Inflammatory profile discriminates clinical subtypes in LRRK2-associated Parkinson's disease.

BACKGROUND AND PURPOSE: The presentation of Parkinson's disease patients with mutations in the LRRK2 gene (PDLRRK2 ) is highly variable, suggesting a strong influence of modifying factors. In this context, inflammation is a potential candidate inducing clinical subtypes. METHODS: An extensive battery of peripheral inflammatory markers was measured in human serum in a multicentre cohort of 142 PDLRRK2 patients from the MJFF LRRK2 Consortium, stratified by three different subtypes as recently proposed for idiopathic Parkinson's disease: diffuse/malignant, intermediate and mainly pure motor. RESULTS: Patients classified as diffuse/malignant presented with the highest levels of the pro-inflammatory proteins interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1) and macrophage inflammatory protein 1-ß (MIP-1-ß) paralleled by high levels of the neurotrophic protein brain-derived neurotrophic factor (BDNF). It was also possible to distinguish the clinical subtypes based on their inflammatory profile by using discriminant and area under the receiver operating characteristic curve analysis. CONCLUSIONS: Inflammation seems to be associated with the presence of a specific clinical subtype in PDLRRK2 that is characterized by a broad and more severely affected spectrum of motor and non-motor symptoms. The pro-inflammatory metabolites IL-8, MCP-1 and MIP-1-ß as well as BDNF are interesting candidates to be included in biomarker panels that aim to differentiate subtypes in PDLRRK2 and predict progression.

Elevated α-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson's patient-derived induced pluripotent stem cells.

We have assessed the impact of α-synuclein overexpression on the differentiation potential and phenotypic signatures of two neural-committed induced pluripotent stem cell lines derived from a Parkinson's disease patient with a triplication of the human SNCA genomic locus. In parallel, comparative studies were performed on two control lines derived from healthy individuals and lines generated from the patient iPS-derived neuroprogenitor lines infected with a lentivirus incorporating a small hairpin RNA to knock down the SNCA mRNA. The SNCA triplication lines exhibited a reduced capacity to differentiate into dopaminergic or GABAergic neurons and decreased neurite outgrowth and lower neuronal activity compared with control cultures. This delayed maturation phenotype was confirmed by gene expression profiling, which revealed a significant reduction in mRNA for genes implicated in neuronal differentiation such as delta-like homolog 1 (DLK1), gamma-aminobutyric acid type B receptor subunit 2 (GABABR2), nuclear receptor related 1 protein (NURR1), G-protein-regulated inward-rectifier potassium channel 2 (GIRK-2) and tyrosine hydroxylase (TH). The differentiated patient cells also demonstrated increased autophagic flux when stressed with chloroquine. We conclude that a two-fold overexpression of α-synuclein caused by a triplication of the SNCA gene is sufficient to impair the differentiation of neuronal progenitor cells, a finding with implications for adult neurogenesis and Parkinson's disease progression, particularly in the context of bioenergetic dysfunction.

Phenotype in parkinsonian and nonparkinsonian LRRK2 G2019S mutation carriers.

OBJECTIVES: Using a family study design, we describe the motor and nonmotor phenotype in probands with LRRK2 G2019S mutations and family members and compare these individuals to patients with idiopathic Parkinson disease (iPD) and unrelated controls. METHODS: Probands with G2019S mutations and their first-degree relatives, subjects with iPD, and unrelated control subjects were identified from 4 movement disorders centers. All underwent neurologic examinations and tests of olfaction, color vision, anxiety, and depression inventories. RESULTS: Tremor was more often a presenting feature among 25 individuals with LRRK2-associated PD than among 84 individuals with iPD. Subjects with LRRK2-PD had better olfactory identification compared with subjects with iPD, higher Beck Depression Inventory scores, and higher error scores on Farnsworth-Munsell 100-Hue test of color discrimination. Postural or action tremor was more common among 29 nonmanifesting mutation carriers compared with 53 noncarriers within the families. Nonparkinsonian family members had higher Unified Parkinson's Disease Rating Scale motor scores, more constipation, and worse color discrimination than controls, regardless of mutation status. CONCLUSIONS: Although tremor is a more common presenting feature of LRRK2-PD than iPD and some nonmotor features differed in degree, the phenotype is largely overlapping. Postural or action tremor may represent an early sign. Longitudinal evaluation of a large sample of nonmanifesting carriers will be required to describe any premotor phenotype that may allow early diagnosis.

