Adult-onset autosomal dominant demyelinating leukodystrophy

disease
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Also known as ADLDadult-onset autosomal dominant leukodystrophyautosomal dominant adult-onset demyelinating leukodystrophyautosomal dominant leukodystrophy with autonomic diseaseleukodystrophy, adult-onset, autosomal dominantleukodystrophy, demyelinating, ADULT-onset, autosomal dominantmultiple sclerosis-like disorder

Summary

Adult-onset autosomal dominant demyelinating leukodystrophy (MONDO:0008215) is a disease caused by LMNB1 (GenCC Strong), with 2 cohort genes and 2 clinical trials.

At a glance

  • Prevalence: (Worldwide) [Orphanet-validated]
  • Causal gene: LMNB1 (GenCC Strong)
  • Cohort genes: 2
  • ClinVar variants: 54
  • Phenotypes (HPO): 61
  • Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

TypeClassValueGeographyValidation
Cases/families20WorldwideValidated
Point prevalence<1 / 1 000 000WorldwideNot yet validated

Signs & symptoms

Clinical features (HPO)

61 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO IDTermFrequency
HP:0001251AtaxiaVery frequent (80-99%)
HP:0012332Abnormal autonomic nervous system physiologyVery frequent (80-99%)
HP:0001257SpasticityFrequent (30-79%)
HP:0001288Gait disturbanceFrequent (30-79%)
HP:0001324Muscle weaknessFrequent (30-79%)
HP:0001337TremorFrequent (30-79%)
HP:0001347HyperreflexiaFrequent (30-79%)
HP:0002066Gait ataxiaFrequent (30-79%)
HP:0002493Upper motor neuron dysfunctionFrequent (30-79%)
HP:0002936Distal sensory impairmentFrequent (30-79%)
HP:0003487Babinski signFrequent (30-79%)
HP:0005341Autonomic bladder dysfunctionFrequent (30-79%)
HP:0006827Atrophy of the spinal cordFrequent (30-79%)
HP:0006958Abnormal auditory evoked potentialsFrequent (30-79%)
HP:0007256Abnormal pyramidal signFrequent (30-79%)
HP:0007366Atrophy/Degeneration affecting the brainstemFrequent (30-79%)
HP:0007377Abnormality of somatosensory evoked potentialsFrequent (30-79%)
HP:0011931Abnormality of the cerebellar peduncleFrequent (30-79%)
HP:0030890Hyperintensity of cerebral white matter on MRIFrequent (30-79%)
HP:0000010Recurrent urinary tract infectionsOccasional (5-29%)
HP:0000012Urinary urgencyOccasional (5-29%)
HP:0000016Urinary retentionOccasional (5-29%)
HP:0000496Abnormality of eye movementOccasional (5-29%)
HP:0000639NystagmusOccasional (5-29%)
HP:0000802ImpotenceOccasional (5-29%)
HP:0000970AnhidrosisOccasional (5-29%)
HP:0001260DysarthriaOccasional (5-29%)
HP:0001276HypertoniaOccasional (5-29%)
HP:0001278Orthostatic hypotensionOccasional (5-29%)
HP:0001310DysmetriaOccasional (5-29%)
HP:0001371Flexion contractureOccasional (5-29%)
HP:0002015DysphagiaOccasional (5-29%)
HP:0002019ConstipationOccasional (5-29%)
HP:0002045HypothermiaOccasional (5-29%)
HP:0002064Spastic gaitOccasional (5-29%)
HP:0002075DysdiadochokinesisOccasional (5-29%)
HP:0002080Intention tremorOccasional (5-29%)
HP:0002169ClonusOccasional (5-29%)
HP:0002200Pseudobulbar signsOccasional (5-29%)
HP:0002273TetraparesisOccasional (5-29%)
HP:0002345Action tremorOccasional (5-29%)
HP:0002599Head titubationOccasional (5-29%)
HP:0003326MyalgiaOccasional (5-29%)
HP:0004302Functional motor deficitOccasional (5-29%)
HP:0004395MalnutritionOccasional (5-29%)
HP:0005968Temperature instabilityOccasional (5-29%)
HP:0006886Impaired distal vibration sensationOccasional (5-29%)
HP:0007351Upper limb postural tremorOccasional (5-29%)
HP:0007360Aplasia/Hypoplasia of the cerebellumOccasional (5-29%)
HP:0007369Atrophy/Degeneration affecting the cerebrumOccasional (5-29%)

