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|LETTER TO EDITOR
|Year : 2017 | Volume
| Issue : 2 | Page : 386-388
Young onset Parkinsonism in a patient with familial central core disease
P Samuel Joseph1, DM Syam Krishnan1, Gayathri Narayanappa2, Muralidharan Nair1
1 Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India
2 Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
|Date of Web Publication||10-Mar-2017|
Dr. P Samuel Joseph
Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Joseph P S, Syam Krishnan D M, Narayanappa G, Nair M. Young onset Parkinsonism in a patient with familial central core disease. Neurol India 2017;65:386-8
Central core disease (CCD) is a congenital myopathy often linked to ryanodine receptor (RyR1). The association of Parkinsonism More Details with CCD has not been reported so far. Genetic defects in calcium signaling as well as S-nitrosylation pathways could underlie the clinical phenotype.
CCD is one among the earliest congenital myopathies to be described  and has been linked to mutations in RyR1, an intracellular calcium ion release channel located in the sarcoplasmic reticulum., However, genetic heterogeneity is known and mutation in other genes, such as the β-myosin heavy chain gene, has also been reported. The clinical presentation is also heterogeneous, and is typically static, even though severe and progressive forms are recognized. The associations include malignant hyperthermia  and cardiomyopathy. The characteristic clinical features of the disease include hypotonia and delay in motor development in infancy, varying degrees of symmetrical proximal muscle weakness and wasting, and a non-progressive or a slowly progressive course.
Parkinsonism or other central nervous system (CNS) manifestations have not been described as an association in CCD. We describe a patient with familial CCD with levodopa responsive young onset Parkinsonism, satisfying the United Kingdom Parkinson's Disease Brain Bank diagnostic criteria  for Parkinson's disease (PD), and hypothesize the possible points where the pathogenetic cascade of the two conditions could meet.
A 45-year-old gentleman born of nonconsanguinous parentage had a history of very slowly progressing symmetric proximal lower limb weakness since 3 years of age followed by symmetric proximal upper limb weakness since the age of 30 years. At 38 years of age, he developed left upper limb rest tremor followed by dragging of the left lower limb during walking. Subsequently, he developed bradykinesia and rigidity of limbs, more involving the left side. He was initiated on levodopa with an excellent response. He had motor fluctuations for the past two years and then experienced mild and non-disabling peak-dose dyskinesia until his admission. His neurological examination revealed proximal weakness of all four limbs with preserved deep tendon reflexes and pseudohypertrophy of calves. In addition, he had asymmetric Parkinsonism, and the Unified Parkinson's Disease Rating Scale (UPDRS) part 3 score after overnight withdrawal of levodopa was 42; the score improved to 12 after levodopa administration. His creatinine phosphokinase (CPK) was 180 U/L. Electromyography showed a myopathic pattern. Muscle biopsy from the vastus lateralis [Figure 1] showed rounding and variation in fiber diameter with central/eccentric, round-to-oval intensely stained areas in majority of fibers, which was suggestive of cores. Immunohistochemical staining to monoclonal antibodies against desmin showed abnormal expression within and/or around the core area [Figure 2]. Magnetic resonance imaging of the brain was normal.
|Figure 1: Transversely cut skeletal muscle tissue showing intensely stained (→) central /eccentric areas suggestive of cores (hematoxylin and eosin ×400)|
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|Figure 2: Immunostaining to antibodies against desmin shows abnormal expression within (*) and around (arrow) the core area (Desmin ×400)|
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His 8-year-old son had a similar history of symmetric proximal limb weakness since 3 years of age. On examination, the child had symmetric proximal limb weakness without muscle hypertrophy or extrapyramidal features. His muscle biopsy had been done earlier and was reviewed. The histopathological features were similar to those of his father and were suggestive of CCD. There was no history suggestive of myopathy or Parkinsonism in any other family member.
CNS involvement in CCD has not been reported so far. We describe a patient with familial CCD, with coexisting levodopa responsive young onset Parkinsonism satisfying the standard diagnostic criteria for PD. The patient's age of onset of Parkinsonism favors a genetic etiology; further, CCD and Parkinsonism being the phenotypic expressions of a single genetic abnormality is a plausibility.
There are more than one potential pathways where the pathogenetic cascade of the two conditions could meet. RyR1 dysfunction (due to various mutations) leading to disturbed intracellular calcium handling is one of the mechanisms underlying CCD. Dysregulation of intracellular calcium homeostasis can contribute to mitochondrial dysfunction, increased oxidative stress, and neurodegeneration., RyR1 is expressed in the brain, especially the microglia, which is known to be important in neuroinflammation. Microglial activation  associated with neuroinflammation is one among the important mechanisms underlying cell death in PD  and ryanodine receptors have been proposed to be potential therapeutic targets for neuroprotection in PD. Diverse genetic and environmental etiological factors underlie PD and the current understanding favors multiple factors. Thus, we subsume that the dysfunctional RyR leads to disturbed intracellular calcium handling, which could, in the presence of additional susceptibility factors, lead to mitochondrial dysfunction and/or neuroinflammation and initiate the pathogenetic cascade of PD.
Another potential point of interaction between the two conditions is the involvement of the S-nitrosylation pathway. Accumulation of misfolded proteins in many neurodegenerative disorders, including PD, have been found to be associated with increased levels of oxidative and nitrosative stress. The deleterious effects of increased generation of nitric oxide (NO)-related species, on neuronal function, and its contribution to neurodegeneration is now being increasingly recognized. Mutations in RyR causing excessive “calcium leak” have been shown to increase the generation of reactive nitrogen species. The mutant RyR, in turn, is prone to S-nitrosylation induced malfunction. Thus, it is hypothesized that a malfunctioning RyR causing increased nitrosative stress could result in PD, or else a primary defect in nitrosylation pathway could result in PD as well as worsen the RyR dysfunction in the muscle, resulting in CCD.
There are rare reports of association of myopathy with Parkinsonism, and to the best of our knowledge, there have been no reports of Parkinsonism or other CNS manifestations of CCD. Our case is interesting because of the phenotypic features present in the patient. A link between RyR and PD has been proposed by others, and we believe that RyR malfunction and the resulting disturbances in cytosolic calcium homeostasis, mitochondrial dysfunction, and aberrant oxidative/nitrosative stress could contribute to the association in this case.
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[Figure 1], [Figure 2]