Leukodystrophy, Demyelinating, Adult-Onset, Autosomal Dominant

A number sign (#) is used with this entry because autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) is caused by a heterozygous tandem genomic duplication resulting in an extra copy of the lamin B1 gene (LMNB1; 150340) on chromosome 5q.

One family with a complex deletion upstream of the LMNB1 gene has also been reported (Giorgio et al., 2015).

Description

Autosomal dominant adult-onset demyelinating leukodystrophy is a slowly progressive and fatal disorder that presents in the fourth or fifth decade of life and is characterized clinically by early autonomic abnormalities, pyramidal and cerebellar dysfunction, and symmetric demyelination of the CNS. ADLD differs from multiple sclerosis and other demyelinating disorders in that neuropathology shows preservation of oligodendroglia in the presence of subtotal demyelination and lack of astrogliosis (summary by Padiath et al., 2006). Characteristic MRI findings include T2-weighted hyperintense changes in the upper corticospinal tract and cerebellar peduncles, with later development of confluent white matter changes in the frontoparietal area with relative sparing of the periventricular white matter (summary by Schuster et al., 2011).

Clinical Features

Zerbin-Rudin and Peiffer (1964) described a familial disorder similar to Pelizaeus-Merzbacher disease (PMD; 312080) except that it showed later onset and autosomal dominant inheritance rather than X-linked inheritance typical of PMD. The disease was noted to be similar to multiple sclerosis (MS; 126200) in some respects. It may be the same disorder as that reported by Camp and Lowenberg (1941).

Eldridge et al. (1984) described a large American-Irish kindred with a chronic progressive neurologic disorder affecting at least 10 men and 11 women in 4 generations in an autosomal dominant pattern. Multiple sclerosis was diagnosed in 20 of the patients evaluated before the availability of CT imaging and without regard to the family history. Neurologic symptoms began in the 4th and 5th decades and included cerebellar, pyramidal, and autonomic abnormalities. The autonomic dysfunction involved bowel and bladder regulation and orthostatic hypotension; these were often the earliest changes but were frequently disregarded. Survival for 20 years after onset was common. CT imaging showed symmetrical decreases in white-matter density, beginning in the frontal lobes and extending to all of the centrum ovale and cerebellar white matter. In patients from this family, Brown et al. (1987) demonstrated findings consistent with denervation supersensitivity, suggesting a distal lesion of sympathetic noradrenergic neurons. Absence of the epinephrine response to insulin-induced hypoglycemia indicated that autonomic neuropathy was attended by severe adrenal medullary dysfunction.

Laxova et al. (1985) described a Scottish-Irish family with a similar, possibly identical disorder. Onset in the late 30s was marked by autonomic symptoms, including postural hypotension, neurogenic bladder, and rectal incontinence. Progressive spasticity followed, with death in 10 to 15 years. Orientation and affect remained intact. CT scans and magnetic resonance imaging showed symmetric atrophy of white matter. Some clinically unaffected offspring showed the same change. The condition was often misdiagnosed as multiple sclerosis.

Schwankhaus et al. (1994) reported autopsy findings from a 64-year-old affected woman of the kindred reported by Eldridge et al. (1984). Her symptoms began at age 44 years. The most striking finding was leukoencephalopathy preferentially affecting the frontal and parietal lobes, including the lateral margins of the corpus callosum, and diminishing in severity toward the occipital lobes. Subcortical U fibers were spared. There was no inflammation or metachromasia. No lipid accumulation was seen by oil red O or with Sudan black. No histologic abnormality was seen in the peripheral nervous system or in the adrenal glands, despite clinical evidence of autonomic dysfunction which is typically a presenting feature of adult-onset leukodystrophy. Although there were vacuolar changes in the white matter reminiscent of a classic spongiform encephalopathy, Schwankhaus et al. (1994) thought that the large size of the vacuoles, the absence of any changes in the gray matter, and the clinical course argued against this. No prion studies were done. The authors suggested that the early autonomic insufficiency seen in their patient was a feature that distinguished autosomal dominant, adult-onset leukodystrophy from adult-onset Pelizaeus-Merzbacher disease, which they referred to as Lowenberg-Hill disease (Rodriguez et al., 1983).

