Incidence of mutations in the PARK2, PINK1, PARK7 genes in Polish early-onset Parkinson disease patients.

BACKGROUND AND PURPOSE: Parkinson disease (PD) is a complex disease, comprising genetic and environmental factors. Despite the vast majority of sporadic cases, three genes, i.e. PARK2, PINK1 and PARK7 (DJ-1), have been identified as responsible for the autosomal recessive form of early-onset Parkinson disease (EO-PD). Identified changes of these genes are homozygous or compound heterozygous mutations. The frequency of PARK2, PINK1 and PARK7 mutations is still under debate, as is the significance and pathogenicity of the single heterozygous mutations/variants, which are also detected among PD patients. The aim of the study was to analyze the incidence of autosomal recessive genes PARK2, PINK1, PARK7 mutations in Polish EO-PD patients. MATERIAL AND METHODS: The analysis of the PARK2, PINK1 and PARK7 genes was performed in a group of 150 Polish EO-PD patients (age of onset < 45 years). Mutation analysis was based on sequencing and gene dosage abnormality identification. RESULTS: Mutations were identified only in the PARK2 and PINK1 genes with the frequency of 4.7% and 2.7% of subjects, respectively. In PARK2, point mutations and exons' rearrangements, and in PINK1 only missense mutations were detected. In both genes mutations were found as compound heterozygous/homozygous and single heterozygous. EO-PD patients' genotype-phenotype correlation revealed similarities of clinical features in mutation carriers and non-carriers. CONCLUSIONS: The frequency of the PARK2, PINK1, PARK7 mutations among Polish EO-PD patients seems to be low. The role of single heterozygous mutations remains a matter of debate and needs further investigations.

Late onset GM2 gangliosidosis mimicking spinal muscular atrophy.

A case of late onset GM2 gangliosidodis with spinal muscular atrophy phenotype followed by cerebellar and extrapyramidal symptoms is presented. Genetic analysis revealed compound heterozygous mutation in exon 10 of the HEXA gene. Patient has normal intelligence and emotional reactivity. Neuroimaging tests of the brain showed only cerebellar atrophy consistent with MR spectroscopy (MRS) abnormalities. (18)F-fluorodeoxyglucose positron emission tomography (18)F-FDG PET/CT of the brain revealed glucose hypometabolism in cerebellum and in temporal and occipital lobes bilaterally.

Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options.

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia.

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD, OMIM 167320) has recently been attributed to eight missense mutations in valosin-containing protein (VCP). We report novel VCP mutations N387H and L198W in six individuals from two families who presented with proximal muscle weakness at a mean age of diagnosis of 40 years, most losing the ability to walk within a few years of onset. Electromyographic studies in four individuals were suggestive of 'myopathic' changes, and neuropathic pattern was identified in one individual in family 1. Muscle biopsy in four individuals showed myopathic changes characterized by variable fiber size, two individuals showing rimmed vacuoles and IBM-type cytoplasmic inclusions in muscle fibers, and electron microscopy in one individual revealing abundant intranuclear inclusions. Frontotemporal dementia associated with characteristic behavioral changes including short-term memory loss, language difficulty, and antisocial behavior was observed in three individuals at a mean age of 47 years. Detailed brain pathology in one individual showed cortical degenerative changes, most severe in the temporal lobe and hippocampus. Abundant ubiquitin-positive tau-, alpha-synuclein-, polyglutamine repeat-negative neuronal intranuclear inclusions and only rare intracytoplasmic VCP positive inclusions were seen. These new mutations may cause structural changes in VCP and provide some insight into the functional effects of pathogenic mutations.

[The effect of selegiline and vitamin E in the treatment of ALS: an open randomized clinical trials]. / Ocena skutecznosci selegiliny i witaminy E w leczeniu SLA: otwarta randomizowana próba kliniczna.

