Parkinson's disease (PD) is a chronic neurodegenerative disease that has relatively slow progress... more Parkinson's disease (PD) is a chronic neurodegenerative disease that has relatively slow progression with motor symptoms. Leucine-rich repeat kinase 2 (LRRK2) gene mutations and polymorphisms are suggested to be associated with PD. In this study, we aimed to investigate the association between single-nucleotide polymorphisms (SNPs) of the LRRK2 gene, namely, rs11176013, rs10878371, rs11835105, and PD. Genotypes of 132 PD cases and 133 healthy individuals were determined by qRT-PCR. Haplotype analysis was performed. Additionally, LRRK2 mRNA expression levels were determined in 83 PD cases and 55 healthy subjects. The relationship between LRRK2 mRNA levels, the target SNPs, and clinical data was also investigated. Our results indicated that the "GG" genotype and "G" allele of rs11176013 and the "CC" genotype and "C" allele of rs10878371 were more frequent in cases. The "GCG" haplotype was significantly more frequent in cases. LRRK2 mRNA expression levels in patients were significantly lower than those in healthy individuals. The patients with the "CC" genotype for rs10878371 and the "GG" genotype for rs11176013 had decreased LRRK2 mRNA levels. We found that the rs11176013 "GG" genotype and the rs10878371 "CC" genotype were less frequently seen in cases with akinetic rigid or combined akinetic rigid and tremor-dominant initial symptoms. Consequently, our results demonstrate that the rs11176013 and rs10878371 polymorphisms are associated with PD in a Turkish cohort, and moreover, these results suggest that these polymorphisms may affect the expression of the LRRK2 gene and disease progression and thus play a role in the pathogenesis of PD.
The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice
Movement Disorders, 2021
The genetic and epidemiological features of hereditary ataxias have been reported in several popu... more The genetic and epidemiological features of hereditary ataxias have been reported in several populations; however, Turkey is still unexplored. Due to high consanguinity, recessive ataxias are more common in Turkey than in Western European populations.
Background: Brain derived neurotrophic factor (BDNF) may play a role in the pathogenesis of Alzhe... more Background: Brain derived neurotrophic factor (BDNF) may play a role in the pathogenesis of Alzheimer's disease (AD) through neurotrophic effects on basal cholinergic neurons. We have previously
Ataxia in a Movement Disorders Outpatient Clinic: a Single-Center Experience in Turkey
The Cerebellum, 2022
The etiology may not be determined in patients with ataxia despite detailed evaluations. The aim ... more The etiology may not be determined in patients with ataxia despite detailed evaluations. The aim of this study was to investigate the clinical and laboratory characteristics of a large cohort of patients with adult-onset ataxia of different etiologies, particularly, undetermined etiologies despite extensive clinical, genetic, laboratory, electrophysiological, and imaging investigations. The medical records of all patients diagnosed with ataxia of subacute-chronic onset between January 2011 and March 2021 were reviewed retrospectively. The records of patients with symptom onset after 16 years of age were included in the study. In all patients, clinical and demographic findings were noted. Etiologies were classified as acquired, hereditary, degenerative (multiple system atrophy-cerebellar, MSA-C), functional, and undetermined. During the study period, we determined 74 patients with ataxia and 59 (35 males) patients met the study criteria. The age range was 22-87 years. The etiologies were hereditary (n = 19), acquired (n = 14), MSA-C (n = 9), functional (n = 2), and undetermined (n = 15). The patients with hereditary etiologies and undetermined causes were significantly younger at admission and at symptom onset (p = 0.001 and p = 0.000). There was a significant delay until diagnosis in patients with hereditary etiologies compared to other etiologies. In acquired etiologies, axial findings (71.4%) were more prominent whereas extremity and axial findings were more common in patients with hereditary etiologies (83.3%, p = 0.030). There were systemic and radiological indicators such as hearing loss, juvenile cataract, or dentate hyperintensity in certain disorders. Hereditary etiologies are as common as acquired or degenerative etiologies in adults. However, they have an earlier onset and delayed diagnosis. Therefore, we should recognize the extracerebellar neurological, systemic, and neuroimaging findings.