Identifiers

Disease identifiers

FieldValue
Canonical nameadult-onset autosomal dominant demyelinating leukodystrophy
Mondo IDMONDO:0008215
MeSHC566813
OMIM169500
Orphanet99027
DOIDDOID:0051015, DOID:0060785
SNOMED CT448054001
UMLSC1868512
MedGen356995
GARD0010587
Is cancer (heuristic)no

Also known as: ADLD · adult-onset autosomal dominant demyelinating leukodystrophy · adult-onset autosomal dominant leukodystrophy · autosomal dominant adult-onset demyelinating leukodystrophy · autosomal dominant leukodystrophy with autonomic disease · leukodystrophy, adult-onset, autosomal dominant · leukodystrophy, demyelinating, ADULT-onset, autosomal dominant · multiple sclerosis-like disorder

Data availability: 54 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › chromosomal disordersyndrome caused by partial chromosomal duplication › partial trisomy/tetrasomy of chromosome 5 › partial trisomy of the long arm of chromosome 5 › adult-onset autosomal dominant demyelinating leukodystrophy

Related subtypes (2): 5q35 microduplication syndrome, distal trisomy 5q

Subtypes (2): leukodystrophy, demyelinating, adult-onset, autosomal dominant, atypical, leukodystrophy, demyelinating, adult-onset, autosomal dominant, typical

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

54 retrieved; paginated sample, class counts are floors:

23 uncertain significance, 18 benign, 8 conflicting classifications of pathogenicity, 3 benign/likely benign, 1 pathogenic, 1 likely benign

ClinVarVariant (HGVS)GeneClassificationReview
1342147NC_000005.10:g.126508361_126769360delALDH7A1Pathogeniccriteria provided, single submitter
1366654NM_005573.4(LMNB1):c.1306G>A (p.Ala436Thr)LMNB1Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
350615NM_005573.4(LMNB1):c.676C>T (p.Arg226Cys)LMNB1Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
350617NM_005573.4(LMNB1):c.1190G>A (p.Arg397His)LMNB1Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
905851NM_005573.4(LMNB1):c.*54A>TLMNB1Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
905854NM_005573.4(LMNB1):c.*284T>GLMNB1Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
907306NM_005573.4(LMNB1):c.700C>T (p.Arg234Cys)LMNB1Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
907308NM_005573.4(LMNB1):c.853A>G (p.Thr285Ala)LMNB1Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
976612NM_005573.4(LMNB1):c.1178G>A (p.Ser393Asn)LMNB1Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
1032338NM_005573.4(LMNB1):c.360-8T>CLMNB1Uncertain significancecriteria provided, single submitter
1803279NM_005573.4(LMNB1):c.889C>T (p.Arg297Cys)LMNB1Uncertain significancecriteria provided, single submitter
2420729NM_005573.4(LMNB1):c.1528C>T (p.Pro510Ser)LMNB1Uncertain significancecriteria provided, multiple submitters, no conflicts
2582601NM_005573.4(LMNB1):c.227C>T (p.Thr76Ile)LMNB1Uncertain significancecriteria provided, single submitter
2585444NM_005573.4(LMNB1):c.916C>T (p.Gln306Ter)LMNB1Uncertain significancecriteria provided, single submitter
3065585NM_005573.4(LMNB1):c.89T>A (p.Leu30His)LMNB1Uncertain significancecriteria provided, single submitter
3391068NM_005573.4(LMNB1):c.1400G>T (p.Gly467Val)LMNB1Uncertain significancecriteria provided, single submitter
350610NM_005573.4(LMNB1):c.-159C>GLMNB1Uncertain significancecriteria provided, single submitter
350618NM_005573.4(LMNB1):c.1387-3T>CLMNB1Uncertain significancecriteria provided, single submitter
350626NM_005573.4(LMNB1):c.*629G>ALMNB1Uncertain significancecriteria provided, single submitter
350627NM_005573.4(LMNB1):c.*629G>CLMNB1Uncertain significancecriteria provided, single submitter
905852NM_005573.4(LMNB1):c.*189T>GLMNB1Uncertain significancecriteria provided, single submitter
905853NM_005573.4(LMNB1):c.*270T>CLMNB1Uncertain significancecriteria provided, single submitter
906293NM_005573.4(LMNB1):c.-76G>TLMNB1Uncertain significancecriteria provided, single submitter
906362NM_005573.4(LMNB1):c.*301T>CLMNB1Uncertain significancecriteria provided, single submitter
906363NM_005573.4(LMNB1):c.*631G>ALMNB1Uncertain significancecriteria provided, single submitter
906364NM_005573.4(LMNB1):c.*634A>GLMNB1Uncertain significancecriteria provided, single submitter
906365NM_005573.4(LMNB1):c.*640G>ALMNB1Uncertain significancecriteria provided, single submitter
907307NM_005573.4(LMNB1):c.775C>T (p.Leu259=)LMNB1Uncertain significancecriteria provided, single submitter
907309NM_005573.4(LMNB1):c.987T>C (p.Ala329=)LMNB1Uncertain significancecriteria provided, single submitter
907310NM_005573.4(LMNB1):c.1010G>A (p.Arg337His)LMNB1Uncertain significancecriteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