Labauge et al. (2005) reported a mother and son with an adult-onset disorder similar to vanishing white matter disease (VWM; 603896) except for apparent autosomal dominant inheritance. At age 35, the son had an acute episode of brain dysfunction after a viral illness. Features included excessive somnolence and mental confusion, apathy, vomiting, and left-sided hemiparesis requiring mechanical ventilation. Brain CT scan showed extensive hypodensity of the cerebral white matter. Similar episodes occurred following viral infections at ages 36, 39, and 40 years. After the fourth episode, progressive neurologic deterioration was observed, including cerebellar ataxia, spastic quadriparesis, and pseudobulbar syndrome. MRI showed progressive cortical and subcortical diffuse white matter abnormalities suggesting cavitating white matter degeneration. The patient's mother developed progressive ataxia at age 38, suffered a fall with head trauma, and subsequently died. Neuropathologic examination showed grayish, gelatinous, and precavitary changes in the white matter; U fibers and part of the optic radiations were unaffected. Myelin stains showed a severe depletion of myelin sheaths with spongiform changes and precavitary appearance in the most affected areas. There was a preservation of oligodendrocytes with abundant foamy cytoplasm and decreased numbers of astrocytes, although those that remained showed highly reactive features. Although Labauge et al. (2005) concluded that the phenotype was consistent with VWM disease, genetic analysis of the proband excluded mutations in the EIF2B genes (see, e.g., EIF2B1; 606686).

Ptacek et al. (2006) suggested that the mother and son reported by Labauge et al. (2005) had ADLD. They suggested that the acute episodes of brain dysfunction after mild insults may represent uncovering of compromised nervous system function. In a response to Ptacek et al. (2006), Labauge et al. (2006) stated that their patients lacked early autonomic features characteristic of ADLD and that acute neurologic deterioration observed in their patients had not been described in ADLD, but noted that overlap exists among various leukodystrophies.

Brussino et al. (2009) reported a 3-generation Italian family with ADLD that was confirmed genetically in 2 affected individuals. These 2 patients presented as adults with autonomic dysfunction, including micturition defects and impotence. The disorder progressed to involve walking difficulties; 1 patient became wheelchair-bound. Brain MRI of both patients showed diffuse subcortical infra- and supratentorial white matter abnormalities with sparing of the U-fibers and optic radiations. Genetic analysis identified a heterozygous 140- to 190-kb duplication of a region including the LMNB1 gene as well as neighboring sequences. There was a positive family history of a similar neurodegenerative disorder.

Sundblom et al. (2009) reported 2 unrelated Swedish families with ADLD. Twelve individuals examined, including 11 patients and 1 asymptomatic individual, were found to have a thin spinal cord on MRI. There was also a slight general white matter signal intensity increase in the whole spinal cord, mainly visible in T2-weighted transverse images. Postmortem examination of 1 patient showed discrete demyelination in the spinal cord.

Schuster et al. (2011) reported 4 unrelated families with ADLD. Two families were of Swedish origin and had previously been reported (Sundblom et al., 2009). The other 2 families were of German and Israeli-Arab descent, respectively. One of the Swedish families had 31 affected individuals spanning at least 4 generations. Disease onset occurred in the fifth or sixth decade. Autonomic symptoms included urinary bladder symptoms, constipation, postural hypotension, erectile dysfunction, and heat intolerance. Affected individuals later developed ataxia and pyramidal signs. Some patients showed cognitive decline. Brain MRI showed signs characteristic of this type of leukodystrophy.

Dos Santos et al. (2012) reported a 3-generation family in Germany with ADLD. The proband presented at age 47 with a 2-year history of urinary difficulties, personality changes, and depression. He was found to have gait and limb ataxia, spastic paraparesis, hyperreflexia, and extensor plantar responses. Brain MRI showed extensive T2-weighted hyperintense lesions in the subcortical and deep cerebral white matter with relative sparing of the periventricular rim and corpus callosum. Other affected brain regions included the middle cerebellar peduncles, the pyramidal tracts, medial lemniscus in the midbrain, pons, medulla, and the decussation of the superior cerebellar peduncles. Family history revealed numerous affected members in an autosomal dominant pattern. The patient's 44-year-old sister was clinically asymptomatic, but her cerebral MRI showed extensive bilateral signal hyperintensities in the subcortical and deep cerebral white matter and in the middle cerebellar peduncles.

