VPS13D-based disease: Expansion of the clinical phenotype in two brothers and mutation diversity in the Turkish population.

VPS13D is a recently described gene. Worldwide, only 15 families with 23 affected individuals have been reported with a VPS13D-based disease. Mutated VPS13D causes a complex phenotype with a hyperkinetic movement disorder and ataxia, especially in childhood onset disease. The clinical phenotype of the rare adult-onset cases consists of cerebellar ataxia and/or spastic paraplegia. Here, we report the extensive clinical, laboratory and genetic findings of two offspring from consanguineous parents, with ages of disease onset at 57 and 49 with VPS13D-based ataxia. Although conventional magnetic resonance imaging showed mild cerebellar and cerebral atrophy, diffusion tensor imaging, applied for the first time for VPS13D patients, revealed prominent atrophy in U fibers and cerebellopontine tracts. Whole exome sequencing analysis revealed a biallelic Ala4210Val mutation in the VPS13D, reported only once in the literature. Complementary screening of our in-house database consisting of 295 ataxia and hereditary spastic paraplegia patients revealed two further ataxia patients with novel VPS13D variants. Screening the control cohort for VPS13D variants revealed one asymptomatic individual carrying a novel VPS13D variant. In this study, the phenotypic spectrum of VPS13D-based disease is expanded with the description of pre-senile onset predominant ataxia. Further, with the additional novel mutations described, the report is expected to contribute to the understanding of the yet elusive phenotype-genotype correlations in the rare VPS13D-based movement disorder.

Sleep parameters associated with long-term outcome following subthalamic deep brain stimulation in Parkinson's disease.

INTRODUCTION: We aimed to investigate the effects of changes in sleep architecture on long-term clinical outcome in patients with Parkinson's disease (PD) who underwent deep brain stimulation of subthalamic nuclei (STN DBS). METHODS: We followed up eight PD patients before and three years after STN DBS surgery. In addition to clinical assessments, polysomnography (PSG) followed by multiple sleep latency tests was performed before and after STN DBS, while stimulator was ON and OFF. RESULTS: Subjective sleep latency was significantly decreased (P=0.033) and sleep duration was increased (P=0.041), as measured by Pittsburgh sleep quality index. Latency to REM sleep stage was shortened after surgery with STN DBS ON (P=0.002). Index of central type of abnormal respiratory events was significantly increased while stimulator was ON (P=0.034). Total number of major body movements was found to be increased when stimulator was turned OFF (P=0.012). Among PSG data obtained during STN DBS ON, it was observed that duration of N3 sleep was negatively correlated with UPDRS scores at 1st (P=0.038) and 3rd (P=0.045) post-operative years. Among PSG variables during STN DBS OFF, durations of N3 sleep (P=0.017) and REM sleep (P=0.041) were negatively correlated with UPDRS scores at post-operative 1st year. CONCLUSION: Disturbances in sleep architecture are associated with higher UPDRS scores and worse prognosis at 1st and 3rd post-operative years. Similar results obtained while stimulator was OFF at the end of 1st year support the presence of microlesion effect after STN DBS, which is probably not long lasting.

Cerebellar cognitive-affective syndrome preceding ataxia associated with complex extrapyramidal features in a Turkish SCA48 family.

SCA48 is a novel spinocerebellar ataxia (SCA) originally and recently characterized by prominent cerebellar cognitive-affective syndrome (CCAS) and late-onset ataxia caused by mutations on the STUB1 gene. Here, we report the first SCA48 case from Turkey with novel clinical features and diffusion tensor imaging (DTI) findings, used for the first time to evaluate a SCA48 patient. A 65-year-old female patient with slowly progressive cerebellar ataxia, cognitive impairment, behavioral changes, and a vertical family history was evaluated. Following the exclusion of repeat expansion ataxias, whole exome sequencing (WES) was performed. Brain magnetic resonance imaging (MRI), including DTI, and single-photon emission computed tomography (SPECT) were used to study the primarily affected tracts and regions. WES revealed the previously reported heterozygous truncating mutation in ubiquitin ligase domain of STUB1 (ENST00000219548:c.823_824delCT, ENSP00000219548:p.L275Dfs*16) leading to a frameshift. Patient's cognitive status was compatible with CCAS. Novel clinical features different from the original report include later onset chorea, dystonia, general slowness of movements, apraxia, and palilalia, some of which have been recently reported in two families with different STUB1 mutations. CCAS is a prominent and often early feature of SCA48 which may be followed years after the onset of the disease by other complex neurological signs and symptoms. DTI may be helpful for demonstrating the cerebello-frontal tracts, involved in CCAS-associated SCA48, the differential diagnosis of which may be challenging especially in its early years.

Specific brainstem and cortico-spinal reflex abnormalities in coexisting essential tremor and Parkinson's disease (ET-PD).

OBJECTIVE: We aimed to analyze functional changes at brainstem and spinal levels in essential tremor (ET), Parkinson's disease (PD) and coexisting essential tremor and Parkinson's disease (ET-PD). PATIENTS AND METHOD: Age- and gender-matched patients with tremor (15 ET, 7 ET with resting tremor, 25 ET-PD and 10 PD) and 12 healthy subjects were enrolled in the study. Diagnosis was established according to standardized clinical criteria. Electrophysiological studies included blink reflex (BR), auditory startle reaction (ASR) and long latency reflex (LLR). RESULTS: Blink reflex was normal and similar in all groups. Probability of ASR was significantly lower in ET-PD group whereas it was similar to healthy subjects in ET and PD (P<0.001). LLR was recorded during voluntary activity in all three groups. LLR II was more common in ET, PD and ET-PD groups. LLR III was far more common in the PD group (n=3, 13.6% in ET; n=4, 16.0% in ET-PD and n=7, 46.7% in PD; p=0.037). CONCLUSIONS: Despite the integrity of BR pathways, ASR and LLR show distinctive abnormalities in ET-PD. In our opinion, our electrophysiological findings support the hypothesis that ET-PD is a distinct entity.

