Genetic and phenotypic variability in adult patients with Niemann Pick type C from Serbia: single-center experience.

BACKGROUND: Niemann Pick type C is an autosomal recessive lysosomal storage disorder caused by mutations in NPC1 and NPC2 genes. It is a neuro-visceral disease with a heterogeneous phenotype. Clinical features depend on the age at onset. Visceral manifestations are more prominent in the early onset (infantile) form, while neuro-psychiatric symptoms are more prominent in the late disease onset (juvenile and adult forms). METHODS: A total number of 150 patients have been screened for changes in NPC1 and NPC2 gene at the Neurology Clinic, University Clinical Centre of Serbia in the period 2012-2020. Clinical data were extracted for patients with biallelic mutations. RESULTS: Fifteen patients carried biallelic mutations in the NPC1. Out of eight different reported NPC1 variants, four are novel (c.1204_1205TT>GC, p.F402A; c.2486T>G, p.L829R; c.2795+5 G>C; c.3722T>A, p.L1241*). The mean age at the disease onset was 20.3 ± 11.9 years with the average diagnostic delay of 7.7 ± 4.3 years. Movement disorders and psychiatric or cognitive disturbances were the most common initial symptoms (in 33% and 28% patients, respectively). The average age at the first neurological manifestation was 21 ± 12.0 years. At the last examination, eye movement abnormalities (vertical slow saccades or vertical supranuclear gaze palsy), and ataxia were present in all patients, while dystonia was common (in 78.6% of patients). Presence of c.2861C>T, p.S954L mutation in homozygous state was associated with older age at the neurological symptom onset. CONCLUSIONS: Clinical findings were in line with the expected, but the diagnostic delay was common. We hypothesize that the presence of c.2861C>T, p.S954L mutation may contribute to the phenotype attenuation.

NBIA Syndromes: A Step Forward from the Previous Knowledge.

A disturbed iron metabolism may damage brain and trigger disorders known as neurodegeneration with brain iron accumulation (NBIA). NBIAs are rare, inherited disorders in which responsible mutations affect the function of proteins that participate in tissue iron homeostasis. Accumulated iron, which may be recognized as a low signal intensity on T2-weighted MRI images, oftentimes points to a diagnosis. Recent genetic discoveries confirm that NBIA is not a homogenous group of diseases. Fifteen different NBIAs have been described to date; among these, autosomal recessive inheritance was reported in 13, and autosmal dominant and X-linked dominant inheritance in one disease, respectively. Among NBIAs, the most common is pantothenate kinase-associated neurodegeneration (PKAN-NBIA 1) (30%-50% of all NBIA cases), that occurrs as a consequence of the autosomal recessive mutation in PANK2 gene, followed by phospholipase 2-associated neurodegeneration (PLAN, NBIA 2), due to mutation in PLA2G6 gene, and mitochondrial membrane protein-associated neurodegeneration (MPAN) with the underlying C19orf12 mutation [Table 1]. NBIAs are characterized by complex motor presentations from early-onset degeneration and premature fatality to adult-onset parkinsonism and dystonia. Epileptic seizures, pyramidal signs, visual disorders, and cognitive deterioration can develop. NBIAs are often refractory to therapeutical strategies, although certain interventions may provide significant symptomatic relief in selected patients. In this review, we discuss the expanding clinical spectrum of these complex and rare syndromes, their genetic and imaging features, and potential therapeutical targets and strategies.

Optical coherence tomography in patients with Wilson's disease.

