multiple acyl-CoA dehydrogenase deficiency, severe neonatal type

Summary

multiple acyl-CoA dehydrogenase deficiency, severe neonatal type (MONDO:0018332) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple acyl-CoA dehydrogenase deficiency, severe neonatal type
Mondo ID	MONDO:0018332
Orphanet	394529
UMLS	C5680029
MedGen	1842925
GARD	0017626
Is cancer (heuristic)	no

Also known as: glutaric aciduria type 2, severe neonatal type · MAD deficiency, severe neonatal type · MADD, severe neonatal type

Data availability: 1 ClinVar variant.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › glutaric aciduria › multiple acyl-CoA dehydrogenase deficiency › multiple acyl-CoA dehydrogenase deficiency, severe neonatal type

Related subtypes (4): multiple acyl-CoA dehydrogenase deficiency, mild type, glutaric acidemia IIa, glutaric acidemia IIb, glutaric acidemia IIc

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1699228	NM_001376571.1(MADD):c.4109T>A (p.Leu1370Ter)	MADD	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ETFA	Orphanet:394529	Multiple acyl-CoA dehydrogenase deficiency, severe neonatal type
ETFA	Orphanet:394532	Multiple acyl-CoA dehydrogenase deficiency, mild type
MADD	Orphanet:528084	Non-specific syndromic intellectual disability
MADD	Orphanet:686495	MADD-related developmental delay-endocrine dysfunction-hypohemoglobinemia syndrome

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
ETFA	HGNC:3481	ENSG00000140374	P13804	Electron transfer flavoprotein subunit alpha, mitochondrial	clinvar
MADD	HGNC:6766	ENSG00000110514	Q8WXG6	MAP kinase-activating death domain protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ETFA	Electron transfer flavoprotein subunit alpha, mitochondrial	Heterodimeric electron transfer flavoprotein that accepts electrons from several mitochondrial dehydrogenases, including acyl-CoA dehydrogenases, glutaryl-CoA and sarcosine dehydrogenase.
MADD	MAP kinase-activating death domain protein	Guanyl-nucleotide exchange factor that regulates small GTPases of the Rab family.

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)
ETFA	Other/Unknown	no		ETF_a/FixB, Rossmann-like_a/b/a_fold, ETF_a/b_N
MADD	Other/Unknown	no		cDENN_dom, dDENN_dom, uDENN_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
jejunal mucosa	1
oocyte	1
secondary oocyte	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ETFA	297	ubiquitous	marker	oocyte, secondary oocyte, jejunal mucosa
MADD	280	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ETFA	3,353
MADD	1,021

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ETFA	P13804	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MADD	Q8WXG6	64.59

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Regulation of TNFR1 signaling	1	112.0×	0.021	MADD
RAB GEFs exchange GTP for GDP on RABs	1	62.1×	0.021	MADD
Respiratory electron transport	1	47.6×	0.021	ETFA

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
regulation of extrinsic apoptotic signaling pathway	1	1685.2×	0.002	MADD
amino acid catabolic process	1	1404.3×	0.002	ETFA
regulation of Rab protein signal transduction	1	1203.7×	0.002	MADD
regulation of extrinsic apoptotic signaling pathway via death domain receptors	1	1203.7×	0.002	MADD
fatty acid beta-oxidation using acyl-CoA dehydrogenase	1	702.2×	0.003	ETFA
respiratory electron transport chain	1	421.3×	0.004	ETFA
execution phase of apoptosis	1	383.0×	0.004	MADD
regulation of apoptotic process	1	41.7×	0.029	MADD
positive regulation of MAPK cascade	1	40.3×	0.029	MADD
regulation of cell cycle	1	37.3×	0.029	MADD
cell surface receptor signaling pathway	1	32.0×	0.031	MADD

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
ETFA	0	0
MADD	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
ETFA	1	Binding: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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ETFA, MADD

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)
ETFA	1	—
MADD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.