Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome

Summary

Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome (MONDO:0018820) is a disease caused by TANGO2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TANGO2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 45
• Phenotypes (HPO): 51

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		24	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0002151	Increased circulating lactate concentration	Very frequent (80-99%)
HP:0002919	Ketonuria	Very frequent (80-99%)
HP:0003115	Abnormal EKG	Very frequent (80-99%)
HP:0003236	Elevated circulating creatine kinase concentration	Very frequent (80-99%)
HP:0003458	EMG: myopathic abnormalities	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001657	Prolonged QT interval	Frequent (30-79%)
HP:0001943	Hypoglycemia	Frequent (30-79%)
HP:0001987	Hyperammonemia	Frequent (30-79%)
HP:0002071	Abnormality of extrapyramidal motor function	Frequent (30-79%)
HP:0002283	Global brain atrophy	Frequent (30-79%)
HP:0002311	Incoordination	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002579	Gastrointestinal dysmotility	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0003128	Lactic acidosis	Frequent (30-79%)
HP:0004305	Involuntary movements	Frequent (30-79%)
HP:0008223	Compensated hypothyroidism	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0008942	Acute rhabdomyolysis	Frequent (30-79%)
HP:0011343	Moderate global developmental delay	Frequent (30-79%)
HP:0011675	Arrhythmia	Frequent (30-79%)
HP:0031936	Delayed ability to walk	Frequent (30-79%)
HP:0002173	Hypoglycemic seizures	Occasional (5-29%)
HP:0002384	Focal impaired awareness seizure	Occasional (5-29%)
HP:0003487	Babinski sign	Occasional (5-29%)
HP:0010818	Generalized tonic seizure	Occasional (5-29%)
HP:0011342	Mild global developmental delay	Occasional (5-29%)
HP:0011344	Severe global developmental delay	Occasional (5-29%)
HP:0012469	Infantile spasms	Occasional (5-29%)
HP:0031165	Multifocal seizures	Occasional (5-29%)
HP:0045045	Elevated plasma acylcarnitine levels	Occasional (5-29%)
HP:0100704	Cerebral visual impairment	Occasional (5-29%)
HP:0000605	Supranuclear gaze palsy	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000646	Amblyopia	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001297	Stroke	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002123	Generalized myoclonic seizure	Occasional (5-29%)
HP:0002169	Clonus	Occasional (5-29%)
HP:0000252	Microcephaly	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome
Mondo ID	MONDO:0018820
OMIM	616878
Orphanet	480864
DOID	DOID:0081386
UMLS	C5567524
MedGen	1798947
GARD	0013423
NORD	1944
Is cancer (heuristic)	no

Also known as: MECRCN · TANGO2 deficiency · TANGO2 Deficiency Disorder · transport and golgi organisation protein 2 (TANGO2) deficiency · transport and golgi organization protein 2 (TANGO2) deficiency

Data availability: 45 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome

Related subtypes (81): Huntington disease and related disorders, agenesis of the corpus callosum with peripheral neuropathy, striatonigral degeneration, angioid streaks of choroid, amyotrophic lateral sclerosis-parkinsonism-dementia complex, inherited Creutzfeldt-Jakob disease, mitochondrial DNA depletion syndrome 4a, cerebellar ataxia-hypogonadism syndrome, myoclonic cerebellar dyssynergia, cerebral sclerosis similar to Pelizaeus-Merzbacher disease, Chediak-Higashi syndrome, encephalopathy due to beta-mercaptolactate-cysteine disulfiduria, PEHO syndrome, deafness dystonia syndrome, Kennedy disease, fatal familial insomnia, Huntington disease-like 1, neuronal intranuclear inclusion disease, ataxia-telangiectasia-like disorder, radiation sensitivity/chromosome instability syndrome, autosomal dominant, Huntington disease-like 2, microphthalmia-brain atrophy syndrome, neurodegenerative syndrome due to cerebral folate transport deficiency, hereditary sensory neuropathy-deafness-dementia syndrome, infantile cerebellar-retinal degeneration, Alzheimer disease 17, hypotonia, infantile, with psychomotor retardation and characteristic facies, Alzheimer disease 18, diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome, severe neurodegenerative syndrome with lipodystrophy, developmental and epileptic encephalopathy, 35, combined oxidative phosphorylation deficiency 29, neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, neuronal ceroid lipofuscinosis, frontotemporal dementia with motor neuron disease, frontotemporal dementia, GM2 gangliosidosis, attenuated Chédiak-Higashi syndrome, autosomal recessive cerebral atrophy, neurodegeneration with brain iron accumulation, fatal post-viral neurodegenerative disorder, ferro-cerebro-cutaneous syndrome, PRKAR1B-related neurodegenerative dementia with intermediate filaments, ITM2B amyloidosis, corticobasal syndrome, infantile-onset axonal motor and sensory neuropathy-optic atrophy-neurodegenerative syndrome, posterior cortical atrophy, progressive supranuclear palsy, leukodystrophy, hereditary spastic paraplegia, facial onset sensory and motor neuronopathy, X-linked neurodegenerative syndrome, Bertini type, X-linked neurodegenerative syndrome, Hamel type, boylan dew greco syndrome, hereditary motor neuron disease, neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, frontotemporal dementia and/or amyotrophic lateral sclerosis, neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities, neurodegeneration with ataxia and late-onset optic atrophy, neurodegeneration, childhood-onset, with cerebellar atrophy, neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, neurodegeneration, infantile-onset, biotin-responsive, hereditary optic atrophy, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome, familial Alzheimer disease, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, hereditary cerebellar ataxia, DCTN1-related neurodegeneration, early-childhood-onset neurodegeneration with retinitis pigmentosa, sensorineural hearing loss, and demyelinating peripheral neuropathy, TUBB4A-related neurologic disorder, neurodegeneration, childhood-onset, with progressive microcephaly, neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, neurodegeneration and seizures due to copper transport defect, neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairment, neurodegenerative disorder with cerebellar and caudate atrophy, APP-related brain and vascular amyloidosis

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

45 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 13 pathogenic, 9 pathogenic/likely pathogenic, 6 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1312508	NM_152906.7(TANGO2):c.262C>T (p.Arg88Ter)	TANGO2	Pathogenic	criteria provided, multiple submitters, no conflicts
1710052	NM_152906.7(TANGO2):c.280del (p.His94fs)	TANGO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1810218	NM_152906.7(TANGO2):c.57-1G>C	TANGO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208823	NM_152906.7(TANGO2):c.460G>A (p.Gly154Arg)	TANGO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208824	NM_152906.7(TANGO2):c.605+1G>A	TANGO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224770	NM_152906.5(TANGO2):c.57-1743_*10769del	TANGO2	Pathogenic	criteria provided, multiple submitters, no conflicts
224772	NM_152906.7(TANGO2):c.146-3605_451+2245del	TANGO2	Pathogenic	criteria provided, single submitter
224773	NM_152906.7(TANGO2):c.4del (p.Cys2fs)	TANGO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224774	NM_152906.7(TANGO2):c.418C>T (p.Arg140Ter)	TANGO2	Pathogenic	criteria provided, multiple submitters, no conflicts
2500728	NC_000022.11:g.20041466_20075200del	TANGO2	Pathogenic	criteria provided, single submitter
2788154	NM_152906.7(TANGO2):c.634C>T (p.Gln212Ter)	TANGO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
378700	NM_152906.7(TANGO2):c.94C>T (p.Arg32Ter)	TANGO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4056473	Single allele	TANGO2	Pathogenic	criteria provided, single submitter
4056474	Single allele	TANGO2	Pathogenic	criteria provided, single submitter
432207	NM_152906.7(TANGO2):c.711-3C>G	TANGO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4528934	NC_000022.11:g.20041486_20075431del	TANGO2	Pathogenic	criteria provided, single submitter
4535883	NC_000022.10:g.(20024378_20030877)(20054688?)del	TANGO2	Pathogenic	criteria provided, single submitter
617515	NM_152906.7(TANGO2):c.256C>T (p.Arg86Ter)	TANGO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
915958	GRCh37/hg19 22q11.21(chr22:20029135-20062954)	TANGO2	Pathogenic	no assertion criteria provided
915959	GRCh37/hg19 22q11.21(chr22:20036384-20045784)	TANGO2	Pathogenic	no assertion criteria provided
984372	NC_000022.11:g.20039637_20075714del	TANGO2	Pathogenic	no assertion criteria provided
984373	NC_000022.11:g.20041469_20075432del	TANGO2	Pathogenic	no assertion criteria provided
3370482	NM_152906.7(TANGO2):c.145+1G>T	TANGO2	Likely pathogenic	criteria provided, single submitter
3731479	NM_152906.7(TANGO2):c.648C>G (p.Tyr216Ter)	TANGO2	Likely pathogenic	criteria provided, single submitter
3767164	NM_152906.7(TANGO2):c.59T>C (p.Leu20Pro)	TANGO2	Likely pathogenic	criteria provided, single submitter
4796737	NM_152906.7(TANGO2):c.710G>A (p.Arg237Lys)	TANGO2	Likely pathogenic	criteria provided, single submitter
813936	NM_152906.7(TANGO2):c.380+1G>A	TANGO2	Likely pathogenic	criteria provided, single submitter
984648	NM_152906.7(TANGO2):c.569_592del (p.Ile190_Leu197del)	TANGO2	Likely pathogenic	criteria provided, single submitter
1301615	NM_152906.7(TANGO2):c.703G>A (p.Gly235Ser)	TANGO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2436951	NM_152906.7(TANGO2):c.443T>G (p.Leu148Trp)	TANGO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
TANGO2	Definitive	Autosomal recessive	recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TANGO2	Orphanet:480864	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome
BICD2	Orphanet:363454	BICD2-related autosomal dominant childhood-onset proximal spinal muscular atrophy

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
TANGO2	HGNC:25439	ENSG00000183597	Q6ICL3	Transport and Golgi organization protein 2 homolog	gencc,clinvar
BICD2	HGNC:17208	ENSG00000185963	Q8TD16	Protein bicaudal D homolog 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TANGO2	Transport and Golgi organization protein 2 homolog	May be involved in lipid homeostasis.
BICD2	Protein bicaudal D homolog 2	Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TANGO2	Other/Unknown	no		TANGO2
BICD2	Other/Unknown	no		BICD

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
apex of heart	1
blood	1
granulocyte	1
gingiva	1
gingival epithelium	1
hair follicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TANGO2	217	ubiquitous	marker	apex of heart, granulocyte, blood
BICD2	290	ubiquitous	marker	gingival epithelium, gingiva, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BICD2	2,275
TANGO2	831

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TANGO2	Q6ICL3	3
BICD2	Q8TD16	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
COPI-independent Golgi-to-ER retrograde traffic	1	207.6×	0.016	BICD2
Golgi-to-ER retrograde transport	1	132.8×	0.016	BICD2
Intra-Golgi and retrograde Golgi-to-ER traffic	1	104.8×	0.016	BICD2
Membrane Trafficking	1	37.1×	0.029	BICD2
Vesicle-mediated transport	1	34.8×	0.029	BICD2

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
microtubule anchoring at microtubule organizing center	1	4213.0×	0.003	BICD2
minus-end-directed organelle transport along microtubule	1	2106.5×	0.003	BICD2
centrosome localization	1	443.5×	0.007	BICD2
protein localization to Golgi apparatus	1	401.2×	0.007	BICD2
regulation of microtubule cytoskeleton organization	1	271.8×	0.008	BICD2
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	168.5×	0.009	BICD2
microtubule-based movement	1	147.8×	0.009	BICD2
protein secretion	1	131.7×	0.009	TANGO2
mRNA transport	1	131.7×	0.009	BICD2
Golgi organization	1	66.9×	0.016	TANGO2
protein transport	1	21.9×	0.045	BICD2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
TANGO2	0	0
BICD2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TANGO2, BICD2

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)
TANGO2	0	—
BICD2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.