A role for oxidative stress in the etiology or progression of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases has been recently proposed. We conducted the 18-month, randomized treatment trial with oral vitamin E (600 IU daily) and selegiline (10 mg daily) in 67 patients with sporadic ALS. Thirty five patients were randomly assigned to receive antioxidative therapy (vitamin E plus selegiline) and the remaining 32 patients were the ALS controls who received symptomatic treatment. The primary end point was survival and functional status. At the end of 18-month study, 13 patients in the treatment group and 14 in the control group died or were tracheostomized. A decline in functional disability was also similar in both groups. Long-term antioxidative treatment did not benefit patients with ALS.

[Neurotoxic activity of serum and cerebrospinal fluid of amyotrophic lateral sclerosis patients against some enzymes of glutamate metabolism]. / Neurotoksyczne dzialanie surowicy krwi i plynu mózgowo- rdzeniowego chorych na stwardnienie boczne zanikowe na aktywnosc niektórych enzymów przemiany glutaminianu.

One of the hypotheses in amyotrophic lateral sclerosis (ALS) indicates on excitatory amino acids as the cause of neuronal death. Changes in their concentration in the tissues and body fluids may be the consequence of a defect in their transport, as well as abnormal activities of glutamate metabolizing enzymes. Abnormal synthesis/degradation of these enzymes and/or influence of activators/inhibitors should be taken into account. The activity of enzymes of glutamate metabolism of rat spinal cord in vitro in the presence of serum and cerebrospinal fluid (CSF) of 20 patients with ALS and 20 healthy controls was tested. In the presence of serum of the ALS patients glutaminase was significantly stimulated, instead of being inhibited; the inhibition of GABA aminotransferase, glutamate decaboxylase and aspartate aminotransferase was less evident than in the controls, glutamate dehydrogenase lost its activity more than in control conditions, the inhibition of glutamine synthetase was comparable to that when normal serum was applied. The activity of the enzymes in the presence of CSF of ALS patients was generally similar to that of normal CSF, except of glutaminase which was stimulated and GABA aminotransferase, which was inhibited stronger than in the presence of normal CSF. This study indicates, that changes in glutamate concentration in tissues and body fluids in ALS may be caused, at least partly, by abnormalities in the activity of glutamate metabolism enzymes, which are in turn induced by neurotoxic agents present in body fluids of ALS patients.

[The role of mitochondrial respiratory chain in the pathogenesis of ALS]. / Rola mitochondrialnego lancucha oddechowego w patogenezie SLA.

Mitochondrial dysfunction and abnormal electron chain transport (ECT) may be involved in the pathogenesis of ALS. The aim of this study was to investigate the effect of cerebrospinal fluid (CSF) from ALS patients on the activity of ECT enzymes in mitochondrial cerebral crude preparations in the rats. We found that CSF inhibited the activity of complex I-III in 20%, complex II-III in 12% and complex IV in 33% of the ALS patients. CSF from the controls did not affect the activity of complex I-III and II-III. The effect of the CSF ultrafiltrates with cut off below 5000 daltons on the activity of ECT enzymes was also investigated. The CSF ultrafiltrates inhibited the activity of complex I-III, complex II-III and complex IV in 38%, 44% and 53% of the ALS patients, and in 80%, 53% and 43% of the controls, respectively. The results of this study and our previously reported experiments on the sera of ALS patients may indicate that neurotoxic effects of body fluids from ALS patients could be mediated by inhibition of the respiratory chain enzymes. This confirms an important role of mitochondrial dysfunction in the pathogenesis of ALS.

Correlative ultrastructural and immunohistochemical study of developing vascular basement membrane in postnatal rat spinal cord.

We investigated the development of vascular basement membrane in immature spinal cord vessels during rat spinal cord myelination. Correlative ultrastructural and immunohistochemical study indicated that fibronectin was the first component of extracellular matrix. Then, on the 9th postnatal day, laminin appeared. At that time, lamina lucida of vascular basement membrane was not detectable. On the 15th day, when collagen IV was visible, lamina densa and lamina lucida were occasionally observed. All components of basement membrane--fibronectin, laminin, collagen IV, alpha-2 laminin (merosin)--and ultrastructural division into two layers were detected on the 25th postnatal day. The results of this study indicates that a gradual development of endothelium in immature rat spinal cord blood vessels leads to a gradual increase of synthesis of extracellular matrix components.

