Alexander disease

Summary

Alexander disease (MONDO:0008752) is a disease caused by GFAP (GenCC Definitive), with 1 cohort gene and 5 clinical trials. Top therapeutic interventions include zilganersen.

At a glance

• Prevalence: <1 / 1 000 000 (Japan) [Orphanet-validated]
• Causal gene: GFAP (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 178
• Phenotypes (HPO): 61
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.037	Japan	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001274	Agenesis of corpus callosum	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0001355	Megalencephaly	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0002017	Nausea and vomiting	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0002169	Clonus	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0002360	Sleep abnormality	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0007256	Abnormal pyramidal sign	Very frequent (80-99%)
HP:0100729	Large face	Very frequent (80-99%)
HP:0000496	Abnormality of eye movement	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000651	Diplopia	Frequent (30-79%)
HP:0000712	Emotional lability	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0001618	Dysphonia	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002045	Hypothermia	Frequent (30-79%)
HP:0002381	Aphasia	Frequent (30-79%)
HP:0002445	Tetraplegia	Frequent (30-79%)
HP:0002514	Cerebral calcification	Frequent (30-79%)
HP:0002615	Hypotension	Frequent (30-79%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0010535	Sleep apnea	Frequent (30-79%)
HP:0010628	Facial palsy	Frequent (30-79%)
HP:0100247	Recurrent singultus	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000470	Short neck	Occasional (5-29%)
HP:0000819	Diabetes mellitus	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0000826	Precocious puberty	Occasional (5-29%)
HP:0000938	Osteopenia	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Alexander disease
Mondo ID	MONDO:0008752
MeSH	D038261
OMIM	203450
Orphanet	58
DOID	DOID:4252
ICD-11	2023359698
NCIT	C84545
SNOMED CT	81854007
UMLS	C0270726
MedGen	78724
GARD	0005774
NORD	749
Is cancer (heuristic)	no

Also known as: Alexander disease · alexanders leukodystrophy · ALXDRD · AxD · megalencephaly in infancy accompanied by progressive spasticity and dementia

Data availability: 178 ClinVar variants · 5 GenCC gene-disease records · 35 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › leukodystrophy › Alexander disease

Related subtypes (64): cerebrotendinous xanthomatosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, dermatoleukodystrophy, Krabbe disease, Sjogren-Larsson syndrome, Canavan disease, Pelizaeus-Merzbacher spectrum disorder, hereditary spastic paraplegia 2, megalencephalic leukoencephalopathy with subcortical cysts, ribose-5-P isomerase deficiency, hypomyelinating leukodystrophy 5, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, hypomyelinating leukodystrophy 6, cystic leukoencephalopathy without megalencephaly, sterol carrier protein 2 deficiency, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, hypomyelination with brain stem and spinal cord involvement and leg spasticity, leukoencephalopathy with mild cerebellar ataxia and white matter edema, progressive encephalopathy with leukodystrophy due to DECR deficiency, hypomyelinating leukodystrophy 9, multiple mitochondrial dysfunctions syndrome 4, hypomyelinating leukodystrophy 10, hypomyelinating leukodystrophy 12, hypomyelinating leukodystrophy 13, leukoencephalopathy with bilateral anterior temporal lobe cysts, progressive cavitating leukoencephalopathy, Pelizaeus-Merzbacher-like disease, CADDS, adrenoleukodystrophy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Aicardi-Goutieres syndrome, metachromatic leukodystrophy, peroxisome biogenesis disorder, unknown leukodystrophy, ravine syndrome, leukodystrophy, hypomyelinating, 22, leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy, neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, leukodystrophy, hypomyelinating, 18, leukodystrophy, hypomyelinating, 19, transient infantile, spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, leukodystrophy, hypomyelinating, 14, leukodystrophy, hypomyelinating, 20, early-onset calcifying leukoencephalopathy-skeletal dysplasia, c11orf73-related autosomal recessive hypomyelinating leukodystrophy, alkaline ceramidase 3 deficiency, leukodystrophy, hypomyelinating, 15, leukodystrophy, hypomyelinating, 16, leukodystrophy, hypomyelinating, 17, POLR-related leukodystrophy, leukoencephalopathy, diffuse hereditary, with spheroids 1, leukoencephalopathy with vanishing white matter, leukodystrophy, hypomyelinating, 24, leukodystrophy, childhood-onset, remitting, leukodystrophy, hypomyelinating, 25, leukodystrophy, hypomyelinating, 26, with chondrodysplasia, adult-onset progressive leukoencephalopathy-early-onset deafness, leukoencephalopathy, porphyria-related, episodic memory defect leukoencephalopathy, leukodystrophy, hypomyelinating, 28, leukodystrophy, demyelinating, adult-onset, leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy, leukoencephalopathy without lacunae, adult-onset, AARS1-related leukoencephalopathy

