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author:("lauge, Pierre")
1.  Inflammatory-like presentation of CADASIL: a diagnostic challenge 
BMC Neurology  2012;12:78.
Background
CADASIL is an autosomal dominant genetic leukoencephalopathy linked to mutations in the Notch3 gene. In rare cases, widespread brain lesions on T2 MRI mimicking multiple sclerosis are observed. From a national registry of 268 patients with adult-onset leukodystrophy, we identified two patients with an atypical presentation of CADASIL without co-occurrence of another systemic disease.
Case presentations
Patient 1 experienced progressive gait disability and patient 2 relapsing optic neuritis and sensory-motor deficit in the leg. Both patients responded to corticotherapy and patient 2 was also responsive to glatiramer acetate. No oligoclonal bands were found in the CSF, and MRI showed myelitis and lesions with gadolinium enhancement in brain (patient 1) or incomplete CADASIL phenotype (patient 2).
Conclusions
In rare cases, an inflammatory-like process can occur in CADASIL. In these patients, immunomodulatory treatments, including corticosteroids, could be effective.
doi:10.1186/1471-2377-12-78
PMCID: PMC3488471  PMID: 22905984
CADASIL; Multiple sclerosis; Leukoencephalopathy; Notch3; Cerebral vasculitis
2.  Painful camptocormia: the relevance of shaking your patient’s hand 
European Spine Journal  2009;19(Suppl 2):87-90.
Camptocormia is an abnormal posture with marked flexion of thoracolumbar spine that abates in the recumbent position. Camptocormia has been described in various neurological (Parkinsonism), muscular (myopathy), psychogenic or orthopedic disorders. There are several hypotheses that can explain this impaired posture but they are usually related to the concomitant pathologies. We report the first case of a patient with confirmed myotonic dystrophy addressed to our medical center for impaired posture who underwent extensive medical exams and explorations because of a myotonic hand. Axial weakness and muscle atrophy, validated by CT-scan imaging, are discussed independent of the concomitant pathology (Parkinson, myopathy).
doi:10.1007/s00586-009-1086-6
PMCID: PMC2899637  PMID: 19590905
Posture; Camptocormia; Myotonic dystrophy; Muscular atrophy
3.  A MANBA mutation resulting in residual beta-mannosidase activity associated with severe leukoencephalopathy: a possible pseudodeficiency variant 
BMC Medical Genetics  2009;10:84.
Background
β-Mannosidosis (OMIM 248510) is a rare inborn lysosomal storage disorder caused by the deficient activity of β-mannosidase, an enzyme encoded by a single gene (MANBA) located on chromosome 4q22-25. To date, only 20 cases of this autosomal recessive disorder have been described and 14 different MANBA mutations were incriminated in the disease. These are all null mutations or missense mutations that abolish β-mannosidase activity. In this study, we characterized the molecular defect of a new case of β-mannosidosis, presenting with a severe neurological disorder.
Methods
Genomic DNA was isolated from peripheral blood leukocytes of the patient to allow MANBA sequencing. The identified mutation was engineered by site-directed mutagenesis and the mutant protein was expressed through transient transfection in HEK293T cells. The β-mannosidase expression and activity were respectively assessed by Western blot and fluorometric assay in both leukocytes and HEK293T cells.
Results
A missense disease-associated mutation, c.1922G>A (p.Arg641His), was identified for which the patient was homozygous. In contrast to previously described missense mutations, this substitution does not totally abrogate the enzyme activity but led to a residual activity of about 7% in the patient's leukocytes, 11% in lymphoblasts and 14% in plasma. Expression studies in transfected cells also resulted in 7% residual activity.
Conclusion
Correlations between MANBA mutations, residual activity of β-mannosidase and the severity of the ensuing neurological disorder are discussed. Whether the c.1922G>A mutation is responsible for a yet undescribed pseudodeficiency of β-mannosidase is also discussed.
doi:10.1186/1471-2350-10-84
PMCID: PMC2745377  PMID: 19728872
4.  Warmer Weather Linked to Tick Attack and Emergence of Severe Rickettsioses 
The impact of climate on the vector behaviour of the worldwide dog tick Rhipicephalus sanguineus is a cause of concern. This tick is a vector for life-threatening organisms including Rickettsia rickettsii, the agent of Rocky Mountain spotted fever, R. conorii, the agent of Mediterranean spotted fever, and the ubiquitous emerging pathogen R. massiliae. A focus of spotted fever was investigated in France in May 2007. Blood and tissue samples from two patients were tested. An entomological survey was organised with the study of climatic conditions. An experimental model was designed to test the affinity of Rh. sanguineus for biting humans in variable temperature conditions. Serological and/or molecular tools confirmed that one patient was infected by R. conorii, whereas the other was infected by R. massiliae. Dense populations of Rh. sanguineus were found. They were infected with new genotypes of clonal populations of either R. conorii (24/133; 18%) or R. massiliae (13/133; 10%). April 2007 was the warmest since 1950, with summer-like temperatures. We show herein that the human affinity of Rh. sanguineus was increased in warmer temperatures. In addition to the originality of theses cases (ophthalmic involvements, the second reported case of R. massiliae infection), we provide evidence that this cluster of cases was related to a warming-mediated increase in the aggressiveness of Rh. sanguineus, leading to increased human attacks. From a global perspective, we predict that as a result of globalisation and warming, more pathogens transmitted by the brown dog tick may emerge in the future.
Author Summary
The impact of climate on the behaviour of the worldwide dog tick Rhipicephalus sanguineus is a cause of concern. This tick is a vector for life-threatening organisms including Rickettsia rickettsii, the agent of Rocky Mountain spotted fever, R. conorii, the agent of Mediterranean spotted fever, and the ubiquitous emerging pathogen R. massiliae. A focus of spotted fever was investigated in France in May 2007. One patient was found to be infected by R. conorii, whereas the other was infected by R. massiliae. Theses cases were original because of ophthalmic involvements, and the report of the second case of R. massiliae infection in the scientific literature. During an entomological survey, dense populations of Rh. sanguineus were found in the house where the patient had been bitten by ticks. Ticks were infected with either R. conorii or R. massiliae. Interestingly, April 2007 was the warmest since 1950, with summer-like temperatures. In this work, we show that the human affinity of Rh. sanguineus is increased in warmer temperatures, and provide evidence that this cluster of cases was related to a warming-mediated increase in the aggressiveness of Rh. sanguineus, leading to increased human attacks. From a global perspective, we predict that as a result of globalisation and warming, more pathogens transmitted by the brown dog tick may emerge in the future.
doi:10.1371/journal.pntd.0000338
PMCID: PMC2581602  PMID: 19015724
5.  Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele-Specific Expression 
Human Mutation  2013;34(8):1160-1171.
ABSTRACT
Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication-based mechanisms such fork stalling and template switching or microhomology-mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele-specific LMNB1 expression levels.
doi:10.1002/humu.22348
PMCID: PMC3714349  PMID: 23649844
Lamin B1; leukodystrophy; ADLD; duplication Alu; NHEJ; FoSTeS; MMBIR

Results 1-5 (5)