Clinical phenotype heterogeneity in a family with ε-sarcoglycan gene mutation

Aim of the study. This paper describes six cases of patients with myoclonus-dystonia syndrome who are members of a family in which an SGCE gene mutation has been confirmed.Clinical rationale for the study. Myoclonus-dystonia syndrome is a very rare disease, with an incidence in Europe of about 2 in every million. Due to the fact that only a few case reports of this illness are accessible in the literature, the material we collected seems to be valuable for clinical practice.Materials and methods. A history was taken, and physical and genetic examinations of the patients were performed. Furthermore, the clinical examination of three patients was video-recorded. Results. The clinical picture of the disease varied significantly between the described individuals, from a healthy carrier of the SGCE mutation to patients presenting mild to moderate symptoms. The differences concerned the age at onset of the disease, the initial symptoms, the intensity of involuntary movements, and the predominant symptoms. In addition to the typical movement disorders which are myoclonus and dystonia, in the described family there was also the coexistence of epilepsy, obsessive-compulsive behaviour, dyslexia, dysgraphia, non-harmonious development of cognitive processes, as well as mildphenotypic features of muscular dystrophy. The mutation (NM_001099401.2:c.806-809delACTG) found in the presented family has not been described elsewhere.Conclusions and clinical implications. Our description of six cases of patients demonstrates the heterogeneity of the natural course of the disease, even in patients with the same mutation. It seems reasonable to regularly examine relatives of patients with myoclonus-dystonia syndrome, who should be observed for involuntary movements as well as non-motor symptoms

Electrophysiological and clinical assessment of dysautonomia in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP): a comparative study

Clinical rationale for the study. Autonomic nervous system (ANS) involvement in different parkinsonian syndromes has been frequently discussed. It is well established in multiple system atrophy (MSA), whereas it is less evident in progressive supranuclear palsy (PSP). Aims of the study. The aims were to assess the presence and pattern of ANS involvement in MSA and PSP using noninvasive tests i.e. the sympathetic skin response (SSR) test and the R-R interval variation (RRIV) test; to analyse the relationship between clinical and electrophysiological abnormalities in both disorders; and to assess whether an autonomic profile might help to differentiate them. Materials and methods. Clinical and electrophysiological assessments of dysautonomia were performed in 59 patients with MSA (24 cases of MSA-C and 35 cases of MSA-P), these 59 cases including 31 females, mean disease duration 4.2 ± 2.7 years, mean age 60.3 ± 8.4 years, and in 37 patients with PSP (12 females, mean disease duration 4.6 ± 3.6 years, mean age 67.5 ± 6.1 years) and the results were compared to the results obtained from 23 healthy controls matched for age and sex. Results. Clinical dysautonomia assessed by an Autonomic Symptoms Questionnaire was observed in 97% of the MSA patients and in 84% of the PSP patients. SSR was abnormal in 64% and RRIV was abnormal in 73% of MSA cases. In PSP cases, these figures were 78% and 81% respectively. Dysautonomia was clinically more pronounced in MSA compared to PSP (p < 0.05), whereas electrophysiological testing revealed frequently subclinical ANS damage in PSP patients. Conclusions and clinical implications. Our results point to the complementary role of electrophysiological tests in the diagnostic work-up of dysautonomia in parkinsonian syndromes

Encefalopatia Hashimoto - opis przypadku

The impact of thyroid hormones upon the proper function of central nervous system has been known for many years. The neurological symptoms and psychiatric disturbances may occur both in case of hypo- as well as hyperthyreosis. The encephalopathy Hashimoto (EH) described in this paper is a rare illness which occurs in case of patients suffering from the autoimmunological thyroid disease and increased level of antibodies in serum without any connections to the thyroid function. It is characterised by a variety of neurological symptoms and psychotic disturbances, acute state, high reoccurrence and good reaction to glicocorticosteroid treatment. Although we face encephalopathy Hashimoto extremely rarely in the clinical practice one should remember about it during the diagnostic process because when it is a long lasting untreated illness it may lead to the irreversible changes in the central nervous system. (Pol J Endocrinol 2008; 59 (2): 168-171)Wpływ hormonów tarczycy na prawidłowe funkcjonowanie ośrodkowego układu nerwowego (OUN) jest znany od wielu lat. Objawy neurologiczne i zaburzenia psychiatryczne mogą występować zarówno w nadczynności, jak i niedoczynności tarczycy. Opisana w niniejszej pracy encefalopatia Hashimoto (EH) jest rzadkim schorzeniem występującym u chorych z autoimmunologiczną chorobą tarczycy i podwyższonym stężeniem przeciwciał przeciwtarczycowych w surowicy, niemającym związku z funkcją tarczycy. Charakteryzuje się różnorodnością objawów neurologicznych i zaburzeń psychotycznych, podostrym przebiegiem, dużą nawrotowością i dobrą reakcją na leczenie glikokortykosteroidami. Mimo że w praktyce klinicznej z EH można się spotkać niezwykle rzadko, należy o niej pamiętać w diagnostyce różnicowej, ponieważ długotrwała, nieleczona choroba może doprowadzić do nieodwracalnych zmian w OUN. (Endokrynol Pol 2008; 59 (2): 168-171

Przypadek tzw. wariantu choroby Niemanna-Picka typu Ci omówienie propozycji terapeutycznych

