Genetic Analysis of Inherited Leukodystrophies

Guerreiro, Rita; Kara, Eleanna; Ber, Isabelle Le; Brás, José; Rohrer, Jonathan D.; Taipa, Ricardo; Lashley, Tammaryn; Dupuits, Céline; Gurunlian, Nicole; Mochel, Fanny; Warren, Jason D.; Hannequin, Didier; Sedel, Frédéric; Depienne, Christel; Camuzat, Agnès; Golfier, Véronique; Boisguéheneuc, Foucaud Du; Schottlaender, Lucía; Fox, Nick C.; Beck, Jonathan; Mead, Simon; Rossor, Martin N.; Hardy, John; Révész, Tamás; Brice, Alexis; Houlden, Henry

doi:10.1001/jamaneurol.2013.698

Cited by 79 publications

(48 citation statements)

References 23 publications

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“…The median age of onset is 42 ± 13 years (range 8-78) with a disease duration of 5 ± 7 (range 1-34) years that is unrelated to the time of onset (Ahmed et al, 2013; Freeman et al, 2009; Guerreiro et al, 2013; Hoffmann et al, 2014; Karle et al, 2013; Kinoshita et al, 2014; Kleinfeld et al, 2013; Kondo et al, 2013; Konno et al, 2014; Mitsui et al, 2012; Rademakers et al, 2011; Sundal et al, 2012; Van Gerpen et al, 2008; Wider et al, 2009). Symptoms may vary according to gender (Hoffmann et al, 2014), and clinical presentation is variable.…”

Section: Discussionmentioning

confidence: 99%

“…Patients often present with sensorimotor and neuropsychiatric symptoms, including depression, behavioral changes, spastic paraplegia, dementia and seizures, leading to frequent and diverse clinical misdiagnoses. The initial symptoms progress to dementia and death (Axelsson et al, 1984; Guerreiro et al, 2013; Marotti et al, 2004; Sundal et al, 2012; Wider et al, 2009). By MRI, ALSP is characterized by patchy cerebral white matter lesions, often initially asymmetrical, but becoming confluent and symmetrical with disease progression (Freeman et al, 2009; Konno et al, 2014; Sundal et al, 2012; Van Gerpen et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

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Phenotypic characterization of a Csf1r haploinsufficient mouse model of adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP)

Chiţu

Gökhan

Gulinello

et al. 2015

Neurobiology of Disease

147

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Mutations in the colony stimulating factor-1 receptor (CSF1R) that abrogate the expression of the affected allele or lead to the expression of mutant receptor chains devoid of kinase activity have been identified in both familial and sporadic cases of ALSP. To determine the validity of the Csf1r heterozygous mouse as a model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) we performed behavioral, radiologic, histopathologic, ultrastructural and cytokine expression studies of young and old Csf1r+/− and control Csf1r+/+ mice. Six to 8-month old Csf1r+/− mice exhibit cognitive deficits, and by 9-11 months develop sensorimotor deficits and in male mice, depression and anxiety-like behavior. MRIs of one year-old Csf1r+/− mice reveal lateral ventricle enlargement and thinning of the corpus callosum. Ultrastructural analysis of the corpus callosum uncovers dysmyelinated axons as well as neurodegeneration, evidenced by the presence of axonal spheroids. Histopathological examination of 11-week-old mice reveals increased axonal and myelin staining in the cortex, increase of neuronal cell density in layer V and increase of microglial cell densities throughout the brain, suggesting that early developmental changes contribute to disease. By 10-months of age, the neuronal cell density normalizes, oligodendrocyte precursor cells increase in layers II-III and V and microglial densities remain elevated without an increase in astrocytes. Also, the age-dependent increase in CSF-1R+ neurons in cortical layer V is reduced. Moreover, the expression of Csf2, Csf3, Il27 and Il6 family cytokines is increased, consistent with microglia-mediated inflammation. These results demonstrate that the inactivation of one Csf1r allele is sufficient to cause an ALSP-like disease in mice. The Csf1r+/− mouse is a model of ALSP that will allow the critical events for disease development to be determined and permit rapid evaluation of therapeutic approaches. Furthermore, our results suggest that aberrant activation of microglia in Csf1r+/− mice may play a central role in ALSP pathology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phenotypic characterization of a Csf1r haploinsufficient mouse model of adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP)

