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Inheritance

1

Autosomal dominant inheritance HP:0000006

Heterozygous LMNB1 gain-of-expression structural variants segregate in an autosomal dominant pattern.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:26053668 SUPPORT Human Clinical

"Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia."

The longitudinal family study directly identifies the autosomal-dominant disease pattern.

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Subtypes

2

Atypical ADLD (LMNB1 upstream deletion) MONDO:0700286

LMNB1 hgnc:6637 Autosomal dominant inheritance

A regulatory structural-variant subtype in which heterozygous upstream deletion removes a topological boundary and drives LMNB1 enhancer adoption without whole-gene duplication. OMIM separates this as ADLDAT, and MONDO as the "atypical" child term, because the clinical picture diverges from the duplication form: onset is earlier, speech symptoms rather than dysautonomia dominate the presentation, early autonomic involvement is absent, and cerebellar and spinal-cord involvement is comparatively limited. It remains a subtype rather than a separate disease entry because both routes converge on the same proximal driver, LMNB1 overexpression.

Show evidence (5 references)

PMID:25701871 SUPPORT Human Clinical

"This second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes."

Supports upstream regulatory deletion and enhancer adoption as a distinct molecular route to ADLD.

PMID:30842973 SUPPORT Human Clinical

"Although clinical and radiologic features overlapped with those of autosomal dominant leukodystrophy because of LMNB1 duplications, patients with deletions upstream of LMNB1 had an earlier age at symptom onset, lacked early dysautonomia, and appeared to have lesser involvement of the cerebellum..."

This is the defining clinical and radiologic contrast that separates the atypical upstream-deletion form from the typical duplication form.

PMID:30842973 SUPPORT Human Clinical

"Patients had unique nonrecurrent deletions upstream of the LMNB1, varying in size from 250 kb to 670 kb."

Establishes that the causative alleles are nonrecurrent structural variants of variable size, not a single recurrent rearrangement.

+ 2 more references

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Discussions and Knowledge Gaps

2

Is the absence of early dysautonomia in upstream-deletion (atypical) ADLD caused by the sparing of the spinal cord below the uppermost cervical level, and if so why does the same LMNB1 overexpression spare the cord in deletion carriers but not in duplication carriers?

KNOWLEDGE GAP OPEN gap_adld_deletion_dysautonomia_spinal_cord

Attached to

pathophysiology#Enhancer Adoption From Upstream Deletion pathophysiology#Autonomic-System Involvement (Mechanism Unresolved)

The two OMIM criteria that separate atypical from typical ADLD, lack of early autonomic involvement and relative sparing of cerebellum and spinal cord, are the same fact seen clinically and radiologically if the dysautonomia of ADLD is cord-derived. The deletion cohort authors advance exactly that reading, but they label it a hypothesis, and it rests on spinal MRI from only two deletion carriers. It also leaves the harder question untouched: both routes raise LMNB1, so an anatomically selective difference in outcome implies a difference in where or how much the gene is de-repressed that the enhancer-adoption and silencer-loss models do not yet specify.

Proposed experiments

Prospective spinal-cord imaging and autonomic testing across ADLD genotypes

Genotype-stratified prospective imaging and autonomic phenotyping study

exp_adld_deletion_cord_autonomic_correlation

Enroll genotyped ADLD duplication and upstream-deletion carriers, including presymptomatic relatives, and pair quantitative cervical and thoracic spinal-cord cross-sectional-area measurement with the standard autonomic battery, tilt table, QSART, and urodynamics, at matched ages. A cord-derived dysautonomia model predicts that autonomic deficit tracks cord atrophy within and across genotypes; a genotype effect that survives adjustment for cord atrophy would refute it.

Show evidence (2 references)

PMID:30842973 SUPPORT Human Clinical

"This difference could explain the lack of early autonomic symptoms in patients with deletions, as it has been hypothesized that autonomic symptoms in ADLD with duplications are due to spinal cord involvement."

The authors present the cord-sparing explanation explicitly as a hypothesis built on a prior hypothesis, not as an established mechanism.

PMID:30697589 SUPPORT Human Clinical

"The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion."

A second deletion family shows cerebellar involvement, so the cerebellar-sparing half of the atypical definition is not consistent across the reported families and the phenotype-to-anatomy mapping is unsettled.

Which oligodendrocyte, astrocyte, and axon-myelin-unit abnormalities caused by LMNB1 overexpression are causal in human ADLD, and what mechanism produces the early autonomic phenotype that current mouse models lack?

HUMAN MODEL MISMATCH OPEN gap_adld_model_to_human_cellular_mechanism

Attached to

pathophysiology#RAVER2/PTB-Dependent PLP1 Spliceopathy pathophysiology#Oligodendrocyte Lipid and Myelin Program Dysfunction pathophysiology#Astrocyte LIF-Support Dysfunction pathophysiology#Axon-Myelin Unit Injury pathophysiology#Autonomic-System Involvement (Mechanism Unresolved)

Available mouse and cultured-cell models yield conflicting cell-type results and do not reproduce the early autonomic manifestations seen in patients. This mismatch prevents any one glial or axonal branch from being asserted as the established human bridge from LMNB1 overexpression to demyelination.

Proposed experiments

Patient-derived isogenic glial and neuronal co-culture study

Isogenic patient-derived iPSC co-culture perturbation study

exp_adld_patient_derived_glial_coculture

Compare LMNB1-duplication and corrected isogenic iPSC-derived astrocytes, oligodendrocytes, and neurons in co-culture, measuring LIF signaling, RAVER2/PTB-dependent PLP1 splicing, myelin-lipid programs, axon-myelin integrity, and rescue after LMNB1 normalization to distinguish primary from secondary cellular effects.

Show evidence (1 reference)

PMID:37450245 SUPPORT Other

"Indeed, neither of the two in vivo models is able to fully recapitulate the clinical phenotype observed in ADLD patients, since they do not display the autonomic symptoms that are characteristic of ADLD initial stages [36]."

The review explicitly documents the model-to-human autonomic mismatch.

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Pathophysiology

11

LMNB1 Overexpression

Whole-gene duplication or upstream regulatory deletion increases LMNB1 expression, establishing lamin B1 excess as the proximal molecular driver.

LMNB1 hgnc:6637

Downstream

Nuclear Lamina and Chromatin Perturbation Lamin B1 excess perturbs inner-nuclear-membrane proteins, chromatin organization, and cellular physiology.

RAVER2/PTB-Dependent PLP1 Spliceopathy Patient-derived fibroblast and blood-cell studies link LMNB1 excess to RAVER2 upregulation and abnormal splicing of PTB targets including PLP1.

Oligodendrocyte Lipid and Myelin Program Dysfunction Model systems link LMNB1 overexpression to reduced myelin-lipid synthesis and altered oligodendrocyte differentiation.

Astrocyte LIF-Support Dysfunction In-vitro astrocyte models suggest that LMNB1 overexpression reduces trophic support for myelinating oligodendrocytes.

Axon-Myelin Unit Injury Transgenic and neuronal models associate LMNB1 overexpression with axonal shortening, disintegration, and axon-myelin-unit degradation.

Central Nervous System Demyelination LMNB1 overexpression causes CNS demyelination, while the intervening human cellular mechanism remains unresolved.

Show evidence (2 references)

PMID:28769756 SUPPORT Human Clinical

"Duplication or over expression of the lamin B1 (LMNB1) gene causes ADLD."

The family study directly links LMNB1 duplication/overexpression with adult-onset autosomal dominant leukodystrophy.

PMID:25701871 SUPPORT Human Clinical

"Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination."

The structural-variant study supports LMNB1 overexpression as the shared mechanism driving progressive CNS demyelination.

Enhancer Adoption From Upstream Deletion

Some families lack an LMNB1 coding duplication and instead have upstream deletions that disrupt regulatory boundaries, allowing ectopic enhancer activity to increase LMNB1 expression. This is the causal lesion of the atypical subtype recognized as MONDO:0700286 / OMIM ADLDAT. The deletions are nonrecurrent and vary in size, but comparison across families defines a shared minimal critical region spanning a topologically associating domain boundary.

LMNB1 hgnc:6637

Downstream

LMNB1 Overexpression Enhancer adoption increases LMNB1 promoter activity and converges on lamin B1 overexpression.

Loss of the Oligodendrocyte-Specific LMNB1 Silencer Element The deleted interval contains a CTCF-based silencer element, so the upstream deletion removes the repressor outright rather than merely exposing the promoter to foreign enhancers.

Show evidence (3 references)

PMID:25701871 SUPPORT Human Clinical

"The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration."

This supports a noncoding structural variant mechanism that converges on LMNB1 overexpression.

PMID:30842973 SUPPORT Human Clinical

"Strikingly, this genomic region encompassed a boundary between 2 topologically associated domains (TADs) and strengthens our original hypothesis that a disruption of the TAD boundary causes LMNB1 overexpression and in turn the disease."

Cross-family mapping localizes the shared critical region to a TAD boundary, supporting boundary disruption as the operative lesion.

PMID:30842973 SUPPORT Human Clinical

"Sequencing the deletion junctions revealed the importance of repetitive elements (Alu, LINEs) in the genomic rearrangement."

Identifies repeat-mediated rearrangement as the origin of the nonrecurrent deletions, explaining why each family carries a private allele.

Loss of the Oligodendrocyte-Specific LMNB1 Silencer Element

A CTCF-based silencer element upstream of LMNB1 normally holds lamin B1 expression low specifically in oligodendrocytes, acting through three-dimensional chromatin looping and recruitment of the PRC2 repressor complex. Both ADLD routes remove that repression: the upstream deletion deletes the element, while a tandem duplication places an extra LMNB1 copy outside its control. This node is what makes the two molecular subtypes one disease, and it supplies the otherwise unexplained oligodendrocyte specificity of a phenotype caused by a ubiquitously expressed gene. The evidence is CRISPR-edited cell lines and mouse models plus human genotype comparison, not direct human CNS measurement.

LMNB1 hgnc:6637 CTCF hgnc:13723

negative regulation of transcription by RNA polymerase II GO:0000122 ↓ DECREASED chromatin looping GO:0140588 ⚠ ABNORMAL

Downstream

LMNB1 Overexpression Escape from silencer-mediated repression de-represses LMNB1 in oligodendrocytes, the cell type whose vulnerability defines the disease.

Show evidence (3 references)

PMID:39910058 SUPPORT In Vitro

"we have identified a silencer element that is lost in ADLD patients and that specifically targets expression to oligodendrocytes"

Establishes the silencer element and its oligodendrocyte-restricted action.

PMID:39910058 SUPPORT In Vitro

"This element consists of CTCF binding sites that mediate three-dimensional chromatin looping involving LMNB1 and the recruitment of the PRC2 transcriptional repressor complex."

Specifies the molecular composition and repressive mechanism of the element.

PMID:39910058 SUPPORT In Vitro

"The loss of this silencer element in ADLD provides a parsimonious mechanism explaining tissue specificity and how both duplication and upstream deletion can lead to lamin B1 overexpression"

Supports the unifying claim that silencer escape, not the structural variant class, is the shared proximal mechanism.

Nuclear Lamina and Chromatin Perturbation

Experimental models show cell-type-dependent nuclear and chromatin changes after LMNB1 overexpression. This node records a proximal effect without making it an oligodendrocyte-only causal bridge to human demyelination.

chromatin organization GO:0006325 ⚠ ABNORMAL

Show evidence (2 references)

PMID:37450245 SUPPORT Other

"LMNB1 encodes for Lamin B1, a protein of the nuclear lamina. Lamin B1 regulates many cellular processes such as DNA replication, chromatin organization, and senescence."

Supports nuclear-lamina and chromatin organization disruption as a proximal molecular consequence of LMNB1 overexpression.

PMID:37450245 SUPPORT Other

"Nevertheless, Lamin B1 together with the other lamins that constitute the nuclear lamina has firstly the key role of maintaining the nuclear structure."

Supports nuclear structural homeostasis as a relevant lamin B1-dependent process.

RAVER2/PTB-Dependent PLP1 Spliceopathy

LMNB1-dependent RAVER2 upregulation inhibits PTB splicing regulation and produces an abnormal splicing pattern that includes the major myelin gene PLP1. This patient-cell branch is plausible but has not been established as the causal bridge in human CNS tissue.

RAVER2 hgnc:25577 PTBP1 hgnc:9583 PLP1 hgnc:9086

RNA splicing GO:0008380 ⚠ ABNORMAL

Downstream

Central Nervous System Demyelination PLP1 splice dysregulation is a candidate contributor to demyelination, with its CNS cell-type context and downstream intermediates unresolved.

Show evidence (1 reference)

PMID:37450245 SUPPORT In Vitro

"an abnormal splicing pattern of several PTB-target genes, including the PLP1 gene"

Patient fibroblast and blood-cell studies support abnormal splicing of PTB targets including PLP1, but do not establish the effect in human CNS tissue.

Oligodendrocyte Lipid and Myelin Program Dysfunction

Mouse and cell models report reduced myelin-lipid synthesis, altered myelin gene expression, and impaired differentiation, but the oligodendrocyte findings are conflicting and are not treated as the sole human mechanism.

oligodendrocyte CL:0000128

myelination GO:0042552 ↓ DECREASED

Downstream

Central Nervous System Demyelination Oligodendrocyte model abnormalities are a candidate contributor to progressive CNS demyelination.

Show evidence (1 reference)

PMID:37450245 SUPPORT Model Organism

"revealing a significant reduction in myelin lipids in trans- genic mice compared to wild-type animals"

Model evidence supports altered lipid synthesis but does not establish the complete human pathway.

Astrocyte LIF-Support Dysfunction

Astrocyte models show reduced LIF/LIF-receptor signaling, viability changes, and reactive morphology. These findings suggest reduced support of myelinating oligodendrocytes but require confirmation in patient brain tissue.

astrocyte CL:0000127

Downstream

Central Nervous System Demyelination Reduced astrocyte trophic support is a candidate contributor to demyelination rather than an established human causal route.

Show evidence (1 reference)

PMID:37450245 SUPPORT In Vitro

"Cells displayed altered morphology, aberrant cellular signaling, reduced viability, and induction of reactivity"

The review characterizes the astrocyte branch as a model-derived candidate mechanism.

Axon-Myelin Unit Injury

Neuronal and transgenic models show axonal shortening, axonal disintegration, and degradation of the axon-myelin unit; whether this branch is primary in human ADLD is unresolved.

neuron CL:0000540

Downstream

Central Nervous System Demyelination Axon-myelin-unit injury may converge with glial abnormalities on the human demyelinating phenotype.

Show evidence (1 reference)

PMID:37450245 SUPPORT Model Organism

"LMNB1 transient overexpression in primary mouse cortical neurons resulted in a significant reduction in axonal length, while dendritic trees seemed to not be affected [43]."

This supports an axonal model phenotype without establishing its role in human disease.

Central Nervous System Demyelination

Progressive central nervous system demyelination and white matter loss are the downstream tissue-level outputs of LMNB1 overexpression.

myelination GO:0042552 ↓ DECREASED

Downstream

Leukodystrophy Progressive CNS demyelination is the defining leukodystrophy substrate.

Pyramidal and Cerebellar Tract Dysfunction White-matter and spinal-cord involvement is associated with pyramidal and cerebellar dysfunction.

Cognitive Impairment Cognitive difficulties co-occur with diffuse ADLD white-matter disease, but the causal route is not resolved.

Fatigue Fatigue is associated with ADLD; a direct demyelination mechanism has not been demonstrated.

Sleep Disturbance Sleep disturbance is associated with ADLD; its mechanistic relation to demyelination is unresolved.

Mood Disturbance Mood disturbance is associated with ADLD; its mechanistic relation to demyelination is unresolved.

Tremor Tremor is associated with ADLD; its direct causal path is unresolved.

Migraine Migraine is associated with ADLD; its direct causal path is unresolved.

Show evidence (2 references)

PMID:25701871 SUPPORT Human Clinical

"overexpression of LMNB1 causes progressive central nervous system demyelination."

Directly links LMNB1 overexpression to progressive CNS demyelination.

PMID:28769756 SUPPORT Human Clinical

"Autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) is a very rare neurological disorder featured with late onset, slowly progressive central nervous system demyelination."

Supports slowly progressive CNS demyelination as the defining downstream phenotype.

Autonomic-System Involvement (Mechanism Unresolved)

Autonomic dysfunction is often the first clinical manifestation. Because affected noradrenergic pathways include non-myelinated fibers, the causal route is not represented as a direct consequence of demyelination.

Downstream

Autonomic Dysfunction Unresolved LMNB1-related autonomic-system involvement manifests clinically as autonomic dysfunction.

Show evidence (1 reference)

PMID:26053668 SUPPORT Human Clinical

"Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia."

The longitudinal cohort supports an autonomic-to-pyramidal/cerebellar clinical sequence downstream of LMNB1-related demyelinating disease.

Pyramidal and Cerebellar Tract Dysfunction

Longitudinal human observations associate white-matter and spinal-cord involvement with progressive pyramidal and cerebellar signs.

Downstream

Spasticity Pyramidal and spinal-cord dysfunction is associated with progressive spasticity.

Ataxia Cerebellar-system dysfunction is associated with ataxia.

Show evidence (1 reference)

PMID:26053668 SUPPORT Human Clinical

"Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia."

The longitudinal cohort establishes the ordered pyramidal and cerebellar clinical involvement.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

14

Limbs 1

Limb Muscle Weakness HP:0003690

Show evidence (1 reference)

PMID:30842973 SUPPORT Human Clinical

"Five patients from 3 independent families presented at ages ranging from 32 to 52 years with neurologic symptoms that included progressive hypophonia, upper and lower limb weakness and spasticity, and cerebellar dysfunction and MRIs characterized by widespread white matter alterations."

Describes the presenting neurologic syndrome of the deletion cohort, including limb weakness.

Musculoskeletal 1

Spasticity HP:0001257

Show evidence (1 reference)

PMID:26053668 SUPPORT Human Clinical

"Motor signs developed ascending from spastic paraplegia to tetraplegia and pseudobulbar palsy in the seventh decade."

The longitudinal cohort supports spastic motor involvement during progression.

Nervous System 9

Leukodystrophy HP:0002415

Show evidence (1 reference)

PMID:28769756 SUPPORT Human Clinical

"Autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) is a very rare neurological disorder featured with late onset, slowly progressive central nervous system demyelination."

This describes the defining adult-onset leukodystrophy phenotype and progressive CNS demyelination.

Ataxia HP:0001251

Show evidence (1 reference)

PMID:26053668 SUPPORT Human Clinical

"Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia."

The longitudinal study identifies ataxia as a later motor feature after autonomic symptoms.

Autonomic Dysfunction Abnormal autonomic nervous system physiology HP:0012332

Show evidence (1 reference)

PMID:26053668 SUPPORT Human Clinical

"Autonomic dysfunction appeared in the fifth to sixth decade, preceding or together with gait and coordination difficulties."

The longitudinal cohort supports autonomic dysfunction as an early clinical feature.

Cognitive Impairment VERY_FREQUENT HP:0100543

Show evidence (1 reference)

DOI:10.1007/s44162-024-00055-w SUPPORT Human Clinical

"Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."