Do astrocytes participate in rat spinal cord myelination?

Astrocytes play an important role in CNS development phenomena, such as neuron migration and blood-brain barrier formation, but only a little is known of their role in the process of myelination. The aim of our investigation was to examine the relationship between astrocytes and myelin formation. We evaluated rat spinal cords using hematoxylin-eosin and Klüver-Barrera staining methods as well as immunohistochemical methods with antibodies against myelin basic protein (MBP), glial fibrillary acidic protein (GFAP) and lamins A/C and B2. Our investigation revealed that myelination in the rat spinal cord tracts began between the 6th and 9th postnatal day involving the anterior funiculi, then the lateral funiculi and later the posterior ones. The process of myelination finished about the 25th postnatal day. More GFAP immunoreactive astrocytes were detected in parallel to the increase of MBP reactivity. We suggest that the temporary increase of GFAP positive cells accompanying the process of myelination is necessary for normal myelin development and may be connected with local secretion of growth factors by astrocytes.

Immunochemical quantification of glycoconjugates in serum and cerebrospinal fluid of amyotrophic lateral sclerosis patients.

Glycoconjugates in the serum of 73 patients with amyotrophic lateral sclerosis (ALS), 21 cases of other motor neuron diseases and 20 healthy controls were determined. Cerebrospinal fluid (CSF) was studied in 64, 7 and 10 of these subjects, respectively. The level of sialic acid containing glycoconjugates, detected by Maakia amurensis agglutinin (MAA), was decreased in the serum of 61.6% of the ALS patients, while in the CSF it was decreased, on average, in 75% of these cases. Only in single ALS cases was the concentration of these glycoconjugates increased. There was no correlation between the content of MAA-labelled glycoconjugates both in serum and CSF and the titre of sialic acid containing anti-GM1 gangliosides. The glycoconjugates, detected by peanut agglutinin (PNA) which recognizes the disaccharide galactose beta(1-3)N- acetylgalactosamine (GGN), were decreased in the serum of 78.1% of ALS patients, while in CSF they were increased in 54.7% of these cases. There was no correlation between the concentration of PNA-labelled glycoconjugates both in serum and CSF as well as the titre of antibodies against GGN-containing anti-GM1 and anti- AGM1 gangliosides. Changes in the level of the MAA- and PNA- labelled glycoconjugates, as well as the titre of anti-GM1 and anti-AGM1 gangliosides antibodies were not specific for ALS. They were also observed in some cases of other motor neuron diseases. The low level of the lectin-labelled glycoconjugates in serum and partly in CSF of the majority of ALS patients is possibly the consequence of their accelerated clearance and/or specific inactivation by the formation of immune complexes or epitope binding. Degeneration of neurons and muscle cells could also be responsible. The relatively low incidence of high anti- glycolipids antibodies titre may be, at least partly, connected with the low concentration of the appropriate antigens. The increased content of PNA-labelled glycoconjugates in the CSF of the majority of ALS patients, together with the low incidence of high titre of antibodies against the appropriate glycolipids, could indicate that in CSF this lectin binds to the GGN epitope of glycoproteins rather than to the GGN epitope of glycolipids.

Ultrastructural features of immaturity in blood vessels of neonatal rat spinal cord.

Ultrastructural study was carried out on the lumbo-sacral segment of the spinal cord in 1, 3, 6, 9, 12, 15, 18, 21 and 25-day-old rats. Unusual features of blood vessels in postnatal life of rats were observed: capillaries with abundant endothelial cells, numerous invaginations and narrow lumen. In addition, microvilli of diverse size and number on the luminal surface of capillaries as well as larger vessels were present. They were more numerous in younger animals. An intriguing finding, not observed in older animals, was the appearance of abluminal protrusions projecting into surrounding tissue. Closed endothelial junctions were noted in all the investigated vessels. The above mentioned ultrastructural features indicate an immature character of blood vessels. The presence of this kind of vessels during the postnatal period may be connected with vascularisation of spinal cord due to the myelination process.

