Frequency of mutations in PRKN, PINK1, and DJ1 in Patients With Early-Onset Parkinson Disease from neighboring countries in Central Europe.

INTRODUCTION: Approximately 10% of patients with Parkinson disease (PD) present with early-onset disease (EOPD), defined as diagnosis before 50 years of age. Genetic factors are known to contribute to EOPD, with most commonly observed mutations in PRKN, PINK1, and DJ1 genes. The aim of our study was to analyze the frequency of PRKN, PINK1, and DJ1 mutations in an EOPD series from 4 neighboring European countries: Czech Republic, Germany, Poland, and Ukraine. METHODS: Diagnosis of PD was made based on UK Brain Bank diagnostic criteria in departments experienced in movement disorders (1 from Czech Republic, 1 from Germany, 9 from Poland, and 3 from Ukraine). EOPD was defined as onset at or before 50 years of age. Of the 541 patients recruited to the study, 11 were Czech, 38 German, 476 Polish, and 16 Ukrainian. All cohorts were fully screened with Sanger sequencing for PRKN, PINK1, and DJ1 and multiplex ligation-dependent probe amplification for exon dosage. RESULTS: PRKN homozygous or double heterozygous mutations were identified in 17 patients: 1 Czech (9.1%), 1 German (2.6%), 14 Polish (2.9%), and 1 Ukrainian (6.3%). PINK1 homozygous mutations were only identified in 3 Polish patients (0.6%). There were no homozygous or compound heterozygous DJ1 mutations in analyzed subpopulations. One novel variant in PRKN was identified in the Ukrainian series. CONCLUSION: In the analyzed cohorts, mutations in the genes PRKN, PINK1, and DJ1 are not frequently observed.

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 mild phenotypic 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.

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.

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

UNLABELLED: 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.

Expression of RNAs Coding for Metal Transporters in Blood of Patients with Huntington's Disease.

Recent studies have demonstrated elevated levels of iron (Fe) in brains of patients with Huntington's disease (HD). Striatal cells carrying mutated Huntingtin presented increased sensitivity to cadmium (Cd) toxicity, decreased sensitivity to manganese (Mn) toxicity and deficits in Mn uptake. The hypothesis arose that the observed alterations result from the altered expression and/or activity of proteins engaged in the transport of these metals, that is: transferrin (TF), transferrin receptor (TFR), divalent metal transporter 1 (DMT1) and ZIP8 protein. Here we examined the expression levels of genes encoding these proteins in blood of HD patients and control subjects. A decreasing tendency in the level of TF transcript and increasing tendency of SLC11A2 mRNA encoding DMT1 was observed in the blood of HD patients compared to the control subjects, but neither attained statistical significance. No changes were found in the levels of TFRC coding for TFR and SLC39A8 coding for ZIP8 between HD patients and controls. The results indicate that HD-associated changes in metal homeostasis occur are not related to mechanisms other than the expression level of the here analyzed metal transporters.

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.

GSTP1 Polymorphisms and their Association with Glutathione Transferase and Peroxidase Activities in Patients with Motor Neuron Disease.