Severe congenital encephalopathy caused by MECP2 null mutations in males: central hypoxia and reduced neuronal dendritic structure.

Non-mosaic males with a 46,XY karyotype and a MECP2 null mutation display a phenotype of severe neonatal-onset encephalopathy that is distinctly different from Rett syndrome (RTT). To increase awareness of this rare disorder, we are reporting novel findings in a sporadic case, compare them to 16 previously reported cases and establish salient criteria for clinical diagnosis. The proband suffered from general hypotonia and hypoxia caused by hypoventilation and irregular breathing. He developed abnormal movements, seizures and electroencephalogram abnormalities. He failed to thrive and to reach any motor milestones and died at 15 months from central respiratory failure without a diagnosis. In a muscle biopsy, type II fibers were reduced in diameter, indicating central hypoxia. At autopsy, the brain was small with disproportionate reduction of the frontal and temporal lobes. Synaptophysin staining of synaptic vesicles was greatly reduced in cerebellar and spinal cord sections. Analysis of Golgi-stained pyramidal neurons from cortical layers III and V of the frontal and temporal lobes revealed drastically diminished dendritic trees. Post-mortem MECP2 mutation analysis on DNA and RNA from fibroblasts revealed a novel de novo 9-nucleotide deletion including the intron 3/exon 4 splice junction. The two nucleotides flanking the deletion form a new splice site, and the aberrantly spliced transcript lacks seven nucleotides (r.378_384delTCCCCAG), causing a frameshift and premature termination codon (p.I126fsX11). Males with congenital encephalopathy, not females with RTT, represent the true human counterpart for the commonly studied Mecp2-/y mouse model and provide unique insight into the mechanisms of MeCP2 deficiency.

Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication.

BACKGROUND: The "Lister family complex," an extensive Swedish family with autosomal dominant Parkinson disease, was first described by Henry Mjönes in 1949. On the basis of clinical, molecular, and genealogic findings on a Swedish and an American family branch, we provide genetic evidence that explains the parkinsonism in this extended pedigree. METHODS: Clinical methods included a detailed neurologic exam of the proband of the Swedish family branch, MRI, and ([123]I)-beta-CIT SPECT imaging. Genomic analysis included alpha-synuclein sequencing, SNCA real-time PCR dosage, chromosome 4q21 microsatellite analysis, and high-resolution microarray genotyping. The geographic origin and ancestral genealogy of each pedigree were researched in the medical literature and Swedish Parish records. RESULTS: The proband of the Swedish family branch presented with early dysautonomia followed by progressive parkinsonism suggestive of multiple system atrophy. Molecular analysis identified a genomic duplication of <0.9 Mb encompassing alpha-synuclein and multimerin 1 (SNCA-MMRN1), flanked by long interspersed repeat sequences (LINE L1). Microsatellite variability within the genomic interval was identical to that previously described for a Swedish American family with an alpha-synuclein triplication. Subsequent genealogic investigation suggested that both kindreds are ancestrally related to the Lister family complex. CONCLUSION: Our findings extend clinical, genetic, and genealogical research on the Lister family complex. The genetic basis for familial parkinsonism is an SNCA-MMRN11 multiplication, but whereas SNCA-MMRN1 duplication in the Swedish proband (Branch J) leads to late-onset autonomic dysfunction and parkinsonism, SNCA-MMRN1 triplication in the Swedish American family (Branch I) leads to early-onset Parkinson disease and dementia.

Novel features in a patient homozygous for the L347P mutation in the PINK1 gene.

The purpose of this study was to assess the genotype-phenotype of PINK1 mutations. We genotyped eight known mutations in three clinic-based cohorts with Parkinsonism and found one homozygous p.L347P mutation in PINK1. Clinically, hypo-osmia and profound diurnal variation of symptoms were identified as novel features; fluorodopa positron emission tomography revealed striking decline in striatal fluorodopa uptake. We suggest that it may be possible to clinically separate this form of Parkinsonism from dopa-responsive dystonia and Parkin-related Parkinsonism. Furthermore, as this mutation has only been reported in Filipinos (two originated from Luzon island), our results support the hypothesis of a common founder.

Genetic heterogeneity in ten families with myoclonus-dystonia.

