Adult-onset Autosomal Dominant Leukodystrophy Research Articles

Nuclear lamins

ADLD= : adult-onset autosomal dominant leukodystrophy; CMT= : Charcot-Marie-Tooth; EDMD= : Emery-Dreifuss muscular dystrophy; LAP= : lamin-associated polypeptide; LBR= : lamin B receptor; LGMD1B= : autosomal dominant limb-girdle muscular dystrophy The nuclear envelope is the interface between the nucleus and the rest of the cell and consists of inner and outer nuclear membranes. The nuclear lamina underlies the inner nuclear membrane and is an essential structural element of the nuclear envelope. The nuclear lamina maintains the nuclear architecture and regulates DNA replication and chromatin organization. The major components of the nuclear lamina are the nuclear lamins, including lamin A/C and lamin B. Lamins interact with several other inner nuclear proteins, such as emerin; these interactions are critical for the functional organization of chromatin, transport across the nuclear envelope, and transmission of mechanical signals to the nucleus. Mutations in genes encoding lamins and their associated proteins cause a wide spectrum of diseases called “laminopathies.” Mutations affecting lamin A or associated proteins, such as emerin, produce Emery-Dreifuss muscular dystrophy (EDMD). LMNA mutations also produce autosomal dominant limb-girdle muscular dystrophy (LGMD1B) and Charcot-Marie-Tooth (CMT) disease type 2B1. Duplication in LMNB1 , encoding lamin B1, causes autosomal dominant leukodystrophy. Lamin mutations have also been linked to cardiomyopathy, lipodystrophy, and accelerated aging disorders. The functional organization of the nuclear envelope and the wide spectrum of laminopathies have been the subject of several recent reviews.1,–,7 The principal components of the nuclear envelope are the inner and outer nuclear membranes, separated by the perinuclear space4,8 (figure). The outer nuclear membrane is contiguous with and functionally related …

Adult-onset autosomal dominant leukodystrophy due to LMNB1 gene duplication

Adult-onset autosomal dominant leukodystrophy (ADLD, OMIM accession number 169500) is a slowly progressive neurological disorder involving early autonomic dysfunction, cognitive impairment, pyramidal lesions, and cerebellar dysfunction. Onset is usually in the fourth or fifth decade of life. The disease is caused by a duplication of a region on chromosome 5q23.2 including the Lamin B1 gene (LMNB1) [1]. Neuroradiological characteristics are symmetrical extensive white matter changes predominantly in the frontal and parietal lobes, middle cerebellar peduncles, and specific brain stem tracts. Furthermore, atrophy of the corpus callosum and the brain stem develop. Sparing or less severe alteration of the periventricular white matter is a typical finding [2]. We report on a 47-year-old male patient with a 2-year history of gait disturbance and micturition problems with imperative strangury and, as mentioned by family members, personality changes and depression. On examination he had moderately severe gait ataxia, symmetrical appendicular ataxia, mild spastic paraparesis, brisk deep tendon reflexes, and bilaterally positive Babinski signs. MR imaging of the brain showed extensive bilateral T2hyperintense lesions in the subcortical and deep cerebral white matter with relative sparing of a periventricular rim and the corpus callosum. The middle cerebellar peduncles, the pyramidal tracts, and medial lemniscus in the midbrain, pons, and medulla, and the decussation of the superior cerebellar peduncles were also affected (Fig. 1). Neuropsychological testing yielded results below average regarding the following domains: verbal fluency and flexibility, verbal memory, verbal recall, working memory, several executive functions, and general working velocity. Lumbar puncture, evoked potentials, nerve conduction studies, and electromyography were without abnormal findings. Blood and urine analysis of amino acids, long-chain fatty acids, and lysosomal enzymes (arylsulfatase A, galactocerebrosidase, alpha-galactosidase) were normal. The pedigree showed numerous affected members of father’s family within three generations. Four out of five uncles and aunts and in the grandparents’ generation, six out of eight family members were affected, mainly by gait disturbance but also by neuropsychiatric symptoms (Fig. 2). Seven affected siblings had died; age at death varied between 46 and 71 years. Because of the mode of inheritance and the clinical and MRI findings, ADLD was supposed and the lamin B1 gene was analyzed. Genomic DNA was extracted from venous blood and hybridized on Affymetrix GeneChip Human Mapping SNP6.0 arrays, following the manufacturer’s instructions. M. M. Dos Santos (&) A. J. Grau Department of Neurology, Klinikum Ludwigshafen, Bremserstrasse 79, 67063 Ludwigshafen, Germany e-mail: santosm@klilu.de

