Neutral lipid storage myopathy

Summary

Neutral lipid storage myopathy (MONDO:0012545) is a disease caused by PNPLA2 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PNPLA2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 622
• Phenotypes (HPO): 39
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		36	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0003547	Shoulder girdle muscle weakness	Very frequent (80-99%)
HP:0009073	Progressive proximal muscle weakness	Very frequent (80-99%)
HP:0012240	Increased intramyocellular lipid droplets	Very frequent (80-99%)
HP:0012548	Fatty replacement of skeletal muscle	Very frequent (80-99%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001397	Hepatic steatosis	Frequent (30-79%)
HP:0001638	Cardiomyopathy	Frequent (30-79%)
HP:0002155	Hypertriglyceridemia	Frequent (30-79%)
HP:0002380	Fasciculations	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0003326	Myalgia	Frequent (30-79%)
HP:0003388	Easy fatigability	Frequent (30-79%)
HP:0003391	Gowers sign	Frequent (30-79%)
HP:0003749	Pelvic girdle muscle weakness	Frequent (30-79%)
HP:0008167	Very long chain fatty acid accumulation	Frequent (30-79%)
HP:0009046	Difficulty running	Frequent (30-79%)
HP:0025435	Increased circulating lactate dehydrogenase concentration	Frequent (30-79%)
HP:0040081	Abnormal circulating creatine kinase concentration	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000467	Neck muscle weakness	Occasional (5-29%)
HP:0000819	Diabetes mellitus	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0003805	Rimmed vacuoles	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0006280	Chronic pancreatitis	Occasional (5-29%)
HP:0009027	Foot dorsiflexor weakness	Occasional (5-29%)
HP:0009055	Generalized limb muscle atrophy	Occasional (5-29%)
HP:0009063	Progressive distal muscle weakness	Occasional (5-29%)
HP:0030237	Hand muscle weakness	Occasional (5-29%)
HP:0001513	Obesity	Excluded (0%)
HP:0008064	Ichthyosis	Excluded (0%)
HP:0001082	Cholecystitis	Very rare (<1-4%)
HP:0012683	Pineal cyst	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neutral lipid storage myopathy
Mondo ID	MONDO:0012545
OMIM	610717
Orphanet	98908
ICD-11	1512138529
SNOMED CT	699315005
UMLS	C1853136
MedGen	339913
GARD	0010288
Is cancer (heuristic)	no

Also known as: neutral lipid storage disease with myopathy · neutral lipid storage disease with myopathy without ichthyosis · NLSDM

Data availability: 622 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › disorder of phospholipids, sphingolipids and fatty acids biosynthesis › neutral lipid storage disease › neutral lipid storage myopathy

Related subtypes (2): Dorfman-Chanarin disease, triglyceride deposit cardiomyovasculopathy

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

600 retrieved; paginated sample, class counts are floors:

261 uncertain significance, 245 likely benign, 36 conflicting classifications of pathogenicity, 28 pathogenic, 13 benign, 9 benign/likely benign, 5 likely pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2879553	NM_020376.4(PNPLA2):c.45C>A (p.Cys15Ter)	LOC130005097	Pathogenic	criteria provided, single submitter
1069764	NM_020376.4(PNPLA2):c.792del (p.Leu264fs)	PNPLA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071091	NM_020376.4(PNPLA2):c.999del (p.Ala333_Met334insTer)	PNPLA2	Pathogenic	criteria provided, single submitter
1454498	NM_020376.4(PNPLA2):c.903del (p.Ala302fs)	PNPLA2	Pathogenic	criteria provided, single submitter
1454689	NM_020376.4(PNPLA2):c.440del (p.Phe147fs)	PNPLA2	Pathogenic	criteria provided, single submitter
1456930	NM_020376.4(PNPLA2):c.856_877del (p.Asp286fs)	PNPLA2	Pathogenic	criteria provided, single submitter
1873	NM_020376.4(PNPLA2):c.808del (p.His270fs)	PNPLA2	Pathogenic	criteria provided, single submitter
1874	NM_020376.4(PNPLA2):c.584C>T (p.Pro195Leu)	PNPLA2	Pathogenic	criteria provided, single submitter
1875	NM_020376.4(PNPLA2):c.847del (p.Gln283fs)	PNPLA2	Pathogenic	no assertion criteria provided
1876	NM_020376.4(PNPLA2):c.865C>T (p.Gln289Ter)	PNPLA2	Pathogenic	no assertion criteria provided
2735395	NM_020376.4(PNPLA2):c.231_232insGGGTGGAGACGGGGTTTCGCTGTGTTGGCCGGGCTGGTCTCCAGCTCCTAACCGCGAGTGATCCGCCAGCCTCGNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAGAGGCCCGG (p.Lys78delinsGlyTrpArgArgGlyPheAlaValLeuAlaGlyLeuValSerSerSerTer)	PNPLA2	Pathogenic	criteria provided, single submitter
2757371	NM_020376.4(PNPLA2):c.63C>G (p.Tyr21Ter)	PNPLA2	Pathogenic	criteria provided, single submitter
2900685	NM_020376.4(PNPLA2):c.245G>A (p.Gly82Asp)	PNPLA2	Pathogenic	criteria provided, single submitter
3256770	NM_020376.4(PNPLA2):c.24G>A (p.Trp8Ter)	PNPLA2	Pathogenic	criteria provided, single submitter
3626964	NM_020376.4(PNPLA2):c.1105C>T (p.Gln369Ter)	PNPLA2	Pathogenic	criteria provided, single submitter
3651821	NM_020376.4(PNPLA2):c.875del (p.Gly292fs)	PNPLA2	Pathogenic	criteria provided, single submitter
3720981	NM_020376.4(PNPLA2):c.1051del (p.Arg351fs)	PNPLA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3721929	NM_020376.4(PNPLA2):c.132C>G (p.Tyr44Ter)	PNPLA2	Pathogenic	criteria provided, single submitter
39865	NM_020376.4(PNPLA2):c.757+2T>C	PNPLA2	Pathogenic	no assertion criteria provided
39866	NM_020376.4(PNPLA2):c.749A>C (p.Gln250Pro)	PNPLA2	Pathogenic	no assertion criteria provided
39867	NM_020376.4(PNPLA2):c.757+1G>T	PNPLA2	Pathogenic	criteria provided, multiple submitters, no conflicts
39868	NM_020376.4(PNPLA2):c.467del (p.Pro156fs)	PNPLA2	Pathogenic	no assertion criteria provided
4696746	NM_020376.4(PNPLA2):c.695del (p.Leu232fs)	PNPLA2	Pathogenic	criteria provided, single submitter
4748105	NM_020376.4(PNPLA2):c.1094G>A (p.Trp365Ter)	PNPLA2	Pathogenic	criteria provided, single submitter
4762000	NC_000011.10:g.821628del	PNPLA2	Pathogenic	criteria provided, single submitter
520846	NM_020376.4(PNPLA2):c.187+1G>C	PNPLA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
567557	NM_020376.4(PNPLA2):c.1043del (p.Phe348fs)	PNPLA2	Pathogenic	criteria provided, multiple submitters, no conflicts
65419	NM_020376.4(PNPLA2):c.613dup (p.Leu205fs)	PNPLA2	Pathogenic	criteria provided, multiple submitters, no conflicts
65420	NM_020376.4(PNPLA2):c.543del (p.Ile182fs)	PNPLA2	Pathogenic	no assertion criteria provided
65421	NM_020376.4(PNPLA2):c.475_478dup (p.Gln160fs)	PNPLA2	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
PNPLA2	Strong	Autosomal recessive	neutral lipid storage myopathy	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PNPLA2	Orphanet:565612	Primary triglyceride deposit cardiomyovasculopathy
PNPLA2	Orphanet:98908	Neutral lipid storage disease with myopathy

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
PNPLA2	HGNC:30802	ENSG00000177666	Q96AD5	Patatin-like phospholipase domain-containing protein 2	gencc,clinvar
PHRF1	HGNC:24351	ENSG00000070047	Q9P1Y6	PHD and RING finger domain-containing protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PNPLA2	Patatin-like phospholipase domain-containing protein 2	Catalyzes the initial step in triglyceride hydrolysis in adipocyte and non-adipocyte lipid droplets.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PNPLA2	Other/Unknown	no		PNPLA_dom, Acyl_Trfase/lysoPLipase, PLPL
PHRF1	Transcription factor	no		Znf_RING, Znf_PHD, Znf_FYVE_PHD

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
adipose tissue of abdominal region	1
omental fat pad	1
peritoneum	1
granulocyte	1
right lobe of liver	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PNPLA2	264	ubiquitous	marker	omental fat pad, peritoneum, adipose tissue of abdominal region
PHRF1	140	ubiquitous	yes	sural nerve, granulocyte, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PNPLA2	2,064
PHRF1	1,163

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PNPLA2	Q96AD5	72.56
PHRF1	Q9P1Y6	46.11

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
Acyl chain remodeling of DAG and TAG	1	1631.4×	0.002	PNPLA2
Post-translational protein phosphorylation	1	100.2×	0.012	PNPLA2
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	PNPLA2
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	82.8×	0.012	PNPLA2

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
negative regulation of triglyceride storage	1	2808.7×	0.002	PNPLA2
acylglycerol acyl-chain remodeling	1	2106.5×	0.002	PNPLA2
lipid droplet fusion	1	1685.2×	0.002	PNPLA2
lipid droplet disassembly	1	1203.7×	0.002	PNPLA2
positive regulation of triglyceride catabolic process	1	1053.2×	0.002	PNPLA2
diacylglycerol biosynthetic process	1	936.2×	0.002	PNPLA2
intracellular triglyceride homeostasis	1	842.6×	0.002	PNPLA2
phototransduction, visible light	1	648.1×	0.002	PNPLA2
triglyceride catabolic process	1	401.2×	0.003	PNPLA2
lipid storage	1	271.8×	0.004	PNPLA2
lipid homeostasis	1	168.5×	0.006	PNPLA2
protein ubiquitination	1	20.7×	0.048	PHRF1

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
PNPLA2	0	0
PHRF1	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
PNPLA2	5	Binding:5

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	PNPLA2, PHRF1

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)
PNPLA2	5	—
PHRF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02830763	Not specified	TERMINATED	Clinical Study on the Safety of CNT-02 for TGCV and NLSD-M