Chiţu

Gökhan

Gulinello

et al. 2015

Neurobiology of Disease

147

View full text Add to dashboard Cite

show abstract

“…The screening of larger cohorts might lead to the identification of cases carrying the repeat expansion or pathogenic variants in common FTD genes. The screening for mutations in other uncommon FTD genes such as the charged multivesicular body protein 2B ( CHMP2B ) [42], FUS [43, 44], dynactin ( DCTN1 ) [45], sequestosome 1 ( SQSTM1 ) [46], colony-stimulating factor 1 receptor ( CFS1R ) [47], triggering receptor expressed on myeloid cells ( TREM2 ) [48], ubiquilin-2 ( UBQLN2 ) [49] and heterogeneous nuclear ribonucleoprotein A2B1 ( hnRNPA2B1 ) [50] might be the next step to perform. Ultimately, next generation sequencing methods seem like the efficient strategy to unravel the genetic origin of FTD in our cohort.…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic analyses of familial and sporadic frontotemporal dementia patients in Southern Italy

Capozzo

Sassi

Hammer

et al. 2017

Alzheimer's & Dementia

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Introduction: We investigated the clinical differences between familial and sporadic frontotemporal dementia (FTD), screening for mutations in known FTD genes. Methods: We diagnosed 22 affected individuals belonging to 8 families and 43 sporadic cases with FTD in Apulia, Southern Italy in two years. Mutations in common causative FTD genes (GRN, MAPT, VCP and TARDBP) and C9ORF72 expansions were screened. Results: Behavioural variant of FTD was the most common clinical subtype (50% and 69% in familial and sporadic cases, respectively). Social conduct impairment/disinhibition, loss of insight, and inflexibility were the most frequent clinical features observed at onset. One new mutation was identified in GRN in family A. Conclusion: Disease onset in sporadic FTD was more frequently characterized by a clustering of behavioral symptoms with apathy and loss of personal hygiene. Mutations in common causative FTD genes are not a major cause of familial and sporadic FTD in the Southern Italian population.

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“…2 ALSP is increasingly recognized as one of the most common causes of adult-onset inherited leukoencephalopathy. 3 ALSP diagnosis is still challenging because of the multiple presentations that can mimic frontotemporal lobar degeneration (FTLD), atypical parkinsonism, CADASIL, or primary-progressive MS. 1,[3][4][5] Indeed, initial descriptions of ALSP included lateonset psychiatric and cognitive impairment with MR imaging frontal white matter changes and atrophy. Following the genetic characterization of the disease, more distinctive imaging findings have been identified, including deep punctate calcifications, persistent DWI small diffusion-restricted lesions, and corpus callosum thinning.…”

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confidence: 99%

Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia: An MRI Study of 16 French Cases

Codjia

Ayrignac

Mochel

et al. 2018

AJNR Am J Neuroradiol

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Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is an autosomal dominant leukoencephalopathy related to gene mutations. A growing number of clinicoradiologic phenotypes have been described. In this study, we analyzed brain imaging findings in 16 patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia to refine radiologic diagnostic clues. T2/FLAIR white matter hyperintensities were present in all patients with frontal or frontoparietal predilection, with asymmetric distribution in more than one-third. Brain atrophy and callosal involvement were almost constant, and corticospinal tract involvement was frequent. Moreover, deep white matter hyperintense dots on DWI and deep punctate calcifications on CT were often found. Conversely, deep gray matter nuclei, external capsules, and brain stem were rarely involved. Our series emphasized the great variability of MR imaging findings seen in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. A complete imaging screening including DWI, T2*, and CT is mandatory to accurately assess patients with suspected inherited adult-onset leukoencephalopathy.

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Genetic Analysis of Inherited Leukodystrophies

Cited by 79 publications

References 23 publications

Phenotypic characterization of a Csf1r haploinsufficient mouse model of adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP)

Phenotypic characterization of a Csf1r haploinsufficient mouse model of adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP)

Clinical and genetic analyses of familial and sporadic frontotemporal dementia patients in Southern Italy

Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia: An MRI Study of 16 French Cases

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