[A case of neurogenic dysphagia responding to nitrates]. / Przypadek neurogennej dysfagii z dobra odpowiedzia na leczenie azotanami.

We described a 47-year-old man with ischemic stroke who developed a brainstem syndrome with persistent dysphagia. He was fed by the nasogastric tube placed intermittently by himself for almost 7 months after the stroke. Elective feeding via percutaneous endoscopic gastrostomy (PEG) was not accepted by the patient. All treatment attempts with benzodiazepines, antidepressants and spasmolytic agents were unsuccessful. Videofluoroscopic investigation revealed excessive and long-lasting spasm of the upper esophageal sphincter which was associated with the massive aspiration of the contrast. The patient dramatically improved after treatment with nitroglycerin and long-acting nitrates with almost complete recovery of normal swallowing. A strikingly good effect of nitrates in the treatment of oropharyngeal dysphagia is emphasized by the authors.

Anti-neural antibodies in serum and cerebrospinal fluid of amyotrophic lateral sclerosis (ALS) patients.

OBJECTIVES: An autoimmune basis has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). This hypothesis is supported by the presence of antibodies that interact with motoneuron antigens in serum of these patients. Against autoimmunity are the discrepances in the frequency of the antibodies appearance and also failure of immunosuppression. The aim of our study was to evaluate the titer of antibodies against GM1-gangliosides, AGM1-gangliosides and anti-sulfatides in paired serum and cerebrospinal fluid samples in the ALS patients. MATERIAL AND METHODS: Serum of 103 and CSF of 79 patients with ALS was examined. The "disease controls" consisted of 22 cases of other motor neuron diseases and 50 healthy, age-matched normals. CSF was drawn at the same time from 79 ALS patients, 6 cases of the "disease controls" and 50 normals. To study the titer of antibodies against GM1-gangliosides, AGM1-gangliosides and sulfatides the ELISA technique has been applied. RESULTS: An increased titer against GM1-gangliosides, AGM1-gangliosides and sulfatides in ALS appeared in serum in 18%, 32%, and 11%, resp., in the "disease controls" the increased antibodies titer appeared in single cases. In CSF the appropriate values in ALS were 20%, 15%, 8%, resp. In the "disease controls" a high antibodies titer was a rare finding. CONCLUSIONS: It is concluded that in some ALS cases and also in some patients with other motor neuron diseases an autoimmune mechanism may contribute to motor neuron injury.

[Axonal form of Guillain-Barre syndrome?]. / Aksonalna postac zespolu Guillain-Barré.

Patient, 19 year old man with rapidly developing motor, sensory and autonomic polyneuropathy fulfilling diagnostic criteria for G-B syndrome is presented. Sural nerve biopsy revealed severe axonopathy, however, it seems due to primary demyelinating process.

Obstructive sleep apnea syndrome in patient with Creutzfeldt-Jakob disease. Clinical and morphological report.

We report a case of Creutzfeldt-Jakob disease (CJD) which at the beginning of the disease presented clinical syndrome of progressive supranuclear palsy. Rapid intellectual deterioration, supranuclear palsy, postural instability and myoclonic jerks suggested clinical diagnosis of CJD. After five months suffering from the disease patient developed obstructive sleep apnea syndrome (OSAS) confirmed by serial polysomnograms. OSAS is discussed in the context of the localization of histopathological findings and possible involvement of central autonomic structures. The main structures affected by spongiosis and astrogliosis were cortex, thalamus, basal ganglia and midbrain. OSAS was found as another sleep disturbance in CJD apart from insomnia and sleep-wake cycle abnormalities.

A cerebrospinal fluid turnover in Parkinson's disease.

In 30 patients with Parkinson's disease (PD) CT scan, isotopic cisternography and neuropsychological examination were performed to test possible relationship between cerebrospinal fluid (CSF) turnover, intellectual impairment and brain atrophy. Pathological cisternography was found in one third of the patients and it was positively correlated with the Columbia Rating Scale. Cerebral atrophy on CT was found more frequently in patients with earlier onset of PD. Combined pathological pattern on CT scan and on cisternography was correlated with intellectual decline. We conclude from this study, that in PD intellectual deterioration and brain atrophy separately are not connected with abnormal CSF turnover.