BACKGROUND: Myoclonus-dystonia (M-D) is a movement disorder with autosomal dominant inheritance and reduced penetrance but may also occur sporadically. Recently, mutations in the epsilon-sarcoglycan gene (SGCE) were shown to cause M-D. Furthermore, single variants in the dopamine D2 receptor (DRD2) and DYT1 genes were found in combination with SGCE mutations in two M-D families, and another M-D locus was recently mapped to chromosome 18p11 in one family. METHODS: The authors clinically and genetically characterised ten consecutive cases with myoclonus-dystonia; seven familial and three sporadic. Twenty nine M-D patients and 40 unaffected family members underwent a standardised clinical examination by a movement disorder specialist. Index cases were screened for mutations in the SGCE, DYT1, and DRD2 genes and for deletions of the SGCE gene. Suitable mutation negative families were tested for linkage to the SGCE region and to chromosome 18p11. RESULTS: Two SGCE mutations were detected among the seven familial but no mutation in the sporadic cases. Haplotype analysis at the new M-D locus was compatible with linkage in two families and excluded in another family, suggesting at least one additional M-D gene. There were no obvious clinical differences between M-D families with and without detected mutations. CONCLUSION: M-D is genetically heterogeneous with SGCE mutations accounting for the disease in only part of the clinically typical cases.

[Follow-up control of ultrasonographic neonatal screening of the hip]. / Verlaufskontrollen von Hüftbefunden im sonographischen Neugeborenenscreening.

1656 newborns were examined by ultrasound for early diagnosis of CDH in a screening program. In 2.5% of the cases, dysplasia or dislocation of the hip was diagnosed and required treatment. In all cases the final outcome after adequate treatment showed a hip joint without any abnormalities. 11.3% of type IIa-hips (using Graf's classification) did not reach an alpha-angle of 60 degrees until the 12th week. They were then therefore classified as type IIb. 97% of all hip joints were judged as normal in the course of the 4th month. This study emphasizes the necessity of a general ultrasound screening program. It also demonstrated that early and adequate treatment leads to a normal development of the joint.

[Heparin-induced thrombocytopenia after elective hip joint replacement with postoperative prevention of thromboembolism with low-molecular-weight heparin]. / Heparin-induzierte Thrombozytopenie nach elektivem Hüftgelenksersatz unter einer postoperativen Thromboembolieprophylaxe mit niedermolekularem Heparin.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a severe side effect of the prophylaxis of venous thromboembolism with unfractionated heparin. The aim of the present study is to gain more information on the incidence of HIT during prophylaxis of venous thromboembolism with low-molecular-weight heparin in elective hip surgery. METHODS: 586 consecutive patients were included into the prospective study, who were admitted to hospital for elective hip replacement. The incidence of thrombocytopenia, clinically manifest venous thromboembolism and of the heparin-induced IgG antibodies were analysed during prophylaxis with low molecular-weight heparin. Patients received once daily subcutaneously low molecular-weight heparin for a mean of 28 days postoperatively. Platelet counts and clinical examinations for the presence of venous thromboembolism were done at days 0, 2, 7 (+/- 1) and 12 (+/- 2). Heparin-induced IgG antibodies were determined before and after a 12 (+/- 2) days prophylaxis with low molecular-weight heparin in 265 of 586 patients randomly. Patients were reexamined for thromboembolic complications after 3 and 6 months. The clinical suspicion of thromboembolic complication was documented objectively. RESULTS: None of the patients developed a decrease of platelets of < 50% of the initial value. Ten of 265 patients had elevated IgG antibodies against heparin/platelet factor 4 before prophylaxis (3.8%). After the 12 (+/- 2) days prophylaxis 13 of 265 patients had elevated IgG antibodies (4.9%). C14 serotonin assay was positive in 0 of 10 patients before treatment and in 3 of 19 patients at day 12 (+/- 2). Ten patients developed venous thromboembolism postoperatively (8 x deep venous thrombosis, 2 x pulmonary embolism, no fatal embolism). Only 1/19 patients with elevated antiheparin IgG titres developed venous thromboembolism. The C14 serotonin assay was negative in this patient. Two patients died in the postoperative phase due to underlying cardiovascular diseases. CONCLUSIONS: In patients with elective hip replacement prophylaxis of venous thromboembolism with low molecular-weight heparin was associated with a very low incidence of HIT, and hence screening for HIT antibodies is not required.