Adult-Onset Autosomal Dominant Leukodystrophy: Linking Nuclear Envelope to Myelin

Adult-onset autosomal dominant leukodystrophy (ADLD) was first described for a large kindred with a progressive and fatal neurological white matter disorder in an American-Irish family ([Eldridge et al., 1984][1]). Subsequently, ADLD has been reported in many other ethnic groups including Japanese,

Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms

Adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms features micturition urgency, constipation, erectile dysfunction, and orthostatic hypotension, usually followed by pyramidal signs and ataxia. Peripheral nerve conduction is normal. The disease is often mistaken for multiple sclerosis in the initial phase. There is a characteristic pattern of white matter changes in the brain and spinal cord on magnetic resonance imaging (MRI), mild atrophy of the brain, and a more marked atrophy of the spinal cord. ADLD is associated with duplications of the lamin B1 (LMNB1) gene but the mechanism by which the rearrangement conveys the phenotype is not fully defined. We analyzed four unrelated families segregating ADLD with autonomic symptoms for duplications of the LMNB1 gene. A single nucleotide polymorphism (SNP) array analysis revealed novel duplications spanning the entire LMNB1 gene in probands from each of the four families. We then analyzed the expression of lamin B1 in peripheral leukocytes by Western blot analysis in five patients from two available families. The protein levels of lamin B1 were found significantly increased. These results indicate that the ADLD phenotype associated with LMNB1 duplications is mediated by increased levels of the lamin B1 protein. Furthermore, we show that a molecular diagnosis for ADLD with autonomic symptoms can be obtained by a direct analysis of lamin B1 in peripheral leukocytes.

Isolated noradrenergic failure in adult-onset autosomal dominant leukodystrophy

We evaluated the autonomic control of the cardiovascular system and the skin innervation of a patient from a new Italian family with a genetically proven diagnosis of adult-onset autosomal dominant leukodystrophy (ADLD) due to lamin B1 gene duplication. Cardiovascular reflexes and pharmacological assessment indicated a selective sympathetic failure, sparing cardiovagal function. Microneurography revealed absent sympathetic activity. The evaluation of autonomic innervation of skin annexes showed severely depleted and morphologically abnormal noradrenergic dopamine-β-hydroxylase (DβH) immunoreactive fibres with preserved cholinergic vasoactive intestinal polypeptide (VIP) immunoreactive fibres. This peculiar autonomic dysfunction may represent a hallmark for ADLD.

A family with autosomal dominant leukodystrophy linked to 5q23.2–q23.3 without lamin B1 mutations

Duplications of lamin B1 (LMNB1) at 5q23 are implicated in adult-onset autosomal dominant leukodystrophy (ADLD) having been described in six families with diverse ethnic background but with a homogeneous phenotype. In a large Italian family, we recently identified a variant form of ADLD characterized clinically by absence of the autonomic dysfunction at onset described in ADLD and, on MRI, by milder cerebellar involvement with sparing of hemispheric white matter. Aim of this study was to investigate the genetic basis of this variant form of ADLD. We carried out a genome-wide linkage analysis using microsatellite markers, and the genes in the candidate region were screened for point mutations. LMNB1 was also screened for deletions/duplications by real-time PCR, multiplex ligation-dependent probe amplification and Southern blot. We mapped the variant ADLD locus to 5q23.2-q23.3, a genomic region containing 11 genes including LMNB1. Neither gene copy-number defects nor point mutations in the LMNB1 gene were found. We also excluded point mutations in the coding exons of the other ten genes in the candidate region. However, expression of lamin B1 evaluated in lymphoblastoid cells was higher in patients than in healthy controls, and was similar to the lamin B1 expression levels found in a patient with LMNB1 duplication. This observation suggests that a mutation in an LMNB1 regulatory sequence underlies the variant ADLD phenotype. Thus, adult forms of ADLD linked to 5q23 appear to be more heterogeneous clinically and genetically than previously thought.