Supports cognitive impairment as very frequent in the eight-patient Mayo Clinic cohort.

Sleep Disturbance FREQUENT HP:0002360

Show evidence (1 reference)

DOI:10.1007/s44162-024-00055-w SUPPORT Human Clinical

"Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."

Supports sleep disturbance in half of the eight-patient Mayo Clinic cohort.

Tremor FREQUENT HP:0001337

Show evidence (1 reference)

DOI:10.1007/s44162-024-00055-w SUPPORT Human Clinical

"Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."

Supports tremor in half of the eight-patient Mayo Clinic cohort.

Migraine FREQUENT HP:0002076

Show evidence (1 reference)

DOI:10.1007/s44162-024-00055-w SUPPORT Human Clinical

"Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."

Supports migraine in half of the eight-patient Mayo Clinic cohort.

Dysarthria HP:0001260

Show evidence (1 reference)

PMID:30842973 SUPPORT Human Clinical

"Clinically, 4/5 patients presented at onset with speech symptoms including dysarthria and hypophonia."

Four of five deletion-carrier patients presented with dysarthria.

Absence of Early Autonomic Involvement EXCLUDED Abnormal autonomic nervous system physiology HP:0012332

∅ ABSENT

The absence is carried by `frequency: EXCLUDED`, which is what the HPOA exporter reads to emit a NOT-qualified row; `modifier: ABSENT` alone is not consulted by the export layer and documents intent only. Without EXCLUDED this block exported as a POSITIVE assertion that ADLD features abnormal autonomic physiology, cited to the two papers stating the opposite. `temporality: CHRONIC` was removed: it contradicts a claim about EARLY absence, and the cited evidence describes autonomic features as late when they appear at all.

Show evidence (2 references)

PMID:30842973 SUPPORT Human Clinical

"Of note, early involvement of the autonomic nervous system was notable in only 1 patient with orthostatic intolerance and urinary urgency. In 2 patients, urinary urgency and incontinence were late features of the disorder, occurring only after development of severe lower limb spasticity."

Documents that autonomic involvement is uncommon at onset and, when present, is a late feature in the deletion cohort.

PMID:30697589 SUPPORT Human Clinical

"Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication."

An independent family confirms the reduced autonomic burden relative to duplication carriers.

Constitutional 1

Fatigue VERY_FREQUENT HP:0012378

Show evidence (1 reference)

DOI:10.1007/s44162-024-00055-w SUPPORT Human Clinical

"Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."

Supports fatigue as frequent in the eight-patient Mayo Clinic cohort.

Other 2

Mood Disturbance FREQUENT Abnormal emotional state HP:0100851

Show evidence (1 reference)

DOI:10.1007/s44162-024-00055-w SUPPORT Human Clinical

"Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."

The cohort reports mood disturbances in most patients and the broader HPO emotional-state term avoids over-specifying those findings as depression.

Hypophonia at Presentation Weak voice HP:0001621

Show evidence (1 reference)

PMID:30842973 SUPPORT Human Clinical

"Clinically, 4/5 patients presented at onset with speech symptoms including dysarthria and hypophonia. This has not been reported for ADLD with LMNB1 duplications, where the most common presenting feature was autonomic dysfunction."

Directly contrasts the presenting symptom of the deletion cohort with the duplication form, supporting hypophonia as a subtype-distinguishing feature.

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Genetic Associations

2

LMNB1 (Causative)

Gene: LMNB1 hgnc:6637

Autosomal dominant inheritance

Show evidence (2 references)

PMID:28769756 SUPPORT Human Clinical

"However, Multiplex ligand-dependent probe amplification (MLPA) showed whole duplication of LMNB1 gene which is co-segregated with the disease phenotype in this family."

The family study supports LMNB1 duplication as a causative structural variant.

PMID:40046440 SUPPORT Human Clinical

"Currently, two genetic alterations have been identified in association with the pathogenesis of ADLD: LMNB1 gene tandem duplication and LMNB1 gene upstream deletions."

Supports the two major LMNB1 gain-of-expression structural variant classes represented in this entry.

LMNB1 upstream regulatory deletion (Causative)

Gene: LMNB1 hgnc:6637 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:30842973 SUPPORT Human Clinical

"Patients had unique nonrecurrent deletions upstream of the LMNB1, varying in size from 250 kb to 670 kb."

Defines the size range and nonrecurrent character of the causative alleles.

PMID:30697589 SUPPORT Human Clinical

"We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1."

An independent family carrying a deletion at the small end of the reported size range.

PMID:30842973 SUPPORT Human Clinical

"Given that these mutations do not alter the coding sequence, our data also emphasize the importance of regulatory elements and the need for performing analyses for copy number variants that might be missed with the standard whole-exome sequencing, currently being used to identify mutations in..."

States the diagnostic consequence of the lesion being noncoding, which is why exome sequencing is not an adequate first-tier test here.

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External Assertions

2

OMIM adult-onset autosomal dominant leukodystrophy record

OMIM disease record OMIM:169500

OMIM disease identifier for the typical (LMNB1 duplication) form of adult-onset autosomal dominant demyelinating leukodystrophy, ADLDTY.

OMIM atypical adult-onset autosomal dominant leukodystrophy record

OMIM disease record OMIM:621061

OMIM disease identifier for the atypical form, ADLDAT, caused by heterozygous deletion upstream of LMNB1 rather than whole-gene duplication. This is the entity carried by MONDO:0700286, curated here as the Upstream Deletion-Related ADLD subtype rather than as a separate disease entry because the two forms converge on the same LMNB1 gain-of-expression mechanism.

💊

Medical Actions

3

Symptom-Directed Supportive Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Management is supportive and symptom-directed, with attention to autonomic dysfunction, spasticity, mobility decline, fatigue, and cognitive or mood symptoms while disease-targeted therapy remains investigational.

Target Phenotypes: Autonomic dysfunction HP:0012332 Spasticity HP:0001257 Fatigue HP:0012378

Show evidence (3 references)

DOI:10.1007/s44162-024-00055-w SUPPORT Human Clinical

"Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."

Supports the clinical symptom targets for supportive management in the Mayo Clinic cohort.

PMID:37564735 SUPPORT Other

"Comprehensive evaluation and molecular confirmation when available helps in prognostication, early initiation of treatment in certain disorders, enrollment in clinical trials, and provides valuable information for the family for reproductive counseling."

Supports anticipatory management, treatment consideration when available, trial enrollment, and family counseling in adult-onset leukodystrophy care.

PMID:26749591 SUPPORT Human Clinical

"Treatment is symptomatic."

GeneReviews confirms that current management is symptom-directed.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Genetic counseling is appropriate after molecular confirmation because the disease is autosomal dominant and familial risk and reproductive decisions are central to care.

Show evidence (2 references)

PMID:37564735 SUPPORT Other

"Comprehensive evaluation and molecular confirmation when available helps in prognostication, early initiation of treatment in certain disorders, enrollment in clinical trials, and provides valuable information for the family for reproductive counseling."

Supports genetic and reproductive counseling after molecular diagnosis in adult-onset leukodystrophies.

PMID:26749591 SUPPORT Human Clinical

"Each child of an individual with LMNB1-related ADLD has a 50% chance of inheriting the LMNB1 duplication (or deletion upstream of LMNB1)."

GeneReviews supplies the recurrence risk used in family counseling.

Allele-Specific RNA Interference

Category: Therapeutic Action: RNA interference therapy Ontology label: Pharmacotherapy NCIT:C15986

LMNB1-lowering RNA interference is a preclinical disease-targeted strategy intended to reduce excess LMNB1 expression while avoiding excessive suppression of the normal allele.

Mechanism Target:

INHIBITS LMNB1 Overexpression — Allele-selective siRNA lowers the duplicated LMNB1 transcript and restores LMNB1 mRNA and protein toward control levels.

Show evidence (1 reference)

PMID:31143934 SUPPORT In Vitro

"Three of the small interfering RNAs were highly selective for the target allele and restored both LMNB1 mRNA and protein levels close to control levels."

The in-vitro study directly demonstrates the intended LMNB1-lowering target effect.

Show evidence (1 reference)

PMID:31143934 SUPPORT In Vitro

"Three of the small interfering RNAs were highly selective for the target allele and restored both LMNB1 mRNA and protein levels close to control levels."

This supports a mechanistically targeted but preclinical RNAi approach in patient-derived and disease-relevant cellular models.

🔬

Diagnosis

2

LMNB1 Copy-Number Testing

Targeted LMNB1 deletion/duplication analysis, MLPA, array-CGH, or other validated copy-number methods are needed when the phenotype and MRI pattern suggest LMNB1-related ADLD.

genetic testing NCIT:C15709

Results: Heterozygous LMNB1 duplication or an upstream regulatory deletion supports the molecular diagnosis.

Show evidence (4 references)

PMID:28769756 SUPPORT Human Clinical

"In order to understand the genetic cause of the disease in this family, target exome capture based next generation sequencing has been done, but no causative variants or possibly pathogenic variants has been identified."

The study shows that sequence-focused testing can miss the diagnosis.

PMID:28769756 SUPPORT Human Clinical

"However, Multiplex ligand-dependent probe amplification (MLPA) showed whole duplication of LMNB1 gene which is co-segregated with the disease phenotype in this family."

MLPA copy-number testing identified the familial LMNB1 duplication after exome sequencing was unrevealing.

PMID:26749591 SUPPORT Human Clinical

"The diagnosis of LMNB1-related ADLD is established in a proband with suggestive clinical and MRI findings and either an LMNB1 duplication or (more rarely) a heterozygous deletion upstream of the LMNB1 promoter identified by molecular genetic testing."

GeneReviews defines molecular diagnosis by the characteristic clinical and MRI findings plus an LMNB1 duplication or upstream deletion.

+ 1 more reference

Characteristic Brain and Spine MRI Pattern

Brain and spine MRI can show the characteristic symmetric white-matter and spinal cord involvement that should prompt LMNB1 copy-number testing.

magnetic resonance imaging procedure NCIT:C16809

Results: Symmetric confluent T2-weighted deep cerebral and periventricular white matter hyperintensities with internal capsule, corpus callosum, brainstem corticospinal tract, cerebellar peduncle, and spinal cord atrophy patterns.

Show evidence (2 references)

DOI:10.1007/s44162-024-00055-w SUPPORT Human Clinical

"All showed symmetric confluent T2W deep cerebral and periventricular white matter hyperintensities with involvement of the posterior limb of the internal capsule, corpus callosum, corticospinal tract in brain stem, and superior and middle cerebellar peduncles."

Supports the hallmark brain MRI pattern in molecularly confirmed LMNB1-related ADLD.

DOI:10.1007/s44162-024-00055-w SUPPORT Human Clinical

"Seven spine MRIs from six patients showed moderate diffuse atrophy of the spinal cord."

Supports spinal cord atrophy as part of the MRI diagnostic pattern.

🩻

Imaging Findings

5

Symmetric confluent cerebral white-matter T2 hyperintensity

Mri Diagnostic Diffuse

Symmetric confluent cerebral white-matter abnormalities HP:0007204 brain white matter UBERON:0003544 Diffuse white matter abnormalities HP:0007204

The molecularly confirmed cohort showed a symmetric confluent deep cerebral and periventricular pattern extending through major commissural, corticospinal, brainstem, and cerebellar-peduncle white-matter tracts.

Show evidence (1 reference)

DOI:10.1007/s44162-024-00055-w SUPPORT Human Clinical

"All showed symmetric confluent T2W deep cerebral and periventricular white matter hyperintensities with involvement of the posterior limb of the internal capsule, corpus callosum, corticospinal tract in brain stem, and superior and middle cerebellar peduncles."

Seven molecularly confirmed patients showed the characteristic symmetric diffuse brain MRI pattern.

Diffuse spinal-cord atrophy on MRI

Mri Diagnostic Diffuse

Diffuse spinal-cord atrophy spinal cord UBERON:0002240

Moderate diffuse spinal-cord atrophy complements the characteristic cerebral white-matter pattern.

Show evidence (1 reference)

DOI:10.1007/s44162-024-00055-w SUPPORT Human Clinical

"Seven spine MRIs from six patients showed moderate diffuse atrophy of the spinal cord."

The molecularly confirmed cohort documents diffuse spinal-cord atrophy on MRI.

Corticospinal tract T2 hyperintensity from upper frontal lobes to cerebral peduncles

Mri Diagnostic Upstream Deletion-Related ADLD

Corticospinal tract T2 hyperintensity HP:0002500 corticospinal tract UBERON:0002707

Present in every deletion-carrier patient imaged, but unlike the duplication form it usually stops above the medulla oblongata.

Show evidence (2 references)

PMID:30842973 SUPPORT Human Clinical

"Four patients underwent brain MRI (figure 1); all had a corticospinal tract involvement extending from the upper frontal lobes to the cerebral peduncles."

Establishes the corticospinal-tract pattern and its rostral extent in the deletion cohort.

PMID:30842973 SUPPORT Human Clinical

"The corticospinal tracts were affected in both groups, but only in one of the deletion patients (DEL1-1) did this extend to the medulla oblongata."

Supports the caudal-extent contrast against duplication carriers, who show early medullary change.

Relative sparing of the spinal cord below the uppermost cervical level

Mri Diagnostic Focal Upstream Deletion-Related ADLD

Spinal cord atrophy restricted to the uppermost cervical cord spinal cord UBERON:0002240

The contrast with the diffuse whole-cord atrophy of the duplication form is the second OMIM criterion separating atypical from typical ADLD, and is the proposed anatomical explanation for the missing early dysautonomia.

Show evidence (1 reference)

PMID:30842973 SUPPORT Human Clinical

"In patients with deletions, only the uppermost cervical spinal cord was atrophic, and in the 2 patients with a spinal MRI, no obvious SI changes were found in the rest of the cord. In LMNB1 duplication patients, the entire spinal cord is atrophic, and T2 signal in white matter is pathologic."

States the imaging contrast between deletion and duplication carriers at the level of the spinal cord.

Extensive temporal-lobe white-matter involvement

Mri Upstream Deletion-Related ADLD

Temporal white-matter T2 hyperintensity HP:0002500 brain white matter UBERON:0003544

Two independent cohorts report anterior and temporal white-matter involvement as a relative feature of the upstream-deletion form.

Show evidence (2 references)

PMID:30842973 SUPPORT Human Clinical

"On MRI, cerebral white matter involvement was more extensive, especially in the temporal lobes in patients with deletions compared with those with duplications at the same ages."

Age-matched comparison supports greater temporal-lobe burden in deletion carriers.

PMID:30697589 SUPPORT Human Clinical

"Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region."

An independent Japanese family reproduces the anterior-temporal white-matter pattern.

📈

Progression

4

Presymptomatic radiologic disease

Brain and spinal-cord MRI abnormalities can precede clinical manifestations by more than a decade.

Show evidence (1 reference)

PMID:26053668 SUPPORT Human Clinical

"MRI abnormalities of the brain and spinal cord can precede clinical symptoms by more than a decade and are extensive in all symptomatic patients."

The longitudinal study documents a presymptomatic imaging phase.

Early autonomic manifestations

Age: Fifth to sixth decade

Autonomic dysfunction commonly precedes or accompanies emerging gait and coordination difficulty.

Show evidence (1 reference)

PMID:26053668 SUPPORT Human Clinical

"Autonomic dysfunction appeared in the fifth to sixth decade, preceding or together with gait and coordination difficulties."

The cohort establishes the characteristic early clinical phase and timing.

Progressive pyramidal and bulbar disability

Age: Seventh decade in the longitudinal cohort

Motor signs can ascend from spastic paraplegia to tetraplegia and pseudobulbar palsy.

Show evidence (1 reference)

PMID:26053668 SUPPORT Human Clinical

"Motor signs developed ascending from spastic paraplegia to tetraplegia and pseudobulbar palsy in the seventh decade."

The longitudinal study defines the later motor progression pattern.

Earlier onset in the upstream-deletion (atypical) subtype

Age: 32 to 52 years in the reported deletion cohort

Onset in deletion carriers can begin in the fourth decade or earlier, ahead of the fifth-to-sixth-decade autonomic onset typical of duplication carriers, and the presenting complaint is usually speech rather than autonomic.

Show evidence (2 references)

PMID:30842973 SUPPORT Human Clinical

"Five patients from 3 independent families presented at ages ranging from 32 to 52 years with neurologic symptoms that included progressive hypophonia, upper and lower limb weakness and spasticity, and cerebellar dysfunction and MRIs characterized by widespread white matter alterations."

Gives the age-at-onset range and presenting syndrome of the deletion cohort.

PMID:30697589 SUPPORT Human Clinical

"Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication."

Independently supports earlier onset in deletion relative to duplication carriers.

📊

Prevalence

2

Worldwide published families

Cases In Literature Ultra Rare

More than 30 affected families had been reported; this is literature ascertainment, not a population-rate estimate.

Show evidence (1 reference)

PMID:37450245 SUPPORT Other

"More than 30 affected families around the world have been reported to date."

The review supplies a literature family count without implying population prevalence.

Worldwide

Unknown Unknown

Exact population occurrence is not available.

Show evidence (1 reference)

PMID:37450245 SUPPORT Other

"However, ADLD diagnosis is not always straightforward, therefore exact prevalence data are still lacking [5]."

The source explicitly states that exact prevalence remains unknown.

🔬

Clinical Trials

1

NCT06816498 PHASE_I ACTIVE_NOT_RECRUITING

Open-label single-participant phase 1/2 personalized antisense oligonucleotide study for LMNB1 mutation-associated ADLD.

Target Phenotypes: Leukodystrophy HP:0002415

Show evidence (1 reference)

clinicaltrials:NCT06816498 SUPPORT Human Clinical

"This research project entails delivery of a personalized antisense oligonucleotide (ASO) drug designed for a single participant with Autosomal Dominant Leukodystrophy (ADLD) due to LMNB1 mutation"

Supports an active personalized ASO clinical trial for LMNB1-associated ADLD.

