Allan-Herndon-Dudley syndrome

Summary

Allan-Herndon-Dudley syndrome (MONDO:0010354) is a disease caused by SLC16A2 (GenCC Definitive), with 2 cohort genes and 11 clinical trials. Top therapeutic interventions include glycerol phenylbutyrate and tiratricol.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: SLC16A2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 109
• Phenotypes (HPO): 54
• Clinical trials: 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		320	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Europe	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0008936	Axial hypotonia	Very frequent (80-99%)
HP:0000275	Narrow face	Frequent (30-79%)
HP:0000276	Long face	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001266	Choreoathetosis	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001531	Failure to thrive in infancy	Frequent (30-79%)
HP:0001649	Tachycardia	Frequent (30-79%)
HP:0001763	Pes planus	Frequent (30-79%)
HP:0002058	Myopathic facies	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0002375	Hypokinesia	Frequent (30-79%)
HP:0002751	Kyphoscoliosis	Frequent (30-79%)
HP:0002926	Abnormality of thyroid physiology	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0008081	Pes valgus	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0011788	Increased circulating free T3	Frequent (30-79%)
HP:0012444	Brain atrophy	Frequent (30-79%)
HP:0012448	Delayed myelination	Frequent (30-79%)
HP:0031936	Delayed ability to walk	Frequent (30-79%)
HP:0045082	Decreased body mass index	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001319	Neonatal hypotonia	Occasional (5-29%)
HP:0001348	Brisk reflexes	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0001558	Decreased fetal movement	Occasional (5-29%)
HP:0002071	Abnormality of extrapyramidal motor function	Occasional (5-29%)
HP:0002342	Intellectual disability, moderate	Occasional (5-29%)
HP:0002421	Poor head control	Occasional (5-29%)
HP:0002509	Limb hypertonia	Occasional (5-29%)
HP:0002510	Spastic tetraplegia	Occasional (5-29%)
HP:0003324	Generalized muscle weakness	Occasional (5-29%)
HP:0003487	Babinski sign	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0006579	Prolonged neonatal jaundice	Occasional (5-29%)
HP:0011448	Ankle clonus	Occasional (5-29%)
HP:0001518	Small for gestational age	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Allan-Herndon-Dudley syndrome
Mondo ID	MONDO:0010354
MeSH	C537047
OMIM	300523
Orphanet	59
DOID	DOID:0050631
ICD-11	56813604
NCIT	C118843
SNOMED CT	702327009
UMLS	C0795889
MedGen	208645
GARD	0005617
NORD	1415
Is cancer (heuristic)	no

Also known as: AHDS · ALLAN-Herndon syndrome · Allan-Herndon-Dudley syndrome · intellectual disability and muscular atrophy · MCT8 deficiency · MCT8-specific thyroid hormone cell Membrane transporter deficiency · MCT8-Specific Thyroid Hormone Cell Transporter Deficiency · mental retardation and muscular atrophy · mental retardation, X-linked, with hypotonia · monocarboxylate transporter 8 deficiency · monocarboxylate transporter-8 deficiency · T3 resisitence · triiodothyronine resistance · X-linked intellectual disability with hypotonia · X-linked intellectual disability-hypotonia syndrome

Data availability: 109 ClinVar variants · 4 GenCC gene-disease records · 11 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › X-linked syndromic intellectual disability › Allan-Herndon-Dudley syndrome

Related subtypes (80): X-linked intellectual disability-psychosis-macroorchidism syndrome, X-linked intellectual disability-plagiocephaly syndrome, intellectual disability, X-linked 49, MEHMO syndrome, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability, Stocco dos Santos type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, X-linked intellectual disability-cerebellar hypoplasia syndrome, syndromic X-linked intellectual disability Claes-Jensen type, X-linked intellectual disability-retinitis pigmentosa syndrome, syndromic X-linked intellectual disability 14, syndromic X-linked intellectual disability 94, intellectual disability, X-linked syndromic, Turner type, syndromic X-linked intellectual disability Shrimpton type, X-linked intellectual disability-craniofacioskeletal syndrome, syndromic X-linked intellectual disability Raymond type, syndromic X-linked intellectual disability 17, syndromic X-linked intellectual disability Nascimento type, syndromic X-linked intellectual disability Chudley-Schwartz type, X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome, X-linked intellectual disability, Cantagrel type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, intellectual disability, X-linked 99, syndromic, female-restricted, intellectual disability, X-linked, syndromic, Bain type, Borjeson-Forssman-Lehmann syndrome, Coffin-Lowry syndrome, syndromic X-linked intellectual disability 5, X-linked intellectual disability-seizures-psoriasis syndrome, Renpenning syndrome, Partington syndrome, syndromic X-linked intellectual disability 12, severe X-linked intellectual disability, Gustavson type, syndromic X-linked intellectual disability Snyder type, Wilson-Turner syndrome, Prieto syndrome, skeletal dysplasia-intellectual disability syndrome, X-linked intellectual disability-spastic quadriparesis syndrome, early-onset parkinsonism-intellectual disability syndrome, X-linked intellectual disability, Schimke type, X-linked intellectual disability, Cilliers type, X-linked intellectual disability, van Esch type, X-linked intellectual disability-epilepsy syndrome, ATR-X-related syndrome, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, X-linked intellectual disability, Schutz type, X-linked intellectual disability-hypotonia-movement disorder syndrome, X-linked intellectual disability with isolated growth hormone deficiency, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-precocious puberty-obesity syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability-macrocephaly-macroorchidism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Seemanova type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, X-linked intellectual disability-acromegaly-hyperactivity syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, fried syndrome, X-linked intellectual disability-ataxia-apraxia syndrome, intellectual developmental disorder, X-linked, syndromic, Pilorge type, Paganini-Miozzo syndrome, intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type, intellectual disability, X-linked, syndromic, 35, intellectual disability, X-linked, syndromic, Houge type, MED12-related intellectual disability syndrome, NAA10-related syndrome, ATP6AP2-related disorder, X-linked intellectual disability with hypopituitarism, SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder, intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, intellectual developmental disorder, X-linked, syndromic 37, CASK-related intellectual disability

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

109 retrieved; paginated sample, class counts are floors:

47 pathogenic, 23 likely pathogenic, 19 uncertain significance, 7 pathogenic/likely pathogenic, 6 conflicting classifications of pathogenicity, 4 benign/likely benign, 2 not provided, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3777725	NC_000023.11:g.(?_7442087)del		Pathogenic	criteria provided, single submitter
1064730	GRCh37/hg19 Xq13.2(chrX:73160043-73703398)	JPX	Pathogenic	no assertion criteria provided
11635	NC_000023.11:g.(74305035_74421492)_(74422068_74520989)del	LOC130068443	Pathogenic	no assertion criteria provided
1031649	NM_006517.5(SLC16A2):c.1070G>A (p.Trp357Ter)	SLC16A2	Pathogenic	criteria provided, single submitter
1031650	NM_006517.5(SLC16A2):c.972G>A (p.Trp324Ter)	SLC16A2	Pathogenic	criteria provided, single submitter
1077180	NM_006517.5(SLC16A2):c.-6_430+5del	SLC16A2	Pathogenic	criteria provided, single submitter
11632	NM_006517.5(SLC16A2):c.1313T>C (p.Leu438Pro)	SLC16A2	Pathogenic	no assertion criteria provided
11633	NM_006517.5(SLC16A2):c.993del (p.Ala332fs)	SLC16A2	Pathogenic	no assertion criteria provided
11634	NM_006517.5(SLC16A2):c.449C>T (p.Ala150Val)	SLC16A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11636	NM_006517.5(SLC16A2):c.1190T>C (p.Leu397Pro)	SLC16A2	Pathogenic	criteria provided, single submitter
11637	NG_011641.2:g.(108110_108560)_(109645_112963)del	SLC16A2	Pathogenic	no assertion criteria provided
11638	NM_006517.5(SLC16A2):c.1481T>C (p.Leu494Pro)	SLC16A2	Pathogenic	no assertion criteria provided
11639	NM_006517.5(SLC16A2):c.1079T>G (p.Leu360Trp)	SLC16A2	Pathogenic	no assertion criteria provided
11640	NM_006517.5(SLC16A2):c.1121C>A (p.Ser374Ter)	SLC16A2	Pathogenic	no assertion criteria provided
11641	NM_006517.5(SLC16A2):c.461TCT[2] (p.Phe156del)	SLC16A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11642	NM_006517.5(SLC16A2):c.1613del (p.Pro538fs)	SLC16A2	Pathogenic	no assertion criteria provided
1327916	NM_006517.5(SLC16A2):c.852_862dup (p.Gln288fs)	SLC16A2	Pathogenic	no assertion criteria provided
1344896	NM_006517.5(SLC16A2):c.431-2A>G	SLC16A2	Pathogenic	criteria provided, single submitter
1366592	NM_006517.5(SLC16A2):c.97dup (p.Ser33fs)	SLC16A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159900	NM_006517.5(SLC16A2):c.916C>T (p.Gln306Ter)	SLC16A2	Pathogenic	criteria provided, single submitter
159901	NM_006517.5(SLC16A2):c.979G>A (p.Gly327Arg)	SLC16A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159902	NM_006517.5(SLC16A2):c.1111C>T (p.Arg371Cys)	SLC16A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159906	NM_006517.5(SLC16A2):c.277C>T (p.Gln93Ter)	SLC16A2	Pathogenic	criteria provided, single submitter
1686195	NM_006517.5(SLC16A2):c.407del (p.Asn136fs)	SLC16A2	Pathogenic	criteria provided, single submitter
1711189	NM_006517.5(SLC16A2):c.640C>T (p.Gln214Ter)	SLC16A2	Pathogenic	criteria provided, single submitter
212186	NM_006517.5(SLC16A2):c.940C>T (p.Arg314Ter)	SLC16A2	Pathogenic	criteria provided, multiple submitters, no conflicts
212188	NM_006517.5(SLC16A2):c.1392dup (p.Ile465fs)	SLC16A2	Pathogenic	criteria provided, single submitter
212189	NM_006517.5(SLC16A2):c.1474_1481del (p.Val492fs)	SLC16A2	Pathogenic	criteria provided, single submitter
212191	NM_006517.5(SLC16A2):c.256del (p.Arg86fs)	SLC16A2	Pathogenic	criteria provided, single submitter
212192	NM_006517.5(SLC16A2):c.374del (p.Tyr125fs)	SLC16A2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
SLC16A2	Definitive	X-linked	Allan-Herndon-Dudley syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC16A2	Orphanet:59	Allan-Herndon-Dudley syndrome

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC16A2	HGNC:10923	ENSG00000147100	P36021	Monocarboxylate transporter 8	gencc,clinvar
JPX	HGNC:37191	ENSG00000225470		JPX transcript, XIST activator	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC16A2	Monocarboxylate transporter 8	Specific thyroid hormone transmembrane transporter, that mediates both uptake and efflux of thyroid hormones across the cell membrane independently of pH or a Na(+) gradient.

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
Transporter	1	38.9×	0.051
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC16A2	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
JPX	Other/Unknown	no

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
right adrenal gland	1
right adrenal gland cortex	1
right lobe of liver	1
calcaneal tendon	1
colonic epithelium	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC16A2	183	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, right lobe of liver
JPX	246	ubiquitous	marker	colonic epithelium, calcaneal tendon, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC16A2	1,242
JPX	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC16A2	P36021	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 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
Organic anion transport by SLCO transporters	1	1038.2×	0.004	SLC16A2
Transport of vitamins, nucleosides, and related molecules	1	271.9×	0.007	SLC16A2
SLC-mediated transmembrane transport	1	59.2×	0.023	SLC16A2
Transport of small molecules	1	25.1×	0.040	SLC16A2

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
thyroid-stimulating hormone secretion	1	8426.0×	0.001	SLC16A2
thyroid hormone transport	1	1685.2×	0.001	SLC16A2
monocarboxylic acid transport	1	1532.0×	0.001	SLC16A2
negative regulation of neural precursor cell proliferation	1	1532.0×	0.001	SLC16A2
thyroid hormone metabolic process	1	1404.3×	0.001	SLC16A2
amino acid import across plasma membrane	1	1053.2×	0.001	SLC16A2
thyroid hormone generation	1	991.3×	0.001	SLC16A2
amino acid metabolic process	1	802.5×	0.001	SLC16A2
transport across blood-brain barrier	1	179.3×	0.006	SLC16A2

Therapeutics

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
SLC16A2	0	0
JPX	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC16A2	1	Functional:1

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	SLC16A2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	JPX

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)
SLC16A2	1	—
JPX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 11.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	7
PHASE2	2
PHASE2/PHASE3	1
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05019417	PHASE2/PHASE3	UNKNOWN	Glycerol-Phenylbutyrate Treatment in Children With MCT Mutation (Allan-Herndon- Dudley Syndrome)
NCT05579327	PHASE3	COMPLETED	Withdrawal of Tiratricol Treatment in Males With Monocarboxylate Transporter 8 Deficiency (MCT8 Deficiency)
NCT02396459	PHASE2	ACTIVE_NOT_RECRUITING	Triac Trial II in MCT8 Deficiency Patients
NCT02060474	PHASE2	COMPLETED	Thyroid Hormone Analog Therapy in MCT8 Deficiency: Triac Trial Patients
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT04143295	Not specified	AVAILABLE	Rescue of Infants With MCT8 Deficiency
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT05911399	Not specified	AVAILABLE	Expanded Access Program for Tiratricol in Patients With Monocarboxylate Transporter 8 Deficiency
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT06060197	Not specified	COMPLETED	MCT8 Deficiency Caregiver Study

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
GLYCEROL PHENYLBUTYRATE	4	1
TIRATRICOL	3	4