severe X-linked mitochondrial encephalomyopathy

Summary

severe X-linked mitochondrial encephalomyopathy (MONDO:0010437) is a disease caused by AIFM1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: AIFM1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 49
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001284	Areflexia	Very frequent (80-99%)
HP:0001290	Generalized hypotonia	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0003324	Generalized muscle weakness	Very frequent (80-99%)
HP:0003390	Sensory axonal neuropathy	Very frequent (80-99%)
HP:0003557	Increased variability in muscle fiber diameter	Very frequent (80-99%)
HP:0006829	Severe muscular hypotonia	Very frequent (80-99%)
HP:0009830	Peripheral neuropathy	Very frequent (80-99%)
HP:0010994	Abnormal corpus striatum morphology	Very frequent (80-99%)
HP:0011343	Moderate global developmental delay	Very frequent (80-99%)
HP:0000737	Irritability	Frequent (30-79%)
HP:0001308	Tongue fasciculations	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0002098	Respiratory distress	Frequent (30-79%)
HP:0002151	Increased circulating lactate concentration	Frequent (30-79%)
HP:0002375	Hypokinesia	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002490	Increased CSF lactate	Frequent (30-79%)
HP:0003542	Increased serum pyruvate	Frequent (30-79%)
HP:0004305	Involuntary movements	Frequent (30-79%)
HP:0009025	Increased connective tissue	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	severe X-linked mitochondrial encephalomyopathy
Mondo ID	MONDO:0010437
OMIM	300816
Orphanet	238329
DOID	DOID:0111502
SNOMED CT	722212004
UMLS	C3151753
MedGen	463103
GARD	0017171
Is cancer (heuristic)	no

Also known as: combined oxidative phosphorylation deficiency 6 · combined oxidative phosphorylation deficiency 6, X-linked recessive · combined oxidative phosphorylation deficiency type 6 · COXPD6 · mitochondrial encephalomyopathy due to combined oxidative phosphorylation defect 6 · mitochondrial encephalomyopathy due to COXPD6

Data availability: 49 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › combined oxidative phosphorylation deficiency › severe X-linked mitochondrial encephalomyopathy

Related subtypes (57): hepatoencephalopathy due to combined oxidative phosphorylation defect type 1, combined oxidative phosphorylation defect type 2, fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3, combined oxidative phosphorylation defect type 4, hypotonia with lactic acidemia and hyperammonemia, combined oxidative phosphorylation defect type 7, combined oxidative phosphorylation defect type 8, combined oxidative phosphorylation defect type 9, mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, combined oxidative phosphorylation defect type 11, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, combined oxidative phosphorylation defect type 13, combined oxidative phosphorylation defect type 14, combined oxidative phosphorylation defect type 15, infantile hypertrophic cardiomyopathy due to MRPL44 deficiency, combined oxidative phosphorylation defect type 17, growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome, combined oxidative phosphorylation deficiency 19, combined oxidative phosphorylation defect type 20, combined oxidative phosphorylation defect type 21, mitochondrial proton-transporting ATP synthase complex deficiency, combined oxidative phosphorylation defect type 23, combined oxidative phosphorylation defect type 24, combined oxidative phosphorylation defect type 25, combined oxidative phosphorylation defect type 26, combined oxidative phosphorylation defect type 27, combined oxidative phosphorylation deficiency 28, combined oxidative phosphorylation deficiency 29, combined oxidative phosphorylation defect type 30, lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome, combined oxidative phosphorylation deficiency 40, combined oxidative phosphorylation deficiency 41, combined oxidative phosphorylation deficiency 42, combined oxidative phosphorylation deficiency 43, combined oxidative phosphorylation deficiency 44, combined oxidative phosphorylation deficiency 52, combined oxidative phosphorylation deficiency 53, combined oxidative phosphorylation deficiency 54, combined oxidative phosphorylation deficiency 37, combined oxidative phosphorylation deficiency 38, combined oxidative phosphorylation deficiency 39, combined oxidative phosphorylation deficiency 45, combined oxidative phosphorylation deficiency 46, combined oxidative phosphorylation deficiency 47, combined oxidative phosphorylation deficiency 48, combined oxidative phosphorylation deficiency 51, combined oxidative phosphorylation deficiency 32, combined oxidative phosphorylation deficiency 33, combined oxidative phosphorylation deficiency 34, combined oxidative phosphorylation deficiency 35, combined oxidative phosphorylation deficiency 36, combined oxidative phosphorylation deficiency 55, combined oxidative phosphorylation deficiency 56, combined oxidative phosphorylation deficiency 57, combined oxidative phosphorylation deficiency 58, combined oxidative phosphorylation deficiency 59, combined oxidative phosphorylation deficiency 60