GeneClassificationInheritanceDiseaseRecords
LMNB1StrongAutosomal dominantadult-onset autosomal dominant demyelinating leukodystrophy10

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
LMNB1Orphanet:2514Autosomal dominant primary microcephaly
LMNB1Orphanet:99027Adult-onset autosomal dominant leukodystrophy
ALDH7A1Orphanet:3006Pyridoxine-dependent-developmental and epileptic encephalopathy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

SubsetGenes
multi_evidence2

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
LMNB1HGNC:6637ENSG00000113368P20700Lamin-B1gencc,clinvar
ALDH7A1HGNC:877ENSG00000164904P49419Alpha-aminoadipic semialdehyde dehydrogenaseclinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
LMNB1Lamin-B1Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.
ALDH7A1Alpha-aminoadipic semialdehyde dehydrogenaseAldehyde dehydrogenase enzyme that mediates important protective effects.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

FamilyGenesFoldFDR
Enzyme (other)16.0×0.320
Other/Unknown10.9×0.805

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
LMNB1Other/UnknownnoLamin_tail_dom, IF_conserved, Lamin_tail_dom_sf
ALDH7A1Enzyme (other)yes1.2.1.3Aldehyde_DH_dom, Ald_DH/histidinol_DH, Ald_DH_N

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)0
broad (>20)2
unknown0

Top tissues across cohort

TissueCohort genes
ventricular zone2
embryo1
ganglionic eminence1
left ovary1
right lobe of liver1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
LMNB1226ubiquitousmarkerventricular zone, ganglionic eminence, embryo
ALDH7A1255ubiquitousmarkerright lobe of liver, ventricular zone, left ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

SymbolInteractor count
LMNB15,226
ALDH7A14,544

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
ALDH7A1P4941920
LMNB1P207007

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 44. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