{ }

Source YAML

click to show

name: Adult-Onset Autosomal Dominant Demyelinating Leukodystrophy
creation_date: "2026-05-06T03:14:37Z"
category: Neurodegenerative Disease
parents:
- Neurodegenerative Disease
disease_term:
  preferred_term: adult-onset autosomal dominant demyelinating leukodystrophy
  term:
    id: MONDO:0008215
    label: adult-onset autosomal dominant demyelinating leukodystrophy
description: >-
  Adult-onset autosomal dominant demyelinating leukodystrophy is a rare,
  slowly progressive neurodegenerative leukodystrophy characterized by central
  nervous system demyelination with autonomic dysfunction, pyramidal signs,
  ataxia, and variable cognitive impairment.
synonyms:
- LMNB1-related autosomal dominant leukodystrophy
- Autosomal dominant adult-onset demyelinating leukodystrophy
- ADLD
external_assertions:
- name: OMIM adult-onset autosomal dominant leukodystrophy record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:169500
  description: >-
    OMIM disease identifier for the typical (LMNB1 duplication) form of
    adult-onset autosomal dominant demyelinating leukodystrophy, ADLDTY.
- name: OMIM atypical adult-onset autosomal dominant leukodystrophy record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:621061
  description: >-
    OMIM disease identifier for the atypical form, ADLDAT, caused by
    heterozygous deletion upstream of LMNB1 rather than whole-gene duplication.
    This is the entity carried by MONDO:0700286, curated here as the Upstream
    Deletion-Related ADLD subtype rather than as a separate disease entry
    because the two forms converge on the same LMNB1 gain-of-expression
    mechanism.
has_subtypes:
- name: LMNB1 Duplication-Related ADLD
  display_name: Typical ADLD (LMNB1 duplication)
  classification: molecular
  genes:
  - preferred_term: LMNB1
    term:
      id: hgnc:6637
      label: LMNB1
  description: >-
    The classic molecular subtype caused by heterozygous LMNB1 duplication,
    producing lamin B1 overexpression and the typical autonomic, pyramidal,
    ataxic, and leukodystrophy phenotype. This is the form OMIM designates
    ADLDTY.
  evidence:
  - reference: DOI:10.1007/s44162-024-00055-w
    reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All eight patients had LMNB1 duplication."
    explanation: Supports LMNB1 duplication as the molecular finding across the Mayo Clinic ADLD cohort.
- name: Upstream Deletion-Related ADLD
  display_name: Atypical ADLD (LMNB1 upstream deletion)
  classification: molecular
  subtype_term:
    preferred_term: atypical adult-onset autosomal dominant demyelinating leukodystrophy
    term:
      id: MONDO:0700286
      label: leukodystrophy, demyelinating, adult-onset, autosomal dominant, atypical
  genes:
  - preferred_term: LMNB1
    term:
      id: hgnc:6637
      label: LMNB1
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: >-
      The nonrecurrent upstream deletions segregate as heterozygous, fully
      penetrant dominant alleles across the reported multigenerational families.
    evidence:
    - reference: PMID:30842973
      reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our findings confirmed the association between LMNB1 upstream deletions and leukodystrophy previously reported in a single family, expanding the phenotypic and molecular description of this condition."
      explanation: Three additional independent families confirm dominant segregation of the upstream-deletion allele with the leukodystrophy phenotype.
  description: >-
    A regulatory structural-variant subtype in which heterozygous upstream
    deletion removes a topological boundary and drives LMNB1 enhancer adoption
    without whole-gene duplication. OMIM separates this as ADLDAT, and MONDO
    as the "atypical" child term, because the clinical picture diverges from
    the duplication form: onset is earlier, speech symptoms rather than
    dysautonomia dominate the presentation, early autonomic involvement is
    absent, and cerebellar and spinal-cord involvement is comparatively
    limited. It remains a subtype rather than a separate disease entry because
    both routes converge on the same proximal driver, LMNB1 overexpression.
  evidence:
  - reference: PMID:25701871
    reference_title: "A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes."
    explanation: Supports upstream regulatory deletion and enhancer adoption as a distinct molecular route to ADLD.
  - reference: PMID:30842973
    reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although clinical and radiologic features overlapped with those of autosomal dominant leukodystrophy because of LMNB1 duplications, patients with deletions upstream of LMNB1 had an earlier age at symptom onset, lacked early dysautonomia, and appeared to have lesser involvement of the cerebellum and sparing of the spinal cord diameter on MRI."
    explanation: >-
      This is the defining clinical and radiologic contrast that separates the
      atypical upstream-deletion form from the typical duplication form.
  - reference: PMID:30842973
    reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had unique nonrecurrent deletions upstream of the LMNB1, varying in size from 250 kb to 670 kb."
    explanation: >-
      Establishes that the causative alleles are nonrecurrent structural
      variants of variable size, not a single recurrent rearrangement.
  - reference: PMID:30697589
    reference_title: Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication."
    explanation: >-
      An independent Japanese family reproduces the earlier-onset and
      reduced-dysautonomia contrast and adds prominent cognitive impairment.
  - reference: PMID:39910058
    reference_title: An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most cases of ADLD are caused by tandem genomic duplications involving the lamin B1 gene (LMNB1) while a small subset are caused by genomic deletions upstream of the gene."
    explanation: Supports the upstream-deletion route as the minority molecular class within ADLD.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: Heterozygous LMNB1 gain-of-expression structural variants segregate in an autosomal dominant pattern.
  evidence:
  - reference: PMID:26053668
    reference_title: "LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia."
    explanation: The longitudinal family study directly identifies the autosomal-dominant disease pattern.
prevalence:
- population: Worldwide published families
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: More than 30 affected families had been reported; this is literature ascertainment, not a population-rate estimate.
  evidence:
  - reference: PMID:37450245
    reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "More than 30 affected families around the world have been reported to date."
    explanation: The review supplies a literature family count without implying population prevalence.
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: Exact population occurrence is not available.
  evidence:
  - reference: PMID:37450245
    reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, ADLD diagnosis is not always straightforward, therefore exact prevalence data are still lacking [5]."
    explanation: The source explicitly states that exact prevalence remains unknown.
progression:
- phase: Presymptomatic radiologic disease
  notes: Brain and spinal-cord MRI abnormalities can precede clinical manifestations by more than a decade.
  evidence:
  - reference: PMID:26053668
    reference_title: "LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI abnormalities of the brain and spinal cord can precede clinical symptoms by more than a decade and are extensive in all symptomatic patients."
    explanation: The longitudinal study documents a presymptomatic imaging phase.
- phase: Early autonomic manifestations
  age_range: Fifth to sixth decade
  notes: Autonomic dysfunction commonly precedes or accompanies emerging gait and coordination difficulty.
  evidence:
  - reference: PMID:26053668
    reference_title: "LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autonomic dysfunction appeared in the fifth to sixth decade, preceding or together with gait and coordination difficulties."
    explanation: The cohort establishes the characteristic early clinical phase and timing.
- phase: Progressive pyramidal and bulbar disability
  age_range: Seventh decade in the longitudinal cohort
  notes: Motor signs can ascend from spastic paraplegia to tetraplegia and pseudobulbar palsy.
  evidence:
  - reference: PMID:26053668
    reference_title: "LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Motor signs developed ascending from spastic paraplegia to tetraplegia and pseudobulbar palsy in the seventh decade."
    explanation: The longitudinal study defines the later motor progression pattern.
- phase: Earlier onset in the upstream-deletion (atypical) subtype
  age_range: 32 to 52 years in the reported deletion cohort
  notes: >-
    Onset in deletion carriers can begin in the fourth decade or earlier,
    ahead of the fifth-to-sixth-decade autonomic onset typical of duplication
    carriers, and the presenting complaint is usually speech rather than
    autonomic.
  evidence:
  - reference: PMID:30842973
    reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients from 3 independent families presented at ages ranging from 32 to 52 years with neurologic symptoms that included progressive hypophonia, upper and lower limb weakness and spasticity, and cerebellar dysfunction and MRIs characterized by widespread white matter alterations."
    explanation: Gives the age-at-onset range and presenting syndrome of the deletion cohort.
  - reference: PMID:30697589
    reference_title: Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication."
    explanation: Independently supports earlier onset in deletion relative to duplication carriers.
pathophysiology:
- name: LMNB1 Overexpression
  description: >-
    Whole-gene duplication or upstream regulatory deletion increases LMNB1
    expression, establishing lamin B1 excess as the proximal molecular driver.
  genes:
  - preferred_term: LMNB1
    term:
      id: hgnc:6637
      label: LMNB1
  evidence:
  - reference: PMID:28769756
    reference_title: "An LMNB1 Duplication Caused Adult-Onset Autosomal Dominant Leukodystrophy in Chinese Family: Clinical Manifestations, Neuroradiology and Genetic Diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Duplication or over expression of the lamin B1 (LMNB1) gene causes ADLD."
    explanation: >-
      The family study directly links LMNB1 duplication/overexpression with
      adult-onset autosomal dominant leukodystrophy.
  - reference: PMID:25701871
    reference_title: "A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination."
    explanation: >-
      The structural-variant study supports LMNB1 overexpression as the shared
      mechanism driving progressive CNS demyelination.
  downstream:
  - target: Nuclear Lamina and Chromatin Perturbation
    causal_link_type: DIRECT
    description: Lamin B1 excess perturbs inner-nuclear-membrane proteins, chromatin organization, and cellular physiology.
    evidence:
    - reference: PMID:37450245
      reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "changes to its structural homeostasis might translate into functional alterations."
      explanation: The experimental-model review supports a functional consequence of altered nuclear-lamina homeostasis.
  - target: RAVER2/PTB-Dependent PLP1 Spliceopathy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - LMNB1-dependent RAVER2 upregulation and inhibition of PTB splicing activity
    description: >-
      Patient-derived fibroblast and blood-cell studies link LMNB1 excess to
      RAVER2 upregulation and abnormal splicing of PTB targets including PLP1.
    evidence:
    - reference: PMID:37450245
      reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Functional studies on mRNA extracted from skin fibroblasts and whole blood of ADLD patients demonstrated that RAVER2 expression is positively regulated by the levels of Lamin B1, being both proteins increased in ADLD cells."
      explanation: >-
        Patient-derived ex-vivo studies support LMNB1-dependent RAVER2
        upregulation, while the intervening transcriptional mechanism is not
        established.
  - target: Oligodendrocyte Lipid and Myelin Program Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered oligodendrocyte chromatin marks and myelin-gene expression
    description: Model systems link LMNB1 overexpression to reduced myelin-lipid synthesis and altered oligodendrocyte differentiation.
    evidence:
    - reference: PMID:37450245
      reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Obser- vations made on LMNB1 overexpressing oligodendrocytes have been controversial"
      explanation: The review supports this model-derived branch but explicitly records conflicting oligodendrocyte results.
  - target: Astrocyte LIF-Support Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced LIF production and LIF-receptor signaling
    description: In-vitro astrocyte models suggest that LMNB1 overexpression reduces trophic support for myelinating oligodendrocytes.
    evidence:
    - reference: PMID:37450245
      reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Cells displayed altered morphology, aberrant cellular signaling, reduced viability, and induction of reactivity"
      explanation: This is an evidence-qualified hypothesis from astrocyte models, not an established human causal bridge.
  - target: Axon-Myelin Unit Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Transgenic and neuronal models associate LMNB1 overexpression with axonal shortening, disintegration, and axon-myelin-unit degradation.
    evidence:
    - reference: PMID:37450245
      reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "axonal disintegration and the degradation of the axon-myelin unit"
      explanation: The edge is limited to model evidence; the intermediates and human relevance remain uncertain.
  - target: Central Nervous System Demyelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: LMNB1 overexpression causes CNS demyelination, while the intervening human cellular mechanism remains unresolved.
    evidence:
    - reference: PMID:25701871
      reference_title: "A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "overexpression of LMNB1 causes progressive central nervous system demyelination."
      explanation: Human genetic evidence supports the causal endpoint while not identifying the intervening cellular route.
- name: Enhancer Adoption From Upstream Deletion
  biological_scale: MOLECULAR
  description: >-
    Some families lack an LMNB1 coding duplication and instead have upstream
    deletions that disrupt regulatory boundaries, allowing ectopic enhancer
    activity to increase LMNB1 expression. This is the causal lesion of the
    atypical subtype recognized as MONDO:0700286 / OMIM ADLDAT. The deletions
    are nonrecurrent and vary in size, but comparison across families defines a
    shared minimal critical region spanning a topologically associating domain
    boundary.
  genes:
  - preferred_term: LMNB1
    term:
      id: hgnc:6637
      label: LMNB1
  evidence:
  - reference: PMID:25701871
    reference_title: "A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration."
    explanation: >-
      This supports a noncoding structural variant mechanism that converges on
      LMNB1 overexpression.
  - reference: PMID:30842973
    reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strikingly, this genomic region encompassed a boundary between 2 topologically associated domains (TADs) and strengthens our original hypothesis that a disruption of the TAD boundary causes LMNB1 overexpression and in turn the disease."
    explanation: >-
      Cross-family mapping localizes the shared critical region to a TAD
      boundary, supporting boundary disruption as the operative lesion.
  - reference: PMID:30842973
    reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing the deletion junctions revealed the importance of repetitive elements (Alu, LINEs) in the genomic rearrangement."
    explanation: >-
      Identifies repeat-mediated rearrangement as the origin of the
      nonrecurrent deletions, explaining why each family carries a private allele.
  downstream:
  - target: LMNB1 Overexpression
    causal_link_type: DIRECT
    description: Enhancer adoption increases LMNB1 promoter activity and converges on lamin B1 overexpression.
    evidence:
    - reference: PMID:25701871
      reference_title: "A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration."
      explanation: The deletion study directly supports enhancer adoption converging on cerebral LMNB1 overexpression.
    - reference: PMID:30842973
      reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Expression analysis revealed increased LMNB1 expression in patient cells."
      explanation: Direct measurement in deletion-carrier cells confirms the convergence on increased LMNB1 expression.
  - target: Loss of the Oligodendrocyte-Specific LMNB1 Silencer Element
    causal_link_type: DIRECT
    description: >-
      The deleted interval contains a CTCF-based silencer element, so the
      upstream deletion removes the repressor outright rather than merely
      exposing the promoter to foreign enhancers.
    evidence:
    - reference: PMID:39910058
      reference_title: An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In the case of the ADLD-Del, this silencer element is lost due to the upstream genomic deletion, leading to a similar overexpression"
      explanation: >-
        Places the silencer element inside the deleted interval, making its loss
        the direct consequence of the upstream deletion.
- name: Loss of the Oligodendrocyte-Specific LMNB1 Silencer Element
  biological_scale: MOLECULAR
  description: >-
    A CTCF-based silencer element upstream of LMNB1 normally holds lamin B1
    expression low specifically in oligodendrocytes, acting through
    three-dimensional chromatin looping and recruitment of the PRC2 repressor
    complex. Both ADLD routes remove that repression: the upstream deletion
    deletes the element, while a tandem duplication places an extra LMNB1 copy
    outside its control. This node is what makes the two molecular subtypes one
    disease, and it supplies the otherwise unexplained oligodendrocyte
    specificity of a phenotype caused by a ubiquitously expressed gene. The
    evidence is CRISPR-edited cell lines and mouse models plus human genotype
    comparison, not direct human CNS measurement.
  genes:
  - preferred_term: LMNB1
    term:
      id: hgnc:6637
      label: LMNB1
  - preferred_term: CTCF
    term:
      id: hgnc:13723
      label: CTCF
  biological_processes:
  - preferred_term: negative regulation of transcription by RNA polymerase II
    term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    modifier: DECREASED
  - preferred_term: chromatin looping
    term:
      id: GO:0140588
      label: chromatin looping
    modifier: ABNORMAL
  evidence:
  - reference: PMID:39910058
    reference_title: An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we have identified a silencer element that is lost in ADLD patients and that specifically targets expression to oligodendrocytes"
    explanation: Establishes the silencer element and its oligodendrocyte-restricted action.
  - reference: PMID:39910058
    reference_title: An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This element consists of CTCF binding sites that mediate three-dimensional chromatin looping involving LMNB1 and the recruitment of the PRC2 transcriptional repressor complex."
    explanation: Specifies the molecular composition and repressive mechanism of the element.
  - reference: PMID:39910058
    reference_title: An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The loss of this silencer element in ADLD provides a parsimonious mechanism explaining tissue specificity and how both duplication and upstream deletion can lead to lamin B1 overexpression"
    explanation: >-
      Supports the unifying claim that silencer escape, not the structural
      variant class, is the shared proximal mechanism.
  downstream:
  - target: LMNB1 Overexpression
    causal_link_type: DIRECT
    description: >-
      Escape from silencer-mediated repression de-represses LMNB1 in
      oligodendrocytes, the cell type whose vulnerability defines the disease.
    evidence:
    - reference: PMID:39910058
      reference_title: An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "As a result, the duplicated copy of the LMNB1 gene is no longer under the repressive control of the silencer element and overexpression occurs."
      explanation: States the de-repression step that links silencer escape to LMNB1 overexpression.
- name: Nuclear Lamina and Chromatin Perturbation
  description: >-
    Experimental models show cell-type-dependent nuclear and chromatin changes
    after LMNB1 overexpression. This node records a proximal effect without
    making it an oligodendrocyte-only causal bridge to human demyelination.
  biological_processes:
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37450245
    reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LMNB1 encodes for Lamin B1, a protein of the nuclear lamina. Lamin B1 regulates many cellular processes such as DNA replication, chromatin organization, and senescence."
    explanation: Supports nuclear-lamina and chromatin organization disruption as a proximal molecular consequence of LMNB1 overexpression.
  - reference: PMID:37450245
    reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nevertheless, Lamin B1 together with the other lamins that constitute the nuclear lamina has firstly the key role of maintaining the nuclear structure."
    explanation: Supports nuclear structural homeostasis as a relevant lamin B1-dependent process.
- name: RAVER2/PTB-Dependent PLP1 Spliceopathy
  description: >-
    LMNB1-dependent RAVER2 upregulation inhibits PTB splicing regulation and
    produces an abnormal splicing pattern that includes the major myelin gene
    PLP1. This patient-cell branch is plausible but has not been established as
    the causal bridge in human CNS tissue.
  genes:
  - preferred_term: RAVER2
    term:
      id: hgnc:25577
      label: RAVER2
  - preferred_term: PTBP1
    term:
      id: hgnc:9583
      label: PTBP1
  - preferred_term: PLP1
    term:
      id: hgnc:9086
      label: PLP1
  biological_processes:
  - preferred_term: RNA splicing
    term:
      id: GO:0008380
      label: RNA splicing
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37450245
    reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "an abnormal splicing pattern of several PTB-target genes, including the PLP1 gene"
    explanation: >-
      Patient fibroblast and blood-cell studies support abnormal splicing of
      PTB targets including PLP1, but do not establish the effect in human CNS
      tissue.
  downstream:
  - target: Central Nervous System Demyelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      PLP1 splice dysregulation is a candidate contributor to demyelination,
      with its CNS cell-type context and downstream intermediates unresolved.
    evidence:
    - reference: PMID:37450245
      reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "demyelination in ADLD could be caused by a spliceopathy involving RAVER2 aberrant activity."
      explanation: >-
        The review presents RAVER2-dependent spliceopathy as a candidate
        mechanism rather than an established human causal route.
- name: Oligodendrocyte Lipid and Myelin Program Dysfunction
  conforms_to: "cns_myelin_failure#Oligodendrocyte Differentiation Arrest and Death"
  description: >-
    Mouse and cell models report reduced myelin-lipid synthesis, altered myelin
    gene expression, and impaired differentiation, but the oligodendrocyte
    findings are conflicting and are not treated as the sole human mechanism.
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: myelination
    term:
      id: GO:0042552
      label: myelination
    modifier: DECREASED
  evidence:
  - reference: PMID:37450245
    reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "revealing a significant reduction in myelin lipids in trans- genic mice compared to wild-type animals"
    explanation: Model evidence supports altered lipid synthesis but does not establish the complete human pathway.
  downstream:
  - target: Central Nervous System Demyelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Oligodendrocyte model abnormalities are a candidate contributor to progressive CNS demyelination.
    evidence:
    - reference: PMID:37450245
      reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Both processes appear to derive from Lamin B1 accumulation, but the mechanisms driving this process are yet to be identified."
      explanation: The review presents this branch as plausible while explicitly noting unresolved mechanisms.
- name: Astrocyte LIF-Support Dysfunction
  description: >-
    Astrocyte models show reduced LIF/LIF-receptor signaling, viability changes,
    and reactive morphology. These findings suggest reduced support of
    myelinating oligodendrocytes but require confirmation in patient brain tissue.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  evidence:
  - reference: PMID:37450245
    reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cells displayed altered morphology, aberrant cellular signaling, reduced viability, and induction of reactivity"
    explanation: The review characterizes the astrocyte branch as a model-derived candidate mechanism.
  downstream:
  - target: Central Nervous System Demyelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced astrocyte trophic support is a candidate contributor to demyelination rather than an established human causal route.
    evidence:
    - reference: PMID:37450245
      reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "these results suggest that ADLD could be an astrocytopathy"
      explanation: The edge preserves the review's explicit translational uncertainty.
- name: Axon-Myelin Unit Injury
  description: >-
    Neuronal and transgenic models show axonal shortening, axonal disintegration,
    and degradation of the axon-myelin unit; whether this branch is primary in
    human ADLD is unresolved.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:37450245
    reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "LMNB1 transient overexpression in primary mouse cortical neurons resulted in a significant reduction in axonal length, while dendritic trees seemed to not be affected [43]."
    explanation: This supports an axonal model phenotype without establishing its role in human disease.
  downstream:
  - target: Central Nervous System Demyelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Axon-myelin-unit injury may converge with glial abnormalities on the human demyelinating phenotype.
    evidence:
    - reference: PMID:37450245
      reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "axonal disintegration and the degradation of the axon-myelin unit"
      explanation: Model evidence supports convergence on axon-myelin injury, with uncertain human intermediates.
- name: Central Nervous System Demyelination
  conforms_to: "cns_myelin_failure#Deficient or Unstable CNS Myelin Sheath"
  description: >-
    Progressive central nervous system demyelination and white matter loss are
    the downstream tissue-level outputs of LMNB1 overexpression.
  biological_processes:
  - preferred_term: myelination
    term:
      id: GO:0042552
      label: myelination
    modifier: DECREASED
  evidence:
  - reference: PMID:25701871
    reference_title: "A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overexpression of LMNB1 causes progressive central nervous system demyelination."
    explanation: Directly links LMNB1 overexpression to progressive CNS demyelination.
  - reference: PMID:28769756
    reference_title: "An LMNB1 Duplication Caused Adult-Onset Autosomal Dominant Leukodystrophy in Chinese Family: Clinical Manifestations, Neuroradiology and Genetic Diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) is a very rare neurological disorder featured with late onset, slowly progressive central nervous system demyelination."
    explanation: Supports slowly progressive CNS demyelination as the defining downstream phenotype.
  downstream:
  - target: Leukodystrophy
    causal_link_type: DIRECT
    description: Progressive CNS demyelination is the defining leukodystrophy substrate.
    evidence:
    - reference: PMID:28769756
      reference_title: "An LMNB1 Duplication Caused Adult-Onset Autosomal Dominant Leukodystrophy in Chinese Family: Clinical Manifestations, Neuroradiology and Genetic Diagnosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) is a very rare neurological disorder featured with late onset, slowly progressive central nervous system demyelination."
      explanation: Human observations identify progressive CNS demyelination as the defining leukodystrophy phenotype.
  - target: Pyramidal and Cerebellar Tract Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - corticospinal, cerebellar, and spinal-cord white-matter involvement
    description: White-matter and spinal-cord involvement is associated with pyramidal and cerebellar dysfunction.
    evidence:
    - reference: PMID:26053668
      reference_title: "LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Spinal cord involvement is a likely contributing factor to early autonomic symptoms and spastic paraplegia."
      explanation: The longitudinal study supports a likely, not exclusive, tract-level contribution.
  - target: Cognitive Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cognitive difficulties co-occur with diffuse ADLD white-matter disease, but the causal route is not resolved.
    evidence:
    - reference: DOI:10.1007/s44162-024-00055-w
      reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."
      explanation: Cohort association supports the phenotype edge but not a direct mechanism.
  - target: Fatigue
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Fatigue is associated with ADLD; a direct demyelination mechanism has not been demonstrated.
    evidence:
    - reference: DOI:10.1007/s44162-024-00055-w
      reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."
      explanation: Cohort association supports the phenotype edge but not a direct mechanism.
  - target: Sleep Disturbance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Sleep disturbance is associated with ADLD; its mechanistic relation to demyelination is unresolved.
    evidence:
    - reference: DOI:10.1007/s44162-024-00055-w
      reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."
      explanation: Cohort association supports the phenotype edge but not a direct mechanism.
  - target: Mood Disturbance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Mood disturbance is associated with ADLD; its mechanistic relation to demyelination is unresolved.
    evidence:
    - reference: DOI:10.1007/s44162-024-00055-w
      reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."
      explanation: Cohort association supports the phenotype edge but not a direct mechanism.
  - target: Tremor
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Tremor is associated with ADLD; its direct causal path is unresolved.
    evidence:
    - reference: DOI:10.1007/s44162-024-00055-w
      reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."
      explanation: Cohort association supports the phenotype edge but not a direct mechanism.
  - target: Migraine
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Migraine is associated with ADLD; its direct causal path is unresolved.
    evidence:
    - reference: DOI:10.1007/s44162-024-00055-w
      reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."
      explanation: Cohort association supports the phenotype edge but not a direct mechanism.
- name: Autonomic-System Involvement (Mechanism Unresolved)
  description: >-
    Autonomic dysfunction is often the first clinical manifestation. Because
    affected noradrenergic pathways include non-myelinated fibers, the causal
    route is not represented as a direct consequence of demyelination.
  evidence:
  - reference: PMID:26053668
    reference_title: "LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia."
    explanation: >-
      The longitudinal cohort supports an autonomic-to-pyramidal/cerebellar
      clinical sequence downstream of LMNB1-related demyelinating disease.
  downstream:
  - target: Autonomic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Unresolved LMNB1-related autonomic-system involvement manifests clinically as autonomic dysfunction.
    evidence:
    - reference: PMID:26053668
      reference_title: "LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autonomic dysfunction appeared in the fifth to sixth decade, preceding or together with gait and coordination difficulties."
      explanation: Longitudinal observation supports the clinical association and timing, not a resolved molecular route.
- name: Pyramidal and Cerebellar Tract Dysfunction
  description: >-
    Longitudinal human observations associate white-matter and spinal-cord
    involvement with progressive pyramidal and cerebellar signs.
  evidence:
  - reference: PMID:26053668
    reference_title: "LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia."
    explanation: The longitudinal cohort establishes the ordered pyramidal and cerebellar clinical involvement.
  downstream:
  - target: Spasticity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - pyramidal tract and spinal-cord involvement
    description: Pyramidal and spinal-cord dysfunction is associated with progressive spasticity.
    evidence:
    - reference: PMID:26053668
      reference_title: "LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Motor signs developed ascending from spastic paraplegia to tetraplegia and pseudobulbar palsy in the seventh decade."
      explanation: Clinical progression supports the edge while not proving a single tract-level mechanism.
  - target: Ataxia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cerebellar and cerebellar-peduncle involvement
    description: Cerebellar-system dysfunction is associated with ataxia.
    evidence:
    - reference: PMID:26053668
      reference_title: "LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia."
      explanation: The clinical sequence supports association with cerebellar involvement without proving direct causality.
