Sjogren-Larsson syndrome

Summary

Sjogren-Larsson syndrome (MONDO:0010031) is a disease caused by ALDH3A2 (GenCC Definitive), with 2 cohort genes and 6 clinical trials. Top therapeutic interventions include reproxalap.

At a glance

• Prevalence: 1-5 / 10 000 (Taiwan, Province of China) [Orphanet-validated]
• Causal gene: ALDH3A2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 270
• Phenotypes (HPO): 28
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	16	Taiwan, Province of China	Validated
Prevalence at birth	1-9 / 1 000 000	0.6	Sweden	Validated
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0000958	Dry skin	Very frequent (80-99%)
HP:0000962	Hyperkeratosis	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001264	Spastic diplegia	Very frequent (80-99%)
HP:0002652	Skeletal dysplasia	Very frequent (80-99%)
HP:0002808	Kyphosis	Very frequent (80-99%)
HP:0007256	Abnormal pyramidal sign	Very frequent (80-99%)
HP:0008064	Ichthyosis	Very frequent (80-99%)
HP:0010783	Erythema	Very frequent (80-99%)
HP:0000488	Retinopathy	Frequent (30-79%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0000608	Macular degeneration	Frequent (30-79%)
HP:0000613	Photophobia	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0007440	Generalized hyperpigmentation	Frequent (30-79%)
HP:0007703	Abnormality of retinal pigmentation	Frequent (30-79%)
HP:0100533	Inflammatory abnormality of the eye	Frequent (30-79%)
HP:0200020	Corneal erosion	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000682	Abnormality of dental enamel	Occasional (5-29%)
HP:0001025	Urticaria	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001387	Joint stiffness	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Sjogren-Larsson syndrome
Mondo ID	MONDO:0010031
MeSH	D016111
OMIM	270200
Orphanet	816
DOID	DOID:14501
ICD-11	418359090
NCIT	C85070
SNOMED CT	111303009
UMLS	C0037231
MedGen	11443
GARD	0007654
MedDRA	10048676
NORD	1377
Is cancer (heuristic)	no

Also known as: FADH deficiency · FAO deficiency · fatty acid alcohol oxidoreductase deficiency · Senior-Løken Syndrome · Sjogren-Larsson syndrome · Sjögren-Larsson syndrome · SLS

Data availability: 270 ClinVar variants · 5 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › Sjogren-Larsson syndrome

Related subtypes (35): Neu-Laxova syndrome, cutaneous mycosis, integumentary system benign neoplasm, integumentary system cancer, nipple neoplasm, nail disorder, disorder of pilosebaceous unit, Bartholin duct cyst, benign mammary dysplasia, skin disorder, breast fibrosis, breast mucosa-associated lymphoid tissue lymphoma, panniculitis, alopecia-epilepsy-pyorrhea-intellectual disability syndrome, autosomal dominant deafness - onychodystrophy syndrome, keratoderma hereditarium mutilans, Rombo syndrome, mucosulfatidosis, ichthyosis prematurity syndrome, ANE syndrome, frontonasal dysplasia with alopecia and genital anomaly, peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome, mandibulofacial dysostosis with alopecia, cutis laxa, X-linked ichthyosis syndrome, demodicidosis, Proteus-like syndrome, familial atypical multiple mole melanoma syndrome, familial tumoral calcinosis, subcutaneous tissue disorder, Bartholin gland neoplasm, pseudoxanthoma elasticum (inherited or acquired), skin appendage disorder, keratinization disease, paraneoplastic cutaneous 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

270 retrieved; paginated sample, class counts are floors:

73 uncertain significance, 64 likely pathogenic, 47 pathogenic, 30 pathogenic/likely pathogenic, 22 conflicting classifications of pathogenicity, 15 likely benign, 14 benign, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
438264	NM_000382.2(ALDH3A2):c.[733G>A;901G>C;906delT;909T>G]		Pathogenic	criteria provided, single submitter
1068916	NM_000382.3(ALDH3A2):c.286_296del (p.Tyr96fs)	ALDH3A2	Pathogenic	criteria provided, multiple submitters, no conflicts
1068917	NM_000382.3(ALDH3A2):c.680+1del	ALDH3A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071062	NM_000382.3(ALDH3A2):c.681-2A>G	ALDH3A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076911	NM_000382.3(ALDH3A2):c.821_822del (p.Lys274fs)	ALDH3A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1174486	NM_000382.3(ALDH3A2):c.1003C>T (p.Pro335Ser)	ALDH3A2	Pathogenic	no assertion criteria provided
1322990	NM_000382.3(ALDH3A2):c.1187_1188del (p.Ser396fs)	ALDH3A2	Pathogenic	criteria provided, multiple submitters, no conflicts
1322996	NM_000382.3(ALDH3A2):c.639_640del (p.Cys214fs)	ALDH3A2	Pathogenic	criteria provided, single submitter
1403786	NM_000382.3(ALDH3A2):c.1137del (p.Ser380fs)	ALDH3A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454705	NM_000382.3(ALDH3A2):c.699dup (p.Tyr234fs)	ALDH3A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459314	NM_000382.3(ALDH3A2):c.1268G>A (p.Arg423His)	ALDH3A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1636	NM_000382.3(ALDH3A2):c.521del (p.Leu174fs)	ALDH3A2	Pathogenic	no assertion criteria provided
1637	NM_000382.3(ALDH3A2):c.809del (p.Gly270fs)	ALDH3A2	Pathogenic	no assertion criteria provided
1638	NM_000382.3(ALDH3A2):c.941_943delinsGGGCTAAAAGTACTGTTGGGG (p.Ala314_Pro315delinsGlyAlaLysSerThrValGlyAla)	ALDH3A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1639	NM_000382.3(ALDH3A2):c.641G>A (p.Cys214Tyr)	ALDH3A2	Pathogenic	no assertion criteria provided
1640	NM_000382.3(ALDH3A2):c.943C>T (p.Pro315Ser)	ALDH3A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1641	NM_000382.3(ALDH3A2):c.1297_1298del (p.Glu433fs)	ALDH3A2	Pathogenic	criteria provided, multiple submitters, no conflicts
1642	NM_000382.3(ALDH3A2):c.1307_1311dup (p.Leu438fs)	ALDH3A2	Pathogenic	criteria provided, multiple submitters, no conflicts
1643	NM_000382.3(ALDH3A2):c.798G>C (p.Lys266Asn)	ALDH3A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1644	NM_000382.3(ALDH3A2):c.1157A>G (p.Asn386Ser)	ALDH3A2	Pathogenic	criteria provided, multiple submitters, no conflicts
1685517	NM_000382.3(ALDH3A2):c.608del (p.Pro203fs)	ALDH3A2	Pathogenic	criteria provided, single submitter
1724236	NM_000382.3(ALDH3A2):c.653_654del (p.Lys218fs)	ALDH3A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1878338	NM_000382.3(ALDH3A2):c.680+1G>A	ALDH3A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188768	NM_000382.3(ALDH3A2):c.551C>T (p.Thr184Met)	ALDH3A2	Pathogenic	criteria provided, multiple submitters, no conflicts
188833	NM_000382.3(ALDH3A2):c.28C>T (p.Gln10Ter)	ALDH3A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189079	NM_000382.3(ALDH3A2):c.798+5G>A	ALDH3A2	Pathogenic	criteria provided, single submitter
189163	NM_000382.3(ALDH3A2):c.471+1del	ALDH3A2	Pathogenic	criteria provided, multiple submitters, no conflicts
189187	NM_000382.3(ALDH3A2):c.901_903delinsCC (p.Ala301fs)	ALDH3A2	Pathogenic	criteria provided, single submitter
2089934	NM_000382.3(ALDH3A2):c.171C>G (p.Tyr57Ter)	ALDH3A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2102212	NM_000382.3(ALDH3A2):c.292C>T (p.Gln98Ter)	ALDH3A2	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 8 · 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
ALDH3A2	Definitive	Autosomal recessive	Sjogren-Larsson syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALDH3A2	Orphanet:816	Sjögren-Larsson syndrome
KRT14	Orphanet:69087	Naegeli-Franceschetti-Jadassohn syndrome
KRT14	Orphanet:79396	Autosomal dominant generalized epidermolysis bullosa simplex, severe form
KRT14	Orphanet:79397	Epidermolysis bullosa simplex with mottled pigmentation
KRT14	Orphanet:79399	Autosomal dominant generalized epidermolysis bullosa simplex, intermediate form
KRT14	Orphanet:79400	Localized epidermolysis bullosa simplex
KRT14	Orphanet:86920	Dermatopathia pigmentosa reticularis
KRT14	Orphanet:89838	Autosomal recessive generalized epidermolysis bullosa simplex

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALDH3A2	HGNC:403	ENSG00000072210	P51648	Aldehyde dehydrogenase family 3 member A2	gencc,clinvar
KRT14	HGNC:6416	ENSG00000186847	P02533	Keratin, type I cytoskeletal 14	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALDH3A2	Aldehyde dehydrogenase family 3 member A2	Catalyzes the oxidation of medium and long chain aliphatic aldehydes to fatty acids.
KRT14	Keratin, type I cytoskeletal 14	The nonhelical tail domain is involved in promoting KRT5-KRT14 filaments to self-organize into large bundles and enhances the mechanical properties involved in resilience of keratin intermediate filaments in vitro.