Subtypes (2): Alexander disease type I, Alexander disease type II

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

178 retrieved; paginated sample, class counts are floors:

54 not provided, 46 pathogenic, 37 uncertain significance, 17 conflicting classifications of pathogenicity, 13 likely pathogenic, 4 benign/likely benign, 3 likely benign, 2 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
190336	NM_002055.4(GFAP):c.[236G>A;667G>C]		Pathogenic	no assertion criteria provided
190352	NM_002055.4(GFAP):c.[988C>G;994G>A]		Pathogenic	no assertion criteria provided
1173085	NM_002055.5(GFAP):c.217A>G (p.Met73Val)	GFAP	Pathogenic	no assertion criteria provided
16167	NM_002055.5(GFAP):c.715C>T (p.Arg239Cys)	GFAP	Pathogenic	criteria provided, multiple submitters, no conflicts
16168	NM_002055.5(GFAP):c.716G>A (p.Arg239His)	GFAP	Pathogenic	criteria provided, multiple submitters, no conflicts
16169	NM_002055.5(GFAP):c.1246C>T (p.Arg416Trp)	GFAP	Pathogenic	criteria provided, multiple submitters, no conflicts
16170	NM_002055.5(GFAP):c.236G>A (p.Arg79His)	GFAP	Pathogenic	criteria provided, multiple submitters, no conflicts
16171	NM_002055.5(GFAP):c.235C>T (p.Arg79Cys)	GFAP	Pathogenic	criteria provided, multiple submitters, no conflicts
16172	NM_002055.5(GFAP):c.262C>T (p.Arg88Cys)	GFAP	Pathogenic	criteria provided, multiple submitters, no conflicts
16173	NM_002055.5(GFAP):c.262C>A (p.Arg88Ser)	GFAP	Pathogenic	no assertion criteria provided
16174	NM_002055.5(GFAP):c.226C>T (p.Leu76Phe)	GFAP	Pathogenic	criteria provided, single submitter
16175	NM_002055.5(GFAP):c.229A>T (p.Asn77Tyr)	GFAP	Pathogenic	no assertion criteria provided
16176	NM_002055.5(GFAP):c.1086G>C (p.Glu362Asp)	GFAP	Pathogenic	no assertion criteria provided
16177	NM_002055.5(GFAP):c.827G>T (p.Arg276Leu)	GFAP	Pathogenic	no assertion criteria provided
16178	NM_002055.5(GFAP):c.1055T>C (p.Leu352Pro)	GFAP	Pathogenic	no assertion criteria provided
16179	NM_002055.5(GFAP):c.234C>A (p.Asp78Glu)	GFAP	Pathogenic	criteria provided, single submitter
1685846	NM_002055.5(GFAP):c.1087A>G (p.Ile363Val)	GFAP	Pathogenic	criteria provided, single submitter
190334	NM_002055.5(GFAP):c.218T>C (p.Met73Thr)	GFAP	Pathogenic	criteria provided, single submitter
190339	NM_002055.5(GFAP):c.259G>A (p.Val87Ile)	GFAP	Pathogenic	criteria provided, multiple submitters, no conflicts
190345	NM_002055.5(GFAP):c.772C>T (p.Arg258Cys)	GFAP	Pathogenic	criteria provided, multiple submitters, no conflicts
190346	NM_002055.5(GFAP):c.791T>C (p.Leu264Pro)	GFAP	Pathogenic	criteria provided, single submitter
190348	NM_002055.5(GFAP):c.799G>C (p.Ala267Pro)	GFAP	Pathogenic	criteria provided, single submitter
190349	NM_002055.5(GFAP):c.803C>A (p.Ala268Asp)	GFAP	Pathogenic	no assertion criteria provided
190357	NM_002055.5(GFAP):c.1085A>G (p.Glu362Gly)	GFAP	Pathogenic	no assertion criteria provided
190359	NP_002046.1(GFAP):p.Glu373Asp	GFAP	Pathogenic	no assertion criteria provided
190362	NM_002055.5(GFAP):c.1154C>G (p.Ser385Cys)	GFAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190363	NM_002055.5(GFAP):c.1193C>T (p.Ser398Phe)	GFAP	Pathogenic	no assertion criteria provided
190364	NP_002046.1(GFAP):p.Met415Ile	GFAP	Pathogenic	no assertion criteria provided
190366	NM_002055.5(GFAP):c.1171+475_1171+482delinsATC	GFAP	Pathogenic	no assertion criteria provided
190369	NP_002046.1:p.Phe261_Thr302del	GFAP	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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.

Gene	Classification	Inheritance	Disease	Records
GFAP	Definitive	Autosomal dominant	Alexander disease	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GFAP	Orphanet:363717	Alexander disease type I
GFAP	Orphanet:363722	Alexander disease type II

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GFAP	HGNC:4235	ENSG00000131095	P14136	Glial fibrillary acidic protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GFAP	Glial fibrillary acidic protein	GFAP, a class-III intermediate filament, is a cell-specific marker that, during the development of the central nervous system, distinguishes astrocytes from other glial cells.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GFAP	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
dorsal motor nucleus of vagus nerve	1
inferior olivary complex	1
medulla oblongata	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GFAP	210	broad	marker	medulla oblongata, inferior olivary complex, dorsal motor nucleus of vagus nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GFAP	6,997

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GFAP	P14136	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Chaperone Mediated Autophagy	1	496.5×	0.003	GFAP
Nuclear signaling by ERBB4	1	346.1×	0.003	GFAP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of Schwann cell proliferation	1	16852.0×	8e-04	GFAP
Schwann cell proliferation	1	5617.3×	8e-04	GFAP
regulation of neurotransmitter uptake	1	5617.3×	8e-04	GFAP
neuron projection regeneration	1	4213.0×	8e-04	GFAP
D-aspartate import across plasma membrane	1	3370.4×	8e-04	GFAP
regulation of chaperone-mediated autophagy	1	3370.4×	8e-04	GFAP
Bergmann glial cell differentiation	1	1532.0×	0.002	GFAP
astrocyte development	1	1123.5×	0.002	GFAP
enteric nervous system development	1	991.3×	0.002	GFAP
regulation of protein-containing complex assembly	1	732.7×	0.002	GFAP
neural crest cell migration	1	337.0×	0.005	GFAP
long-term synaptic potentiation	1	280.9×	0.005	GFAP
intermediate filament organization	1	240.7×	0.005	GFAP
negative regulation of neuron projection development	1	237.3×	0.005	GFAP
extracellular matrix organization	1	122.1×	0.009	GFAP
gene expression	1	79.9×	0.013	GFAP
intracellular protein transport	1	64.8×	0.015	GFAP

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Zilganersen	Phase 3 (in late-stage trials)

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GFAP	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GFAP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GFAP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04849741	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Efficacy of Zilganersen (ION373) in Patients With Alexander Disease (AxD)
NCT02714764	Not specified	RECRUITING	Evaluation of Outcome Metrics in Alexander Disease
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT07487389	Not specified	AVAILABLE	Zilganersen Expanded Access Program for Individuals With Alexander Disease
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ZILGANERSEN	3	2