The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice.

BACKGROUND: 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. OBJECTIVE: To identify the prevalence and genetic structure of hereditary ataxias in the Turkish population. METHODS: Our cohort consisted of 1296 index cases and 324 affected family members. Polymerase chain reaction followed by Sanger sequencing or fragment analysis were performed to screen for the trinucleotide repeat expansions in families with a dominant inheritance pattern, as well as in sporadic cases. The expansion in the frataxin (FXN) gene was tested in all autosomal recessive cases and in sporadic cases with a compatible phenotype. Whole-exome sequencing was applied to 251 probands, selected based on the family history, age of onset, and phenotype. RESULTS: Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix-Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole-exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty-eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data. CONCLUSION: With the large sample size recruited across the country, we consider that our results provide an accurate picture of the frequency of hereditary ataxias in Turkey. © 2021 International Parkinson and Movement Disorder Society.

The Parkinson's Story of a Neurologist with 32 Years of Experience on Parkinson's Disease.

As a neurologist who has followed up countless Parkinson's patients over the last 32 years of my fifty-year career; I denied diagnosing myself with Parkinson's disease (PD), although the seldom mild involuntary "twitches" that occurred in the thumb of my right hand over a two-year period, resembled Parkinson's disease tremor. However, when these involuntary contractions became persistent; considering its similarity to characteristic resting tremor in typical PD, the positive effect of dopaminergic medications, the development of levodopa-induced dyskinesias and other non-motor symptoms, it was clear that the PD diagnosis was accurate. This situation naturally caused me anxiety, and for a year and a half, I kept my diagnosis hidden from everyone except a few close relatives. However, with the encouragement of a psychiatrist friend, when I was able to share my condition with my loved ones, I felt a relative reduction in the burden I was carrying and consequently experienced emotional relief. I am still able to carry out my daily activities independently with a rather low dose of medication, and my PD symptoms do not attract noticeable attention.

Acute-Onset Hemiparkinsonism Secondary to Subacute-Chronic Subdural Hematoma.

Subdural hematomas constitute rare causes of secondary Parkinsonism in elderly. Subacute or chronic subdural hematomas occur in the elderly following minor head trauma or even without a remarkable history of trauma. A 69-year-old woman admitted with a rapidly progressive acute-onset hemiparkinsonism on the left side of her body. She denied any precipitating event before the onset of her symptoms, and her medical history was unremarkable. The anti-Parkinsonian therapy showed no benefit, but gradually worsening of the symptoms was observed. Her brain magnetic resonance imaging revealed a large subacute-chronic subdural hematoma on the right side with a mass effect on the basal ganglia structures, contralateral to her symptomatology. On thorough questioning, she confessed to having fallen out of the bed at night almost four weeks ago, three-weeks before the onset of her symptomatology. She had no complications associated with this fall and merely remembered this event. She denied any history of rapid eye movements (REM) sleep behavior disorder. The anti-Parkinsonian treatment was discontinued; the subdural hematoma was evacuated via burr hole drainage surgery. Her symptoms disappeared instantly after the surgery, with a normal neurologic examination one week after the surgery.

Quantitative analysis of reduced arm swing frequency in essential tremor.

BACKGROUND: Essential tremor (ET) has recently been accepted as a heterogeneous disorder which may be associated with synuclein pathology or a variety of other genetic disorders. METHODS: We observed decreased arm swing frequency in 18 of 136 definite ET patients, and recorded the associated arm movements in 18 ET patients and 33 sex- and age-matched healthy controls. RESULTS: The mean frequency of the right arm (p = 0.047), left arm (p = 0.025) and leg (p = 0.030), and the mean arm/leg frequency on the right side (p = 0.048) were significantly lower in ET patients. The mean frequencies for both arms and legs were significantly lower for the more affected side of the body (p = 0.034 and p = 0.036, respectively). CONCLUSION: We conclude that ET may be associated with decreased arm and leg swing frequencies, especially on the more affected side of the body.

Clinical characteristics of 49 patients with psychogenic movement disorders in a tertiary clinic in Turkey.