Glutathione S-transferase pi (GSTP1) is a crucial enzyme in detoxification of electrophilic compounds and organic peroxides. Together with Se-dependent glutathione peroxidase (Se-GSHPx) it protects cells against oxidative stress which may be a primary factor implicated in motor neuron disease (MND) pathogenesis. We investigated GSTP1 polymorphisms and their relationship with GST and Se-GSTPx activities in a cohort of Polish patients with MND. Results were correlated with clinical phenotypes. The frequency of genetic variants for GSTP1 exon 5 (I105V) and exon 6 (A114V) was studied in 104 patients and 100 healthy controls using real-time polymerase chain reaction. GST transferase activity was determined in serum with 1-chloro-2,4-dinitrobenzene, its peroxidase activity with cumene hydroperoxide, and Se-GSHPx activity with hydrogen peroxide. There were no differences in the prevalence of GSTP1 polymorphism I105V and A114V between MND and controls, however the occurrence of CT variant in codon 114 was associated with a higher risk for MND. GSTP1 polymorphisms were less frequent in classic ALS than in progressive bulbar palsy. In classic ALS C* (heterozygous I /V and A /V) all studied activities were significantly lower than in classic ALS A* (homozygous I /I and A/A). GST peroxidase activity and Se-GSHPx activity were lower in classic ALS C* than in control C*, but in classic ALS A* Se-GSHPx activity was significantly higher than in control A*. It can be concluded that the presence of GSTP1 A114V but not I105V variant increases the risk of MND, and combined GSTP1 polymorphisms in codon 105 and 114 may result in lower protection of MND patients against the toxicity of electrophilic compounds, organic and inorganic hydroperoxides.

A case report of amyotrophic lateral sclerosis in a patient with Klippel-Feil syndrome­a familial occurrence: a potential role of TGF-ß signaling pathway.

The rationale for this article is a description of a unique, familial case of a patient with amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder of unknown etiology coexisting with Klippel-Feil syndrome (KFS), a congenital malformation of cervical vertebrae, characterized by a fusion of minimum 2 cervical vertebrae. We report a 68-year-old man with moderate dysarthria, fasciculations, short neck, hearing deficit, and low posterior hairline. Definite ALS was diagnosed based on neurological abnormalities and electromyography results. Magnetic resonance imaging and computed tomography showed bony abnormalities of the craniocervical junction, fusion of 2 cervical vertebrae, and syringomyelia at the level of C6-C7. KFS phenotype was noted in 2 more family members, and patient's stepsister with KFS phenotype died due to ALS. The pedigree of our family suggests an autosomal-dominant inheritance of both syndromes. Cosegregation of ALS and KFS with an autosomal-dominant trait suggests an impairment of transforming growth factor ß signaling pathway, and its potential role is discussed. Further evaluation of patients with autosomal-dominant and sporadic KFS by genetic testing, biochemical measurements, such as plasma transforming growth factor ß1, and systematic follow-up electromyography seems warranted.

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.

Novel A18T and pA29S substitutions in α-synuclein may be associated with sporadic Parkinson's disease.

OBJECTIVE: Mutations in the α-synuclein-encoding gene SNCA are considered as a rare cause of Parkinson's disease (PD). Our objective was to examine the frequency of the SNCA point mutations among PD patients of Polish origin. METHODS: Detection of the known SNCA point mutations A30P (c.88G>C), E46K (c.136G>A) and A53T (c.157A>T) was performed either using the Sequenom MassArray iPLEX platform or by direct sequencing of the SNCA exons 2 and 3. As the two novel substitutions A18T (c.52G>A) and A29S (c.85G>T) were identified, their frequency in a control population of Polish origin was assessed and in silico analysis performed to investigate the potential impact on protein structure and function. RESULTS: We did not observe the previously reported point mutations in the SNCA gene in our 629 PD patients; however, two novel potentially pathogenic substitutions A18T and A29S were identified. Each variant was observed in a single patient presenting with a typical late-onset sporadic PD phenotype. Although neither variant was observed in control subjects and in silico protein analysis predicts a damaging effect for A18T and pA29S substitutions, the lack of family history brings into question the true pathogenicity of these rare variants. CONCLUSIONS: Larger population based studies are needed to determine the pathogenicity of the A18T and A29S substitutions. Our findings highlight the possible role of rare variants contributing to disease risk and may support further screening of the SNCA gene in sporadic PD patients from different populations.

Intraosseous lipoma of the sphenoid: a case study.