Diverse Neurological Symptoms in Chronic Liver Failure : Difficulties in Etiological Diagnosis
Acquired hepatocerebral degeneration (AHCD) describes a neurological disorder in the context of c... more Acquired hepatocerebral degeneration (AHCD) describes a neurological disorder in the context of chronic hepatic failure which is not related to acute encephalopathy and not explained by an alternative cause. Patients with AHCD may have cognitive deficits, cerebellar findings, hypoor hyperkinetic movement disorders, and sometimes myelopathy with typical magnetic resonance imaging (MRI) abnormalities, particularly T1 hyperintensity in the internal pallidum. Here, we report five patients ranging between 45-73 years-old. All had liver disease, four of them were diagnosed as chronic liver failure and one had portosystemic shunts secondary to portal vein thrombosis. Presenting neurological symptoms were parkinsonism (4), ataxia (3), postural and action tremor (3) and cognitive deficit (2). MRI findings were compatible with AHCD. This report shows the variability of neurological symptoms in AHCD. Possibility of liver disease or portosystemic shunts should be kept in mind before diagnosing ...
Cortical relay time shortens in parkinsons disease with apraxia
Journal of Neurological Sciences (Turkish), 2017
Cortical Relay Time Shortens in Parkinson's Disease with Apraxia Ayşegül GÜNDÜZ, Meral E. KIZ... more Cortical Relay Time Shortens in Parkinson's Disease with Apraxia Ayşegül GÜNDÜZ, Meral E. KIZILTAN, Hatice KUMRU, Semra OĞUZ, Günes KIZILTAN, Sibel ERTAN, Hülya APAYDIN Department of Neurology, Cerrahpasa School of Medicine, Istanbul University Institut Guttmann, Institut Universitari de Neurorehabilitació adscrit a la UAB, Badalona, Barcelona, Spain Institut Guttmann, Institut Universitari de Neurorehabilitació adscrit a la UAB, Badalona, Barcelona, Spain Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Barcelona, Spain Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Marmara University
Secondary dystonias due to ischemic and/or hemorrhagic lesions of the basal ganglia and thalamus ... more Secondary dystonias due to ischemic and/or hemorrhagic lesions of the basal ganglia and thalamus are rare. Among 2369 patients with stroke, only 12 patients (0.5%) developed posthemiplegic dystonia, which constituted 4.9% of 506 patients with dystonia. Posthemiplegic dystonia appeared as slow, twisting clonic spasms (mobile dystonia) in eight patients who had the distal parts of their extremities affected. On the other hand, in case of an arm or leg involved as a whole, posthemiplegic dystonia appeared as prolonged abnormal postures (fixed dystonia), as observed in our four patients. The latency till the appearance of dystonia following stroke was significantly shorter in mobile dystonia (9 months versus 61.5 months, p=0.05). The fixed dystonia resulted from thalamic involvement in all four cases. On the other hand, mobile dystonia developed in three patients with thalamic involvement, but in all five patients with infarctions in putamen, caudate and lentiform nuclei. The rather low number of cases with basal ganglia/capsular lesions resulting in hemiplegia and leading to subsequent dystonia may be due to selective lesioning and blockade of selective neurotransmitter systems.
Holmes' tremor is a low frequency tremor which is diagnosed clinically, appears during rest,... more Holmes' tremor is a low frequency tremor which is diagnosed clinically, appears during rest, posture and action on especially proximal parts. It is generally associated with lesions (cerebrovascular diseases, trauma or multiple sclerosis) localized in midbrain or thalamus. Symptoms generally develop weeks, months and even years after the underlying cause. In this article, a case of Holmes' tremor which developed approximately five months after the hemorrhage localized at upper part of midbrain secondary to cavernoma and the clinical ...
Deep brain stimulation in movement disorders treatment is applied in cases of Parkinson's di... more Deep brain stimulation in movement disorders treatment is applied in cases of Parkinson's disease resistant to medical treatment as well as in drug-resistant essential tremor and dystonia. Basis of this application is chronic electrical stimulation of certain nuclei by the way of electrode placed in the relevant nuclei. Currently, target nuclei include thalamic ventral intermediate nucleus, subthalamic nucleus, globus pallidus interna and more recently listed pedunculopontine nucleus although the target varies depending on the indication. Here, ...