Niemann-Pick disease type C is a rare hereditary disorder caused by mutation-disrupted metabolism of cholesterol and low-density lipoprotein (LDL). In most patients, symptoms begin in childhood with severe clinical progression. We present a patient with heterozygote mutations 3001A>G and 3019C>G with late onset of the disease and positive response to treatment with miglustat. Behaviour and educational problems in childhood were probably related to the disease diagnosed later.Choroba Niemanna-Picka typu C jest rzadkim schorzeniem dziedziczonym autosomalnie recesywnie, spowodowanym zaburzeniem metabolizmu i transportu cholesterolu i LDL. Zachorowanie w większości przypadków dotyczy okresu dziecięcego i ma ciężki przebieg kliniczny. W artykule przedstawiono przypadek pacjenta z potwierdzoną złożoną mutacją 3001A>G i 3019C>G o późnym początku wystąpienia zaburzeń neurologicznych i korzystną odpowiedzią na leczenie miglustatem. Zaburzenia zachowania w wieku dziecięcym i trudności w nauce są najprawdopodobniej związane przyczynowo z później zdiagnozowaną chorobą

Diagnostic value of blink reflex in multisystem atrophy, progressive supranuclear palsy and Parkinson disease

Abnormal blink reflex (BR) is a result of reticular brainstem pathways dysfunction and seems to be one of the features of brain degenerative disorders. The aim of the study was to estimate the diagnostic value of blink reflex in neurodegenerative diseases such as: multisystem atrophy (MSA), progressive supranuclear palsy (PSP) and Parkinson disease (PD). Material consisted of 99 patients with clinically probable MSA (51), PSP (28) and PD (20). MSA patients were divided into two subgroups, with dominant cerebellar (MSA-C) and parkinsonian signs (MSA-P). The mean age of patients was 64.9 years (47–79 years); males – 55.3%. Blink reflex was obtained in a typical way. Results The significant differences in mean values of blink reflex latencies between PD and other subgroups (MSA-P, MSA-C, PSP) were found, but all of them were in normal range. In individual patients with PD and PSP (50% and 18%, respectively) delayed R2 latencies were recorded. Conclusions The most frequently abnormal blink reflexes, comparing the MSA, PSP and PD groups, were present in PD patients. We postulate that this may be explained by pathological influence of nigrostriatal pathway on the circuit linking the basal ganglia, cerebellum and brainstem

The role of neuroimaging in the diagnosis of the atypical parkinsonian syndromes in clinical practice

Atypical parkinsonian disorders (APD) are a heterogenous group of neurodegenerative diseases such as: progressive supranuclear palsy (PSP), multiple system atrophy (MSA), cortico-basal degeneration (CBD) and dementia with Lewy bodies (DLB). In all of them core symptoms of parkinsonian syndrome are accompanied by many additional clinical features not typical for idiopathic Parkinson's disease (PD) like rapid progression, gaze palsy, apraxia, ataxia, early cognitive decline, dysautonomia and usually poor response to levodopa therapy. In the absence of reliably validated biomarkers the diagnosis is still challenging and mainly based on clinical criteria. However, robust data emerging from routine magnetic resonance imaging (MRI) as well as from many advanced MRI techniques such as: diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), voxel-based morphometry (VBM), susceptibility-weighted imaging (SWI) may help in differential diagnosis. The main aim of this review is to summarize briefly the most important and acknowledged radiological findings of conventional MRI due to its availability in standard clinical settings. Nevertheless, we present shortly other methods of structural (like TCS – transcranial sonography) and functional imaging (like SPECT – single photon emission computed tomography or PET – positron emission tomography) as well as some selected advanced MRI techniques and their potential future applications in supportive role in distinguishing APD

Mitochondrial encephalomyopathy: Towards diagnosis. A case report

Mitochondrial diseases may cause a wide range of central and peripheral nervous system disorders, as well as muscle disorders. The diagnostic workup routinely includes electrophysiological, morphological, neuroimaging and genetic studies. In some cases, the diagnosis may be ascertained only when mitochondrial DNA (mtDNA) examination in the muscle is performed. We report on a case of a 24-year-old woman, with a 7-year history of slowly progressive cerebellar syndrome and bilateral ptosis. Mitochondrial encephalomyopathy was suspected, based on the clinical picture and results of examinations, but the typical red ragged fibers were not found in the muscle biopsy. The results of molecular analysis of mtDNA showed a mtDNA deletion in the muscle and, on a level detectable only with polymerase chain reaction method, in blood leukocytes. This case emphasizes the important role of mtDNA studies in muscle in nonspecific multisystem mitochondrial disorders, even without clinical muscle involvement

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Serum amino acid profile in patients with Parkinson's disease.

Amino acids play numerous roles in the central nervous system, serving as neurotransmitters, neuromodulators and regulators of energy metabolism. The free amino acid profile in serum of Parkinson's disease (PD) patients may be influenced by neurodegeneration, mitochondrial dysfunction, malabsorption in the gastroenteric tract and received treatment. The aim of our study was the evaluation of the profile of amino acid concentrations against disease progression. We assessed the amino acid profile in the serum of 73 patients divided into groups with early PD, late PD with dyskinesia and late PD without dyskinesia. Serum amino acid analysis was performed by high-pressure liquid chromatography with fluorescence detection. We observed some significant differences amongst the groups with respect to concentrations of alanine, arginine, phenylalanine and threonine, although no significant differences were observed between patients with advanced PD with and without dyskinesia. We conclude that this specific amino acid profile could serve as biochemical marker of PD progression