OBJECTIVES: Wilson disease (WD) is an autosomal recessive disorder that leads to copper accumulation and deposition in different organs, frequently affecting visual pathways. Recent studies have detected morphological changes of the retina in patients with WD using optical coherence tomography (OCT). Measuring the thickness of the retinal nerve fibre layer (RNFL) with OCT provides an objective assessment of integrity and morphological abnormalities of the retina. The aim of this study was to evaluate the relationship between OCT parameters and form of the disease, therapy and symptoms duration, as well as severity of neurological impairment. METHODS: The study comprised of 52 patients with WD and 52 healthy controls (HC). All the patients were on a regular and stable chelation therapy and/or zinc salts. Patients were divided into two groups, with neurological (NWD) or hepatic form of the disease (HWD). OCT was performed to assess the RNFL thickness. RESULTS: The WD patients had significantly lower intraocular pressure in both eyes and lower RNFL thickness than the HC. There were no differences between NWD and HWD in any of the ophthalmologically tested parameters. No significant correlations were found between clinical features and retinal thickness parameters. Stratification of the cohort according to the disease duration showed that disease duration did not influence the RNFL thickness. CONCLUSION: We found that involvement of the retina represented a subclinical finding in neurologically intact patients in the HWD group. Nevertheless, the value of OCT as a biomarker for the assessment of the clinical course and progression of WD still remains uncertain.

Perspectives on the pharmacological management of dystonia.

Introduction: Treatment of dystonia is particularly complex due to various etiologies and heterogeneous clinical manifestation, as well as different degrees of disability. In absence of causative treatment, all symptomatic therapy should be predominantly tailored to ameliorate those symptoms (motor and non/motor) that mostly affect patients' daily life and regular activities. Many different treatment options, including oral medications, neurosurgical interventions, physical and occupational therapy are available in treatment of dystonia.Areas covered: The aim of this perspective is to point out different possibilities in pharmacological management of dystonic movements. Due to pure clinical presentation, the authors concentrate mainly on the isolated dystonias, which are presented solely as dystonic movements. Combined and complex dystonias are not instructive due to compound clinical presentation and consequently, complicated treatment. The article is based on a literature search from sources including PubMed, the Cochrane Library, Web of Science, PiCarta, and PsycINFO.Expert opinion: Although dystonia therapy should be adapted according to the individual needs, severity, age, type, symptoms distribution and acceptable side-effect profile, certain principles should be followed to reach the optimal result. Furthermore, the authors believe that a better understanding of the pathophysiology of dystonia will bring with it the development of new and improved treatment approaches and medications.

Clinical course of patients with pantothenate kinase-associated neurodegeneration (PKAN) before and after DBS surgery.

INTRODUCTION: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder with a progressive clinical course. In addition to symptomatic therapy, DBS has been increasingly recognized as a potential therapeutic strategy, especially in severe cases. Therefore, we wanted to report our experience regarding benefits of DBS in five PKAN cases in 3-year follow-up study. METHODS: Five genetically confirmed PKAN patients from Serbia underwent GPi-DBS. To assess clinical outcome, we reviewed medical charts and applied: Schwab and England Activities of Daily Living Scale (S&E), EQ-5D questionnaire for quality of life, Patient Global Impression of Improvement (GPI-I), Functional Independence Measure (FIM), Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), Barry Albright Dystonia Scale (BAD). Patients were evaluated in five visits: at the disease onset, 5 years after the onset, before surgery, 6 months and 14-36 months after the surgery. Improvement of 20% was accepted as significant. RESULTS: Overall, dystonia significantly improved after GPi-DBS at 6 and 14-36 months postoperatively, when assessed by the BFMDRS and BAD. However, two patients failed to improve considerably. Four patients reported improvement on GPI-I, while one remained unchanged. Three patients reported significant improvement, when assessed with S&E and FIM. EQ-5D showed the most prominent improvement in the domains of mobility and pain/discomfort. CONCLUSION: Three out of our five patients experienced beneficial effects of the GPi-DBS, in up to 36 months follow-up. Two patients who had not reached significant improvement had longer disease duration; therefore, it might be reasonable to recommend GPi-DBS as soon as dystonia became disabling.

An Expert System for Quantification of Bradykinesia Based on Wearable Inertial Sensors.