Mitochondrial dysfunctions are significant contributors to neurodegeneration. One result or a cau... more Mitochondrial dysfunctions are significant contributors to neurodegeneration. One result or a cause of mitochondrial dysfunction might be the disruption of mtDNA transcription. Limited data indicated an altered expression of mtDNA encoded transcripts in Alzheimer's disease (AD) or Parkinson's disease (PD). The number of mitochondria is high in cells with a high energy demand, such as muscle or nerve cells. AD or PD involves increased risk of cardiomyopathy, suggesting that mitochondrial dysfunction might be systemic. If it is systemic, we should observe it in different cell types. Given that, we wanted to investigate any disruption in the regulation of mtDNA encoded gene expression in addition to PINK1, PARKIN, and ATP levels in peripheral mononuclear blood cells of PD cases who are affected by a neurodegenerative disorder that is very well known by its mitochondrial aspects. Our results showed for the first time that: 1) age of onset > 50 PD sporadic (PDS) cases: mtDNA transcription and quality control genes were affected; 2) age of onset <50 PDS cases: only mtDNA transcription was affected; and 3) PD cases with familial background: only quality control genes were affected. mtDNA
Accompanying neurological signs are not expected in primary cervical dystonia (PCD), characterize... more Accompanying neurological signs are not expected in primary cervical dystonia (PCD), characterized by involuntary muscle contractions resulting in abnormal posture of the neck. We aimed to assess the associated arm movements during walking in patients with PCD in compared to age-, sex-, weight-and height-matched controls. Methods: We examined 16 consecutive de novo patients with PCD and controls in a quantitative trial, and calculated the mean gait speed, mean number of steps, mean frequencies of right and left arms, mean frequencies of right and left legs, and mean arm/leg frequencies for right and left sides. Results: Eleven patients (68,8%) had right-sided cervical dystonia, 5 patients (31,2%) had left-sided cervical dystonia. The mean speed of gait and the mean number of steps were similar between patients and controls. The mean frequencies of bilateral upper extremities and arm/ leg frequencies were significantly slower in patients with PCD (p<0,05). In patient group, the mean armswing frequency was significantly lower in symptomatic side versus asymptomatic side (p=0,038). The disease duration was positively associated with the mean arm/leg frequency (p=0,042). Discussion: Our results imply that the reduced armswing in cervical dystonia might be a feature of primary cervical dystonia.
Parkinson's disease (PD) is a chronic neurodegenerative disease that has relatively slow progress... more Parkinson's disease (PD) is a chronic neurodegenerative disease that has relatively slow progression with motor symptoms. Leucine-rich repeat kinase 2 (LRRK2) gene mutations and polymorphisms are suggested to be associated with PD. In this study, we aimed to investigate the association between single-nucleotide polymorphisms (SNPs) of the LRRK2 gene, namely, rs11176013, rs10878371, rs11835105, and PD. Genotypes of 132 PD cases and 133 healthy individuals were determined by qRT-PCR. Haplotype analysis was performed. Additionally, LRRK2 mRNA expression levels were determined in 83 PD cases and 55 healthy subjects. The relationship between LRRK2 mRNA levels, the target SNPs, and clinical data was also investigated. Our results indicated that the "GG" genotype and "G" allele of rs11176013 and the "CC" genotype and "C" allele of rs10878371 were more frequent in cases. The "GCG" haplotype was significantly more frequent in cases. LRRK2 mRNA expression levels in patients were significantly lower than those in healthy individuals. The patients with the "CC" genotype for rs10878371 and the "GG" genotype for rs11176013 had decreased LRRK2 mRNA levels. We found that the rs11176013 "GG" genotype and the rs10878371 "CC" genotype were less frequently seen in cases with akinetic rigid or combined akinetic rigid and tremor-dominant initial symptoms. Consequently, our results demonstrate that the rs11176013 and rs10878371 polymorphisms are associated with PD in a Turkish cohort, and moreover, these results suggest that these polymorphisms may affect the expression of the LRRK2 gene and disease progression and thus play a role in the pathogenesis of PD.
The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice
Movement Disorders, 2021
The genetic and epidemiological features of hereditary ataxias have been reported in several popu... more The genetic and epidemiological features of hereditary ataxias have been reported in several populations; however, Turkey is still unexplored. Due to high consanguinity, recessive ataxias are more common in Turkey than in Western European populations.