[Review of the results of the ARO multicenter study]. / Uberblick und Ergebnisse der ARO-Multicenterstudie.

The ARO multicenter study intended to show clinical and radiological differences with regard to different systems of fixation and designs of the prothesis in total hip replacement in patients with hip dysplasia, osteoarthritis and rheumatoid arthritis. In 1987 and 1988 5255 total hip prothesis were implanted by the 24 hospitals which took part in the study. 3133 prothesis (95.6%) were clinically and radiologically examined. The follow-up period averaged 6.9 years. The results of the Aro multicenter-study showed that despite difficult preoperative conditions especially in cases of rheumatoid arthritis the satisfaction rate improved remarkably. During the operation less complications arose in comparison to patients with hip dysplasia and osteoarthritis. Regarding the rate of infection after operation there were no differences between the 3 groups. Only the rate of post-operative luxation concerning rheumatoid patients turned out to be twice the number of the others. In our opinion this is due to the fact that these rheumatics were operated by posterior approach. Patients with rheumatoid arthritis were satisfied most with their surgeries. Results of rheumatic patients according to Harris hip score were slightly worse than the results of the two other groups. This was due to systemic involvement and bad preoperative function of the hip. As a result of the study there were no differences in using cemented or cementless techniques for rheumatic hip replacement. The decision for the method of fixation should depend on the patient's ability to relief the prothesis after operation. The study has shown that cementless implantation can also be used for young rheumatics provided that a suitable design of prothesis will be selected.

[Radiologic results of the ARO multicenter study]. / Die Radiologischen Ergebnisse der ARO-Multicenterstudie.

We present the radiological results of 2286 total hip replacements (THR) from the multicenter study. Concerning the acetabular component the analysis showed that socket migration and radiolucent lines were much more dependent on the specific design of the socket than on the primary diagnosis. A similar results was found for the femoral stems: rheumatoid arthritis did not cause a higher percentage of stem subsidence, radiolucent lines or bone remodeling. Within a mid-term follow-up period the reduced bone quality in rheumatoid arthritis is not associated to premature failure of a cemented or cementless prosthesis. THR failure seems to be more dependent on specific construction features of the individual socket and stem.

[Implant failure after total hip replacement. Comparison of patients with primary coxarthrosis, rheumatoid arthritis and dysplastic coxarthrosis]. / Implantatversager nach Hüft-TEP-Implantation. Vergleich bei Patienten mit primärer Koxarthrose, rheumatischer Arthritis und Dysplasiekoxarthrose.

The analysis of THR-failures showed that the acetabular component still is the main problem of total hip replacement. The acetabular cup fails more often than the stem. In the midterm analysis the failure rate is a little bit higher in cementless than in cement fixed cups. The known effect that the failure rate of cups fixed with cement increases exponentially 8 to 10 years after implantation, could of course not be seen in this study. The success of the cementless fixation was negatively influenced by the diagnosis rheumatoid arthritis, age over 70 and the fixation manner: the failure rate of threaded cups was higher than the one of press-fit cups although the Zweymüller-cup as well as the Link type V-cup showed good results. The midterm results of the stem were very good for the cementless as for the cemented technique. Some implants showed compared to others significantly worse results. The further implantation should be thought of, what partially has already happened. The results of cementless stem fixation in patients with rheumatoid arthritis, osteoarthrosis and dysplastic osteoarthritis is comparable, so that cementless fixation should be thought of in case of adequate conditions (ability of partial weight bearing for some weeks, age under 60).

[Pyogenic spondylitis in the interarticular portion of the vertebral arch. Case report on primary dorsal spondylitis]. / Die pyogene Spondylitis in der Interartikularportion des Wirbelbogens. Kasuistischer Beitrag zu den primär dorsalen S pondylitiden.

The manifestation of a pyogenic spondylitis only in the dorsal part of a spinal segment is very rare and causes even more diagnostic problems than the typically anterior located spondylitis. We are reporting on a patient with known isthmic spondylolisthesis who developed the inflammatory process primarily in the intervertebral joint and in the interarticular portion. For a few months the cause of his complaints was thought to be due to spondylolisthesis till radiological adn laboratory methods lead to the correct diagnosis and adequate therapy.

Phase-I trial of intravenous continuous infusion of tumor necrosis factor in advanced metastatic carcinomas.