Wearable sensors and advanced algorithms can provide significant decision support for clinical practice. Currently, the motor symptoms of patients with neurological disorders are often visually observed and evaluated, which may result in rough and subjective quantification. Using small inertial wearable sensors, fine repetitive and clinically important movements can be captured and objectively evaluated. In this paper, a new methodology is designed for objective evaluation and automatic scoring of bradykinesia in repetitive finger-tapping movements for patients with idiopathic Parkinson's disease and atypical parkinsonism. The methodology comprises several simple and repeatable signal-processing techniques that are applied for the extraction of important movement features. The decision support system consists of simple rules designed to match universally defined criteria that are evaluated in clinical practice. The accuracy of the system is calculated based on the reference scores provided by two neurologists. The proposed expert system achieved an accuracy of 88.16% for files on which neurologists agreed with their scores. The introduced system is simple, repeatable, easy to implement, and can provide good assistance in clinical practice, providing a detailed analysis of finger-tapping performance and decision support for symptom evaluation.

Factors associated with deterioration of health-related quality of life in multiple system atrophy: 1-year follow-up study.

The aim of this study was to identify the main contributors to the health-related quality of life (HRQoL) in multiple system atrophy with predominant parkinsonism (MSA-P) and to determine the usefulness of SF-36 in capturing the HRQoL changes over 1-year follow-up. A total of 45 MSA-P and 150 Parkinson's disease (PD) patients were studied. The hierarchical multiple regression analysis was conducted to identify predictors of the SF-36 total score. The magnitude of any change for the HRQoL over 1-year of follow-up, was calculated as an effect size. The average scores for each SF-36 domains, except for the bodily pain, were lower in MSA-P than in PD patients (p < 0.05). The most important predictors of HRQoL in MSA-P, were female gender, older age at onset, SCOPA-AUT score and UMSARS IV, which together with other selected clinical variables accounted for 84% of the variance in the total SF-36 score in the final model in hierarchical analyses. During the 1-year follow-up, the SF 36 was found capable of detecting changes in MSA-P. Our study provided some new insights into potential predictors of the HRQoL and its longitudinal changes in MSA-P, which should be considered when healthcare programs are developed.

Presenting symptoms of GBA-related Parkinson's disease.

BACKGROUND: Mutations in the Glucocerebrosidase gene (GBA) are associated with Parkinson's disease (PD). It has been shown that GBA-related PD (PD-GBA) patients had an earlier age at PD onset and more prevalent non-motor symptoms when compared to "sporadic" PD patients without such mutations (sPD). AIM: To explore whether presenting symptoms differ between PD-GBA and sPD patients. METHODS: Demographic and clinical features (including presenting symptoms) were collected for 578 PD patients. Sequence analysis was performed for exons 8-11 of the GBA gene for all participants. RESULTS: 39 PD patients (6.7%) with GBA mutations were compared to 539 PD patients without them. Although no statistically significant differences were found regarding the presenting symptoms, we observed that pain was more frequently reported as an initial problem in the PD-GBA (10.3%) than in the sPD group (3.0%) (chi square p = 0.039; logistic regression analysis OR = 3.74; p = 0.024). CONCLUSIONS: Overall, the presenting symptoms were similar in PD-GBA and sPD patients, with the exception that pain might be more frequent in PD-GBA.

Characteristic "Forcible" Geste Antagoniste in Oromandibular Dystonia Resulting From Pantothenate Kinase-Associated Neurodegeneration.

Geste antagonistes are usually considered typical of primary dystonia, although rarely they have been described in secondary/heredodegenerative dystonias. We have recently come across a particular geste antagoniste in 5 of 10 patients with pantothenate kinase-associated neurodegeneration (PKAN) who had prominent oromandibular involvement with severe jaw-opening dystonia. It consists of touching the chin with both hands characteristically clenched into a fist with flexion at the elbows. Because of the resemblance of this geste antagoniste with the praying-like posture of Mantis religiosa, we coined the term "mantis sign." Reviewing videos of PKAN cases in literature, including what is considered the first cinematic depiction of a case of this disorder, 3 additional cases with akin maneuvers were identified. In contrast, examining 205 videos of non-PKAN dystonic patients from our database for the presence of a similar maneuver was unrevealing. Thus, we consider the mantis sign to be quite typical of PKAN and propose it to be added as a clinical hint toward diagnosis.