Flanagan et al. (2013) reported a 63-year-old man with genetically confirmed ADLD who presented with REM sleep behavior disorder (RBD) characterized by dream enactment behavior up to 3 times per week for the previous 4 years. During the episodes, he would scream, shout, flail his arms, and kick his legs. Polysomnography showed markedly increased muscle tone during REM sleep. Additional neurologic features included left-sided spasticity and cerebellar signs, hyperreflexia, and rare bowel incontinence. Brain MRI showed cervical spinal cord atrophy and T2-weighted hyperintense lesions in the brainstem, cerebellar peduncles, and subcortical white matter. Flanagan et al. (2013) postulated that damage to the myelinated axons from the subceruleus nucleus and adjacent areas to alpha-motor neurons may have impaired normal motor inhibition during REM sleep.

Clinical Variability

Quattrocolo et al. (1997) reported a large multigenerational family from northern Italy with adult-onset leukoencephalopathy. Patients presented in the fifth decade with insidious and variable symptoms, including gait impairment, pyramidal signs, lower limb weakness/paraplegia, action tremor, dysarthria, and dysphagia. The full clinical picture included spastic quadriparesis, pseudobulbar dysfunction, and urinary incontinence. Cognition was mostly spared. Brain imaging showed marked atrophy of the cerebral cortex and white matter signal abnormalities in the cortex and brainstem, with sparing of the cerebellum. Brussino et al. (2010) reported follow-up of the Italian family (ADLD-1-TO) reported by Quattrocolo et al. (1997), noting that the disorder had some distinguishing features from classic ADLD in that the Italian family lacked autonomic involvement and had sparing of the cerebellar white matter on brain imaging. Linkage analysis showed significant linkage to a region on chromosome 5q23 that included the LMNB1 gene (Zmax of 6.83 at marker D5S2955), but no point mutations or copy number defects were detected in LMNB1. Patient-derived lymphoblasts showed increased LMNB1 expression, consistent with a diagnosis of ADLD. Giorgio et al. (2015) reported follow-up of family ADLD-1-TO. Postmortem examination of an affected individual showed overexpression of LMNB1 in the cortical frontal lobe. Patient fibroblasts showed accumulation of LMNB1 within the nuclear lamina, abnormal nuclear morphology, and a 44% increase in nuclear rigidity compared to controls. Genetic analysis identified a deletion upstream of the LMNB1 gene that affected gene expression via an enhancer adoption mechanism (see CYTOGENETICS).

Inheritance

The transmission pattern of ADLD in the 4 unrelated families reported by Schuster et al. (2011) was consistent with autosomal dominant inheritance.

Diagnosis

Schuster et al. (2011) found about a 2-fold increased level of LMNB1 protein in white blood cells from 5 patients with genetically confirmed ADLD. LMNB1 mRNA was also increased compared to controls. Schuster et al. (2011) concluded that an accurate molecular diagnosis of the disorder could be made by direct analysis of LMNB1 in peripheral leukocytes.

Mapping

Coffeen et al. (2000) reported additional clinical, neuroradiologic, and neuropathologic data from the family with autosomal dominant leukodystrophy originally reported by Eldridge et al. (1984). Furthermore, they localized the ADLD gene 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.

Molecular Genetics

Padiath et al. (2006) found duplication of the LMNB1 gene (150340.0001) as the cause of ADLD in affected members of 4 families. One of these was the family described by Eldridge et al. (1984); haplotype analysis suggested that this family and a second Irish-American family shared a common founder. Lamin B1 was found to be overexpressed in brain tissue from affected individuals. 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. The clinical similarity of ADLD to multiple sclerosis and the identification of autoantibodies to lamin B suggested to Padiath et al. (2006) that a closer examination of the involvement of lamin B in multiple sclerosis is warranted.