Patients admitted to movement disorders outpatient unit at a university hospital between January 2002 and June 2007 were screened for psychogenic movement disorders (PMDs). Out of 1,743 patients, 49 patients (2.8%), including four children, were diagnosed to have PMDs. Women to men ratio was 34/15. The mean age and the age-at-onset were 41 +/- 17 years and 36 +/- 15 years in the adult group, and 10 +/- 2 and 9 +/- 2 years in children. Among the whole group, 44% had tremor, 24% dystonia, 12% pure gait disorders, 8% parkinsonism, 6% chorea-ballism, and 4% tic disorder. PMD developed acutely in 85% of patients, and distractibility was observed in 83%. Of the patients, 81% met the criteria for clinically established PMD, whereas 16% for documented and 2% for probable PMD. Although our data was obtained from a different culture, our results showed that hospital-based frequency and phenomenological features between our PMD group and previously reported ones are similar.

Hypertrophy of intima media of the carotid artery due to L-dopa therapy in Parkinson's disease.

INTRODUCTION: Recent studies have shown that L-dopa therapy used in patients with Parkinson's disease might cause thickening of the carotid artery intima media. It is known that intima-media thickening is a sign of systemic atherosclerosis. The purpose of this study was to clarify the correlation between L-dopa medication and carotid artery intima-media thickness (IMT) in patients with Parkinson's disease. METHODS: Twenty-five patients with Parkinson's disease who used L-dopa (LD+) and 17 patients who did not use L-dopa (LD-) treatment were included in this study. Colour Doppler with B-mode carotid ultrasonography was performed. The Hoehn-Yahr scale was used for staging of Parkinson's disease in an 'on' state. The Student t test was used for statistical analysis. RESULTS: The IMT of the left internal carotid and external carotid arteries were found to be thicker in patients treated with L-dopa. The mean IMT of the left internal carotid artery was 0.937+/-0.391 mm in the LD+ group and 0.677+/-0.138 mm in the LD-group (P=0.013). The mean IMT of the left external carotid artery was 0.956+/-0.531 mm in the LD+ group and 0.646+/-0.18 mm in the LD-group (P=0.037). CONCLUSION: The IMT of the carotid artery was found to be thicker in patients who were treated with L-dopa. In conclusion, patients treated with L-dopa appear to be at a higher risk of thickening of the intima media of the carotid artery.

Use of anti-Parkinson medication during pregnancy: a case series.

INTRODUCTION: Experience about the use and safety of anti-Parkinson (anti-PD) medication during pregnancy is scarce. METHODS: We have retrospectively evaluated the course and outcome of pregnancy in PD patients who used anti-PD medication during their pregnancy. RESULTS: 14 PD patients who used anti-PD medication during part or whole of their pregnancy were included. Dopamine agonists were used in 13 patients, levodopa/benserazide in 4, levodopa/carbidopa/entacapone in 1, rasagiline in 7, amantadine in 4, and biperiden in 1 patient. Nine patients were on combination treatment at the time of their pregnancy. During their whole pregnancy, dopamine agonists had been used in six patients, levodopa in four, and rasagiline in one. Four patients experienced adverse outcomes: one had spontaneous abortion while receiving pramipexole, one elderly mother gave birth to a child with Down syndrome, while receiving pramipexole and rasagiline, in one case, there was fetal distress under levodopa/benserazide, piribedil, and rasagiline which resolved spontaneously, in one case, one of the twins did not survive after the birth while the mother was receiving pramipexole and rasagiline. In none of these cases an association with the use of anti-PD medication and adverse outcomes was clearly established. In one patient, motor symptoms worsened despite high dose levodopa, four others experienced transient worsening upon dose reduction. CONCLUSION: Results in our case series suggest that levodopa, rasagiline, pramipexole, and ropinirole alone or in combination with each other may be considered relatively safe during pregnancy. Expected benefits and risks should be considered when prescribing anti-PD medication in pregnant women.

Hemihypomimia, a rare persistent sign in Parkinson's disease: follow up of 11 patients.

BACKGROUND: Typical hypomimia develops in almost all Parkinson's disease (PD) patients. We observed the presence of hemihypomimia (HH) in some of our PD patients. OBJECTIVE: To discern the presence of hemihypomimia, to compare clinical features of these patients with the patients without HH and then to evaluate HH prospectively. METHODS: Among 353 patients with PD followed-up between September 2003 and December 2004, 204 patients in stage 2 of Hoehn-Yahr were evaluated and hemihypomimia was observed in 13 PD patients (6.4%). Two groups were compared with respect to the age of onset of the first PD symptom, duration of PD and the body side affected predominantly. In addition, persistence of HH was prospectively evaluated in 11 of 13 patients with HH up to two-year-follow up period. RESULTS: Hemihypomimia was interestingly on the right side of the face in all patients. Of these 13 HH patients, all but one had predominantly right-sided PD symptomatology. In the comparison of HH patients with the remaining group (n=191), patients with HH had significantly earlier onset of PD symptoms (mean: 53.9 vs 58.5 years), and shorter PD duration (mean: 4.0 vs 6.2 years) (p<0.01). Up to two-year-follow up, hemihypomimia, which was not changed by several triggered emotional facial expressions, clinically persisted. CONCLUSION: Our observations suggest that hemihypomimia is a rare phenomenon in PD, especially in PD patients having early-onset and shorter PD duration which may persist for several years in concordance with typical asymmetrical involvement of the limbs. HH developed in the right side, prominently on the lower part of the face. Understanding the underlying mechanism(s) about how hemihypomimia appears, and why it dominantly affects the right side of the face deserves further assessment.