Apraxia in Parkinson's disease and multiple system atrophy.

OBJECTIVE: To determine praxis function in patients with Parkinson's disease (PD) and multiple system atrophy (MSA). METHODS: Nineteen patients with PD and 16 patients with probable MSA were recruited into study. Twenty-five age-matched, healthy subjects were included as controls. The Mayo Clinic praxis test battery was applied. Pantomime tasks, including oral/facial, trunk, and upper extremity movement, were used to evaluate ideomotor apraxia (IMA). Sequential tasks, including Luria test for ideational apraxia (IDA) and use of actual objects, were also tested. In addition, Standardized Mini Mental Test (MMSE), Hamilton Depression (HAM-D), and Anxiety (HAM-A) Scales were used. RESULTS: Mean ages of the study participants were 66 +/- 7, 68 +/- 5, and 65 +/- 7 years in PD, MSA, and control groups, respectively. Mean total praxis score was significantly lower for patients with PD (92.4 +/- 4) and MSA (75.9 +/- 18) than for controls (97.4 +/- 2) (P = 0.000). Transitive performances of upper extremities and sequential tasks were significantly impaired in patients with PD compared to control subjects (P < 0.05). There was no correlation between total praxis scores and sum scores of tremor, bradykinesia, and rigidity of both of the upper limbs of patients with PD. Subgroup praxis scores were substantially worse in MSA group (P < 0.0001). Compared to control subjects, mean scores for MMSE, HAM-D, and HAM-A tests were significantly worse in MSA group, but, for PD patient group, only HAM-A scores were worse. CONCLUSION: Our results indicate that although not a presenting symptom, IMA and IDA may be features of MSA and, to a lesser degree, of PD. Also, it seems to be unrelated to the motor features of patients with PD.

A LRRK2 G2019S mutation carrier from Turkey shares the Japanese haplotype.

The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is recognized as the most common cause of familial autosomal dominant and also sporadic forms of Parkinson disease (PD). A common founder has been described for most Europeans and all North Africans and Jews; besides, two distinct G2019S LRRK2 haplotypes were found in a small proportion of European families and in Japanese PD patients. This study revealed a Turkish patient heterozygous for the G2019S mutation sharing the Japanese haplotype. To the best of our knowledge, it is the first time that the G2019S-associated Japanese haplotype has been reported in a different population.

Phenytoin-induced parkinsonism.

This report presents a 30-year-old man who developed subacute phenytoin-induced cerebellar ataxia and parkinsonism that resolved after discontinuation of the phenytoin treatment. Phenytoin was started for seizure prophylaxis in another health institution where he was referred for bilateral intracerebral orbitofrontal haemorrhage due to a head trauma. To our knowledge, there has been only one other case report describing phenytoin-induced parkinsonism, which was also reversible. The issue of the development of parkinsonism due to the phenytoin toxicity in the case of bilateral orbitofrontal lesion is addressed.

Haemodialysis-related headache.

Dialysis may induce severe headache as a result of a large amount of water and electrolyte shifts. It is important to recognize it because it can be a great problem to the patient and changing dialysis parameters or methods can prevent it. In this study we investigated the frequency and clinical characteristics of headaches occurring during haemodialysis (HD). Thirty female and 33 male patients with chronic renal failure on regular dialysis for at least 6 months in the HD unit of the Internal Medicine Department from 1996 to 2000 participated in the study. The dialysis solution contained acetate in 35 patients and bicarbonate in 28 patients. In all patients capillary dialysers and Cuprophan membranes were used and every session of dialysis lasted 4 h. All patients received the same questionnaire and they were visited randomly. Dialysis headache (DH) diagnosis was made according to the criteria of the International Headache Society. Patients with primary headache and under drug treatment during HD, which can cause headache, were excluded from the study. The frequency of DH, its relation to gender, age, dialysis technique and parameters and its features were investigated. DH was detected in 48% (n = 30) of the study group. Compared with dialysis solutions, no difference was found between patients with and without DH. The difference in the pre- and post-dialysis value of urea in patients with DH was statistically significant (P < 0.05). Patients with DH showed significantly higher mean systolic and diastolic blood pressure predialysis values in comparison with patients without DH (systolic, P < 0.001; diastolic, P < 0.01), whereas post-treatment values did not differ between the two groups. Fronto-temporal location, moderate severity, throbbing quality and short duration (<4 h) were the most prevalent features of DH in patients.

Extrapyramidal type rigidity in rheumatoid arthritis.

OBJECTIVES: We had noted cogwheel rigidity in a number of patients with rheumatoid arthritis (RA). Based on this finding, we aimed to investigate formally the presence of rigidity and cogwheeling in RA patients. Our secondary aim was to survey the co-existence of RA and Parkinson's disease (PD). METHODS: A total of 87 consecutive patients with a diagnosis of RA, 78 patients with PD and 67 otherwise healthy patients attending a dedicated headache clinic participated in the study. RESULTS: Rigidity was observed in 24% of RA, 60% of PD and 2% of headache patients. The frequency among the RA patients was significantly higher compared to that of patients with headache (chi 2 = 15.2; P = 0.00009). The frequency of PD among the RA patients was 2/87 (2.3%), while the frequency of RA among the PD patients was 6/78 (7.7%). CONCLUSION: Rigidity can be observed in approximately a quarter of patients with RA.