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

49 retrieved; paginated sample, class counts are floors:

17 uncertain significance, 10 benign/likely benign, 8 conflicting classifications of pathogenicity, 7 benign, 4 pathogenic, 2 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
11546	NM_004208.4(AIFM1):c.603_605del (p.Arg201del)	AIFM1	Pathogenic	no assertion criteria provided
1343826	NM_004208.4(AIFM1):c.1164+5G>A	AIFM1	Pathogenic	no assertion criteria provided
162479	NM_004208.4(AIFM1):c.1264C>T (p.Arg422Trp)	AIFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
369972	NM_004208.4(AIFM1):c.1436A>G (p.Gln479Arg)	AIFM1	Pathogenic	no assertion criteria provided
162480	NM_004208.4(AIFM1):c.1265G>A (p.Arg422Gln)	RAB33A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
732668	NM_004208.4(AIFM1):c.1013G>A (p.Gly338Glu)	RAB33A	Pathogenic	no assertion criteria provided
2444188	NM_004208.4(AIFM1):c.1267G>A (p.Val423Ile)	AIFM1	Likely pathogenic	criteria provided, single submitter
367897	NM_004208.4(AIFM1):c.-185G>A	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
732675	NM_004208.4(AIFM1):c.727G>T (p.Val243Leu)	AIFM1	Conflicting classifications of pathogenicity	no assertion criteria provided
857026	NM_004208.4(AIFM1):c.340G>A (p.Ala114Thr)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
914371	NM_004208.4(AIFM1):c.-90G>C	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
982823	NM_004208.4(AIFM1):c.506C>T (p.Pro169Leu)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
367889	NM_004208.4(AIFM1):c.1647A>G (p.Ala549=)	RAB33A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
445310	NM_004208.4(AIFM1):c.170C>G (p.Ser57Cys)	RAB33A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
732658	NM_004208.4(AIFM1):c.923G>A (p.Gly308Glu)	RAB33A	Conflicting classifications of pathogenicity	no assertion criteria provided
214082	NM_004208.4(AIFM1):c.452G>A (p.Arg151Gln)	AIFM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2441878	NM_004208.4(AIFM1):c.1596T>A (p.Ser532Arg)	AIFM1	Uncertain significance	criteria provided, single submitter
2584682	NM_004208.4(AIFM1):c.782-3C>T	AIFM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
367888	NM_004208.4(AIFM1):c.*49C>T	AIFM1	Uncertain significance	criteria provided, single submitter
3759672	NM_004208.4(AIFM1):c.1288C>T (p.Arg430Cys)	AIFM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
912874	NM_004208.4(AIFM1):c.1355T>C (p.Val452Ala)	AIFM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
913253	NM_004208.4(AIFM1):c.858+13T>G	AIFM1	Uncertain significance	criteria provided, single submitter
367895	NM_004208.4(AIFM1):c.-140C>G	LOC130068679	Uncertain significance	criteria provided, single submitter
1028702	NM_004208.4(AIFM1):c.147G>C (p.Gln49His)	RAB33A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1179012	NM_004208.4(AIFM1):c.1227TGG[1] (p.Gly411del)	RAB33A	Uncertain significance	criteria provided, single submitter
1312954	NM_004208.4(AIFM1):c.460G>A (p.Asp154Asn)	RAB33A	Uncertain significance	criteria provided, single submitter
2661431	NM_004208.4(AIFM1):c.458G>A (p.Arg153Gln)	RAB33A	Uncertain significance	criteria provided, multiple submitters, no conflicts
3391178	NM_004208.4(AIFM1):c.1342G>A (p.Gly448Arg)	RAB33A	Uncertain significance	criteria provided, single submitter
642792	NM_004208.4(AIFM1):c.1693A>G (p.Ile565Val)	RAB33A	Uncertain significance	criteria provided, multiple submitters, no conflicts
836428	NM_004208.4(AIFM1):c.1586G>A (p.Arg529Gln)	RAB33A	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 4 · 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
AIFM1	Definitive	X-linked	X-linked hereditary sensory and autonomic neuropathy with hearing loss	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AIFM1	Orphanet:101078	X-linked Charcot-Marie-Tooth disease type 4
AIFM1	Orphanet:139583	X-linked hereditary sensory and autonomic neuropathy with deafness
AIFM1	Orphanet:238329	Severe X-linked mitochondrial encephalomyopathy
AIFM1	Orphanet:83629	Leukoencephalopathy-spondyloepimetaphyseal dysplasia 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
AIFM1	HGNC:8768	ENSG00000156709	O95831	Apoptosis-inducing factor 1, mitochondrial	gencc,clinvar
RAB33A	HGNC:9773	ENSG00000134594	Q14088	Ras-related protein Rab-33A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AIFM1	Apoptosis-inducing factor 1, mitochondrial	Functions both as NADH oxidoreductase and as regulator of apoptosis.
RAB33A	Ras-related protein Rab-33A	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.