Intraosseous lipoma is very rare, usually benign tumor of flat bones. However, the localization in skull bones is described in sporadic cases. The differential diagnosis includes end stage of infection, infarct lesions, intraosseous meningioma, angiolipoma, or myxofibrous tumors. We report a patient with intraosseous lipoma located in the sphenoid bone. The diagnosis was established due to the characteristic radiological features. According to the history of seizures, the lesion was removed via endoscopic endonasal approach. Histopathological examination showed adipocytes. The patient underwent control neuroimaging studies.

Analysis of PITX3 gene in patients with multisystem atrophy, progressive supranuclear palsy and corticobasal degeneration.

Interactions of transcriptions factors Nurr1, Pitx3, and EN1 are involved in the maturation and survival of adult midbrain dopaminergic neurons during a lifetime. The aim of the study was to evaluate the presence of mutations and single nucleotide polymorphisms in PITX3 gene in clinically diagnosed multisystem atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). In the group of 77 patients with MSA, 44 with PSP, and 6 with CBD, no pathogenic mutations were identified.

A case report of 'variant' biochemical phenotype of Niemann-Pick C disease and a discussion of therapeutic options.

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.

Electrophysiological features of lower motor neuron involvement in progressive supranuclear palsy.

BACKGROUND: Abnormalities of the spinal cord were considered uncommon in progressive supranuclear palsy (PSP), and therefore spinal symptoms were not included among PSP characteristic features. However there have been some neuropathological reports of spinal cord lesions in patients with PSP. The aim of our study was to find out if the possible lower motor neuron involvement in PSP is reflected by electromyographic (EMG) and/or electroneurographic (ENG) abnormalities. MATERIAL: 24 patients with clinically probable PSP (mean age 67.5 yrs; 66% males) were included in the study. The control group for ENG studies consisted 25 age matched healthy volunteers. METHODS: Nerve conduction studies in the ulnar, peroneal and sural nerves and EMG of the first interosseus dorsal and tibial anterior muscles were performed. RESULTS: The only ENG abnormality observed was decreased compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes in the ulnar nerve. Such decrease was registered in 8.3% and 20% of PSP patients respectively. There was no significant difference between the values of ENG parameters between PSP patients and the control group. In EMG abnormalities suggesting chronic reinnervation were recorded in the first interosseous dorsal (FID) muscle in 45.8%, and in the tibialis anterior (TA) muscle in 37.5% of PSP patients. A significant correlation was found between the age of PSP patients and their mean motor unit potential (MUP) amplitude in TA muscle (p=0.04) and also between the age of onset and MUP amplitude in both, the TA and FID muscles (p=0.026 and p=0.03 respectively). CONCLUSIONS: In PSP, neurogenic EMG abnormalities in skeletal muscles are present in nearly half the patients suggesting a loss of motor neurons in the anterior horns of the spinal cord which is in line with our histopathological findings. In contrast, electrophysiological signs of neuropathy in peripheral nerves in PSP are very rare. Concluding, although PSP is characterized by the pathological process in specific basal ganglia and brainstem areas, our electromyographic study suggests the need for broadening the spectrum of PSP for lower motor neurons degeneration.

A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants.

BACKGROUND: Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. METHODS AND RESULTS: We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. CONCLUSIONS: Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

Is peripheral neuron degeneration involved in multiple system atrophy? A clinical and electrophysiological study.

