulnaris, tibialis and peroneus nerves were all normal. In the needle electromyography voluntary activity was marked by a reduced number of motor unit action potentials (MUAP) in the extensor digitorum brevis, tibialis anterior and vastus medialis. In all these muscles, MUAP were increased in amplitude and duration and some polyphasic MUAPs were observed. The main etiologies of axonal neuropathy were excluded (no history of drug therapy or toxic exposure, no evidence of infection, metabolic disorders, vitamin deficiency, connective tissue disorders, paraproteinemia or thyroid dysfunction). Two years later, he had developed a symmetrical distal weakness of the lower limbs, with atrophy of the intrinsic muscles of the hands and feet. Ankle and brachioradialis reflexes were absent. He had steppage gait, with normal sensation. During the next 6 years, falls became frequent and he became progressively slower with difficulty with fine movements of the hands. He had a slight hypomimic face, a resting and postural tremor of all four limbs, cogwheel rigidity and bilateral bradykinesia with fatigability on finger/foot tapping. He could not stand up, had a stooped posture, a shuffling gait, decreased bilateral arm swing and severe postural instability (mixed parkinsonian syndrome UPDRS-III scale: 48 points; Hoehn and Yahr stage 4).
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Neurol Sci (2015) 36:341–343
Fig. 1 Semithin section stained with toluidine blue showing loss of myelinated fibers (on the left). Histogram showing loss of large myelinated fibers (on the right)
The brain MRI was normal and the Dat SCAN identified a presynaptic dopaminergic deficit. PARK2 mutation analysis was performed by bidirectional sequencing of the coding region and multiplex ligation-dependent probe amplification for large gene rearrangements. A homozygous deletion encompassing exon 4 was found (c.413-?_534??del). Mutations for CMT2B, CMT2E/1F, CMT1B/2I/2J, CMT2A2, CMT2B1, CMT2L, CMT2F, CMT2K/4A and CMT1D/4E were not found. In order to exclude other causes, a nerve biopsy was performed. It showed a moderate axonal chronic neuropathy, affecting predominantly large diameter myelinated fibers with no evidence of regeneration (Fig. 1). He started therapy with levodopa up to 400 mg/day with an excellent response, but with a rapid-onset of dyskinesia, after 8 months. He had no impulse control disorder. At last follow-up, on levodopa 200 mg/day and ropirinole 10 mg/day, he showed a non-disabling akinetic-rigid parkinsonian syndrome with slight left foot dyskinesia. His main disability was steppage gait (video). This is the first description of a PARK2 patient presenting with a disabling peripheral neuropathy preceding parkinsonian symptoms. The first reported case of PARK2 associated with peripheral axonal neuropathy occurred in 1998. A few subsequent cases have been described. A PARK2 patient developed autonomic dysfunction with axonal neuropathy demonstrated on nerve conduction studies (NCS), 11 years after the onset of parkinsonism [1]. Another presented 30 years after disease onset with neuropathy with liability to pressure palsies. NCS and sural nerve biopsy showed a motor and sensory neuropathy [2]. Another, 24 years after disease onset, had a sensory axonal neuropathy on NCS [3]. A small study that compared PARK2 patients with idiopathic PD hypothesized that sensory axonal neuropathy
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might be a common feature of PARK2 patients, although asymptomatic [4]. In our case, in contrast to those previously reported, the clinical presentation was a disabling peripheral neuropathy preceding parkinsonian symptoms, which led to a delay in the diagnosis. Similar to the single case descriptions in the literature, nerve biopsy showed loss of myelinated fibers preferentially affecting large diameter fibers. However, we did not find evidence of axonal regeneration (regenerative clusters) or myelin abnormalities. Electron microscopy showed that axonal degeneration affected myelinated and non myelinated fibers (watery appearance fibers and dense bodies). This finding suggests a progressive loss from large myelinated to small myelinated and non myelinated fibers. There is evidence in the literature of parkin protein in the axoplasm of myelinated fibers and the cytoplasm of Schwann cells [5], but the function of parkin in the peripheral nerve remains unknown. Our findings support the hypothesis that fiber susceptibility to degeneration, at least earlier in the process, is related to fiber diameter. Further studies are needed to find the role of parkin in peripheral neuropathy. Acknowledgments The authors would like to acknowledge the patient for his kind cooperation. This research received no specific grant from any funding agency. Conflict of interest
The authors have no competing interests.