The topography of brain damage at different stages of Parkinson's disease.

This study investigated gray matter (GM) and white matter (WM) damage in 89 patients at different clinical stages of Parkinson's disease (PD) (17 early, 46 mild, 14 moderate, and 12 severe) to differentiate the trajectories of tissue injury in this condition. PD patients had a very little GM atrophy even at the more advanced stages of the disease. Microstructural damage to the WM occurs with increasing PD severity and involves the brainstem, thalamocortical pathways, olfactory tracts, as well as the major interhemispheric, limbic, and extramotor association tracts. The most marked WM damage was found in moderate vs. mild cases. WM damage correlated with the degree of global cognitive deficits. WM abnormalities beyond the nigrostriatal system accumulate with increasing PD severity. WM damage is likely to contribute to the more severe motor and nonmotor dysfunctions occurring in patients at the later stages.

[Mitochondrial myopathy, encephalopathy, lactate acidosis with stroke-like episodes syndrome (MELAS): a case report].

INTRODUCTION: Mitochondrial encephalopathy, lactacidosis and stroke-like episodes (MELAS) represent a multisystemic dysfunction due to various mutations in mitochondrial DNA. Here we report a patient with genetically confirmed MELAS. CASE OUTLINE: A patient is presented whose clinical features involved short stature, easy tendency to fatigue, recurrent seizures, progressive cognitive decline, myopathy, sensorineural deafness, diabetes mellitus as well as stroke-like episodes. The major clinical feature of migraine type headache was not present. Neuroimaging studies revealed signs of ischemic infarctions localized in the posterior regions of the brain cortex. Electron microscopy of the skeletal muscle biopsy showed subsarcolemmal accumulation of a large number of mitochondria with paracristal inclusions in the skeletal muscle cells. The diagnosis of MELAS was definitively confirmed by the detection of a specific point mutation A to G at nucleotide position 3243 of mitochondrial DNA. CONCLUSION: When a relatively young patient without common risk factors for ischemic stroke presents with signs of occipitally localized brain infarctions accompanied with multisystemic dysfunction, MELAS syndrome, it is necessary to conduct investigations in order to diagnose the disease.

Fluoxetine does not impair motor function in patients with Parkinson's disease: correlation between mood and motor functions with plasma concentrations of fluoxetine/norfluoxetine.

BACKGROUND/AIM: Selective serotonin reuptake inhibitors are the most commonly chosen antidepressants in patients with Parkinson's disease (PD). The aim of our study was to assess the influence of fluoxetine (Flu) on motor functions in patients with PD. METHODS: In this prospective, controlled, open-label study, 18 patients with PD and mild depression [(10 < or = Hamilton Rating Scale for Depression (HDRS) < or = 23)] without dementia [(25 < or = Mini-Mental State Examination (MMSE)] were treated with Flu. Both single and repeated dose effects of Flu were assessed on days 1-80. Plasma concentrations of Flu and norfluoxetine (NORFlu) were correlated with the results of selected motor function performance scores: The Unified Parkinsons Disease Rating Score (UPDRS), Finger Tapping Test (FTT) and Purdue Pegboard Test (PPT). Severity of PD, depression and dementia were evaluated using standard tests [(Hoehn and Yahr stages (HY), activity of daily living (ADL), UPDRS, HDRS, MMSE)]. RESULTS: Steady-state for Flu/NORFlu was reached after 18 days of treatment. Such a plateau correlated with significant improvements in both scores of depression and Parkinson's disability (HDRS, UPDRS and ADL, respectively). In addition, FTT and PPT scores also increased until day 18, with further slight fluctuations around the plateau. Optimal motor performances correlated with Flu concentrations of approximately 60-110 microg/L. CONCLUSION: Flu (20 mg/day) significantly reduced depression in PD patients while it did not impair their motor performances. Because substantial placebo effects may arise in studies of PD and depression, large, prospective, randomized, placebo-controlled clinical trials are warranted.