Relationship between age and subtypes of psychotic symptoms in Parkinson's disease.

OBJECTIVE: Psychotic symptoms (PS) in Parkinson's disease (PD) usually develop as a side effect of the dopaminergic therapy and consist of hallucinations and delusions. We observed that PD patients who developed delusions tend to be younger than those with hallucinations and we aimed to investigate the validity of this observation. METHODS: The medical records of 127 PD patients with PS were reviewed and 76 patients who were on treatment with dopamine agonists with or without levodopa at the time of developing PS were included. Patients were stratified into 3 groups according to the subtypes of PS: patients with solely hallucinations (n = 46), solely delusions (n = 18), and both types (n = 12). The groups were compared with respect to the age-at-onset of PD and PS, duration of PD, Activities of Daily Living (ADL) and motor subscale scores of Unified PD Rating Scale (UPDRS), and levodopa equivalent dose of the dopaminergic agents administered at the time of PS onset. RESULTS: The mean age-at onset of PD and PS was significantly younger (p = 0.0001) in patients with delusions (49 and 55.9 years) than those with hallucinations (61.9 and 68.9 years). The same parameters were also significantly different (p = 0.002 and p = 0.001, respectively) between the groups of patients with concurrent delusions and hallucinations (51.7 and 57.2 years) and those with only hallucinations. ADL and motor subscale scores were higher in patients with hallucinations (p = 0.016 and p = 0.013) compared with those noted in patients with delusions despite similar disease duration. The mean levodopa equivalent doses of the dopaminergic agents administered at the time of onset of PS did not differ between the groups. CONCLUSION: This study supported an association of delusions with younger onset of both PD and psychosis as compared with hallucinations. However, additional factors related to this association remain to be elucidated.

Assessment of valvulopathy in Parkinson's disease patients on pergolide and/or cabergoline.

OBJECTIVE: To assess the effect of ergot derivatives on cardiac valves in patients with Parkinson's disease (PD). MATERIALS AND METHODS: Echocardiography was performed on 46 PD patients who used either pergolide or cabergoline (MonoPD) or both (MixPD) for a minimum of 1 year and 49 age-matched healthy controls. Valvular regurgitation was graded as mild, moderate and severe. MonoPD and MixPD groups were compared with regard to demographic features, drug profile and valvulopathy. RESULTS: The PD group had a mean age of 63 years, agonist duration of 3.8 years and agonist equivalent dose of 3.5mg/day. Moderate regurgitation in all three valves was significantly more common in the PD group than the controls. Severe valvular regurgitation was not observed in either group, with the exception of one PD patient. The frequency of valvulopathy and doses of agonists did not differ between MixPD and MonoPD groups. CONCLUSION: PD patients on dopamine ergot agonists are prone to moderate valvular regurgitation more than age-matched controls. However, the frequency of valvulopathy was similar in patients who used either one or more agonists.

A hospital-based study: risk factors in development of motor complications in 555 Parkinson's patients on levodopa therapy.

OBJECTIVES: Although levodopa (LD) is the gold standard therapy for symptomatic treatment of Parkinson's disease (PD), the chronic use of LD leads to the development of motor complications in almost all patients. PATIENTS AND METHODS: We assessed the presence and risk factors for motor complications in PD patients on LD therapy. We examined 555 PD patients on LD for the presence or absence of wearing-off (WO+/-) and dyskinesia (DK+/-). RESULTS: WO was present in 46.3%, and DK in 30.1% of patients. The mean age at onset of symptoms were earlier in WO(+)/DK(+) groups (p<0.001). The duration of PD was longer in WO(+)/DK(+) groups (p<0.001). The time between the first symptom and the occurrence of WO/DK, or LD initiation were not significantly different. The initial LD dose was significantly higher in WO(+) compared to WO(-) (300.1mg/d versus 232.5mg/d, p<0.001), and DK(+) compared to DK(-) groups (291.4 mg/d versus 251.9 mg/d, p=0.001). The time until dopamine agonist (DA) initiation was longer in WO(+)/DK(+) groups (p<0.001). WO (p<0.001) and DK (p=0.002) were more common in patients with H&Y stages 3+4. UPDRS scores were higher in WO(+) and DK(+) patients (p<0.001 and p=0.027). CONCLUSION: Our study showed that the development of motor complications was associated with early onset PD, longer disease duration, advanced disease, higher initial LD dose, longer LD use, and late DA initiation, but not with the timing of LD initiation.

