Myopathy with abnormal lipid metabolism

Summary

Myopathy with abnormal lipid metabolism (MONDO:0009703) is a disease caused by FLAD1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: FLAD1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myopathy with abnormal lipid metabolism
Mondo ID	MONDO:0009703
MeSH	C562935
OMIM	255100
SNOMED CT	240095001
UMLS	C4310822
MedGen	934789
GARD	0024689
Is cancer (heuristic)	no

Also known as: LSMFLAD · myopathy with abnormal lipid metabolism

Data availability: 18 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › myopathy with abnormal lipid metabolism

Related subtypes (31): polyglucosan body myopathy, muscular atrophy, myopathy of extraocular muscle, acute quadriplegic myopathy, myofascial pain syndrome, proximal myopathy with focal depletion of mitochondria, Brody myopathy, rippling muscle disease, myopathy due to myoadenylate deaminase deficiency, proximal myopathy with extrapyramidal signs, intermediate nemaline myopathy, hereditary inclusion-body myopathy, hereditary continuous muscle fiber activity, congenital myopathy, muscular dystrophy, metabolic myopathy, myositis disease, collagen 6-related myopathy, myopathy caused by variation in CRPPA, drug-induced myopathy, myopathy caused by variation in FKRP, myopathy caused by variation in FKTN, myopathy caused by variation in POMGNT1, myopathy caused by variation in POMGNT2, myopathy caused by variation in POMT1, myopathy caused by variation in POMT2, myopathy caused by variation in GMPPB, FHL1-related myopathy, myopathy, sarcoplasmic body, myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 2, myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis

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

18 retrieved; paginated sample, class counts are floors:

8 pathogenic, 2 conflicting classifications of pathogenicity, 2 uncertain significance, 2 pathogenic/likely pathogenic, 2 likely pathogenic, 1 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1184538	NM_025207.5(FLAD1):c.797del (p.Glu266fs)	FLAD1	Pathogenic	no assertion criteria provided
224727	NM_025207.5(FLAD1):c.1484_1486del (p.Ser495del)	FLAD1	Pathogenic	criteria provided, single submitter
224728	NM_025207.5(FLAD1):c.568_569dup (p.Val191fs)	FLAD1	Pathogenic	criteria provided, single submitter
224729	NM_025207.5(FLAD1):c.1588C>T (p.Arg530Cys)	FLAD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224730	NM_025207.5(FLAD1):c.836del (p.Phe279fs)	FLAD1	Pathogenic	criteria provided, single submitter
224731	NM_025207.5(FLAD1):c.526_537delinsCA (p.Ala176fs)	FLAD1	Pathogenic	criteria provided, single submitter
224732	NM_025207.5(FLAD1):c.401_404del (p.Phe134fs)	FLAD1	Pathogenic	criteria provided, multiple submitters, no conflicts
3382319	NM_025207.5(FLAD1):c.442C>T (p.Arg148Ter)	FLAD1	Pathogenic	criteria provided, multiple submitters, no conflicts
373037	NM_025207.5(FLAD1):c.408C>A (p.Cys136Ter)	FLAD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
801554	NM_025207.5(FLAD1):c.745C>T (p.Arg249Ter)	FLAD1	Pathogenic	criteria provided, multiple submitters, no conflicts
3600995	NM_025207.5(FLAD1):c.512_528del (p.Thr171fs)	FLAD1	Likely pathogenic	criteria provided, single submitter
4537458	NM_025207.5(FLAD1):c.749A>C (p.Asn250Thr)	FLAD1	Likely pathogenic	criteria provided, single submitter
1211105	NM_025207.5(FLAD1):c.683G>A (p.Arg228His)	FLAD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1898504	NM_025207.5(FLAD1):c.1748G>A (p.Arg583Gln)	FLAD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1299478	NM_025207.5(FLAD1):c.1610G>C (p.Cys537Ser)	FLAD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1500405	NM_025207.5(FLAD1):c.803T>G (p.Met268Arg)	FLAD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1641695	NM_025207.5(FLAD1):c.372+24_372+25del	FLAD1	Likely benign	criteria provided, multiple submitters, no conflicts
382590	NM_025207.5(FLAD1):c.729C>T (p.Phe243=)	FLAD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

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
FLAD1	Definitive	Autosomal recessive	myopathy with abnormal lipid metabolism	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FLAD1	Orphanet:394529	Multiple acyl-CoA dehydrogenase deficiency, severe neonatal type
FLAD1	Orphanet:394532	Multiple acyl-CoA dehydrogenase deficiency, mild type

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FLAD1	HGNC:24671	ENSG00000160688	Q8NFF5	Bifunctional FAD diphosphatase/FAD synthase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FLAD1	Bifunctional FAD diphosphatase/FAD synthase	This enzyme has two activities: FAD diphosphatase activity and FAD synthase activity.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLAD1	Enzyme (other)	yes	2.7.7.2	MoaB/Mog_dom, PAPS_reduct_dom, FLAD1

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
granulocyte	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FLAD1	260	ubiquitous	marker	apex of heart, granulocyte, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLAD1	2,820

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FLAD1	Q8NFF5	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 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
Vitamin B2 (riboflavin) metabolism	1	1631.4×	6e-04	FLAD1

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
FAD biosynthetic process	1	16852.0×	1e-04	FLAD1
riboflavin metabolic process	1	3370.4×	3e-04	FLAD1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FLAD1	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
FLAD1	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FLAD1	2.7.7.2	FAD synthase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	FLAD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FLAD1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.