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.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALDH3A2	Enzyme (other)	yes	1.2.1.48	Aldehyde_DH_NAD(P), Aldehyde_DH_dom, Ald_DH_CS_CYS
KRT14	Other/Unknown	no		Keratin_I, IF_conserved, IF_rod_dom

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)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
right adrenal gland	1
right adrenal gland cortex	1
gingiva	1
gingival epithelium	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALDH3A2	298	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
KRT14	193	broad	marker	gingiva, gingival epithelium, upper arm skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH3A2	4,773
KRT14	3,351

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRT14	P02533	2
ALDH3A2	P51648	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. 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.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Alpha-oxidation of phytanate	1	951.7×	0.013	ALDH3A2
Type I hemidesmosome assembly	1	519.1×	0.013	KRT14
Sphingolipid catabolism	1	439.2×	0.013	ALDH3A2
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	271.9×	0.013	KRT14
Class I peroxisomal membrane protein import	1	259.6×	0.013	ALDH3A2
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	1	237.9×	0.013	ALDH3A2
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	139.3×	0.016	KRT14
RND1 GTPase cycle	1	132.8×	0.016	ALDH3A2
RND2 GTPase cycle	1	129.8×	0.016	ALDH3A2
Developmental Cell Lineages	1	112.0×	0.017	KRT14
Cell junction organization	1	93.6×	0.018	KRT14
Cell-Cell communication	1	68.8×	0.023	KRT14
Formation of the cornified envelope	1	43.9×	0.033	KRT14
RHO GTPase cycle	1	30.1×	0.045	ALDH3A2
Keratinization	1	27.9×	0.045	KRT14
Signaling by Rho GTPases	1	17.1×	0.066	ALDH3A2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.066	ALDH3A2
Developmental Biology	1	7.2×	0.141	KRT14
Signal Transduction	1	5.1×	0.187	ALDH3A2

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 term	Cohort genes	Fold	FDR	Sample cohort genes
epidermis development	2	210.7×	3e-04	ALDH3A2, KRT14
sesquiterpenoid metabolic process	1	8426.0×	6e-04	ALDH3A2
hexadecanal metabolic process	1	8426.0×	6e-04	ALDH3A2
phytol metabolic process	1	4213.0×	9e-04	ALDH3A2
intermediate filament bundle assembly	1	1404.3×	0.002	KRT14
aldehyde metabolic process	1	648.1×	0.004	ALDH3A2
response to radiation	1	601.9×	0.004	KRT14
hair cycle	1	468.1×	0.004	KRT14
peripheral nervous system development	1	290.6×	0.006	ALDH3A2
morphogenesis of an epithelium	1	172.0×	0.009	KRT14
stem cell differentiation	1	150.5×	0.009	KRT14
keratinocyte differentiation	1	123.9×	0.010	KRT14
intermediate filament organization	1	120.4×	0.010	KRT14
fatty acid metabolic process	1	96.8×	0.011	ALDH3A2
central nervous system development	1	57.7×	0.017	ALDH3A2

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
Reproxalap	Phase 3 (in late-stage trials)

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALDH3A2	0	0
KRT14	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ALDH3A2	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALDH3A2	1.2.1.48	long-chain-aldehyde 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

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	1	ALDH3A2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	KRT14

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ALDH3A2	3	—
KRT14	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE3	1
PHASE2	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03445650	PHASE3	COMPLETED	RESET Trial - Part 1 - A Phase 3 Trial in Subjects With Sjögren-Larsson Syndrome (SLS)
NCT02402309	PHASE2	COMPLETED	A Study of Topical NS2 Cream to Treat Ichthyosis in Sjögren-Larsson Syndrome (SLS)
NCT05443685	PHASE1/PHASE2	COMPLETED	ADX-629 Therapy for Sjogren-Larsson Syndrome
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT01971957	Not specified	COMPLETED	Sjogren-Larsson Syndrome: Natural History, Clinical Variation and Evaluation of Biochemical Markers
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
REPROXALAP	3	1