Assessment of movement time in patients with essential tremor.

BACKGROUND: We have observed mild bradykinesia in essential tremor (ET) patients, which do not satisfy the criteria of Parkinson's disease (PD). OBJECTIVE: To compare the mean movement time for repetitive movements around distal and proximal joints in ET patients with normal controls by using a simple test paradigm. PATIENTS AND METHODS: Seventeen patients with ET and 14 control subjects were instructed to tap with the index finger sequentially on push-button microswitches. Movement times around metacarpophalangeal, wrist, elbow, and shoulder joints of the right side were tested. The data collected were stored on a computer and the time elapsed between sequential taps on two keys (ms) and number of taps on the left key for 15 seconds were evaluated offline. RESULTS: Movement times of the patients with ET were not found to be significantly different from those of the controls at all joints tested despite slight prolongation for movements around the shoulder joint. CONCLUSION: The simple test paradigm we have used showed that there is no difference in the movement time for repetitive movements around four joints of the upper extremity between patients with ET and normal control subjects. The slightly prolonged movement time around the shoulder joint noted in patients with ET may be ascribed to tremor, not bradykinesia. Tremor may cause these patients to pay more attention to the performance of goal-directed finger movements and consequently prolong movement time slightly or it may simply delay the time elapsed to reach the goal in the absence of overt intention tremor.

Clinical features of 35 patients with Parkinson's disease displaying REM behavior disorder.

OBJECTIVE: To assess and compare the disease severity, the treatment properties and the frequency of motor complications in the patients with Parkinson's disease (PD) having and not having REM sleep behavior disorder (RBD). PATIENTS AND METHODS: Based on chart review, patients with Parkinson's disease whose bed partners have reported prominent motor activity while dreaming were identified. Standard questionnaires assessing the presence of RBD have been addressed to these patients and their informants. Obtained data fulfilled clinical diagnostic criteria of probable RBD in 35 patients (RBD group) with the mean age at symptom onset was 61.8 years. Of them 77% were men. Clinical features of these patients concerning Hoehn-Yahr stage of PD, the severity of PD according to the Unified Parkinson's disease rating scale (UPDRS), the mean dose and duration of levodopa (LD) therapy, the presence of motor complications were compared with those of gender and age at PD-onset matched 35 PD patients without RBD (NRBD group). RESULTS: The mean values of PD duration, Hoehn-Yahr stage and UPDRS scores did not differ between groups. The duration of LD therapy was significantly longer in RBD group in comparison to NRBD group (6.2 years versus 3.05 years, respectively, P<0.005) and also mean actual dose of LD was higher (460.3 mg/day versus 320.3 mg/day respectively, P<0.02). The dose and duration of dopamine agonists did not differ between groups. In RBD group, wearing-off phenomenon was significantly common (P<0.01), its duration was longer (P<0.005), and LD-related dyskinesias were more frequent (P<0.01). CONCLUSION: In the current study, when compared with NRBD group, the patients with RBD required higher doses of LD treatment at an earlier stage of PD which eventually led to motor complications. In these patients, dopaminergic treatment restored UPDRS scores, but did not prevent the occurrence of RBD.

Compulsive behaviors in patients with Parkinson's disease.