N‐CAM Dysfunction and Unexpected Accumulation of PSA‐NCAM in Brain of Adult‐Onset Autosomal‐Dominant Leukodystrophy

Previously, myelin from cerebral white matter (CWM) of two subjects of a family with orthochromatic adult-onset autosomal-dominant leukodystrophy (ADLD) was disclosed to exhibit defective large isoform of myelin-associated glycoprotein (L-MAG) and patchy distribution only in the elder subject. L-MAG and neural cell adhesion molecule (N-CAM) (N-CAM 180, 140, and 120) are structurally related and concur to myelin/axon interaction. In early developmental stages, in neurons and glia N-CAM is converted into polysialylated (PSA)-NCAM by two sialyltransferases sialyltransferase-X (STX) and polysialyltransferase-1 (PST). Notably, PSA-NCAM disrupts N-CAM adhesive properties and is nearly absent in the adult brain. Here, CWM extracts and myelin of the two subjects were searched for the expression pattern of the N-CAM isoforms and PSA-NCAM, and their CWM was evaluated for N-CAM, STX and PST gene copy number and gene expression as mRNA. Biochemically, we disclosed that in CWM extracts and myelin from both subjects, PSA-NCAM accumulates, N-CAM 180 considerably increases, N-CAM 140 is modestly modified and N-CAM 120 remarkably decreases; duplication of genes encoding N-CAM, STX and PST was not revealed, whereas PST mRNA was clearly increased. Immunohistochemically, in CWM of both subjects, we found an unusually diffuse accumulation of PSA-NCAM without inflammation markers. PSA-NCAM persistence, up-regulated PST mRNA and previously uncovered defective L-MAG may be early pathogenetic events in this ADLD form.

Mutations in the lamin B1 gene are not present in multiple sclerosis

Whole gene duplication of the lamin B1 gene (LMNB1), encoding for a protein of the nuclear lamina, causes an adult-onset autosomal dominant leukodystrophy (ADLD). Clinical features of ADLD (onset in adult life, dysautonomic symptoms, followed by pyramidal and cerebellar dysfunctions) partially resemble those of multiple sclerosis (MS), particularly the primary-progressive form. Our aim was to test whether LMNB1 gene mutations were present amongst patients with a diagnosis of MS. One hundred eighty-two MS patients were screened for copy number variations of the LMNB1 gene using a qPCR assay. Point mutations in the LMNB1 gene were searched by denaturing high-performance liquid chromatography and direct sequencing in a subgroup of 16 patients with familial MS. No duplication/deletion of the lamin B1 gene was found amongst MS patients, and no point mutation was identified in the familial cases. Our work indicates that lamin B1 defects are probably not responsible for signs and symptoms resembling multiple sclerosis.

MiR-23regulation of lamin B1 is crucial for oligodendrocyte development and myelination

Duplication of the gene encoding lamin B1 (LMNB1) with increased mRNA and protein levels has been shown to cause severe myelin loss in the brains of adult-onset autosomal dominant leukodystrophy patients. Similar to many neurodegenerative disorders, patients with adult-onset autosomal dominant leukodystrophy are phenotypically normal until adulthood and the defect is specific to the central nervous system despite the ubiquitous expression pattern of lamin B1. We set out to dissect the molecular mechanisms underlying this demyelinating phenotype. Increased lamin B1 expression results in disturbances of inner nuclear membrane proteins, chromatin organization and nuclear pore transport in vitro. It also leads to premature arrest of oligodendrocyte differentiation, which might be caused by reduced transcription of myelin genes and by mislocalization of myelin proteins. We identified the microRNA miR-23 as a negative regulator of lamin B1 that can ameliorate the consequences of excessive lamin B1 at the cellular level. Our results indicate that regulation of lamin B1 is important for myelin maintenance and that miR-23 contributes to this process, at least in part, by downregulating lamin B1, therefore establishing novel functions of lamin B1 and miR-23 in the regulation of oligodendroglia development and myelin formation in vitro.

A Novel Duplication Confirms the Involvement of 5q23.2 in Autosomal Dominant Leukodystrophy

To identify the underlying locus and disease-causing mutation for adult-onset autosomal dominant leukodystrophy (ADLD). Previously, an adult-onset ADLD locus on chromosome 5q23 was mapped between markers D5S1495 and CTT/CCT15. This region contains 13 known and putative candidate genes. A 2-point linkage analysis confirmed linkage of a large multigenerational French Canadian family to chromosome 5q23. In addition, screening of the 13 genes within the candidate interval as well as 5 neighboring genes was completed, followed by comparative genomic hybridization. A multigenerational French Canadian family with ADLD mimicking progressive multiple sclerosis was identified and studied. Eight affected family members were available for the study and presented with autonomic dysfunction as well as upper motorneuron signs affecting gait. The thorough candidate gene approach did not identify any mutation. Consequently, a whole-chromosome comparative genomic hybridization for chromosome 5 identified a 280-kilobase duplication within the chromosomal band 5q23.2 in 2 affected individuals. This duplication contains 3 genes: LMNB1, FLJ36242, and MARCH3. We have identified a novel duplication on chromosomal band 5q23.2 in a French Canadian family with ADLD that supports the implication of duplicated LMNB1 as the disease-causing mutation. However, additional functional studies of lamin B1 overexpression are necessary to elucidate the involvement of lamin B1 in myelination and in degenerative disorders such as ADLD and multiple sclerosis.