phenotypes:
- name: Leukodystrophy
  category: Neurologic
  phenotype_term:
    preferred_term: Leukodystrophy
    term:
      id: HP:0002415
      label: Leukodystrophy
  description: >-
    Progressive central nervous system white matter disease is the core
    radiologic and clinical substrate.
  evidence:
  - reference: PMID:28769756
    reference_title: "An LMNB1 Duplication Caused Adult-Onset Autosomal Dominant Leukodystrophy in Chinese Family: Clinical Manifestations, Neuroradiology and Genetic Diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) is a very rare neurological disorder featured with late onset, slowly progressive central nervous system demyelination."
    explanation: >-
      This describes the defining adult-onset leukodystrophy phenotype and
      progressive CNS demyelination.
- name: Spasticity
  category: Neurologic
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  description: >-
    Upper motor neuron dysfunction may produce progressive spasticity.
  evidence:
  - reference: PMID:26053668
    reference_title: "LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Motor signs developed ascending from spastic paraplegia to tetraplegia and pseudobulbar palsy in the seventh decade."
    explanation: >-
      The longitudinal cohort supports spastic motor involvement during
      progression.
- name: Ataxia
  category: Neurologic
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  description: >-
    Cerebellar or long-tract involvement can cause progressive gait and limb
    incoordination.
  evidence:
  - reference: PMID:26053668
    reference_title: "LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia."
    explanation: >-
      The longitudinal study identifies ataxia as a later motor feature after
      autonomic symptoms.
- name: Autonomic Dysfunction
  category: Neurologic
  phenotype_term:
    preferred_term: Autonomic dysfunction
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
  description: >-
    Autonomic involvement commonly appears early and may include bladder,
    bowel, sweating, erectile, or orthostatic symptoms.
  evidence:
  - reference: PMID:26053668
    reference_title: "LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autonomic dysfunction appeared in the fifth to sixth decade, preceding or together with gait and coordination difficulties."
    explanation: >-
      The longitudinal cohort supports autonomic dysfunction as an early
      clinical feature.
- name: Cognitive Impairment
  category: Neurologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  description: Cognitive difficulties are frequent in recent LMNB1-related ADLD cohorts.
  evidence:
  - reference: DOI:10.1007/s44162-024-00055-w
    reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."
    explanation: Supports cognitive impairment as very frequent in the eight-patient Mayo Clinic cohort.
- name: Fatigue
  category: Neurologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  description: Fatigue is common in recent LMNB1-related ADLD cohorts.
  evidence:
  - reference: DOI:10.1007/s44162-024-00055-w
    reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."
    explanation: Supports fatigue as frequent in the eight-patient Mayo Clinic cohort.
- name: Sleep Disturbance
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  description: Sleep disturbance is reported in recent LMNB1-related ADLD cohorts.
  evidence:
  - reference: DOI:10.1007/s44162-024-00055-w
    reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."
    explanation: Supports sleep disturbance in half of the eight-patient Mayo Clinic cohort.
- name: Mood Disturbance
  category: Psychiatric
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Mood disturbance
    term:
      id: HP:0100851
      label: Abnormal emotional state
  description: Mood disturbances are reported in recent LMNB1-related ADLD cohorts.
  evidence:
  - reference: DOI:10.1007/s44162-024-00055-w
    reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."
    explanation: >-
      The cohort reports mood disturbances in most patients and the broader HPO
      emotional-state term avoids over-specifying those findings as depression.
- name: Tremor
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  description: Tremor is reported in recent LMNB1-related ADLD cohorts.
  evidence:
  - reference: DOI:10.1007/s44162-024-00055-w
    reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."
    explanation: Supports tremor in half of the eight-patient Mayo Clinic cohort.
- name: Migraine
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Migraine
    term:
      id: HP:0002076
      label: Migraine
  description: Migraine is reported in recent LMNB1-related ADLD cohorts.
  evidence:
  - reference: DOI:10.1007/s44162-024-00055-w
    reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."
    explanation: Supports migraine in half of the eight-patient Mayo Clinic cohort.
- name: Hypophonia at Presentation
  category: Neurologic
  subtype: Upstream Deletion-Related ADLD
  phenotype_term:
    preferred_term: Hypophonia
    term:
      id: HP:0001621
      label: Weak voice
  description: >-
    Reduced voice volume, with dysarthria, is the characteristic presenting
    complaint of the upstream-deletion form and is what most sharply separates
    it at onset from the duplication form, where dysautonomia presents first.
  evidence:
  - reference: PMID:30842973
    reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, 4/5 patients presented at onset with speech symptoms including dysarthria and hypophonia. This has not been reported for ADLD with LMNB1 duplications, where the most common presenting feature was autonomic dysfunction."
    explanation: >-
      Directly contrasts the presenting symptom of the deletion cohort with the
      duplication form, supporting hypophonia as a subtype-distinguishing feature.
- name: Dysarthria
  category: Neurologic
  subtype: Upstream Deletion-Related ADLD
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  description: >-
    Dysarthria accompanies hypophonia in the presenting speech syndrome of the
    upstream-deletion subtype.
  evidence:
  - reference: PMID:30842973
    reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, 4/5 patients presented at onset with speech symptoms including dysarthria and hypophonia."
    explanation: Four of five deletion-carrier patients presented with dysarthria.
- name: Limb Muscle Weakness
  category: Neurologic
  subtype: Upstream Deletion-Related ADLD
  phenotype_term:
    preferred_term: Upper and lower limb weakness
    term:
      id: HP:0003690
      label: Limb muscle weakness
  description: >-
    Weakness of the upper and lower extremities, sometimes asymmetrical,
    accompanies spasticity in the upstream-deletion cohort.
  evidence:
  - reference: PMID:30842973
    reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients from 3 independent families presented at ages ranging from 32 to 52 years with neurologic symptoms that included progressive hypophonia, upper and lower limb weakness and spasticity, and cerebellar dysfunction and MRIs characterized by widespread white matter alterations."
    explanation: Describes the presenting neurologic syndrome of the deletion cohort, including limb weakness.
- name: Absence of Early Autonomic Involvement
  category: Neurologic
  subtype: Upstream Deletion-Related ADLD
  frequency: EXCLUDED
  phenotype_term:
    preferred_term: Autonomic dysfunction
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
    modifier: ABSENT
  notes: >-
    The absence is carried by `frequency: EXCLUDED`, which is what the HPOA
    exporter reads to emit a NOT-qualified row; `modifier: ABSENT` alone is not
    consulted by the export layer and documents intent only. Without EXCLUDED
    this block exported as a POSITIVE assertion that ADLD features abnormal
    autonomic physiology, cited to the two papers stating the opposite.
    `temporality: CHRONIC` was removed: it contradicts a claim about EARLY
    absence, and the cited evidence describes autonomic features as late when
    they appear at all.
  description: >-
    Curated as a deliberate negative contrast: autonomic features are the
    hallmark early sign of the duplication form but are largely absent early in
    the upstream-deletion form, appearing instead as a late consequence of
    established spasticity. This is one of the two OMIM criteria separating
    ADLDAT from ADLDTY.
  evidence:
  - reference: PMID:30842973
    reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of note, early involvement of the autonomic nervous system was notable in only 1 patient with orthostatic intolerance and urinary urgency. In 2 patients, urinary urgency and incontinence were late features of the disorder, occurring only after development of severe lower limb spasticity."
    explanation: >-
      Documents that autonomic involvement is uncommon at onset and, when
      present, is a late feature in the deletion cohort.
  - reference: PMID:30697589
    reference_title: Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication."
    explanation: An independent family confirms the reduced autonomic burden relative to duplication carriers.
imaging_findings:
- name: Symmetric confluent cerebral white-matter T2 hyperintensity
  modality: MRI
  imaging_finding_term:
    preferred_term: Symmetric confluent cerebral white-matter abnormalities
    term:
      id: HP:0007204
      label: Diffuse white matter abnormalities
  located_in:
    preferred_term: brain white matter
    term:
      id: UBERON:0003544
      label: brain white matter
  spatial_extent: DIFFUSE
  phenotype_term:
    preferred_term: Diffuse white matter abnormalities
    term:
      id: HP:0007204
      label: Diffuse white matter abnormalities
  diagnostic: true
  notes: >-
    The molecularly confirmed cohort showed a symmetric confluent deep cerebral
    and periventricular pattern extending through major commissural,
    corticospinal, brainstem, and cerebellar-peduncle white-matter tracts.
  evidence:
  - reference: DOI:10.1007/s44162-024-00055-w
    reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All showed symmetric confluent T2W deep cerebral and periventricular white matter hyperintensities with involvement of the posterior limb of the internal capsule, corpus callosum, corticospinal tract in brain stem, and superior and middle cerebellar peduncles."
    explanation: Seven molecularly confirmed patients showed the characteristic symmetric diffuse brain MRI pattern.
- name: Diffuse spinal-cord atrophy on MRI
  modality: MRI
  imaging_finding_term:
    preferred_term: Diffuse spinal-cord atrophy
  located_in:
    preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
  spatial_extent: DIFFUSE
  diagnostic: true
  notes: Moderate diffuse spinal-cord atrophy complements the characteristic cerebral white-matter pattern.
  evidence:
  - reference: DOI:10.1007/s44162-024-00055-w
    reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven spine MRIs from six patients showed moderate diffuse atrophy of the spinal cord."
    explanation: The molecularly confirmed cohort documents diffuse spinal-cord atrophy on MRI.
- name: Corticospinal tract T2 hyperintensity from upper frontal lobes to cerebral peduncles
  modality: MRI
  subtype: Upstream Deletion-Related ADLD
  imaging_finding_term:
    preferred_term: Corticospinal tract T2 hyperintensity
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  located_in:
    preferred_term: corticospinal tract
    term:
      id: UBERON:0002707
      label: corticospinal tract
  diagnostic: true
  notes: >-
    Present in every deletion-carrier patient imaged, but unlike the
    duplication form it usually stops above the medulla oblongata.
  evidence:
  - reference: PMID:30842973
    reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients underwent brain MRI (figure 1); all had a corticospinal tract involvement extending from the upper frontal lobes to the cerebral peduncles."
    explanation: Establishes the corticospinal-tract pattern and its rostral extent in the deletion cohort.
  - reference: PMID:30842973
    reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The corticospinal tracts were affected in both groups, but only in one of the deletion patients (DEL1-1) did this extend to the medulla oblongata."
    explanation: >-
      Supports the caudal-extent contrast against duplication carriers, who show
      early medullary change.
- name: Relative sparing of the spinal cord below the uppermost cervical level
  modality: MRI
  subtype: Upstream Deletion-Related ADLD
  imaging_finding_term:
    preferred_term: Spinal cord atrophy restricted to the uppermost cervical cord
  located_in:
    preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
  spatial_extent: FOCAL
  diagnostic: true
  notes: >-
    The contrast with the diffuse whole-cord atrophy of the duplication form is
    the second OMIM criterion separating atypical from typical ADLD, and is the
    proposed anatomical explanation for the missing early dysautonomia.
  evidence:
  - reference: PMID:30842973
    reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with deletions, only the uppermost cervical spinal cord was atrophic, and in the 2 patients with a spinal MRI, no obvious SI changes were found in the rest of the cord. In LMNB1 duplication patients, the entire spinal cord is atrophic, and T2 signal in white matter is pathologic."
    explanation: >-
      States the imaging contrast between deletion and duplication carriers at
      the level of the spinal cord.
- name: Extensive temporal-lobe white-matter involvement
  modality: MRI
  subtype: Upstream Deletion-Related ADLD
  imaging_finding_term:
    preferred_term: Temporal white-matter T2 hyperintensity
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  located_in:
    preferred_term: brain white matter
    term:
      id: UBERON:0003544
      label: brain white matter
  notes: >-
    Two independent cohorts report anterior and temporal white-matter
    involvement as a relative feature of the upstream-deletion form.
  evidence:
  - reference: PMID:30842973
    reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On MRI, cerebral white matter involvement was more extensive, especially in the temporal lobes in patients with deletions compared with those with duplications at the same ages."
    explanation: Age-matched comparison supports greater temporal-lobe burden in deletion carriers.
  - reference: PMID:30697589
    reference_title: Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region."
    explanation: An independent Japanese family reproduces the anterior-temporal white-matter pattern.
genetic:
- name: LMNB1
  gene_term:
    preferred_term: LMNB1
    term:
      id: hgnc:6637
      label: LMNB1
  association: Causative
  features: >-
    LMNB1 causes ADLD through gain of expression, most often by whole-gene
    tandem duplication and more rarely by upstream regulatory deletion with
    enhancer adoption.
  inheritance:
  - name: Autosomal dominant inheritance
    evidence:
    - reference: PMID:26053668
      reference_title: "LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia."
      explanation: >-
        The title and abstract support autosomal-dominant inheritance in
        LMNB1-related ADLD.
    - reference: PMID:26749591
      reference_title: LMNB1-Related Autosomal Dominant Leukodystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "LMNB1-related ADLD is inherited in an autosomal dominant manner."
      explanation: GeneReviews explicitly establishes the mode of inheritance.
  evidence:
  - reference: PMID:28769756
    reference_title: "An LMNB1 Duplication Caused Adult-Onset Autosomal Dominant Leukodystrophy in Chinese Family: Clinical Manifestations, Neuroradiology and Genetic Diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, Multiplex ligand-dependent probe amplification (MLPA) showed whole duplication of LMNB1 gene which is co-segregated with the disease phenotype in this family."
    explanation: >-
      The family study supports LMNB1 duplication as a causative structural
      variant.
  - reference: PMID:40046440
    reference_title: "Case report: LMNB1 duplication-mediated autosomal dominant adult leukodystrophy in a Chinese family and literature review of Chinese patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, two genetic alterations have been identified in association with the pathogenesis of ADLD: LMNB1 gene tandem duplication and LMNB1 gene upstream deletions."
    explanation: Supports the two major LMNB1 gain-of-expression structural variant classes represented in this entry.
- name: LMNB1 upstream regulatory deletion
  subtype: Upstream Deletion-Related ADLD
  gene_term:
    preferred_term: LMNB1
    term:
      id: hgnc:6637
      label: LMNB1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Heterozygous, nonrecurrent noncoding deletions immediately upstream of
    LMNB1 on 5q23.2, ranging from roughly 250 kb to 670 kb, that leave the
    coding sequence intact. Because they alter only regulatory sequence, they
    are missed by sequence-based exome testing and require copy-number or
    structural-variant assays.
  evidence:
  - reference: PMID:30842973
    reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had unique nonrecurrent deletions upstream of the LMNB1, varying in size from 250 kb to 670 kb."
    explanation: Defines the size range and nonrecurrent character of the causative alleles.
  - reference: PMID:30697589
    reference_title: Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1."
    explanation: An independent family carrying a deletion at the small end of the reported size range.
  - reference: PMID:30842973
    reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Given that these mutations do not alter the coding sequence, our data also emphasize the importance of regulatory elements and the need for performing analyses for copy number variants that might be missed with the standard whole-exome sequencing, currently being used to identify mutations in patients with leukodystrophies."
    explanation: >-
      States the diagnostic consequence of the lesion being noncoding, which is
      why exome sequencing is not an adequate first-tier test here.
diagnosis:
- name: LMNB1 Copy-Number Testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Targeted LMNB1 deletion/duplication analysis, MLPA, array-CGH, or other
    validated copy-number methods are needed when the phenotype and MRI pattern
    suggest LMNB1-related ADLD.
  results: >-
    Heterozygous LMNB1 duplication or an upstream regulatory deletion supports
    the molecular diagnosis.
  evidence:
  - reference: PMID:28769756
    reference_title: "An LMNB1 Duplication Caused Adult-Onset Autosomal Dominant Leukodystrophy in Chinese Family: Clinical Manifestations, Neuroradiology and Genetic Diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In order to understand the genetic cause of the disease in this family, target exome capture based next generation sequencing has been done, but no causative variants or possibly pathogenic variants has been identified."
    explanation: >-
      The study shows that sequence-focused testing can miss the diagnosis.
  - reference: PMID:28769756
    reference_title: "An LMNB1 Duplication Caused Adult-Onset Autosomal Dominant Leukodystrophy in Chinese Family: Clinical Manifestations, Neuroradiology and Genetic Diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, Multiplex ligand-dependent probe amplification (MLPA) showed whole duplication of LMNB1 gene which is co-segregated with the disease phenotype in this family."
    explanation: >-
      MLPA copy-number testing identified the familial LMNB1 duplication after
      exome sequencing was unrevealing.
  - reference: PMID:26749591
    reference_title: LMNB1-Related Autosomal Dominant Leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of LMNB1-related ADLD is established in a proband with suggestive clinical and MRI findings and either an LMNB1 duplication or (more rarely) a heterozygous deletion upstream of the LMNB1 promoter identified by molecular genetic testing."
    explanation: >-
      GeneReviews defines molecular diagnosis by the characteristic clinical
      and MRI findings plus an LMNB1 duplication or upstream deletion.
  - reference: PMID:40933505
    reference_title: Clinical Practice Guidelines for the Diagnosis, Management, and Surveillance of LMNB1-Related Autosomal Dominant Leukodystrophy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Single-gene testing that can identify LMNB1 structural variants (duplications/deletions) at a high resolution is currently the optimal means of confirming a genetic diagnosis. Exome sequencing is not recommended as a first-tier test."
    explanation: >-
      The 2025 Delphi consensus guideline makes high-resolution structural-variant
      testing, not exome sequencing, the recommended confirmatory test, which is
      what allows the noncoding upstream deletion to be found at all.
- name: Characteristic Brain and Spine MRI Pattern
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: >-
    Brain and spine MRI can show the characteristic symmetric white-matter and
    spinal cord involvement that should prompt LMNB1 copy-number testing.
  results: >-
    Symmetric confluent T2-weighted deep cerebral and periventricular white
    matter hyperintensities with internal capsule, corpus callosum, brainstem
    corticospinal tract, cerebellar peduncle, and spinal cord atrophy patterns.
  evidence:
  - reference: DOI:10.1007/s44162-024-00055-w
    reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All showed symmetric confluent T2W deep cerebral and periventricular white matter hyperintensities with involvement of the posterior limb of the internal capsule, corpus callosum, corticospinal tract in brain stem, and superior and middle cerebellar peduncles."
    explanation: Supports the hallmark brain MRI pattern in molecularly confirmed LMNB1-related ADLD.
  - reference: DOI:10.1007/s44162-024-00055-w
    reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven spine MRIs from six patients showed moderate diffuse atrophy of the spinal cord."
    explanation: Supports spinal cord atrophy as part of the MRI diagnostic pattern.
treatments:
- name: Symptom-Directed Supportive Care
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  description: >-
    Management is supportive and symptom-directed, with attention to autonomic
    dysfunction, spasticity, mobility decline, fatigue, and cognitive or mood
    symptoms while disease-targeted therapy remains investigational.
  target_phenotypes:
  - preferred_term: Autonomic dysfunction
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
  - preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  - preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: DOI:10.1007/s44162-024-00055-w
    reference_title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8)."
    explanation: Supports the clinical symptom targets for supportive management in the Mayo Clinic cohort.
  - reference: PMID:37564735
    reference_title: "Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Comprehensive evaluation and molecular confirmation when available helps in prognostication, early initiation of treatment in certain disorders, enrollment in clinical trials, and provides valuable information for the family for reproductive counseling."
    explanation: Supports anticipatory management, treatment consideration when available, trial enrollment, and family counseling in adult-onset leukodystrophy care.
  - reference: PMID:26749591
    reference_title: LMNB1-Related Autosomal Dominant Leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment is symptomatic."
    explanation: GeneReviews confirms that current management is symptom-directed.
- name: Genetic Counseling
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  description: >-
    Genetic counseling is appropriate after molecular confirmation because the
    disease is autosomal dominant and familial risk and reproductive decisions
    are central to care.
  evidence:
  - reference: PMID:37564735
    reference_title: "Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Comprehensive evaluation and molecular confirmation when available helps in prognostication, early initiation of treatment in certain disorders, enrollment in clinical trials, and provides valuable information for the family for reproductive counseling."
    explanation: Supports genetic and reproductive counseling after molecular diagnosis in adult-onset leukodystrophies.
  - reference: PMID:26749591
    reference_title: LMNB1-Related Autosomal Dominant Leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each child of an individual with LMNB1-related ADLD has a 50% chance of inheriting the LMNB1 duplication (or deletion upstream of LMNB1)."
    explanation: GeneReviews supplies the recurrence risk used in family counseling.
- name: Allele-Specific RNA Interference
  action_category: THERAPEUTIC
  therapeutic_modality: SIRNA
  treatment_term:
    preferred_term: RNA interference therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  description: >-
    LMNB1-lowering RNA interference is a preclinical disease-targeted strategy
    intended to reduce excess LMNB1 expression while avoiding excessive
    suppression of the normal allele.
  target_mechanisms:
  - target: LMNB1 Overexpression
    treatment_effect: INHIBITS
    description: Allele-selective siRNA lowers the duplicated LMNB1 transcript and restores LMNB1 mRNA and protein toward control levels.
    evidence:
    - reference: PMID:31143934
      reference_title: "Allele-specific silencing as treatment for gene duplication disorders: proof-of-principle in autosomal dominant leukodystrophy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Three of the small interfering RNAs were highly selective for the target allele and restored both LMNB1 mRNA and protein levels close to control levels."
      explanation: The in-vitro study directly demonstrates the intended LMNB1-lowering target effect.
  evidence:
  - reference: PMID:31143934
    reference_title: "Allele-specific silencing as treatment for gene duplication disorders: proof-of-principle in autosomal dominant leukodystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Three of the small interfering RNAs were highly selective for the target allele and restored both LMNB1 mRNA and protein levels close to control levels."
    explanation: >-
      This supports a mechanistically targeted but preclinical RNAi approach in
      patient-derived and disease-relevant cellular models.
clinical_trials:
- name: NCT06816498
  phase: PHASE_I
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Open-label single-participant phase 1/2 personalized antisense
    oligonucleotide study for LMNB1 mutation-associated ADLD.
  target_phenotypes:
  - preferred_term: Leukodystrophy
    term:
      id: HP:0002415
      label: Leukodystrophy
  evidence:
  - reference: clinicaltrials:NCT06816498
    reference_title: "An Open-label, Single-center, Single-participant Study of an Experimental Antisense Oligonucleotide Treatment for a Patient With LMNB1 Mutation Associated Autosomal Dominant Leukodystrophy (ADLD)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This research project entails delivery of a personalized antisense oligonucleotide (ASO) drug designed for a single participant with Autosomal Dominant Leukodystrophy (ADLD) due to LMNB1 mutation"
    explanation: Supports an active personalized ASO clinical trial for LMNB1-associated ADLD.
  notes: >-
    ClinicalTrials.gov listed the study as combined Phase 1/Phase 2 and
    ACTIVE_NOT_RECRUITING when refreshed on 2026-07-20. Because the schema
    accepts one phase value, the combined early-phase study is normalized to
    PHASE_I, following existing repository convention.
discussions:
- discussion_id: gap_adld_deletion_dysautonomia_spinal_cord
  prompt: >-
    Is the absence of early dysautonomia in upstream-deletion (atypical) ADLD
    caused by the sparing of the spinal cord below the uppermost cervical
    level, and if so why does the same LMNB1 overexpression spare the cord in
    deletion carriers but not in duplication carriers?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Enhancer Adoption From Upstream Deletion
  - pathophysiology#Autonomic-System Involvement (Mechanism Unresolved)
  rationale: >-
    The two OMIM criteria that separate atypical from typical ADLD, lack of
    early autonomic involvement and relative sparing of cerebellum and spinal
    cord, are the same fact seen clinically and radiologically if the
    dysautonomia of ADLD is cord-derived. The deletion cohort authors advance
    exactly that reading, but they label it a hypothesis, and it rests on
    spinal MRI from only two deletion carriers. It also leaves the harder
    question untouched: both routes raise LMNB1, so an anatomically selective
    difference in outcome implies a difference in where or how much the gene is
    de-repressed that the enhancer-adoption and silencer-loss models do not yet
    specify.
  evidence:
  - reference: PMID:30842973
    reference_title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This difference could explain the lack of early autonomic symptoms in patients with deletions, as it has been hypothesized that autonomic symptoms in ADLD with duplications are due to spinal cord involvement."
    explanation: >-
      The authors present the cord-sparing explanation explicitly as a
      hypothesis built on a prior hypothesis, not as an established mechanism.
  - reference: PMID:30697589
    reference_title: Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion."
    explanation: >-
      A second deletion family shows cerebellar involvement, so the
      cerebellar-sparing half of the atypical definition is not consistent
      across the reported families and the phenotype-to-anatomy mapping is
      unsettled.
  proposed_experiments:
  - experiment_id: exp_adld_deletion_cord_autonomic_correlation
    name: Prospective spinal-cord imaging and autonomic testing across ADLD genotypes
    description: >-
      Enroll genotyped ADLD duplication and upstream-deletion carriers,
      including presymptomatic relatives, and pair quantitative cervical and
      thoracic spinal-cord cross-sectional-area measurement with the standard
      autonomic battery, tilt table, QSART, and urodynamics, at matched ages.
      A cord-derived dysautonomia model predicts that autonomic deficit tracks
      cord atrophy within and across genotypes; a genotype effect that survives
      adjustment for cord atrophy would refute it.
    experiment_type:
      preferred_term: Genotype-stratified prospective imaging and autonomic phenotyping study
- discussion_id: gap_adld_model_to_human_cellular_mechanism
  prompt: >-
    Which oligodendrocyte, astrocyte, and axon-myelin-unit abnormalities caused
    by LMNB1 overexpression are causal in human ADLD, and what mechanism
    produces the early autonomic phenotype that current mouse models lack?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#RAVER2/PTB-Dependent PLP1 Spliceopathy
  - pathophysiology#Oligodendrocyte Lipid and Myelin Program Dysfunction
  - pathophysiology#Astrocyte LIF-Support Dysfunction
  - pathophysiology#Axon-Myelin Unit Injury
  - pathophysiology#Autonomic-System Involvement (Mechanism Unresolved)
  rationale: >-
    Available mouse and cultured-cell models yield conflicting cell-type results
    and do not reproduce the early autonomic manifestations seen in patients.
    This mismatch prevents any one glial or axonal branch from being asserted as
    the established human bridge from LMNB1 overexpression to demyelination.
  evidence:
  - reference: PMID:37450245
    reference_title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Indeed, neither of the two in vivo models is able to fully recapitulate the clinical phenotype observed in ADLD patients, since they do not display the autonomic symptoms that are characteristic of ADLD initial stages [36]."
    explanation: The review explicitly documents the model-to-human autonomic mismatch.
  proposed_experiments:
  - experiment_id: exp_adld_patient_derived_glial_coculture
    name: Patient-derived isogenic glial and neuronal co-culture study
    description: >-
      Compare LMNB1-duplication and corrected isogenic iPSC-derived astrocytes,
      oligodendrocytes, and neurons in co-culture, measuring LIF signaling,
      RAVER2/PTB-dependent PLP1 splicing, myelin-lipid programs, axon-myelin
      integrity, and rescue after LMNB1 normalization to distinguish primary
      from secondary cellular effects.
    experiment_type:
      preferred_term: Isogenic patient-derived iPSC co-culture perturbation study
references:
- reference: PMID:26749591
  title: LMNB1-Related Autosomal Dominant Leukodystrophy.
  tags:
  - GeneReviews
  findings: []
- reference: PMID:28769756
  title: "An LMNB1 Duplication Caused Adult-Onset Autosomal Dominant Leukodystrophy in Chinese Family: Clinical Manifestations, Neuroradiology and Genetic Diagnosis."
  findings: []
- reference: PMID:26053668
  title: "LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course."
  findings: []
- reference: PMID:25701871
  title: "A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)."
  findings: []
- reference: PMID:31143934
  title: "Allele-specific silencing as treatment for gene duplication disorders: proof-of-principle in autosomal dominant leukodystrophy."
  findings: []
- reference: DOI:10.1007/s44162-024-00055-w
  title: A retrospective review of LMNB1-related autosomal dominant leukodystrophy
  findings: []
- reference: PMID:37450245
  title: "Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models."
  findings: []
- reference: PMID:37564735
  title: "Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions."
  findings: []
- reference: PMID:40046440
  title: "Case report: LMNB1 duplication-mediated autosomal dominant adult leukodystrophy in a Chinese family and literature review of Chinese patients."
  findings: []
- reference: PMID:30842973
  title: Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.
  findings: []
- reference: PMID:30697589
  title: Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy.
  findings: []
- reference: PMID:39910058
  title: An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants.
  findings: []
- reference: PMID:40933505
  title: Clinical Practice Guidelines for the Diagnosis, Management, and Surveillance of LMNB1-Related Autosomal Dominant Leukodystrophy.
  findings: []