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)
AIFM1	Enzyme (other)	yes	7.1.1.2	FAD/NAD-linked_Rdtase_dimer_sf, FAD/NAD-binding_dom, AIF_C
RAB33A	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adult mammalian kidney	1
apex of heart	1
heart left ventricle	1
C1 segment of cervical spinal cord	1
cortical plate	1
prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AIFM1	273	ubiquitous	marker	apex of heart, adult mammalian kidney, heart left ventricle
RAB33A	207	ubiquitous	yes	cortical plate, C1 segment of cervical spinal cord, prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AIFM1	4,780
RAB33A	1,603

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AIFM1	O95831	26

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAB33A	Q14088	81.85

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
TBC/RABGAPs	1	259.6×	0.006	RAB33A
RAB geranylgeranylation	1	173.0×	0.006	RAB33A

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
protein import into mitochondrial intermembrane space	1	2808.7×	0.003	AIFM1
protein import into the intermembrane space via the disulfide relay system	1	2808.7×	0.003	AIFM1
mitochondrial respiratory chain complex assembly	1	1404.3×	0.003	AIFM1
positive regulation of necroptotic process	1	1404.3×	0.003	AIFM1
cellular response to aldosterone	1	1203.7×	0.003	AIFM1
response to L-glutamate	1	842.6×	0.004	AIFM1
Rab protein signal transduction	1	495.6×	0.005	RAB33A
cellular response to nitric oxide	1	468.1×	0.005	AIFM1
antigen processing and presentation	1	351.1×	0.006	RAB33A
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1	240.7×	0.008	AIFM1
cellular response to estradiol stimulus	1	205.5×	0.009	AIFM1
positive regulation of neuron apoptotic process	1	135.9×	0.012	AIFM1
response to ischemia	1	125.8×	0.012	AIFM1
cellular response to hydrogen peroxide	1	117.0×	0.012	AIFM1
autophagosome assembly	1	112.3×	0.012	RAB33A
response to toxic substance	1	105.3×	0.012	AIFM1
cellular response to hypoxia	1	60.6×	0.019	AIFM1
neuron differentiation	1	50.1×	0.022	AIFM1
positive regulation of apoptotic process	1	28.4×	0.037	AIFM1
apoptotic process	1	14.3×	0.068	AIFM1

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
AIFM1	0	0
RAB33A	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
AIFM1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AIFM1	7.1.1.2	NADH:ubiquinone reductase (H+-translocating)

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	AIFM1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RAB33A

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)
AIFM1	2	—
RAB33A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.