OBJECTIVE: Several impulse control disorders (ICDs) may develop in patients with Parkinson's disease (PD). We aimed to identify the frequency and phenomenology of ICDs in our PD population. METHODS: Among 554 PD patients examined in a 3-year period, we identified 33 patients with ICDs. Disease duration, gender, and age-matched 65 PD patients without ICDs were selected as controls. We noted age-at-onset, duration, and severity of PD, dose and types of dopaminergic treatment, as well as presence of motor complications in both groups. RESULTS: Of 554 patients, 33 (5.9%) had ICDs, of whom, 27 were men (81%), mean age-at onset of PD was 48 and disease duration 8 years. While all patients with ICDs were on dopamine agonist drugs (+/- an adjuvant), all but 2 of controls were on dopamine agonists. Punding was the most frequent behavioral problem (57%), 42% exhibited aggressive hypersexuality, 27% compulsive eating, 24% pathologic shopping, and 21% compulsive medication. Severity of PD, presence of l-Dopa-induced motor complications, l-Dopa equivalent doses of dopamine agonists administered were not statistically different between 2 groups. CONCLUSIONS: In this study performed in a tertiary clinic for movement disorders in Turkey, several ICDs occurred in a small group of PD patients, mostly in men with young-onset disease, similar to the previous reported series. However, in contrast to the Western series, the number of gamblers was quite low because gambling is illegal in our country. We did not find any association between ICDs and severity of PD as well as doses of dopaminergic agents.

Long term follow-up of Parkinson's disease patients with impulse control disorders.

OBJECTIVE: Impulse control disorders (ICDs) are mainly triggered by dopaminergic therapy in Parkinson's disease (PD). Previously, we failed to identify a relationship between the types of dopaminergic therapy and occurrence of ICDs in 33 PD patients. In this study, we aim to evaluate the outcome of ICD behaviors in the same patient group. PATIENTS AND METHODS: Among 33 patients with ICDs, 22 patients were included. Demographics, dopaminergic therapy and disease severity were compared between two time points (Time 1: time of diagnosis of ICD, Time 2: last visit) and between patients who recovered from ICDs and with ongoing ICDs. Types of antipsychotic and antidepressant medication were noted. RESULTS: Mean follow-up period was 43.2 months. At Time 2 mean dopamine agonist (DA) dose was significantly lower, levodopa dose and total UPDRS score was significantly higher. ICDs were dissolved in 16 patients (73%), but persisted in six (27%). In ICD(+) subgroup, DA doses in Time 1 was found significantly higher than ICD(-). However, age, PD severity, disease duration and levodopa dosage were similar. Fourteen patients were prescribed atypical antipsychotics and 13 antidepressants. In ICD(+) group, symptoms of ICDs were mainly increased libido and compulsive eating. CONCLUSIONS: Although we studied a small number of patients the recovery from compulsive behaviors may be associated with the decrease in DA dosage and increase in levodopa. Furthermore, majority were given antipsychotic and/or antidepressant drugs. It is difficult to speculate which strategy could be more effective on the improvement of ICDs in such a small group. In patients who were on high doses of DA, ICDs could be persistent.

Progressive motor syndrome in a welder with pallidal T1 hyperintensity on MRI: A two-year follow-up.

Chronic exposure to manganese (Mn) fume during welding may lead to mainly extrapyramidal syndrome that is resistant to treatment. We present a 32-year-old patient who developed severe postural instability, Parkinsonism, dystonia, and pyramidal signs in the 10th year of welding. The neurological condition of the patient worsened markedly in the following 3 years, resulting in severe disability rendering him to be assisted in all his daily activities and he did not benefit from any dopaminergic agent. T1 sequences of the MRI of the brain showed pallidal hyperintensity symmetrically. Welders in our country often protect their eyes but ignore to use tools that protect them from inhalation of the fume. Since chronic Mn toxicity may cause serious disability and irreversible neurological disturbances, we strongly believe that it is necessary to inform welders and their employers about this potential hazard.

Two siblings with homocystinuria presenting with dystonia and parkinsonism.

Movement disorders such as dystonia, chorea or tremor are rarely encountered in patients with homocystinuria. We present 2 siblings with laboratory-confirmed homocystinuria, one with severe generalized dystonia and the other with mild parkinsonism. The movement disorders in our patients appeared in the second and first decades, respectively.

High-dose piracetam is effective on cerebellar ataxia in patient with cerebellar cortical atrophy.

We describe a patient with cerebellar ataxia of degenerative nature who was administered high-dose piracetam in a single-blind trial. Piracetam was demonstrated to be highly effective on tandem gait and gait ataxia in daily doses of 60 g. We suggest piracetam has a potential anti-ataxic effect in human cerebellar ataxia when used in considerably higher doses than those indicated for other purposes.

Psychogenic movement disorders in two children.

Two schoolboys with diagnostic criteria for psychogenic movement disorder (PMD) are described: one with bizarre tremor of the right hand and a very slow and cautious gait, another with exaggerated trunk sway and collapses during standing and walking.