References 1. Khan NL, Graham E, Critchley P, Schrag AE, Wood NW, Lees AJ, Bhatia KP, Quinn N (2003) Parkin disease: a phenotypic study of a large case series. Brain 126:1279–1292 2. Abbruzzese G, Pigullo S, Schenone A, Bellone E, Marchese R, Di Maria E et al (2004) Does parkin play a role in the peripheral nervous system? A family report. Mov Disord 19:978–981
Neurol Sci (2015) 36:341–343 3. Okuma Y, Hattori N, Mizuno Y (2003) Sensory neuropathy in autosomal recessive juvenile parkinsonism (PARK2). Parkinsonism Relat Disord 9(5):313–314 4. Ohsawa Y, Kurokawa K, Sonoo M, Yamada H, Hemmi S, Iwatsuki K et al (2005) Reduced amplitude of the sural nerve sensory action potential in PARK2 patients. Neurology 65:459–462
343 5. Kitada T, Asakawa S, Minoshima S, Mizuno Y, Shimizu N (2000) Molecular cloning, gene expression, and identification of a splicing variant of the mouse parkin gene. Mamm Genome 11:417–421
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LETTER TO THE EDITOR
PARK2 presenting as a disabling peripheral axonal neuropathy Joana Domingos • Teresa Coelho • Ricardo Taipa Jorge P. Basto • Manuel Melo-Pires • Marina J. Magalha˜es
•
Received: 23 April 2014 / Accepted: 16 July 2014 / Published online: 25 July 2014 Ó Springer-Verlag Italia 2014
Dear Sirs, Mutations in parkin gene (PARK2) have been associated with autosomal recessive early-onset Parkinson’s disease (PD), characterized by early onset and marked response to levodopa but with rapid onset of dyskinesia. A 49-year-old male patient, with non-consanguineous parents, presented at the age of 37 with progressive gait difficulties. He complained that the tip of his right foot started to beat on the floor when he walked for an extended period. When first observed at the age of 38, the neurological examination, blood analysis and electromyography were all normal. He has six siblings, all healthy. There is no family history of neuropathy or parkinsonism.
Electronic supplementary material The online version of this article (doi:10.1007/s10072-014-1898-y) contains supplementary material, which is available to authorized users. J. Domingos (&) M. J. Magalha˜es Department of Neurology, Centro Hospitalar do Porto, Hospital de Santo Anto´nio, Largo Prof. Abel Salazar, 4099-001 Porto, Portugal e-mail: [email protected] T. Coelho Department of Neurophysiology, Centro Hospitalar do Porto, Hospital de Santo Anto´nio, Largo Prof. Abel Salazar, 4099-001 Porto, Portugal R. Taipa M. Melo-Pires Neuropathology Unit, Centro Hospitalar do Porto, Hospital de Santo Anto´nio, Largo Prof. Abel Salazar, 4099-001 Porto, Portugal J. P. Basto Instituto de Biologia Molecular e Celular, Rua do Campo Alegre 823, Porto, Portugal
At the age of 40, his walking difficulties increased, with sensation of foot drop after a few meters of walking. Neurological examination remained normal. Electroneuromyography showed a chronic axonal sensory and motor polyneuropathy. The sensory nerve action potential amplitude was reduced in the ulnaris (13 lV), peroneus superficialis (2.8 lV) and suralis (6.8 lV) nerves with normal conduction velocities. The compound muscle action potential of ulnaris, tibialis and peroneus nerves were all normal. In the needle electromyography voluntary activity was marked by a reduced number of motor unit action potentials (MUAP) in the extensor digitorum brevis, tibialis anterior and vastus medialis. In all these muscles, MUAP were increased in amplitude and duration and some polyphasic MUAPs were observed. The main etiologies of axonal neuropathy were excluded (no history of drug therapy or toxic exposure, no evidence of infection, metabolic disorders, vitamin deficiency, connective tissue disorders, paraproteinemia or thyroid dysfunction). Two years later, he had developed a symmetrical distal weakness of the lower limbs, with atrophy of the intrinsic muscles of the hands and feet. Ankle and brachioradialis reflexes were absent. He had steppage gait, with normal sensation. During the next 6 years, falls became frequent and he became progressively slower with difficulty with fine movements of the hands. He had a slight hypomimic face, a resting and postural tremor of all four limbs, cogwheel rigidity and bilateral bradykinesia with fatigability on finger/foot tapping. He could not stand up, had a stooped posture, a shuffling gait, decreased bilateral arm swing and severe postural instability (mixed parkinsonian syndrome UPDRS-III scale: 48 points; Hoehn and Yahr stage 4).