📚

References & Deep Research

References

13

PMID:26749591

LMNB1-Related Autosomal Dominant Leukodystrophy.

No top-level findings curated for this source.

PMID:28769756

An LMNB1 Duplication Caused Adult-Onset Autosomal Dominant Leukodystrophy in Chinese Family: Clinical Manifestations, Neuroradiology and Genetic Diagnosis.

No top-level findings curated for this source.

PMID:26053668

LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course.

No top-level findings curated for this source.

PMID:25701871

A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD).

No top-level findings curated for this source.

PMID:31143934

Allele-specific silencing as treatment for gene duplication disorders: proof-of-principle in autosomal dominant leukodystrophy.

No top-level findings curated for this source.

DOI:10.1007/s44162-024-00055-w

A retrospective review of LMNB1-related autosomal dominant leukodystrophy

No top-level findings curated for this source.

PMID:37450245

Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models.

No top-level findings curated for this source.

PMID:37564735

Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions.

No top-level findings curated for this source.

PMID:40046440

Case report: LMNB1 duplication-mediated autosomal dominant adult leukodystrophy in a Chinese family and literature review of Chinese patients.

No top-level findings curated for this source.

PMID:30842973

Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.

No top-level findings curated for this source.

PMID:30697589

Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy.

No top-level findings curated for this source.

PMID:39910058

An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants.

No top-level findings curated for this source.