Impaired insulin sensitivity and secretion in normoglycemic patients with spinocerebellar ataxia type 1.

We have recently shown an impairment in insulin sensitivity and insulin secretion in normoglycemic patients with Huntington disease (HD). To investigate whether such observations are HD-specific or may be common to other polyglutamine diseases, glucose homeostasis was studied in 12 unrelated, untreated normoglycemic patients with spinocerebellar ataxia type 1 (SCA1), another entity from the family of polyglutamine diseases, and 24 healthy, matched controls. Metabolic investigations included (a) glucose tolerance assessment on the basis of glucose curve during oral glucose challenge; (b) insulin sensitivity assessment by the homeostasis model assessment (HOMA) and the euglycemic insulin clamp (M value); and (c) insulin secretion by acute insulin response (AIR) and insulinogenic index. The evaluation of insulin sensitivity demonstrated higher HOMA-insulin resistance indices, and lower M values (P < 0.001 and P < 0.05, respectively), while both the AIR and the insulinogenic index were lower in patients with SCA1 compared to controls (P < 0.001 and P < 0.05, respectively). Our data suggested an impairment in insulin secretion capacity, as well as simultaneous decrease in insulin sensitivity, with an increase in insulin resistance level in patients with SCA1.

Possible genetic heterogeneity of spinocerebellar ataxia linked to chromosome 15.

Autosomal dominant spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders. We investigated an SCA family from Serbia of Roma ethnic origin; four affected and nine unaffected family members underwent a detailed neurological examination. The presenting symptom in all patients was gait unsteadiness in early adulthood. Additional features included pyramidal signs, depression, and cognitive impairment. The condition follows an autosomal dominant pattern of inheritance. After excluding repeat expansions in nine known SCA genes, a genome-wide linkage analysis with 412 microsatellite markers localized the putative disease gene to a 40.7 cM (42.5 Mb) region on chromosome 15q between markers D15S1006 and D15S116. The maximum model-based multipoint LOD score was 1.75. This region is only 4.3 Mb away from the SCA11 (TTBK2) gene. Accordingly, mutations in TTBK2 were not found, suggesting a second SCA gene on chromosome 15q as cause of this novel form of SCA. In addition, we excluded alterations in two candidate genes in the linked region, namely expansion of a polyglutamine-coding CAG repeat in ARID3B and mutations in SEMA6D.

Neuropsychiatric aspects of treated Wilson's disease.

The objective of the current cross-sectional study was to use standardized psychiatric interviews (the Structured Clinical Interview for DSM-IV Axis I Disorders and the Neuropsychiatric Inventory; NPI) in order to better characterize psychiatric symptoms in 50 consecutive, treated and clinically stable patients with Wilson's disease (WD). Nine patients (18%) had one, 7 patients (14%) had two, and 20 (40%) had >or= 3 neuropsychiatric symptoms present. The most often endosed symptoms were anxiety (62%), depression (36%), irritability (26%), as well as disinhibition and apathy (24% each). Twenty two patients (44%) had a score >or= 4 on at least one of the NPI items: again, most frequently anxiety (17 patients; 34%), depression (13 patients; 26%) and apathy (9 patients; 18%). Therefore, even among stable, long-term treated patients with WD approximately 70% experienced psychiatric symptoms.

Botulinum toxin in the treatment of sialorrhea.