Brussino et al. (2009) found a 140- to 190-kb duplication of 5q including the entire LMNB1 gene, the AX748201 transcript, and the 3-prime end of the MARCH3 gene (613333) in 1 of 8 Italian probands with adult-onset leukoencephalopathy. The patient's affected cousin also carried the duplication, and there was a family history of a similar disorder. Lamin B1 expression was increased in lymphoblasts from one of the patients with the duplication.

In affected members of 4 unrelated families with ADLD, Schuster et al. (2011) found duplication of the LMNB1 gene. All 4 duplications were of different sizes, ranging from 107 to 218 kb, supporting independent events. Each duplication extended over part of the MARCH3 gene, but MARCH3 mRNA was not increased in patient leukocytes.

In a symptomatic man with ADLD and his asymptomatic sister who had leukodystrophy on brain imaging, Dos Santos et al. (2012) identified a 148-kb duplication on chromosome 5q23.2 including the LMNB1 gene, but not the MARCH3 gene. The findings confirmed the central role of the LMNB1 gene in ADLD.

Using a custom array, Giorgio et al. (2013) performed detailed breakpoint junction sequence analysis of the duplicated 5q23 region containing the LMNB1 gene in 20 independent families with ADLD in whom genomic LMNB1 duplication was initially identified by aCGH, QT-PCR, or MLPA. Seven families had previously been reported (Brussino et al., 2009; Schuster et al., 2011; Dos Santos et al., 2012). There were a total of 16 unique rearrangements. Three of the duplications were shared by more than 1 family: 1 was found in 3 families and the other 2 duplications were found in 2 families each. Individuals with identical junctions shared the same haplotype, consistent with a founder effect. Duplication sizes ranged from about 128 kb to 475 kb. The largest duplication also included the PHAX (604924), ALDH7A1 (107323), and GRAMD3 genes. Comparison of all the samples identified a 72-kb minimal critical duplicated region required for ADLD that contained only the LMNB1 gene. All but 1 of the duplications were in the direct tandem orientation; the remaining duplication was inverted. Characterization of the junction sequences showed that most (11 of 15) showed short stretches of microhomology overlap ranging from 1 to 6 nucleotides, whereas the others showed small insertions at the breakpoints. All duplications resulted from intrachromosomal rearrangements. Analysis of the genomic architecture suggested several potential mechanisms for the duplications, including nonhomologous end joining (NHEJ) or fork stalling and template switching/microhomology-mediated break-induced repair (FoSTeS/MMBIR). The enrichment of Alu repetitive elements at the centromeric breakpoints (found in 4 cases), higher GC content, and high frequency of repetitive sequences at breakpoints likely also played a role in mediating ADLD duplications. RT-PCR of patients fibroblasts or blood showed increased LMNB1 expression (2.1- to 4.8-fold compared to controls), as well as increased protein levels (1.6- to 3.2-fold compared to controls). There was no apparent difference in phenotype according to duplication size, with the exception of the 1 family with a large inverted duplication affecting multiple genes.

Cytogenetics

Using custom array CGH to analyze affected members of the Italian family (ADLD-1-TO) with a variant form of ADLD described by Brussino et al. (2010), Giorgio et al. (2015) identified a heterozygous 660-kb deletion on chromosome 5q23 that included 3 genes: PHAX (604924), ALDH7A1 (107323), and GRAMD3, with the closest deletion boundary located 66 kb upstream of the LMNB1 gene. The deletion was not present in the Database of Genomic Variants or in 100 Italian control individuals. Analysis of the breakpoint regions suggested that the deletion was mediated by Alu elements. In vitro studies showed that single-copy loss of the PHAX, ALDH7A1, and GRAMD3 genes did not affect LMNB1 expression, and deletion of these genes was considered unlikely to contribute to disease pathogenesis. A circular chromosome conformation capture (4C) analysis and expression studies in patient fibroblasts showed that the deletion resulted in repositioning of a forebrain-specific enhancer element closer to the LMNB1 promoter ('enhancer adoption'). The findings were consistent with the mainly cerebral localization of LMNB1 overexpression and myelin degeneration in affected members of this family.