MR Imaging Characteristics and Neuropathology of the Spinal Cord in Adult-Onset Autosomal Dominant Leukodystrophy with Autonomic Symptoms

MR imaging findings in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms have been described in the brain, but no descriptions of MR imaging findings in the spinal cord have been published. Here, we describe MR imaging findings in the spinal cord in adult-onset ADLD with autonomic symptoms and histopathologic investigations of the spinal cord. Twelve subjects from 2 families with adult-onset ADLD with autonomic symptoms identified by clinical investigation underwent MR imaging examination of the spinal cord. Sagittal and transverse sections were obtained. MR imaging examination of the brain was performed in 11 patients. One of the patients underwent postmortem examination, and the spinal cord was subjected to histopathologic analysis. In all family members with adult-onset ADLD with autonomic symptoms, even in the asymptomatic person, the spinal cord was thin. All examined family members also had a slight general white matter signal intensity (SI) increase in the whole spinal cord, mainly visible in T2-weighted transverse images. The pathologic examination revealed a discrete demyelination in the spinal cord. Brain MR imaging also showed increased T2 SI in the white matter. The spinal cord is affected in adult-onset ADLD with autonomic symptoms. Findings consist of atrophy and a diffuse T2 SI increase in the white matter. Transverse images are needed to assess these findings. The typical SI changes of the spinal cord are also present in subjects without clinical symptoms of the disease and with very limited changes in the brain.

Lamin B1 duplications cause autosomal dominant leukodystrophy

Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterized by symmetrical widespread myelin loss in the central nervous system, with a phenotype similar to chronic progressive multiple sclerosis. In this study, we identify a genomic duplication that causes ADLD. Affected individuals carry an extra copy of the gene for the nuclear laminar protein lamin B1, resulting in increased gene dosage in brain tissue from individuals with ADLD. Increased expression of lamin B1 in Drosophila melanogaster resulted in a degenerative phenotype. In addition, an abnormal nuclear morphology was apparent when cultured cells overexpressed this protein. This is the first human disease attributable to mutations in the gene encoding lamin B1. Antibodies to lamin B are found in individuals with autoimmune diseases, and it is also an antigen recognized by a monoclonal antibody raised against plaques from brains of individuals with multiple sclerosis. This raises the possibility that lamin B may be a link to the autoimmune attack that occurs in multiple sclerosis.

Autosomal dominant leukodystrophy with axonal spheroids and pigmented glia: clinical and neuropathological characteristics

We report two autopsy cases of siblings with adult-onset autosomal dominant leukodystrophy characterized by destruction of cerebral white matter, large numbers of axonal spheroids and pigmented glia in the fronto-temporal lobes. Both patients presented with motor and cognitive symptoms and aphasia, 2-3 years before death. At autopsy, the brain showed brown coloration and decreased volume of white matter in the frontal and temporal lobes as well as corpus callosum. Microscopically, marked loss of myelin and axons and abundant axonal spheroids without apparent neuronal loss were observed in the frontal and temporal lobes, which was consistent with hereditary diffuse leukodystrophy with spheroids (HDLS). In addition, glial cells, most consistent with macrophages and containing pigments that were stained by Sudan III and PAS, were found in the white matter lesions. The present cases showed overlapping features with HDLS and pigmentary type of orthochromatic leukodystrophy, suggesting that the pathomechanisms of these two diseases are closely related.

Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31.

The hereditary leukodystrophies represent a group of neurological disorders, in which complete or partial dysmyelination occurs in either the central nervous system (CNS) and/or the peripheral nervous system. Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive, neurological disorder characterized by symmetrical widespread myelin loss in the CNS, and the phenotype is similar to that of chronic progressive multiple sclerosis. We report clinical, neuroradiological and neuropathological data from the originally reported ADLD family. Furthermore, we have localized the gene that causes ADLD to a 4 cM region on chromosome 5q31. Linkage analysis of this family yielded a LOD score of 5.72 at theta = 0.0 with the microsatellite marker D5S804. Genetic localization will lead to cloning and characterization of the ADLD gene and may yield new insights into myelin biology and demyelinating diseases.