Fifteen patients with advanced metastatic adenocarcinomas were treated in a phase-I study with continuous intravenous 24 h infusion of recombinant tumor necrosis factor alpha (TNF-alpha) in order to determine the maximum tolerated dose (MTD) and associated side-effects. Patients received 40-400 micrograms/m2 TNF-alpha once (arm A) or twice (arm B) weekly for a scheduled treatment period of 2 months. The observed systemic side-effects resembled those reported for interferons and included fever, chills, fatigue, headaches, myalgias, thrombocytopenia, prostration, and malaise. Dose-limiting toxicities, resulting in a median MTD of 200 micrograms/m2 for 24 h, were fever, chills, fatigue, myalgias, and thrombocytopenia. Out of 15 patients, 11 showed tumor progression, and 3 sustained in no change for over 2 months of treatment. A minor response was seen in 1 patient with a colorectal carcinoma and liver metastases. To reduce side-effects, patients were treated either with paracetamol or indomethacin. Higher MTDs were observed in patients treated with indomethacin. No detectable plasma TNF-alpha levels or TNF antibodies were measured under therapy (plasma TNF-alpha less than 20 pg/ml). We conclude that TNF-alpha appears to have some antineoplastic activity in patients with adenocarcinomas since 4 patients remained in no change or showed a minor response.

The distribution of fibronectin in lymph nodes infiltrated by Hodgkin's disease. An immunoperoxidase study on paraffin sections.

The tissue distribution of fibronectin (FN) was examined using a commercial anti-FN serum, the peroxidase-anti-peroxidase (PaP) technique, and paraffin sections of 22 lymph nodes affected by Hodgkin's disease. Vascular basement membranes and reticulin fibres are selectively stained and their structural changes in this pathological condition become readily visible. In contrast to the normal lymph node and to Hodgkin's disease with lymphocytic predominance, cases of mixed cellularity disease contain individual and focally grouped cells displaying intracytoplasmic FN. In nodular sclerosis these cells with fibroblast morphology are consistently numerous in the marginal zones of the cellular nodes. Strongly reacting mastocytes probably absorbed the applied antiserum non-immunologically. All the other cell types giving rise to the varying appearances of Hodgkin's lesions are consistently negative with respect to intracellular FN, including all forms of Hodgkin cells. We conclude that in Hodgkin's disease the immigration of FN-secreting fibroblasts is an integral part of the early sclerosing reaction, which in itself is a defence/repair mechanism closely related to scar formation.

Conspicuous enterocytic binding pattern for peanut lectin and malignant histiocytosis of the intestine.

We present a case of a 33 year old male with a history of early childhood diarrhoea and more recently diagnosed gluten sensitive enteropathy, who died with active disease, ulcerative proctosigmoiditis and desquamative erythrodermia associated with toxin induced shock. Autopsy revealed a tumour restricted to lymph nodes of the mesentery and the retroperitoneum. This is considered to be malignant histiocytosis of the intestine (MIH). Immunohistological examination of the diagnostic jejunal biopsy showed a pathological binding pattern for peanut lectin (PNL) within the enterocytes. This may be an expression of disturbed production or secretion of a product rich in non-reducing terminal D-galactosyl residues.

J-chain-producing immunoblastic lymphoma in a case of Richter's syndrome. Immunohistochemical evidence for a gradual malignant transformation of a single B-cell clone and flow cytophotometric data.

A 66-year old male with Richter's syndrome died 52 month after diagnosis of chronic lymphocytic leukaemia (CLL). The clinical course was characterized by a marked IgM hypoglobulinaemia which paralleled a chronically relapsing Herpes simplex infection. Autopsy showed a large retroperitoneal and intraabdominal tumour mass and well defined supradiaphragmatic lymphomas. Histological examination revealed a composite tumour consisting of CLL B-cell type (B-CLL) and immunoblastic malignant lymphoma of B-cell type (B-IbL). The lymphocytes bear mu-chains on their surface and to a lesser extend within their cytoplasm, the obviously defective immunoblasts produce J chains exclusively. Flow cytophotometric data seem to indicate an identical diploid stem line of the two tumours. The majority of the cells are in G0/1 phase. The CLL rarely produces mitoses, however, the IbL has a mitotic rate of 7% and a considerable proportion (33%) of cells in the phase of DNA-synthesis. This is the fourth malignant lymphoma and the second immunoblastic lymphoma to be reported that produces J chain in the absence of immunoglobulin.