BACKGROUND/AIM: Botulinum toxin-A (BTX-A) is known to block the release of acetylcholine from motor and autonomic nerve terminals and may significantly decrease saliva production when injected intraglandulary. The aim of this study was to evaluate effects of BTX-A injections in the treatment of disabling sialorrhea in various neurological disorders. METHODS: This study included 19 consecutive patients with significant sialorrhea associated with various neurological disorders. Out of them 13 patients were with Parkinson's disease, two with pantothenate kinase-associated neurodegeneration, two with multiple system atrophy, one with Wilson's disease, and one patient with postoperative sialorrhea. Botulinum toxin-A (Dysport, Ipsen Pharma) was injected into the parotid glands with (n=7 patients) or without (n=12 patients) ultrasound guidance. All the patients were scored before and after the treatment and in weekly intervals thereafter using the salivation item of the part II (Activities of Daily Living) of the Unified Parkinson's Disease Rating Scale (UPDRS). RESULTS: Thirteen patients (68%) reported beneficial effect of BTX-A injection, while 6 of them (32%) had no response at all The sialorrhea scores before and after the treatment were 3.1 +/- 0.1 (range 2-4) and 1.8 +/- 0.1 (range 0-3), respectively (t=5.636; p<0.001). There was no difference in the magnitude of response between the groups with (t=4.500; p=0.004) and without (t=3.674; p=0.005) ultrasound control of injection sites. Adverse effects were registered in 5 patients (26%). CONCLUSIONS: Botulinum toxin-A injections to easily accessible parotid glands, without necessity for ultrasound guidance, are safe and efficaceous treatment for sialorrhea in different neurological disorders.

Quality of life in patients with focal dystonia.

OBJECTIVES: The aims of this study were to identify the clinical and demographic factors influencing health-related quality of life (HR-QoL) and to compare HR-QoL measures between various types of focal dystonia (cervical dystonia, blepharospasm, and writer's cramp). METHODS: We examined 157 consecutive patients with adult-onset primary focal dystonia, and HR-QoL was assessed by using the SF-36 questionnaire. Univariate and multivariate regression analyses were performed. RESULTS: Patients with writer's cramp scored better in all SF-36 domains, except role functioning physical (RP), while these differences were statistically significant for physical functioning (PF) (p=0.020), bodily pain (BP) (p=0.001), and general health (GH) (p=0.004). Patients with writer's cramp and blepharospasm scored significantly better for BP (p=0.001) than patients with cervical dystonia. We found that each of the eight dimensions of SF-36 proved to be significantly correlated to the Hamilton depression rating scale score in patients with torticollis and blepharospasm, while vitality (VT), social functioning (SF), and mental health (MH) scales showed statistically significant correlations in patients with hand dystonia. Similar relationships were observed between anxiety and SF-36 domains. CONCLUSION: Depression and anxiety are the most important predictors of poorer HR-QoL in patients with all three types of focal dystonia.

Transcranial sonography in spinocerebellar ataxia type 2.

OBJECTIVE: To study the use of transcranial brain parenchyma sonography (TCS), in particular the echogenic signal in the substantia nigra (SN), in patients with spinocerebellar ataxia type 2 (SCA2), recently recognized as an uncommon cause of parkinsonism. METHODS: Six consecutive and unrelated SCA2 patients without parkinsonian signs, 30 consecutive patients with Parkinson's disease (PD), and 30 healthy, age- and sexmatched controls were prospectively studied with TCS according to a standardized protocol. RESULTS: Four (67 %) of the six SCA2 patients exhibited SN hyperechogenicity. In two patients, the hyperechogenicity was classified as moderate (unilateral in both) and in two as marked. Differences between the SN echogenicity of the SCA2 group or the PD group and controls were statistically significant (p < 0.001), while there was no difference between the two groups of patients. CONCLUSIONS: Transcranial brain parenchyma sonography detects SN hyperechogenicity in the majority of patients with SCA2 without parkinsonian signs. It would be important to reproduce our TCS findings in a larger number of SCA2 patients, as well as to test their possible significance in differentiating SCA2 from other types of SCA.