[Neurosarcoidosis or Guillain-Barre syndrome complicating sarcoidosis]. / Neurosarkoidoza czy zespól Guillain-Barré w przebiegu sarkoidozy?

We described a young male with severe Guillain-Barré syndrome in whom pulmonary sarcoidosis was also detected. Based upon the results of diagnostic procedures (nerve biopsy, CSF examination, electrophysiological study) we postulate that this was a Guillain-Barré syndrome coexisting with sarcoidosis, and not the case of sarcoid neuropathy.

Neuroacanthocytosis. Review of literature and case report.

Neuroacanthocytosis is a rare disease of nervous system with multisystem pathology. This review presents clinical syndromes and morphological changes of sporadic and familial forms of neuroacanthocytosis and is illustrated by the case of a 27-year-old man. Progressive extrapyramidal syndrome appeared at the age of 22. Dementia preceded by behavioral changes observed since childhood, was noticed when he was 24 years old. Gross examination of the brain showed atrophy of the brain and caudatum. In microscopic examination most intensive changes were manifested by caudate nucleus atrophy of its head and body, loss of small neurons and extensive astrocytic reaction in dorso-lateral part of the putamen. Within the pallidum similar but less intensive pathological changes were visible. These data are in accordance with those found in literature, but in contrary to the authors who gave attention to spared cerebral cortex which distinguishes neuroacanthocytosis from Huntington's chorea. In the examined case hypocellularity of the cerebral mainly frontal cortex with lamina disorganization but without glial reaction was noted. Moreover, in frontal cortex especially within layer III, differently oriented pyramidal cells its conglomerates and very large neurons were observed. Authors suggest that these alterations are probably manifestations of developmental failures of the cerebral cortex. They concluded that anatomical studies support the possibility that lesions of basal ganglia lead to abnormal intellectual functions.

Intrastriatal infusion of amiloride increases rotations in 6-OHDA lesioned rats and "down-regulates" D2 receptors in the striatum and 5-HT2A receptors in the cortex.

Intrastriatal infusion of amiloride and 12-0-tetradeconoyl phorbol-13-acetate (TPA) in 6-OHDA lesioned rats increased the apomorphine (APO)-induced rotation. This behavioral effect occurred in the presence of a decrease in the density and an increase in the affinity of D2 dopamine receptors in the striatum. There was an associated decrease in the number of 5-HT2A receptors labelled with ketanserin in the cortex on the side of infusion. These results suggest that the inositol second-messenger system may be involved in the regulation of D2-dopamine receptors in the striatum and dopamine mediated behavior in the 6-OHDA lesioned rats. They also indicate a possible role for the inositol second messenger system in the regulation of 5-HT2A receptors.

Rare coexistence of congenital malformations in adult.

Coexistence of several developmental abnormalities in adults is very rare and often asymptomatic. In many instances appearance of clinical symptomatology is evoked by some additional factors, not related directly with the basic pathological process. In a 21-year-old oligophrenic man a progressive paresis of inferior limbs appeared in the course of the upper respiratory tract infection. During 5 days of hospitalization transient peripheral paresis of the right facial nerve, tetraplegia, sphincter and respiratory disturbances occurred. Guillain-Barré syndrome and subarachnoid hemorrhage were diagnosed. On autopsy hemorrhagic focus in the medulla and in the cervical and upper thoracic parts of the spinal cord was found. Microscopic examination revealed hypocellularity of the 2nd and 4th layers of the temporal cortex, presence of the central canal within the brain stem, and hemorrhagic focus in the medulla. Two malformations in spinal cord were revealed: intraspinal angioma extending from the C2 to the Th6 segments and diastematomyelia within Th11 and lumbar segments. Diastematomyelia, cortical hypocellularity and angioma composed of fetal, lacunar artery- and vein-like vessels, are related with different periods of the ontogenic development. Coexistence of these malformations indicates prolonged action of the pathogenic factor(s), both in the embryonic and fetal life.