Background: Brain derived neurotrophic factor (BDNF) may play a role in the pathogenesis of Alzhe... more Background: Brain derived neurotrophic factor (BDNF) may play a role in the pathogenesis of Alzheimer's disease (AD) through neurotrophic effects on basal cholinergic neurons. We have previously
Ataxia in a Movement Disorders Outpatient Clinic: a Single-Center Experience in Turkey
The Cerebellum, 2022
The etiology may not be determined in patients with ataxia despite detailed evaluations. The aim ... more The etiology may not be determined in patients with ataxia despite detailed evaluations. The aim of this study was to investigate the clinical and laboratory characteristics of a large cohort of patients with adult-onset ataxia of different etiologies, particularly, undetermined etiologies despite extensive clinical, genetic, laboratory, electrophysiological, and imaging investigations. The medical records of all patients diagnosed with ataxia of subacute-chronic onset between January 2011 and March 2021 were reviewed retrospectively. The records of patients with symptom onset after 16 years of age were included in the study. In all patients, clinical and demographic findings were noted. Etiologies were classified as acquired, hereditary, degenerative (multiple system atrophy-cerebellar, MSA-C), functional, and undetermined. During the study period, we determined 74 patients with ataxia and 59 (35 males) patients met the study criteria. The age range was 22-87 years. The etiologies were hereditary (n = 19), acquired (n = 14), MSA-C (n = 9), functional (n = 2), and undetermined (n = 15). The patients with hereditary etiologies and undetermined causes were significantly younger at admission and at symptom onset (p = 0.001 and p = 0.000). There was a significant delay until diagnosis in patients with hereditary etiologies compared to other etiologies. In acquired etiologies, axial findings (71.4%) were more prominent whereas extremity and axial findings were more common in patients with hereditary etiologies (83.3%, p = 0.030). There were systemic and radiological indicators such as hearing loss, juvenile cataract, or dentate hyperintensity in certain disorders. Hereditary etiologies are as common as acquired or degenerative etiologies in adults. However, they have an earlier onset and delayed diagnosis. Therefore, we should recognize the extracerebellar neurological, systemic, and neuroimaging findings.
Diverse Neurological Symptoms in Chronic Liver Failure : Difficulties in Etiological Diagnosis
Acquired hepatocerebral degeneration (AHCD) describes a neurological disorder in the context of c... more Acquired hepatocerebral degeneration (AHCD) describes a neurological disorder in the context of chronic hepatic failure which is not related to acute encephalopathy and not explained by an alternative cause. Patients with AHCD may have cognitive deficits, cerebellar findings, hypoor hyperkinetic movement disorders, and sometimes myelopathy with typical magnetic resonance imaging (MRI) abnormalities, particularly T1 hyperintensity in the internal pallidum. Here, we report five patients ranging between 45-73 years-old. All had liver disease, four of them were diagnosed as chronic liver failure and one had portosystemic shunts secondary to portal vein thrombosis. Presenting neurological symptoms were parkinsonism (4), ataxia (3), postural and action tremor (3) and cognitive deficit (2). MRI findings were compatible with AHCD. This report shows the variability of neurological symptoms in AHCD. Possibility of liver disease or portosystemic shunts should be kept in mind before diagnosing ...
Cortical relay time shortens in parkinsons disease with apraxia
Journal of Neurological Sciences (Turkish), 2017
Cortical Relay Time Shortens in Parkinson's Disease with Apraxia Ayşegül GÜNDÜZ, Meral E. KIZ... more Cortical Relay Time Shortens in Parkinson's Disease with Apraxia Ayşegül GÜNDÜZ, Meral E. KIZILTAN, Hatice KUMRU, Semra OĞUZ, Günes KIZILTAN, Sibel ERTAN, Hülya APAYDIN Department of Neurology, Cerrahpasa School of Medicine, Istanbul University Institut Guttmann, Institut Universitari de Neurorehabilitació adscrit a la UAB, Badalona, Barcelona, Spain Institut Guttmann, Institut Universitari de Neurorehabilitació adscrit a la UAB, Badalona, Barcelona, Spain Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Barcelona, Spain Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Marmara University
Secondary dystonias due to ischemic and/or hemorrhagic lesions of the basal ganglia and thalamus ... more Secondary dystonias due to ischemic and/or hemorrhagic lesions of the basal ganglia and thalamus are rare. Among 2369 patients with stroke, only 12 patients (0.5%) developed posthemiplegic dystonia, which constituted 4.9% of 506 patients with dystonia. Posthemiplegic dystonia appeared as slow, twisting clonic spasms (mobile dystonia) in eight patients who had the distal parts of their extremities affected. On the other hand, in case of an arm or leg involved as a whole, posthemiplegic dystonia appeared as prolonged abnormal postures (fixed dystonia), as observed in our four patients. The latency till the appearance of dystonia following stroke was significantly shorter in mobile dystonia (9 months versus 61.5 months, p=0.05). The fixed dystonia resulted from thalamic involvement in all four cases. On the other hand, mobile dystonia developed in three patients with thalamic involvement, but in all five patients with infarctions in putamen, caudate and lentiform nuclei. The rather low number of cases with basal ganglia/capsular lesions resulting in hemiplegia and leading to subsequent dystonia may be due to selective lesioning and blockade of selective neurotransmitter systems.