PathwayCohort genesFoldFDRSample cohort genes
Breakdown of the nuclear lamina11903.3×0.014LMNB1
Choline catabolism1713.8×0.014ALDH7A1
Lysine catabolism1571.0×0.014ALDH7A1
Neurodegenerative Diseases1439.2×0.014LMNB1
Depolymerization of the Nuclear Lamina1380.7×0.014LMNB1
Defective Intrinsic Pathway for Apoptosis1380.7×0.014LMNB1
Formation of Senescence-Associated Heterochromatin Foci (SAHF)1335.9×0.014LMNB1
Diseases of programmed cell death1317.2×0.014LMNB1
Initiation of Nuclear Envelope (NE) Reformation1300.5×0.014LMNB1
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models1259.6×0.014LMNB1
Apoptotic cleavage of cellular proteins1237.9×0.014LMNB1
Interleukin-12 family signaling1237.9×0.014LMNB1
Apoptotic execution phase1237.9×0.014LMNB1
Nuclear Envelope Breakdown1228.4×0.014LMNB1
Interleukin-12 signaling1203.9×0.014LMNB1
Mitotic Prophase1184.2×0.015LMNB1
Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation1150.3×0.016LMNB1
Nuclear Envelope (NE) Reassembly1146.4×0.016LMNB1
Meiosis1142.8×0.016LMNB1
RHOF GTPase cycle1129.8×0.017LMNB1
RHOD GTPase cycle1102.0×0.020LMNB1
Reproduction195.2×0.021LMNB1
Apoptosis184.0×0.022LMNB1
DNA Damage/Telomere Stress Induced Senescence181.6×0.022LMNB1
Programmed Cell Death173.2×0.024LMNB1
Meiotic synapsis170.5×0.024LMNB1
Cellular Senescence168.8×0.024LMNB1
Mitotic Metaphase and Anaphase148.4×0.031LMNB1
Mitotic Anaphase148.4×0.031LMNB1
Metabolism of amino acids and derivatives133.8×0.043ALDH7A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO termCohort genesFoldFDRSample cohort genes
L-lysine catabolic process18426.0×0.001ALDH7A1
negative regulation of endosome to plasma membrane protein transport18426.0×0.001ALDH7A1
obsolete glycine betaine biosynthetic process from choline14213.0×0.001ALDH7A1
choline catabolic process12106.5×0.002ALDH7A1
nuclear pore localization11685.2×0.002LMNB1
negative regulation of Golgi to plasma membrane protein transport11404.3×0.002ALDH7A1
obsolete lysine catabolic process11203.7×0.002ALDH7A1
protein localization to nuclear envelope11053.2×0.002LMNB1
plasma membrane to endosome transport1766.0×0.003ALDH7A1
aldehyde metabolic process1648.1×0.003ALDH7A1
Golgi to endosome transport1526.6×0.003ALDH7A1
nuclear envelope organization1495.6×0.003LMNB1
negative regulation of ferroptosis1401.2×0.003ALDH7A1
nuclear migration1366.4×0.004LMNB1
endosome to lysosome transport1168.5×0.007ALDH7A1
energy homeostasis1135.9×0.008ALDH7A1
heterochromatin formation1127.7×0.008LMNB1
sensory perception of sound150.5×0.020ALDH7A1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

SymbolMoleculesMax phase
LMNB112
ALDH7A100

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
MOLIBRESIB2LMNB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

SymbolAssaysType breakdown
LMNB17Binding:7
ALDH7A11Binding:1

Cohort enzymes (BRENDA EC)

SymbolEC numbersNames
ALDH7A11.2.1.3, 1.2.1.31aldehyde dehydrogenase (NAD+), L-aminoadipate-semialdehyde dehydrogenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

CompoundMax phaseCohort target (bioactivity)
MOLIBRESIB2LMNB1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

TierDefinitionGenesSymbols
AApproved (phase 4 drug)0
BPhased (≥1) drug, not yet approved1LMNB1
CDruggable family + PDB, no drug1ALDH7A1
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

SymbolChEMBL assaysDrugged partners (top 3)
ALDH7A11

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

PhaseTrials
Not specified2

Top trials by phase / activity

NCTPhaseStatusTitle
NCT03047369Not specifiedRECRUITINGThe Myelin Disorders Biorepository Project
NCT02699190Not specifiedCOMPLETEDLeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies