Farber lipogranulomatosis

Summary

Farber lipogranulomatosis (MONDO:0009218) is a disease caused by ASAH1 (GenCC Definitive), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ASAH1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 174
• Phenotypes (HPO): 70
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		96	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0001369	Arthritis	Very frequent (80-99%)
HP:0001371	Flexion contracture	Very frequent (80-99%)
HP:0001386	Joint swelling	Very frequent (80-99%)
HP:0001609	Hoarse voice	Very frequent (80-99%)
HP:0007470	Periarticular subcutaneous nodules	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0000707	Abnormality of the nervous system	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001615	Hoarse cry	Frequent (30-79%)
HP:0002086	Abnormality of the respiratory system	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0003444	EMG: chronic denervation signs	Frequent (30-79%)
HP:0003640	Foam cells in visceral organs and CNS	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0010729	Cherry red spot of the macula	Frequent (30-79%)
HP:0011842	Abnormality of skeletal morphology	Frequent (30-79%)
HP:0000502	Abnormal conjunctiva morphology	Occasional (5-29%)
HP:0000608	Macular degeneration	Occasional (5-29%)
HP:0000766	Abnormal sternum morphology	Occasional (5-29%)
HP:0000939	Osteoporosis	Occasional (5-29%)
HP:0001155	Abnormality of the hand	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001433	Hepatosplenomegaly	Occasional (5-29%)
HP:0001612	Weak cry	Occasional (5-29%)
HP:0001618	Dysphonia	Occasional (5-29%)
HP:0001760	Abnormal foot morphology	Occasional (5-29%)
HP:0001954	Recurrent fever	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002207	Diffuse reticular or finely nodular infiltrations	Occasional (5-29%)
HP:0002300	Mutism	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0002788	Recurrent upper respiratory tract infections	Occasional (5-29%)
HP:0002815	Abnormality of the knee	Occasional (5-29%)
HP:0003019	Abnormality of the wrist	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0005483	Abnormal epiglottis morphology	Occasional (5-29%)
HP:0006511	Laryngeal stridor	Occasional (5-29%)
HP:0007957	Corneal opacity	Occasional (5-29%)
HP:0009811	Abnormality of the elbow	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0012444	Brain atrophy	Occasional (5-29%)
HP:0025392	Nodular pattern on pulmonary HRCT	Occasional (5-29%)
HP:0025405	Visual fixation instability	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Farber lipogranulomatosis
Mondo ID	MONDO:0009218
MeSH	D055577
OMIM	228000
Orphanet	333
DOID	DOID:0050464
NCIT	C84710
SNOMED CT	79935000
UMLS	C0268255
MedGen	78654
GARD	0006426
Is cancer (heuristic)	no

Also known as: acid ceramidase deficiency · Farber disease · Farber lipogranulomatosis · Farber’s disease · FRBRL · N-LAURYLSPHINGOSINE deacylase deficiency

Data availability: 174 ClinVar variants · 4 GenCC gene-disease records · 13 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › lysosomal lipid storage disorder › sphingolipidosis › ASAH1-related sphingolipidosis › Farber lipogranulomatosis

Related subtypes (1): spinal muscular atrophy-progressive myoclonic epilepsy syndrome

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

174 retrieved; paginated sample, class counts are floors:

53 uncertain significance, 39 benign, 25 likely pathogenic, 21 pathogenic, 16 conflicting classifications of pathogenicity, 11 pathogenic/likely pathogenic, 6 likely benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1163018	NM_177924.5(ASAH1):c.3G>T (p.Met1Ile)	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299374	NM_177924.5(ASAH1):c.427T>G (p.Cys143Gly)	ASAH1	Pathogenic	no assertion criteria provided
1299375	NM_177924.5(ASAH1):c.358G>C (p.Ala120Pro)	ASAH1	Pathogenic	no assertion criteria provided
1323941	NM_177924.5(ASAH1):c.186G>A (p.Trp62Ter)	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191340	NM_177924.5(ASAH1):c.505T>C (p.Trp169Arg)	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2413836	NM_177924.5(ASAH1):c.177C>A (p.Tyr59Ter)	ASAH1	Pathogenic	criteria provided, multiple submitters, no conflicts
3391818	NM_177924.5(ASAH1):c.80G>A (p.Trp27Ter)	ASAH1	Pathogenic	criteria provided, single submitter
375548	NM_177924.5(ASAH1):c.410A>G (p.Tyr137Cys)	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3912002	NM_177924.5(ASAH1):c.898G>T (p.Glu300Ter)	ASAH1	Pathogenic	criteria provided, single submitter
545563	NM_177924.5(ASAH1):c.703G>C (p.Gly235Arg)	ASAH1	Pathogenic	criteria provided, single submitter
545564	NM_177924.5(ASAH1):c.125+211_383-1330del	ASAH1	Pathogenic	no assertion criteria provided
55908	NM_177924.5(ASAH1):c.917+4A>G	ASAH1	Pathogenic	no assertion criteria provided
585439	NM_177924.5(ASAH1):c.997C>G (p.Arg333Gly)	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812471	NM_177924.5(ASAH1):c.410_411del (p.Phe136_Tyr137insTer)	ASAH1	Pathogenic	criteria provided, multiple submitters, no conflicts
812473	NM_177924.5(ASAH1):c.290T>A (p.Val97Glu)	ASAH1	Pathogenic	criteria provided, single submitter
812477	NM_177924.5(ASAH1):c.502G>T (p.Gly168Trp)	ASAH1	Pathogenic	criteria provided, single submitter
812478	NM_177924.5(ASAH1):c.760A>G (p.Arg254Gly)	ASAH1	Pathogenic	criteria provided, multiple submitters, no conflicts
812480	NM_177924.5(ASAH1):c.518A>T (p.Asn173Ile)	ASAH1	Pathogenic	criteria provided, single submitter
812481	NM_177924.5(ASAH1):c.594_599dup (p.Phe199_Lys200insAsnPhe)	ASAH1	Pathogenic	criteria provided, single submitter
812484	NM_177924.5(ASAH1):c.383-10_383-6del	ASAH1	Pathogenic	criteria provided, single submitter
812486	NM_177924.5(ASAH1):c.174dup (p.Tyr59fs)	ASAH1	Pathogenic	criteria provided, multiple submitters, no conflicts
812490	NM_177924.5(ASAH1):c.997C>T (p.Arg333Cys)	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812496	NM_177924.5(ASAH1):c.412G>T (p.Glu138Ter)	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812498	NM_177924.5(ASAH1):c.1085C>G (p.Pro362Arg)	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812499	NM_177924.5(ASAH1):c.287TGG[1] (p.Val97del)	ASAH1	Pathogenic	criteria provided, single submitter
812501	NM_177924.5(ASAH1):c.457+4A>G	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812502	NM_177924.5(ASAH1):c.256dup (p.Thr86fs)	ASAH1	Pathogenic	criteria provided, single submitter
812507	NM_177924.5(ASAH1):c.1098+1G>T	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
91	NM_177924.5(ASAH1):c.665C>A (p.Thr222Lys)	ASAH1	Pathogenic	no assertion criteria provided
93	NM_177924.5(ASAH1):c.107A>G (p.Tyr36Cys)	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
ASAH1	Definitive	Autosomal recessive	Farber lipogranulomatosis	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ASAH1	Orphanet:2590	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome
ASAH1	Orphanet:333	Farber disease

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
ASAH1	HGNC:735	ENSG00000104763	Q13510	Acid ceramidase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ASAH1	Acid ceramidase	Lysosomal ceramidase that hydrolyzes sphingolipid ceramides into sphingosine and free fatty acids at acidic pH.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ASAH1	Enzyme (other)	yes	3.5.1.23	Acid_ceramidase-like, Acid_ceramidase_N, CBAH/NAAA_C

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
heart right ventricle	1
pancreatic ductal cell	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ASAH1	302	ubiquitous	marker	heart right ventricle, visceral pleura, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ASAH1	2,633

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ASAH1	Q13510	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	671.8×	0.014	ASAH1
Glycosphingolipid metabolism	1	300.5×	0.014	ASAH1
Glycosphingolipid catabolism	1	292.8×	0.014	ASAH1
MITF-M-dependent gene expression	1	181.3×	0.014	ASAH1
Sphingolipid metabolism	1	167.9×	0.014	ASAH1
MITF-M-regulated melanocyte development	1	114.2×	0.018	ASAH1
Metabolism of lipids	1	31.6×	0.054	ASAH1
Innate Immune System	1	25.5×	0.058	ASAH1
Neutrophil degranulation	1	23.1×	0.058	ASAH1
Developmental Biology	1	14.5×	0.083	ASAH1
Immune System	1	13.0×	0.084	ASAH1
Metabolism	1	11.6×	0.086	ASAH1

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
regulation of programmed necrotic cell death	1	16852.0×	5e-04	ASAH1
ceramide catabolic process	1	2407.4×	0.002	ASAH1
regulation of steroid biosynthetic process	1	1532.0×	0.002	ASAH1
sphingosine biosynthetic process	1	1053.2×	0.002	ASAH1
ceramide biosynthetic process	1	421.3×	0.004	ASAH1
keratinocyte differentiation	1	247.8×	0.005	ASAH1
fatty acid metabolic process	1	193.7×	0.006	ASAH1
cellular response to tumor necrosis factor	1	163.6×	0.006	ASAH1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ASAH1	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CARMOFUR	2	ASAH1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ASAH1	111	Binding:108, Functional:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ASAH1	3.5.1.23	ceramidase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ASAH1	111

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

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.

Compound	Max phase	Cohort target (bioactivity)
CARMOFUR	2	ASAH1

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	1	ASAH1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07173010	Not specified	NOT_YET_RECRUITING	Pediatric Arthropathy Beyond Inflammation: Clinical Spectrum and Diagnostic Approach at Assiut University Children Hospital
NCT03233841	Not specified	COMPLETED	Farber Disease Natural History Study