UNLABELLED: Lower motor neuron lesions are not among the characteristic features of multiple system atrophy (MSA), although electromyography (EMG) and autopsy studies revealed peripheral neuron abnormalities in some cases of MSA. The aim of the study was to evaluate subclinical involvement of the peripheral neuron in MSA using EMG and electroneurography (ENG). MATERIAL: 48 patients with clinically probable MSA (mean age 60.6 years; 67% males) were included in the study and divided into subgroups, with predominant cerebellar (MSA-C) and parkinsonian signs (MSA-P). METHODS: ENG in ulnar, peroneal and sural nerves and EMG of the first interosseus dorsal and tibial anterior muscles were performed. RESULTS: Abnormal ENG in one nerve was recorded in 20.8% of patients, and in two nerves in another 20.8% of patients. The most frequent and significant findings were decreased compound motor action potential amplitudes in the ulnar nerve in the overall MSA group as well as in the MSA-P type as compared to controls. Abnormalities suggesting reinnervation was observed in 43 of 96 examined muscles (44.7%). In individual cases, neurogenic features were recorded in one muscle in 31.2% of patients and in two muscles in 29.1% of patients. CONCLUSIONS: Subclinical axonopathy in MSA is not frequent and is more pronounced in MSA with predominant parkinsonian signs. In MSA, neurogenic EMG abnormalities in muscles are more frequent than peripheral nerve lesions and as evidenced by increased motor unit potential amplitudes, could be considered a sign of anterior horn cell involvement and a hallmark of the "continuum" of neurodegeneration in MSA.

Mitochondrial cytopathies: clinical, morphological and genetic characteristics.

BACKGROUND AND PURPOSE: Mitochondrial cytopathies are heterogeneous disorders affecting multiple systems but most commonly involving the skeletal muscle and central nervous system. The variety of symptoms and signs requires biochemical, morphological and genetic evaluation. The results of genetic studies indicate that there is no direct correlation between genotype and phenotype in mitochondrial cytopathies. This study is the first such analysis of a group of Polish patients with mitochondrial cytopathies. Its aim is to define the clinical features of mitochondrial cytopathies in relation to their genetic defects. MATERIAL AND METHODS: In a retrospective study, 46 patients with final diagnosis of mitochondrial cytopathy were evaluated clinically and electrophysiologically. Each patient underwent electromyography, electroneurography, and some patients were also assessed using electroencephalography. Clinical diagnoses were confirmed through the histopathological evaluation of muscle biopsies. In 36 cases mitochondrial DNA (mtDNA) testing was performed. RESULTS: Eight different clinical syndromes were diagnosed among the evaluated patients. In the skeletal muscle biopsy, ragged-red fibres, which are a significant symptom for these disorders, were present in the majority of cases (93%). The presence of specific gene mutations was confirmed in 9 out of the 36 cases in which mtDNA was examined. CONCLUSIONS: The results of our study confirm the remarkable clinical heterogeneity of mitochondrial cytopathies. Final diagnosis in many cases could only be confirmed by detection of the genetic defects. Molecular diagnosis may in the future have a significant impact on new therapeutic approaches.

Oculopharyngeal muscular dystrophy: phenotypic and genotypic characteristics of 9 Polish patients.

BACKGROUND AND PURPOSE: Oculopharyngeal muscular dystrophy (OPMD) is mostly an autosomal dominant myopathic disorder, characterized by progressive bilateral ptosis, dysphagia and proximal muscle weakness, appearing usually in the fifth to sixth decade of life. The underlying cause of OPMD is an expanded GCG repeat in the first exon of the gene encoding poly (A)-binding protein nuclear 1 (PABPN1) localized on chromosome 14.q11.2-q13. The number of GCG expansion ranges from 8 to 13 repeats. PABPN1 is a nuclear multifunctional protein which is involved in transcription regulation and post-transcriptional processes. MATERIAL AND METHODS: We report on clinical characteristics in 9 Polish patients with genetically confirmed OPMD. RESULTS: The expanded repeat ranged from (GCG)8 to (GCG)11. Ptosis and dysphagia were present in all examined cases. In 4 patients weakness of extraocular muscle was found and two of them experienced transient diplopia. Mild limb-girdle weakness was observed in 6 patients. Muscle biopsy performed in all cases showed myopathic changes with rare rimmed vacuoles. Strikingly, despite thorough examination on electron microscopy, intranuclear inclusions typical for OPMD were found only in one patient. CONCLUSIONS: Genetic testing is necessary to confirm the diagnosis of OPMD, especially in cases with ptosis and external ophthalmoparesis, which may be initially diagnosed as mitochondrial myopathy.