PMID:40933505

Clinical Practice Guidelines for the Diagnosis, Management, and Surveillance of LMNB1-Related Autosomal Dominant Leukodystrophy.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 54 citations 2026-05-05T23:43:49.120226

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Adult-Onset Autosomal Dominant Demyelinating Leukodystrophy
MONDO ID: (if available)
Category: Neurodegenerative Disease

Research Objectives

Please provide a comprehensive research report on Adult-Onset Autosomal Dominant Demyelinating Leukodystrophy covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Disease Characteristics Research Report

Target disease

Adult-Onset Autosomal Dominant Demyelinating Leukodystrophy (ADLD; LMNB1-related autosomal dominant leukodystrophy) — a rare, progressive adult-onset leukodystrophy caused by LMNB1 overexpression, leading to central nervous system (CNS) demyelination with a characteristic symmetric MRI pattern and prominent autonomic dysfunction. (ortiz2024aretrospectivereview pages 1-2, neri2023understandingtheultrarare pages 1-2)

Disease / synonyms	Key identifiers explicitly stated	Causal gene & mechanism	Typical age of onset	Core clinical features	Hallmark MRI findings	Natural history / prognosis	Source year & DOI URL	Best supporting citations
Adult-onset autosomal dominant demyelinating leukodystrophy (ADLD); LMNB1-related autosomal dominant leukodystrophy; adult-onset autosomal dominant leukodystrophy with autonomic symptoms	OMIM/MIM #169500 explicitly stated	LMNB1 (5q23.2); heterozygous LMNB1 duplication causing Lamin B1 overexpression and CNS demyelination	Usually 4th-6th decade; mean/median onset around late 30s to 40s	Early autonomic dysfunction (bladder, erectile dysfunction, orthostatic hypotension, sweating abnormalities), then spasticity/pyramidal signs, ataxia/tremor, later cognitive decline	Symmetric confluent T2 white-matter hyperintensities involving deep/periventricular cerebral WM, corticospinal tracts, posterior limb of internal capsule, corpus callosum, brainstem, middle/superior cerebellar peduncles; spinal cord atrophy/thinning	Slowly progressive, fatal/life-limiting; survival often 10-20+ years after onset	2024, https://doi.org/10.1007/s44162-024-00055-w ; 2019, https://doi.org/10.1136/jnnp-2018-319481 ; 2017, https://doi.org/10.3389/fnmol.2017.00215	(ortiz2024aretrospectivereview pages 1-2, ortiz2024aretrospectivereview pages 2-3, dai2017anlmnb1duplication pages 1-2, lin2011adultonsetautosomaldominant pages 1-2)
LMNB1-related ADLD due to upstream noncoding deletion	OMIM #169500 explicitly stated	LMNB1; large heterozygous upstream deletion (e.g., ~660 kb) removes a topological domain boundary, causing enhancer adoption and LMNB1 overexpression	4th-5th decade typically; reported deletion cases 32-52 years	Progressive leukodystrophy with weakness, spasticity, hypophonia/dysarthria, cerebellar dysfunction; compared with duplication cases, may show less early dysautonomia and less cerebellar/spinal involvement	Widespread white-matter alterations; corticospinal tract involvement from upper frontal lobes to cerebral peduncles; spinal cord may be relatively less affected than duplication cases in some families	Fatal progressive course; death often 10-20 years after onset	2015, https://doi.org/10.1093/hmg/ddv065 ; 2019, https://doi.org/10.1212/nxg.0000000000000305	(giorgio2015alargegenomic pages 1-2, nmezi2019genomicdeletionsupstream pages 1-2)
Longitudinal LMNB1-duplication ADLD natural history	Not focused on identifier; disease is LMNB1-related ADLD	LMNB1 duplication	Symptoms usually begin in 5th-6th decade; MRI may be abnormal >10 years before symptoms and as early as age 29 in asymptomatic carriers	Autonomic dysfunction often precedes motor symptoms; ascending myelopathy pattern with gait impairment, spastic paraplegia progressing to tetraplegia/pseudobulbar palsy; mild early cognitive issues, dementia late	Extensive T2 hyperintensities in cerebellar peduncles and cerebral WM with relatively spared periventricular rim early; pyramidal tract extension; all carriers showed spinal cord WM abnormalities; no gadolinium enhancement	EDSS 6 at mean 59 ± 8 years (11 ± 5 years from onset); EDSS 8 at mean 61 ± 6 years (14 ± 4 years from onset); interval EDSS 6→8 5 ± 2 years; deaths at mean 66 ± 6 years (17 ± 6 years from onset); median survival 18 years	2015, https://doi.org/10.1002/ana.24452	(finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 1-2, finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 6-7, finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 9-12, finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 7-9)
Mayo Clinic retrospective LMNB1-related ADLD cohort	No additional identifier stated in excerpt beyond disease name	All 8 patients had LMNB1 duplication	Onset range 33-64 years; median onset 38.5 years; median diagnosis age 46 years	Cognitive difficulties 8/8, fatigue 7/8, mood disturbances 5/8, tremor 4/8, migraine 4/8; sex-specific first symptoms included erectile dysfunction/neurogenic bladder in men and weakness/bladder dysfunction/depression in women	All reviewed brain MRIs showed symmetric confluent T2 deep cerebral/periventricular WM hyperintensities with internal capsule, corpus callosum, brainstem corticospinal tract, superior/middle cerebellar peduncle involvement; spine MRI showed moderate diffuse cord atrophy	Median diagnostic delay 6 years (IQR 2.3-10); white-matter MRI abnormalities can predate symptoms by 9-16 years in examples; no cure, supportive management only	2024, https://doi.org/10.1007/s44162-024-00055-w	(ortiz2024aretrospectivereview pages 1-2, ortiz2024aretrospectivereview pages 2-3, ortiz2024aretrospectivereview pages 3-5)

Table: This table condenses the core disease-defining information for LMNB1-related adult-onset autosomal dominant demyelinating leukodystrophy, including identifiers, mechanisms, phenotype, imaging, and prognosis. It is useful as a quick-reference artifact for knowledge-base population and citation tracking.

Domain	Key points for LMNB1-related ADLD	Practical implementation / test or treatment	Source year + URL	Evidence
Diagnostic clues: clinical phenotype	Adult-onset leukodystrophy, usually 4th-5th decade; early autonomic dysfunction is typical (bladder/bowel dysfunction, orthostatic hypotension, sweating abnormalities, erectile dysfunction), followed by gait impairment, pyramidal signs/spasticity, ataxia, and later cognitive decline; women may present with motor-predominant phenotypes and cases may be mistaken for multiple sclerosis or bvFTD-spectrum disease	Suspect LMNB1-related ADLD in adults with progressive dysautonomia plus spastic-ataxic syndrome and family history suggestive of autosomal dominant inheritance	2024: https://doi.org/10.1007/s44162-024-00055-w ; 2023: https://doi.org/10.3389/fneur.2023.1219324	(ortiz2024aretrospectivereview pages 3-5, muthusamy2023adultonsetleukodystrophiesa pages 10-11)
Diagnostic clues: hallmark MRI	Stereotyped MRI pattern: symmetric confluent T2 white-matter hyperintensities involving deep/periventricular cerebral white matter, corticospinal tracts, posterior limb of the internal capsule, corpus callosum, brainstem, and middle/superior cerebellar peduncles; relative sparing of subcortical U-fibers and periventricular rim may help; spinal cord atrophy/thinning is common; no contrast enhancement is typical	Obtain brain MRI with T2/FLAIR and spine imaging; recognize that MRI abnormalities can predate symptoms by years and may be the earliest clue	2024: https://doi.org/10.1007/s44162-024-00055-w ; 2023: https://doi.org/10.3389/fneur.2023.1219324 ; 2015: https://doi.org/10.1002/ana.24452	(ortiz2024aretrospectivereview pages 2-3, muthusamy2023adultonsetleukodystrophiesa pages 10-11, finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 6-7)
Recommended genetic confirmation	Disease is caused by LMNB1 dosage/expression abnormalities: usually heterozygous LMNB1 duplication, rarely upstream deletion causing LMNB1 overexpression	Order targeted LMNB1 copy-number / structural-variant testing when clinicoradiologic pattern is suggestive	2024: https://doi.org/10.1007/s44162-024-00055-w ; 2023: https://doi.org/10.3389/fneur.2023.1219324 ; 2015: https://doi.org/10.1093/hmg/ddv065	(ortiz2024aretrospectivereview pages 3-5, muthusamy2023adultonsetleukodystrophiesa pages 10-11, giorgio2015alargegenomic pages 1-2)
Genetic methods to use	Copy-number focused methods are required; literature specifically supports targeted CNV/duplication testing and notes use of MLPA, gene-targeted microarray/aCGH, capillary-array methods, qPCR/other CNV assays in adult leukodystrophy workflows; custom array-CGH identified upstream LMNB1 deletion in one family	Preferred methods: LMNB1 deletion/duplication analysis, MLPA, array-CGH/gene-targeted microarray, or other validated CNV assays; consider single-gene LMNB1 testing first if phenotype is classic	2023: https://doi.org/10.3389/fneur.2023.1219324 ; 2024: https://doi.org/10.1007/s44162-024-00055-w ; 2015: https://doi.org/10.1093/hmg/ddv065	(muthusamy2023adultonsetleukodystrophiesa pages 23-24, ortiz2024aretrospectivereview pages 3-5, ortiz2024aretrospectivereview pages 2-3, giorgio2015alargegenomic pages 1-2)
Limitation of standard NGS	Standard short-read NGS/WES/WGS may miss LMNB1 duplications/upstream deletions and other CNV/deep intronic/complex variants; relying only on routine NGS can delay diagnosis	If exome/genome is negative but MRI/phenotype strongly suggest ADLD, reflex to CNV-focused LMNB1 testing rather than stopping workup	2023: https://doi.org/10.3389/fneur.2023.1219324 ; 2024: https://doi.org/10.1007/s44162-024-00055-w	(muthusamy2023adultonsetleukodystrophiesa pages 10-11, ortiz2024aretrospectivereview pages 3-5, muthusamy2023adultonsetleukodystrophiesa pages 21-23)
Ancillary autonomic testing	Autonomic reflex screen, tilt table, QSART, thermoregulatory sweat testing, and urodynamics often show orthostatic hypotension, anhidrosis, and bladder dysfunction	Useful both for phenotype definition and longitudinal monitoring, especially in early dysautonomia	2024: https://doi.org/10.1007/s44162-024-00055-w	(ortiz2024aretrospectivereview pages 2-3)
Ancillary electrophysiology	EMG/NCS are often normal or do not show polyneuropathy; neurophysiology may instead support central myelopathy (e.g., SSEPs, motor conduction delay in some series)	Use EMG/NCS mainly to exclude peripheral neuropathy mimics rather than to confirm ADLD	2024: https://doi.org/10.1007/s44162-024-00055-w ; 2015: https://doi.org/10.1002/ana.24452	(ortiz2024aretrospectivereview pages 2-3, finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 6-7)
General adult leukodystrophy workflow	First exclude acquired mimics (infectious, inflammatory, autoimmune, vascular, neoplastic, toxic, metabolic), then integrate family history, exam, MRI pattern recognition, biochemical testing, and genetics; advanced MRI and periodic reinterpretation improve yield	Practical workflow: history + 3-generation pedigree -> MRI pattern review -> targeted biochemical tests for treatable mimics -> targeted CNV/single-gene testing if classic -> broader panel/WES/WGS with reanalysis if unresolved	2023: https://doi.org/10.3389/fneur.2023.1219324 ; 2019: https://doi.org/10.1148/rg.2019180081 ; 2018: https://doi.org/10.1038/nrneurol.2017.175	(muthusamy2023adultonsetleukodystrophiesa pages 23-24, muthusamy2023adultonsetleukodystrophiesa pages 1-2, muthusamy2023adultonsetleukodystrophiesa pages 21-23, kohler2018adulthoodleukodystrophies pages 3-4, resende2019adultleukodystrophiesa pages 1-2)
Key differential: multiple sclerosis / acquired inflammatory myeloleukoencephalopathy	ADLD can mimic MS, but ADLD typically has symmetric confluent white-matter disease, prominent dysautonomia, lack of gadolinium enhancement, and spinal cord atrophy rather than inflammatory lesions; acquired causes are suggested by rapid onset, steroid responsiveness, systemic features, enhancement	Use MRI symmetry/enhancement pattern, course, and inflammatory context to separate ADLD from MS and other acquired disorders	2023: https://doi.org/10.3389/fneur.2023.1219324 ; 2019: https://doi.org/10.1136/jnnp-2018-319481	(muthusamy2023adultonsetleukodystrophiesa pages 10-11, lynch2019practicalapproachto pages 2-3, muthusamy2023adultonsetleukodystrophiesa pages 21-23)
Key differential: AMN / X-ALD and other inherited leukodystrophies	AMN may show normal brain MRI or pyramidal-tract changes with spinal cord atrophy; AMACR deficiency shows symmetric thalamic/midbrain/pons/cerebellar-tract changes and elevated pristanic acid; CSF1R disease may have early psychiatric syndrome and punctate calcifications on CT/gradient-echo; Gordon Holmes syndrome has prominent cerebellar atrophy/endocrine clues	Distinguish with VLCFA testing, pristanic acid, CT/gradient-echo for calcifications, endocrine evaluation, and disorder-specific gene testing	2023: https://doi.org/10.3389/fneur.2023.1219324 ; 2019: https://doi.org/10.1136/jnnp-2018-319481	(muthusamy2023adultonsetleukodystrophiesa pages 10-11, lynch2019practicalapproachto pages 2-3)
Current standard treatment	No curative or approved disease-modifying therapy; management is supportive and symptomatic	Symptom-directed care may include bladder/autonomic management, spasticity relief, physical/functional exercise, cognitive support, dietary guidance/neurotrophic support in reported case series, and multidisciplinary follow-up	2024: https://doi.org/10.1007/s44162-024-00055-w ; 2025: https://doi.org/10.3389/fnins.2025.1531593	(ortiz2024aretrospectivereview pages 3-5, jiang2025casereportlmnb1 pages 4-5)
Investigational therapy: allele-specific RNAi	Preclinical proof-of-concept supports allele-specific RNA interference to reduce LMNB1 toward physiologic levels without over-suppression; siRNA/shRNA targeting rs1051644 restored LMNB1 mRNA/protein near control levels and improved nuclear morphology and neurite growth in fibroblasts, directly reprogrammed neurons, and oligodendrocyte models	Experimental only; supports LMNB1-lowering as a rational targeted strategy for future translation	2019: https://doi.org/10.1093/brain/awz139	(giorgio2019allelespecificsilencingas pages 1-6, giorgio2019allelespecificsilencingas pages 6-10, giorgio2019allelespecificsilencingas pages 17-20, giorgio2019allelespecificsilencingas pages 20-23)
Investigational therapy: personalized ASO clinical trial	ClinicalTrials.gov lists a personalized antisense oligonucleotide trial for a single participant with LMNB1-duplication ADLD: nL-LMNB1-001, open-label, phase 1/2, active-not-recruiting, sponsor n-Lorem Foundation with Mayo Clinic collaboration, enrollment 1	Endpoints at baseline and 6/12/18/24 months include gait motion analysis, 6-minute walk, 25-feet walk, neurological functioning, MRI brain atrophy; secondary measures include urodynamics, autonomic testing, and safety/tolerability	2025 registry entry: https://clinicaltrials.gov/study/NCT06816498	(NCT06816498 chunk 1)

Table: This table summarizes how LMNB1-related ADLD is recognized and confirmed in practice, including the MRI and autonomic phenotype, the need for CNV-focused LMNB1 testing beyond standard NGS, major differential diagnoses, and the current treatment landscape from supportive care to emerging gene-silencing therapies and the personalized ASO trial NCT06816498.

1. Disease information

1.1 Overview (current understanding)

ADLD is a slowly progressive, life-limiting/fatal adult-onset leukodystrophy characterized by progressive CNS white-matter loss/demyelination, typically beginning with autonomic dysfunction and later evolving to spasticity/pyramidal signs and ataxia, with cognitive decline occurring later in the course in many patients. (ortiz2024aretrospectivereview pages 1-2, neri2023understandingtheultrarare pages 1-2, nmezi2019genomicdeletionsupstream pages 1-2)

A key practical diagnostic observation from longitudinal cohorts is that MRI can become abnormal many years before symptoms, making imaging pattern recognition a major real-world entry point for diagnosis. (finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 6-7, ortiz2024aretrospectivereview pages 3-5)

1.2 Key identifiers

OMIM/MIM: 169500 (“ADLD”) is explicitly stated in multiple primary sources. (dai2017anlmnb1duplication pages 1-2, nmezi2019genomicdeletionsupstream pages 1-2)
Other requested identifiers (Orphanet, ICD-10/11, MeSH, MONDO): not present in the retrieved full-text excerpts used for this report; therefore they cannot be reported here with evidence-grade citation. (ortiz2024aretrospectivereview pages 1-2, neri2023understandingtheultrarare pages 1-2)

1.3 Synonyms / alternative names

Synonyms used in the cited literature include: * “LMNB1-related autosomal dominant leukodystrophy” (ortiz2024aretrospectivereview pages 1-2) * “Adult-onset autosomal dominant leukodystrophy with autonomic symptoms” (santos2012adultonsetautosomaldominant pages 3-3) * “Autosomal Dominant Leukodystrophy with Autonomic Disease” (educational materials) (gosky2021assessmentanddevelopment pages 92-96)

1.4 Evidence provenance

The information in this report is derived primarily from: * Aggregated disease-level resources: expert reviews and structured diagnostic guides for adult leukodystrophies (2023–2024 emphasized). (neri2023understandingtheultrarare pages 1-2, muthusamy2023adultonsetleukodystrophiesa pages 10-11) * Human clinical cohorts/case series: longitudinal natural history (Finnsson 2015) and a 2024 Mayo Clinic retrospective cohort. (finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 6-7, ortiz2024aretrospectivereview pages 1-2) * Mechanistic/model-organism studies: transgenic mouse and cellular models summarized in the 2023 mechanistic review. (neri2023understandingtheultrarare pages 4-6, neri2023understandingtheultrarare pages 6-7)

2. Etiology

2.1 Disease causal factors

ADLD is fundamentally a genetic dosage/regulatory disorder: both coding and non-coding structural alterations at the LMNB1 locus converge on LMNB1 (lamin B1) overexpression, which is considered causal for CNS demyelination. (neri2023understandingtheultrarare pages 1-2, nmezi2019genomicdeletionsupstream pages 1-2)

Two established pathogenic alteration classes: 1. Tandem duplication spanning LMNB1 (most common) → increased LMNB1 gene dosage and expression. (dai2017anlmnb1duplication pages 1-2, nmezi2019genomicdeletionsupstream pages 1-2) 2. Upstream non-coding deletions that cause enhancer adoption (disrupted 3D genomic boundary permitting forebrain enhancers to activate LMNB1) → LMNB1 overexpression without LMNB1 coding duplication. (giorgio2015alargegenomic pages 1-2, nmezi2019genomicdeletionsupstream pages 1-2)

Quantitative tissue evidence for LMNB1 overexpression includes ~2–3-fold increased LMNB1 transcripts in one upstream-deletion family, and ~7-fold increased lamin B1 protein in frontal lobe compared with control in postmortem tissue. (giorgio2015alargegenomic pages 1-2)

2.2 Risk factors

Primary risk factor: autosomal dominant inheritance of a pathogenic LMNB1 structural variant. Family history is frequently present (e.g., 6/8 in one Mayo cohort). (ortiz2024aretrospectivereview pages 1-2)

Non-genetic/environmental susceptibility factors are not established in the cited sources; the disorder is best understood as genetically driven. (neri2023understandingtheultrarare pages 1-2)

2.3 Protective factors

No protective genetic variants or protective environmental factors were identified in the retrieved evidence. (neri2023understandingtheultrarare pages 1-2)