Holmes' tremor is a low frequency tremor which is diagnosed clinically, appears during rest,... more Holmes' tremor is a low frequency tremor which is diagnosed clinically, appears during rest, posture and action on especially proximal parts. It is generally associated with lesions (cerebrovascular diseases, trauma or multiple sclerosis) localized in midbrain or thalamus. Symptoms generally develop weeks, months and even years after the underlying cause. In this article, a case of Holmes' tremor which developed approximately five months after the hemorrhage localized at upper part of midbrain secondary to cavernoma and the clinical ...
Deep brain stimulation in movement disorders treatment is applied in cases of Parkinson's di... more Deep brain stimulation in movement disorders treatment is applied in cases of Parkinson's disease resistant to medical treatment as well as in drug-resistant essential tremor and dystonia. Basis of this application is chronic electrical stimulation of certain nuclei by the way of electrode placed in the relevant nuclei. Currently, target nuclei include thalamic ventral intermediate nucleus, subthalamic nucleus, globus pallidus interna and more recently listed pedunculopontine nucleus although the target varies depending on the indication. Here, ...
Mitochondrial dysfunctions are significant contributors to neurodegeneration. One result or a cau... more Mitochondrial dysfunctions are significant contributors to neurodegeneration. One result or a cause of mitochondrial dysfunction might be the disruption of mtDNA transcription. Limited data indicated an altered expression of mtDNA encoded transcripts in Alzheimer's disease (AD) or Parkinson's disease (PD). The number of mitochondria is high in cells with a high energy demand, such as muscle or nerve cells. AD or PD involves increased risk of cardiomyopathy, suggesting that mitochondrial dysfunction might be systemic. If it is systemic, we should observe it in different cell types. Given that, we wanted to investigate any disruption in the regulation of mtDNA encoded gene expression in addition to PINK1, PARKIN, and ATP levels in peripheral mononuclear blood cells of PD cases who are affected by a neurodegenerative disorder that is very well known by its mitochondrial aspects. Our results showed for the first time that: 1) age of onset > 50 PD sporadic (PDS) cases: mtDNA transcription and quality control genes were affected; 2) age of onset <50 PDS cases: only mtDNA transcription was affected; and 3) PD cases with familial background: only quality control genes were affected. mtDNA
Accompanying neurological signs are not expected in primary cervical dystonia (PCD), characterize... more Accompanying neurological signs are not expected in primary cervical dystonia (PCD), characterized by involuntary muscle contractions resulting in abnormal posture of the neck. We aimed to assess the associated arm movements during walking in patients with PCD in compared to age-, sex-, weight-and height-matched controls. Methods: We examined 16 consecutive de novo patients with PCD and controls in a quantitative trial, and calculated the mean gait speed, mean number of steps, mean frequencies of right and left arms, mean frequencies of right and left legs, and mean arm/leg frequencies for right and left sides. Results: Eleven patients (68,8%) had right-sided cervical dystonia, 5 patients (31,2%) had left-sided cervical dystonia. The mean speed of gait and the mean number of steps were similar between patients and controls. The mean frequencies of bilateral upper extremities and arm/ leg frequencies were significantly slower in patients with PCD (p<0,05). In patient group, the mean armswing frequency was significantly lower in symptomatic side versus asymptomatic side (p=0,038). The disease duration was positively associated with the mean arm/leg frequency (p=0,042). Discussion: Our results imply that the reduced armswing in cervical dystonia might be a feature of primary cervical dystonia.
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