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342
Neurol Sci (2015) 36:341–343
Fig. 1 Semithin section stained with toluidine blue showing loss of myelinated fibers (on the left). Histogram showing loss of large myelinated fibers (on the right)
The brain MRI was normal and the Dat SCAN identified a presynaptic dopaminergic deficit. PARK2 mutation analysis was performed by bidirectional sequencing of the coding region and multiplex ligation-dependent probe amplification for large gene rearrangements. A homozygous deletion encompassing exon 4 was found (c.413-?_534??del). Mutations for CMT2B, CMT2E/1F, CMT1B/2I/2J, CMT2A2, CMT2B1, CMT2L, CMT2F, CMT2K/4A and CMT1D/4E were not found. In order to exclude other causes, a nerve biopsy was performed. It showed a moderate axonal chronic neuropathy, affecting predominantly large diameter myelinated fibers with no evidence of regeneration (Fig. 1). He started therapy with levodopa up to 400 mg/day with an excellent response, but with a rapid-onset of dyskinesia, after 8 months. He had no impulse control disorder. At last follow-up, on levodopa 200 mg/day and ropirinole 10 mg/day, he showed a non-disabling akinetic-rigid parkinsonian syndrome with slight left foot dyskinesia. His main disability was steppage gait (video). This is the first description of a PARK2 patient presenting with a disabling peripheral neuropathy preceding parkinsonian symptoms. The first reported case of PARK2 associated with peripheral axonal neuropathy occurred in 1998. A few subsequent cases have been described. A PARK2 patient developed autonomic dysfunction with axonal neuropathy demonstrated on nerve conduction studies (NCS), 11 years after the onset of parkinsonism [1]. Another presented 30 years after disease onset with neuropathy with liability to pressure palsies. NCS and sural nerve biopsy showed a motor and sensory neuropathy [2]. Another, 24 years after disease onset, had a sensory axonal neuropathy on NCS [3]. A small study that compared PARK2 patients with idiopathic PD hypothesized that sensory axonal neuropathy
123
might be a common feature of PARK2 patients, although asymptomatic [4]. In our case, in contrast to those previously reported, the clinical presentation was a disabling peripheral neuropathy preceding parkinsonian symptoms, which led to a delay in the diagnosis. Similar to the single case descriptions in the literature, nerve biopsy showed loss of myelinated fibers preferentially affecting large diameter fibers. However, we did not find evidence of axonal regeneration (regenerative clusters) or myelin abnormalities. Electron microscopy showed that axonal degeneration affected myelinated and non myelinated fibers (watery appearance fibers and dense bodies). This finding suggests a progressive loss from large myelinated to small myelinated and non myelinated fibers. There is evidence in the literature of parkin protein in the axoplasm of myelinated fibers and the cytoplasm of Schwann cells [5], but the function of parkin in the peripheral nerve remains unknown. Our findings support the hypothesis that fiber susceptibility to degeneration, at least earlier in the process, is related to fiber diameter. Further studies are needed to find the role of parkin in peripheral neuropathy. Acknowledgments The authors would like to acknowledge the patient for his kind cooperation. This research received no specific grant from any funding agency. Conflict of interest
The authors have no competing interests.
References 1. Khan NL, Graham E, Critchley P, Schrag AE, Wood NW, Lees AJ, Bhatia KP, Quinn N (2003) Parkin disease: a phenotypic study of a large case series. Brain 126:1279–1292 2. Abbruzzese G, Pigullo S, Schenone A, Bellone E, Marchese R, Di Maria E et al (2004) Does parkin play a role in the peripheral nervous system? A family report. Mov Disord 19:978–981
Neurol Sci (2015) 36:341–343 3. Okuma Y, Hattori N, Mizuno Y (2003) Sensory neuropathy in autosomal recessive juvenile parkinsonism (PARK2). Parkinsonism Relat Disord 9(5):313–314 4. Ohsawa Y, Kurokawa K, Sonoo M, Yamada H, Hemmi S, Iwatsuki K et al (2005) Reduced amplitude of the sural nerve sensory action potential in PARK2 patients. Neurology 65:459–462
343 5. Kitada T, Asakawa S, Minoshima S, Mizuno Y, Shimizu N (2000) Molecular cloning, gene expression, and identification of a splicing variant of the mouse parkin gene. Mamm Genome 11:417–421
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