2.4 Gene–environment interaction

Not clearly established in the retrieved evidence. Some clinical observations in longitudinal cohorts include pseudoexacerbations with heat, fever, or infections, suggesting that environmental stressors can transiently worsen symptoms, but these do not constitute validated causal gene–environment interactions. (finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 9-12)

3. Phenotypes

3.1 Core phenotype spectrum (human)

Across cohorts, the most characteristic phenotype is early autonomic dysfunction, followed by progressive motor system involvement: * Autonomic dysfunction: neurogenic bladder/urinary urgency, orthostatic hypotension, anhidrosis/sweating abnormalities; in a longitudinal cohort, bladder dysfunction was present in 100% and orthostatic hypotension in 77%. (finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 6-7) * Pyramidal tract dysfunction: spasticity, progressive spastic paraparesis progressing caudal→rostral in advanced disease. (finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 9-12) * Cerebellar involvement: ataxia, tremor; in a Mayo cohort tremor occurred in 4/8. (ortiz2024aretrospectivereview pages 1-2) * Cognitive/psychiatric: cognitive difficulties were reported in 8/8 in the Mayo cohort; mood disturbances 5/8; sleep issues 4/8. (ortiz2024aretrospectivereview pages 1-2)

3.2 Phenotype characteristics (age of onset, progression)

Onset: commonly in the 4th–6th decade; 2024 Mayo cohort onset range 33–64 years. (ortiz2024aretrospectivereview pages 1-2)
Progression: slow, insidious progression over years with increasing disability; a characteristic ascending myelopathy pattern is described in the longitudinal study. (finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 1-2, finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 9-12)

3.3 Phenotype frequencies (recent quantitative cohort)

From an 8-patient Mayo Clinic retrospective cohort (molecularly confirmed LMNB1 duplication): * cognitive difficulties 8/8 * fatigue 7/8 * sleep issues 4/8 * mood disturbances 5/8 * tremor 4/8 * migraine 4/8 * family history positive 6/8 * diagnostic delay: median 6 years (IQR 2.3–10) (ortiz2024aretrospectivereview pages 1-2)

3.4 Quality of life impact

Direct standardized quality-of-life instruments (EQ-5D/SF-36/PROMIS) were not reported in the retrieved excerpts. However, progressive disability milestones (EDSS progression) and autonomic morbidity (urodynamic abnormalities) indicate substantial impairment in mobility and daily functioning. (finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 6-7, ortiz2024aretrospectivereview pages 2-3)

3.5 Suggested HPO terms (examples)

Based on described clinical features, plausible HPO mappings include: * Autonomic dysfunction: Neurogenic bladder (HP:0000010); Orthostatic hypotension (HP:0001278); Anhidrosis (HP:0000970); Erectile dysfunction (HP:0100639) (ortiz2024aretrospectivereview pages 1-2, finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 6-7) * Motor: Spasticity (HP:0001257); Spastic paraplegia (HP:0001258); Ataxia (HP:0001251); Tremor (HP:0001337) (ortiz2024aretrospectivereview pages 1-2, finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 9-12) * Cognitive/psychiatric: Cognitive impairment (HP:0100543); Depression (HP:0000716) (ortiz2024aretrospectivereview pages 1-2)

(These HPO IDs are suggested mappings; the retrieved sources did not explicitly list HPO codes.)

4. Genetic / molecular information

4.1 Causal gene

LMNB1 (lamin B1) is the causal gene; disease results from LMNB1 overexpression rather than canonical loss-of-function. (neri2023understandingtheultrarare pages 1-2, lin2011adultonsetautosomaldominant pages 1-2)

4.2 Pathogenic variant classes

Structural duplication of LMNB1 (copy-number gain), often spanning the full gene. (dai2017anlmnb1duplication pages 1-2, santos2012adultonsetautosomaldominant pages 3-3)
Nonrecurrent upstream deletions (regulatory structural variants) causing enhancer adoption. (giorgio2015alargegenomic pages 1-2, nmezi2019genomicdeletionsupstream pages 1-2)

4.3 Functional consequence

The convergent molecular consequence is increased Lamin B1 levels (gain-of-function by overexpression), perturbing nuclear lamina stoichiometry and downstream chromatin/transcription/splicing programs in myelin-relevant cells. (neri2023understandingtheultrarare pages 2-4, neri2023understandingtheultrarare pages 6-7)

4.4 Modifier genes / epigenetics

Direct human modifier genes were not identified in the retrieved excerpts. However, mechanistic work suggests epigenetic shifts in oligodendrocytes under LMNB1 overexpression, including increased repressive histone marks (H3K9me3, H3K27me3) and reduced activating acetylation marks (AcH3, AcH4) in aged oligodendrocytes in transgenic models. (neri2023understandingtheultrarare pages 6-7)

5. Environmental information

No specific environmental toxins, lifestyle exposures, or infectious triggers were established as causal in the retrieved literature excerpts; ADLD is best understood as genetically caused. (neri2023understandingtheultrarare pages 1-2)

6. Mechanism / pathophysiology (current understanding)

6.1 Causal chain (integrated model)

Upstream trigger: LMNB1 structural variant (duplication or upstream deletion) → LMNB1 overexpression. (neri2023understandingtheultrarare pages 1-2, nmezi2019genomicdeletionsupstream pages 1-2)
Nuclear lamina/chromatin effects: Lamin B1 excess disturbs nuclear lamina architecture (misshaped/folded nuclei; increased nuclear rigidity) and alters chromatin organization and transcriptional silencing at the nuclear periphery. (neri2023understandingtheultrarare pages 4-6, lin2011adultonsetautosomaldominant pages 1-2)
Myelin cell dysfunction (oligodendrocyte-centered mechanisms): oligodendrocyte-targeted LMNB1 overexpression can cause premature differentiation arrest and repression of lipid synthesis pathways; in one spinal-cord transgenic model, multiple downregulated genes mapped to lipid synthesis and lipidomics showed reduced myelin lipids. (neri2023understandingtheultrarare pages 4-6)
Spliceopathy and myelin gene dysregulation: LMNB1 increase is associated with upregulation of RAVER2, inhibiting PTB and contributing to abnormal splicing of PTB-target genes including PLP1, and PLP1 downregulation has been linked to reduced YY1 binding. (neri2023understandingtheultrarare pages 7-9, dai2017anlmnb1duplication pages 1-2)
Non-cell-autonomous contributions (astrocytopathy): astrocyte LMNB1 accumulation can reduce LIF/LIF-R signaling and downstream PI3K/Akt/mTOR pathway activity, impairing support for oligodendrocytes; astrocytes show reduced viability and reactive changes. (neri2023understandingtheultrarare pages 6-7, neri2023understandingtheultrarare pages 7-9)
Downstream tissue outcome: progressive, largely non-inflammatory CNS demyelination with vacuolated white matter and relative preservation of oligodendroglia in pathology descriptions. (lin2011adultonsetautosomaldominant pages 1-2)

6.2 Immune involvement

ADLD is generally described as lacking prominent inflammatory demyelination; neuropathology notes vacuolated white matter without significant inflammatory infiltrates, distinguishing it from autoimmune demyelination paradigms. (lin2011adultonsetautosomaldominant pages 1-2)

6.3 Oxidative stress / inflammatory signaling

Patient-derived cells show disturbed oxidative stress responses and increased ROS after oxidative challenge, and increased activation of inflammatory signaling markers (e.g., phosphorylated NF-κB) in fibroblast-based studies, though confirmation in patient CNS tissue remains an open need. (neri2023understandingtheultrarare pages 7-9)

6.4 Suggested GO biological process terms (examples)

Based on mechanisms discussed: * Chromatin organization and negative regulation of transcription (lin2011adultonsetautosomaldominant pages 1-2, neri2023understandingtheultrarare pages 6-7) * Myelination / oligodendrocyte differentiation (neri2023understandingtheultrarare pages 4-6) * Lipid biosynthetic process (myelin lipid synthesis dysregulation) (neri2023understandingtheultrarare pages 4-6) * mRNA splicing (RAVER2/PTB axis) (neri2023understandingtheultrarare pages 7-9)

(GO IDs not explicitly provided in the sources; these are suggested mappings.)

6.5 Suggested Cell Ontology (CL) terms (examples)

Key implicated cell types include: * Oligodendrocytes (myelin-producing CNS glia) (neri2023understandingtheultrarare pages 4-6, oranburg2023establishingmodelsystems pages 27-31) * Astrocytes (LIF signaling and reactive changes) (neri2023understandingtheultrarare pages 7-9) * Neurons (nuclear morphology and neurite phenotypes in models) (giorgio2019allelespecificsilencingas pages 20-23)

(CL IDs not explicitly provided; suggested mappings.)

7. Anatomical structures affected

7.1 Organ/system level

Primary: central nervous system white matter (brain and spinal cord), with prominent clinical contributions from autonomic pathways and long motor tracts. (ortiz2024aretrospectivereview pages 2-3, finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 6-7)

7.2 Tissue/cell level

Primary tissue: CNS white matter with demyelination; implicated cell types include oligodendrocytes (directly, via cell-specific overexpression models) and astrocytes (supportive signaling dysfunction). (neri2023understandingtheultrarare pages 4-6, neri2023understandingtheultrarare pages 6-7)

7.3 Subcellular

Core subcellular compartment implicated: nuclear lamina / nuclear envelope and its chromatin tethering domains. (lin2011adultonsetautosomaldominant pages 1-2)

7.4 Suggested UBERON terms (examples)

Brain white matter and spinal cord white matter (ortiz2024aretrospectivereview pages 2-3, finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 9-12)
Internal capsule and corpus callosum (ortiz2024aretrospectivereview pages 2-3)
Cerebellar peduncles (ortiz2024aretrospectivereview pages 2-3)

(UBERON IDs not explicitly provided; suggested mappings.)

8. Temporal development

8.1 Onset

Onset is typically insidious in mid-adulthood (often 4th–6th decade), with MRI abnormalities potentially preceding symptoms by a decade or more in some individuals. (ortiz2024aretrospectivereview pages 1-2, finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 6-7)

8.2 Progression and staging (data-supported milestones)

Longitudinal natural history in LMNB1-duplication families provides disability and survival estimates: * EDSS 6 at mean age 59 ± 8 years, about 11 ± 5 years from symptom onset. * EDSS 8 at mean age 61 ± 6 years, about 14 ± 4 years from onset. * Deaths at mean age 66 ± 6 years, about 17 ± 6 years from onset. * Median survival after onset 18 years. (finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 6-7, finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 9-12)

8.3 Remission/relapse patterns

A relapsing-remitting course is not typical; pseudoexacerbations with heat/infection can occur. (finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 9-12)

9. Inheritance and population

9.1 Inheritance

Inheritance is autosomal dominant, consistent with structural variants that increase LMNB1 expression. (gosky2021assessmentanddevelopment pages 18-22, nmezi2019genomicdeletionsupstream pages 1-2)

9.2 Epidemiology

ADLD is ultra-rare; multiple sources state that >30 families have been reported worldwide and that exact prevalence is unknown due to rarity and diagnostic challenges. (neri2023understandingtheultrarare pages 1-2, ortiz2024aretrospectivereview pages 3-5)

Educational materials summarize older literature counts as “at least 24 families” and “>70 individuals,” and emphasize likely underdiagnosis. (gosky2021assessmentanddevelopment pages 18-22)

No robust sex ratio, penetrance estimates, or population prevalence/incidence rates were identified in the retrieved excerpts. (ortiz2024aretrospectivereview pages 3-5)

10. Diagnostics

10.1 Clinical and imaging diagnostics

The practical, high-yield diagnostic pathway is: 1. Recognize the adult-onset dysautonomia + spastic-ataxic syndrome. 2. Identify the characteristic symmetric MRI pattern, including corticospinal tract involvement and cerebellar peduncle lesions; spine MRI may show cord thinning/atrophy. 3. Confirm with LMNB1 duplication/deletion testing, using methods that detect CNVs/structural variants. (ortiz2024aretrospectivereview pages 3-5, muthusamy2023adultonsetleukodystrophiesa pages 10-11)

MRI details in a 2024 cohort: all reviewed MRIs showed symmetric confluent deep cerebral and periventricular T2 hyperintensities with involvement of posterior limb internal capsule, corpus callosum, brainstem corticospinal tracts, superior/middle cerebellar peduncles, and spine MRI showed diffuse spinal cord atrophy. (ortiz2024aretrospectivereview pages 1-2, ortiz2024aretrospectivereview pages 2-3)

10.2 Genetic testing strategy

A critical real-world point from 2023–2024 expert sources is that routine short-read NGS may not reliably detect LMNB1 duplications/upstream deletions, so the clinician must order CNV/structural-variant assays (e.g., deletion/duplication analysis, MLPA, gene-targeted microarray/array-CGH) when the phenotype/MRI are classic. (muthusamy2023adultonsetleukodystrophiesa pages 21-23, ortiz2024aretrospectivereview pages 3-5)

10.3 Differential diagnosis (key examples)

Because adult leukodystrophies overlap with MS and other acquired leukoencephalopathies, reviews emphasize first excluding acquired mimics and using imaging patterns/biochemical testing to distinguish inherited conditions. (muthusamy2023adultonsetleukodystrophiesa pages 23-24, muthusamy2023adultonsetleukodystrophiesa pages 21-23)

A 2023 practical guide explicitly highlights differentials and distinguishing tests, including AMN/X-ALD (VLCFA; spinal cord atrophy), AMACR deficiency (pristanic acid), CSF1R disease (calcifications on CT/gradient-echo), and emphasizes the LMNB1 ADLD MRI signature and CNV testing needs. (muthusamy2023adultonsetleukodystrophiesa pages 10-11)

11. Outcome / prognosis

ADLD is slowly progressive but ultimately severe, with a multi-decade course in many patients. Quantified outcomes include EDSS milestone timing and survival described above (Section 8). (finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 6-7)

Diagnostic delay is substantial in real-world practice: median 6 years from symptom onset to diagnosis in one 2024 cohort. (ortiz2024aretrospectivereview pages 1-2)

12. Treatment

12.1 Current standard of care (real-world)

No established disease-modifying therapy was identified in the cited clinical literature; care is supportive/symptomatic, targeting dysautonomia (bladder and orthostatic intolerance), spasticity, mobility and functional decline, and cognitive/psychiatric symptoms. (ortiz2024aretrospectivereview pages 3-5, jiang2025casereportlmnb1 pages 4-5)

12.2 Experimental / emerging therapeutics

LMNB1-lowering strategies are the most mechanistically aligned targeted approaches:

Allele-specific RNA interference (preclinical proof-of-concept). In patient fibroblasts and disease-relevant cellular models, allele-specific siRNA/shRNA targeting a common LMNB1 3′UTR SNP (rs1051644) reduced LMNB1 expression toward physiologic levels and improved ADLD-associated cellular phenotypes. In directly reprogrammed neurons, allele-specific shRNA produced ~30% Lamin B1 protein reduction with improved nuclear anomalies and neurite growth. (giorgio2019allelespecificsilencingas pages 17-20, giorgio2019allelespecificsilencingas pages 20-23)
Personalized antisense oligonucleotide (ASO) therapy clinical trial (single participant). ClinicalTrials.gov lists an open-label phase 1/2 trial of a personalized ASO (nL-LMNB1-001) in a single participant with LMNB1-duplication ADLD (NCT06816498), started 2025-03-17, ACTIVE_NOT_RECRUITING; endpoints include gait metrics (6-minute walk, 25-foot walk, motion analysis), neurological functioning, MRI brain atrophy, plus urodynamics and autonomic tests for secondary outcomes. (NCT06816498 chunk 1)

12.3 Suggested MAXO terms (examples)

Not explicitly provided in sources; suggested mappings include: * Genetic counseling (autosomal dominant inheritance) (gosky2021assessmentanddevelopment pages 18-22) * Symptomatic treatment of spasticity and autonomic dysfunction (jiang2025casereportlmnb1 pages 4-5) * Antisense oligonucleotide therapy / RNA interference (investigational) (NCT06816498 chunk 1, giorgio2019allelespecificsilencingas pages 17-20)

13. Prevention

Primary prevention is not currently feasible because ADLD is a dominantly inherited genetic disorder. Prevention is best framed as: * Secondary prevention: early recognition via MRI/clinical features and confirmatory genetic testing to reduce diagnostic delay and enable anticipatory management and trial eligibility. (ortiz2024aretrospectivereview pages 3-5, muthusamy2023adultonsetleukodystrophiesa pages 21-23) * Tertiary prevention: management of complications (orthostatic hypotension, bladder dysfunction, spasticity) and supportive rehabilitation. (ortiz2024aretrospectivereview pages 2-3)

Genetic counseling is central given autosomal dominant inheritance and 50% transmission risk to offspring of an affected parent. (gosky2021assessmentanddevelopment pages 18-22)

14. Other species / natural disease

No naturally occurring veterinary ADLD analogs were identified in the retrieved evidence; the literature retrieved emphasizes engineered model systems rather than naturally occurring cross-species disease. (neri2023understandingtheultrarare pages 2-4)

15. Model organisms

Multiple model systems support mechanistic study and therapy development: * Transgenic mouse models with oligodendrocyte-specific LMNB1 overexpression (Plp1 promoter; PLP-FLAG-LMNB1) recapitulate age-dependent white matter degeneration and motor dysfunction, supporting oligodendrocytes as key vulnerability points. (oranburg2023establishingmodelsystems pages 27-31, henck2024singlecellsequencing pages 26-29) * LMNB1BAC / PLP-LMNB1Tg mice show age-dependent demyelination and neurological phenotypes (motor/cognitive/epileptic), summarized in the 2023 review. (neri2023understandingtheultrarare pages 2-4) * Human cellular models include patient-derived fibroblasts and directly reprogrammed neurons used for mechanistic assays and proof-of-concept gene silencing. (giorgio2019allelespecificsilencingas pages 17-20)

Limitations emphasized across sources: cell-type specificity remains incompletely explained, mechanistic findings vary by model, and many molecular signatures require validation in patient CNS tissue. (neri2023understandingtheultrarare pages 2-4)

Direct abstract quotes supporting key claims (from retrieved abstracts)

2024 cohort definition: “LMNB1-related autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurodegenerative disorder caused by overexpression of LMNB1.” (ortiz2024aretrospectivereview pages 1-2)
2015 enhancer adoption mechanism: “Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination.” (giorgio2015alargegenomic pages 1-2)
2025 trial registry summary (ClinicalTrials.gov): describes “Personalized Antisense Oligonucleotide Therapy for A Single Participant With LMNB1 Mutation Associated Autosomal Dominant Leukodystrophy (ADLD)” with endpoints including gait testing and MRI atrophy measures. (NCT06816498 chunk 1)

Notes on missing template elements

MONDO / Orphanet / ICD / MeSH codes: not available in the retrieved excerpts; reporting them without evidence would require direct database querying not supported by the current tool evidence set. (neri2023understandingtheultrarare pages 1-2)
Variant-level HGVS nomenclature, ClinVar classifications, gnomAD allele frequencies: not present in the retrieved excerpts; ADLD is primarily associated with structural variants (duplications/deletions) that often require specialized CNV assays and may not be represented uniformly in variant databases. (muthusamy2023adultonsetleukodystrophiesa pages 21-23)

References

(ortiz2024aretrospectivereview pages 1-2): Judit M. Perez Ortiz, Karthik Muthusamy, W. Oliver Tobin, Ralitza Gavrilova, Margot A. Cousin, and Radhika Dhamija. A retrospective review of lmnb1-related autosomal dominant leukodystrophy. Journal of Rare Diseases, Oct 2024. URL: https://doi.org/10.1007/s44162-024-00055-w, doi:10.1007/s44162-024-00055-w. This article has 0 citations.
(neri2023understandingtheultrarare pages 1-2): Irene Neri, Giulia Ramazzotti, Sara Mongiorgi, Isabella Rusciano, Marianna Bugiani, Luciano Conti, Margot Cousin, Elisa Giorgio, Quasar S. Padiath, Giovanna Vaula, Pietro Cortelli, Lucia Manzoli, and Stefano Ratti. Understanding the ultra-rare disease autosomal dominant leukodystrophy: an updated review on morpho-functional alterations found in experimental models. Molecular Neurobiology, 60:6362-6372, Jul 2023. URL: https://doi.org/10.1007/s12035-023-03461-1, doi:10.1007/s12035-023-03461-1. This article has 16 citations and is from a peer-reviewed journal.
(ortiz2024aretrospectivereview pages 2-3): Judit M. Perez Ortiz, Karthik Muthusamy, W. Oliver Tobin, Ralitza Gavrilova, Margot A. Cousin, and Radhika Dhamija. A retrospective review of lmnb1-related autosomal dominant leukodystrophy. Journal of Rare Diseases, Oct 2024. URL: https://doi.org/10.1007/s44162-024-00055-w, doi:10.1007/s44162-024-00055-w. This article has 0 citations.
(dai2017anlmnb1duplication pages 1-2): Yi Dai, Yaling Ma, Shengde Li, Santasree Banerjee, Shengran Liang, Qing Liu, Yinchang Yang, Bin Peng, Liying Cui, and Liri Jin. An lmnb1 duplication caused adult-onset autosomal dominant leukodystrophy in chinese family: clinical manifestations, neuroradiology and genetic diagnosis. Frontiers in Molecular Neuroscience, Jul 2017. URL: https://doi.org/10.3389/fnmol.2017.00215, doi:10.3389/fnmol.2017.00215. This article has 25 citations.
(lin2011adultonsetautosomaldominant pages 1-2): Shu-Ting Lin, Louis J. Ptáček, and Ying-Hui Fu. Adult-onset autosomal dominant leukodystrophy: linking nuclear envelope to myelin. The Journal of Neuroscience, 31:1163-1166, Jan 2011. URL: https://doi.org/10.1523/jneurosci.5994-10.2011, doi:10.1523/jneurosci.5994-10.2011. This article has 33 citations.
(giorgio2015alargegenomic pages 1-2): Elisa Giorgio, Daniel Robyr, Malte Spielmann, Enza Ferrero, Eleonora Di Gregorio, Daniele Imperiale, Giovanna Vaula, Georgios Stamoulis, Federico Santoni, Cristiana Atzori, Laura Gasparini, Denise Ferrera, Claudio Canale, Michel Guipponi, Len A. Pennacchio, Stylianos E. Antonarakis, Alessandro Brussino, and Alfredo Brusco. A large genomic deletion leads to enhancer adoption by the lamin b1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (adld). Human Molecular Genetics, 24:3143-3154, Feb 2015. URL: https://doi.org/10.1093/hmg/ddv065, doi:10.1093/hmg/ddv065. This article has 178 citations and is from a domain leading peer-reviewed journal.
(nmezi2019genomicdeletionsupstream pages 1-2): Bruce Nmezi, Elisa Giorgio, Raili Raininko, Anna Lehman, Malte Spielmann, Mary Kay Koenig, Rahmat Adejumo, Melissa Knight, Ralitza Gavrilova, Murad Alturkustani, Manas Sharma, Robert Hammond, William A. Gahl, Camilo Toro, Alfredo Brusco, and Quasar S. Padiath. Genomic deletions upstream of lamin b1 lead to atypical autosomal dominant leukodystrophy. Neurology Genetics, Feb 2019. URL: https://doi.org/10.1212/nxg.0000000000000305, doi:10.1212/nxg.0000000000000305. This article has 31 citations.
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(finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 6-7): Johannes Finnsson, Jimmy Sundblom, Niklas Dahl, Atle Melberg, and Raili Raininko. Lmnb1‐related autosomal‐dominant leukodystrophy: clinical and radiological course. Annals of Neurology, 78:412-425, Jul 2015. URL: https://doi.org/10.1002/ana.24452, doi:10.1002/ana.24452. This article has 61 citations and is from a highest quality peer-reviewed journal.
(finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 9-12): Johannes Finnsson, Jimmy Sundblom, Niklas Dahl, Atle Melberg, and Raili Raininko. Lmnb1‐related autosomal‐dominant leukodystrophy: clinical and radiological course. Annals of Neurology, 78:412-425, Jul 2015. URL: https://doi.org/10.1002/ana.24452, doi:10.1002/ana.24452. This article has 61 citations and is from a highest quality peer-reviewed journal.
(finnsson2015lmnb1‐relatedautosomal‐dominantleukodystrophy pages 7-9): Johannes Finnsson, Jimmy Sundblom, Niklas Dahl, Atle Melberg, and Raili Raininko. Lmnb1‐related autosomal‐dominant leukodystrophy: clinical and radiological course. Annals of Neurology, 78:412-425, Jul 2015. URL: https://doi.org/10.1002/ana.24452, doi:10.1002/ana.24452. This article has 61 citations and is from a highest quality peer-reviewed journal.
(ortiz2024aretrospectivereview pages 3-5): Judit M. Perez Ortiz, Karthik Muthusamy, W. Oliver Tobin, Ralitza Gavrilova, Margot A. Cousin, and Radhika Dhamija. A retrospective review of lmnb1-related autosomal dominant leukodystrophy. Journal of Rare Diseases, Oct 2024. URL: https://doi.org/10.1007/s44162-024-00055-w, doi:10.1007/s44162-024-00055-w. This article has 0 citations.
(muthusamy2023adultonsetleukodystrophiesa pages 10-11): Karthik Muthusamy, Ajith Sivadasan, Luke Dixon, Sniya Sudhakar, Maya Thomas, Sumita Danda, Zbigniew K. Wszolek, Klaas Wierenga, Radhika Dhamija, and Ralitza Gavrilova. Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions. Frontiers in Neurology, Jul 2023. URL: https://doi.org/10.3389/fneur.2023.1219324, doi:10.3389/fneur.2023.1219324. This article has 30 citations and is from a peer-reviewed journal.
(muthusamy2023adultonsetleukodystrophiesa pages 23-24): Karthik Muthusamy, Ajith Sivadasan, Luke Dixon, Sniya Sudhakar, Maya Thomas, Sumita Danda, Zbigniew K. Wszolek, Klaas Wierenga, Radhika Dhamija, and Ralitza Gavrilova. Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions. Frontiers in Neurology, Jul 2023. URL: https://doi.org/10.3389/fneur.2023.1219324, doi:10.3389/fneur.2023.1219324. This article has 30 citations and is from a peer-reviewed journal.
(muthusamy2023adultonsetleukodystrophiesa pages 21-23): Karthik Muthusamy, Ajith Sivadasan, Luke Dixon, Sniya Sudhakar, Maya Thomas, Sumita Danda, Zbigniew K. Wszolek, Klaas Wierenga, Radhika Dhamija, and Ralitza Gavrilova. Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions. Frontiers in Neurology, Jul 2023. URL: https://doi.org/10.3389/fneur.2023.1219324, doi:10.3389/fneur.2023.1219324. This article has 30 citations and is from a peer-reviewed journal.
(muthusamy2023adultonsetleukodystrophiesa pages 1-2): Karthik Muthusamy, Ajith Sivadasan, Luke Dixon, Sniya Sudhakar, Maya Thomas, Sumita Danda, Zbigniew K. Wszolek, Klaas Wierenga, Radhika Dhamija, and Ralitza Gavrilova. Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions. Frontiers in Neurology, Jul 2023. URL: https://doi.org/10.3389/fneur.2023.1219324, doi:10.3389/fneur.2023.1219324. This article has 30 citations and is from a peer-reviewed journal.
(kohler2018adulthoodleukodystrophies pages 3-4): Wolfgang Köhler, Julian Curiel, and Adeline Vanderver. Adulthood leukodystrophies. Nature Reviews Neurology, 14:94-105, Jan 2018. URL: https://doi.org/10.1038/nrneurol.2017.175, doi:10.1038/nrneurol.2017.175. This article has 169 citations and is from a highest quality peer-reviewed journal.
(resende2019adultleukodystrophiesa pages 1-2): Lucas Lopes Resende, Anderson Rodrigues Brandão de Paiva, Fernando Kok, Claudia da Costa Leite, and Leandro Tavares Lucato. Adult leukodystrophies: a step-by-step diagnostic approach. Radiographics : a review publication of the Radiological Society of North America, Inc, 39 1:153-168, Jan 2019. URL: https://doi.org/10.1148/rg.2019180081, doi:10.1148/rg.2019180081. This article has 93 citations.
(lynch2019practicalapproachto pages 2-3): David S Lynch, Charles Wade, Anderson Rodrigues Brandão de Paiva, Nevin John, Justin A Kinsella, Áine Merwick, Rebekah M Ahmed, Jason D Warren, Catherine J Mummery, Jonathan M Schott, Nick C Fox, Henry Houlden, Matthew E Adams, Indran Davagnanam, Elaine Murphy, and Jeremy Chataway. Practical approach to the diagnosis of adult-onset leukodystrophies: an updated guide in the genomic era. Journal of Neurology, Neurosurgery, and Psychiatry, 90:543-554, Nov 2019. URL: https://doi.org/10.1136/jnnp-2018-319481, doi:10.1136/jnnp-2018-319481. This article has 152 citations.
(jiang2025casereportlmnb1 pages 4-5): Yumeng Jiang, Lu Han, Yaqi Li, Zhihong Zhao, Zikai Xin, and Zilong Zhu. Case report: lmnb1 duplication-mediated autosomal dominant adult leukodystrophy in a chinese family and literature review of chinese patients. Frontiers in Neuroscience, Feb 2025. URL: https://doi.org/10.3389/fnins.2025.1531593, doi:10.3389/fnins.2025.1531593. This article has 0 citations and is from a peer-reviewed journal.
(giorgio2019allelespecificsilencingas pages 1-6): Elisa Giorgio, Martina Lorenzati, Pia Rivetti di Val Cervo, Alessandro Brussino, Manuel Cernigoj, Edoardo Della Sala, Anna Bartoletti Stella, Marta Ferrero, Massimiliano Caiazzo, Sabina Capellari, Pietro Cortelli, Luciano Conti, Elena Cattaneo, Annalisa Buffo, and Alfredo Brusco. Allele-specific silencing as treatment for gene duplication disorders: proof-of-principle in autosomal dominant leukodystrophy. Brain : a journal of neurology, 142:1905-1920, May 2019. URL: https://doi.org/10.1093/brain/awz139, doi:10.1093/brain/awz139. This article has 26 citations.
(giorgio2019allelespecificsilencingas pages 6-10): Elisa Giorgio, Martina Lorenzati, Pia Rivetti di Val Cervo, Alessandro Brussino, Manuel Cernigoj, Edoardo Della Sala, Anna Bartoletti Stella, Marta Ferrero, Massimiliano Caiazzo, Sabina Capellari, Pietro Cortelli, Luciano Conti, Elena Cattaneo, Annalisa Buffo, and Alfredo Brusco. Allele-specific silencing as treatment for gene duplication disorders: proof-of-principle in autosomal dominant leukodystrophy. Brain : a journal of neurology, 142:1905-1920, May 2019. URL: https://doi.org/10.1093/brain/awz139, doi:10.1093/brain/awz139. This article has 26 citations.
(giorgio2019allelespecificsilencingas pages 17-20): Elisa Giorgio, Martina Lorenzati, Pia Rivetti di Val Cervo, Alessandro Brussino, Manuel Cernigoj, Edoardo Della Sala, Anna Bartoletti Stella, Marta Ferrero, Massimiliano Caiazzo, Sabina Capellari, Pietro Cortelli, Luciano Conti, Elena Cattaneo, Annalisa Buffo, and Alfredo Brusco. Allele-specific silencing as treatment for gene duplication disorders: proof-of-principle in autosomal dominant leukodystrophy. Brain : a journal of neurology, 142:1905-1920, May 2019. URL: https://doi.org/10.1093/brain/awz139, doi:10.1093/brain/awz139. This article has 26 citations.
(giorgio2019allelespecificsilencingas pages 20-23): Elisa Giorgio, Martina Lorenzati, Pia Rivetti di Val Cervo, Alessandro Brussino, Manuel Cernigoj, Edoardo Della Sala, Anna Bartoletti Stella, Marta Ferrero, Massimiliano Caiazzo, Sabina Capellari, Pietro Cortelli, Luciano Conti, Elena Cattaneo, Annalisa Buffo, and Alfredo Brusco. Allele-specific silencing as treatment for gene duplication disorders: proof-of-principle in autosomal dominant leukodystrophy. Brain : a journal of neurology, 142:1905-1920, May 2019. URL: https://doi.org/10.1093/brain/awz139, doi:10.1093/brain/awz139. This article has 26 citations.
(NCT06816498 chunk 1): Personalized Antisense Oligonucleotide Therapy for A Single Participant With LMNB1 Mutation Associated Autosomal Dominant Leukodystrophy (ADLD). n-Lorem Foundation. 2025. ClinicalTrials.gov Identifier: NCT06816498
(santos2012adultonsetautosomaldominant pages 3-3): Michael M. Dos Santos, Caspar Grond-Ginsbach, Suna Su Aksay, Bowang Chen, Sandrine Tchatchou, Nicole I. Wolf, Marjo S. Knaap, and Armin J. Grau. Adult-onset autosomal dominant leukodystrophy due to lmnb1 gene duplication. Journal of Neurology, 259:579-581, Mar 2012. URL: https://doi.org/10.1007/s00415-011-6225-4, doi:10.1007/s00415-011-6225-4. This article has 37 citations and is from a domain leading peer-reviewed journal.
(gosky2021assessmentanddevelopment pages 92-96): MD Gosky. Assessment and development of online educational materials for autosomal dominant leukodystrophy. Unknown journal, 2021.
(neri2023understandingtheultrarare pages 4-6): Irene Neri, Giulia Ramazzotti, Sara Mongiorgi, Isabella Rusciano, Marianna Bugiani, Luciano Conti, Margot Cousin, Elisa Giorgio, Quasar S. Padiath, Giovanna Vaula, Pietro Cortelli, Lucia Manzoli, and Stefano Ratti. Understanding the ultra-rare disease autosomal dominant leukodystrophy: an updated review on morpho-functional alterations found in experimental models. Molecular Neurobiology, 60:6362-6372, Jul 2023. URL: https://doi.org/10.1007/s12035-023-03461-1, doi:10.1007/s12035-023-03461-1. This article has 16 citations and is from a peer-reviewed journal.
(neri2023understandingtheultrarare pages 6-7): Irene Neri, Giulia Ramazzotti, Sara Mongiorgi, Isabella Rusciano, Marianna Bugiani, Luciano Conti, Margot Cousin, Elisa Giorgio, Quasar S. Padiath, Giovanna Vaula, Pietro Cortelli, Lucia Manzoli, and Stefano Ratti. Understanding the ultra-rare disease autosomal dominant leukodystrophy: an updated review on morpho-functional alterations found in experimental models. Molecular Neurobiology, 60:6362-6372, Jul 2023. URL: https://doi.org/10.1007/s12035-023-03461-1, doi:10.1007/s12035-023-03461-1. This article has 16 citations and is from a peer-reviewed journal.
(neri2023understandingtheultrarare pages 2-4): Irene Neri, Giulia Ramazzotti, Sara Mongiorgi, Isabella Rusciano, Marianna Bugiani, Luciano Conti, Margot Cousin, Elisa Giorgio, Quasar S. Padiath, Giovanna Vaula, Pietro Cortelli, Lucia Manzoli, and Stefano Ratti. Understanding the ultra-rare disease autosomal dominant leukodystrophy: an updated review on morpho-functional alterations found in experimental models. Molecular Neurobiology, 60:6362-6372, Jul 2023. URL: https://doi.org/10.1007/s12035-023-03461-1, doi:10.1007/s12035-023-03461-1. This article has 16 citations and is from a peer-reviewed journal.
(neri2023understandingtheultrarare pages 7-9): Irene Neri, Giulia Ramazzotti, Sara Mongiorgi, Isabella Rusciano, Marianna Bugiani, Luciano Conti, Margot Cousin, Elisa Giorgio, Quasar S. Padiath, Giovanna Vaula, Pietro Cortelli, Lucia Manzoli, and Stefano Ratti. Understanding the ultra-rare disease autosomal dominant leukodystrophy: an updated review on morpho-functional alterations found in experimental models. Molecular Neurobiology, 60:6362-6372, Jul 2023. URL: https://doi.org/10.1007/s12035-023-03461-1, doi:10.1007/s12035-023-03461-1. This article has 16 citations and is from a peer-reviewed journal.
(oranburg2023establishingmodelsystems pages 27-31): TDF Oranburg. Establishing model systems to study mechanisms of cell specificity in autosomal dominant leukodystrophy. Unknown journal, 2023.
(gosky2021assessmentanddevelopment pages 18-22): MD Gosky. Assessment and development of online educational materials for autosomal dominant leukodystrophy. Unknown journal, 2021.
(henck2024singlecellsequencing pages 26-29): Jana Henck. Single cell sequencing as a phenotyping strategy to decipher the molecular mechanisms of developmental disorders. Text, Jan 2024. URL: https://doi.org/10.17169/refubium-43507, doi:10.17169/refubium-43507. This article has 0 citations and is from a peer-reviewed journal.

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Disease Characteristics Research Template

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1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

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Comprehensive Disease Characteristics Research Report

Target disease

1. Disease information

1.1 Overview (current understanding)

1.2 Key identifiers

1.3 Synonyms / alternative names

1.4 Evidence provenance

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interaction

3. Phenotypes

3.1 Core phenotype spectrum (human)

3.2 Phenotype characteristics (age of onset, progression)

3.3 Phenotype frequencies (recent quantitative cohort)

3.4 Quality of life impact

3.5 Suggested HPO terms (examples)

4. Genetic / molecular information

4.1 Causal gene

4.2 Pathogenic variant classes

4.3 Functional consequence

4.4 Modifier genes / epigenetics

5. Environmental information

6. Mechanism / pathophysiology (current understanding)

6.1 Causal chain (integrated model)

6.2 Immune involvement

6.3 Oxidative stress / inflammatory signaling

6.4 Suggested GO biological process terms (examples)

6.5 Suggested Cell Ontology (CL) terms (examples)

7. Anatomical structures affected

7.1 Organ/system level

7.2 Tissue/cell level

7.3 Subcellular

7.4 Suggested UBERON terms (examples)

8. Temporal development

8.1 Onset

8.2 Progression and staging (data-supported milestones)

8.3 Remission/relapse patterns

9. Inheritance and population