| Knowledge-base field | Summary | Best supporting citations |
|---|---|---|
| Disease name / synonyms | Neutral lipid storage myopathy; neutral lipid storage disease with myopathy; NLSDM; NLSD-M; NLSM | (pqac-00000001, pqac-00000004, pqac-00000008) |
| Key identifiers | MONDO: MONDO_0012545; OMIM/MIM: #610717 | (pqac-00000000, pqac-00000004) |
| Causal gene | **PNPLA2** encodes adipose triglyceride lipase (ATGL), the rate-limiting intracellular triglyceride lipase | (pqac-00000010, pqac-00000027) |
| Inheritance | Autosomal recessive; affected individuals typically have biallelic PNPLA2 variants, while heterozygous relatives may be unaffected | (pqac-00000008, pqac-00000013) |
| Core pathobiology | Defective ATGL-mediated TAG hydrolysis causes cytosolic lipid-droplet accumulation in skeletal muscle, heart, and other tissues, with downstream lipotoxicity, impaired FA signaling/PPARα activation, and mitochondrial dysfunction | (pqac-00000026, pqac-00000027, pqac-00000031) |
| Typical onset | Usually adult onset around the 3rd–4th decade / early 30s, but onset can range from childhood to late adulthood; asymptomatic hyperCKemia may precede weakness | (pqac-00000008, pqac-00000019, pqac-00000024) |
| Major skeletal-muscle phenotype | Progressive proximal-predominant weakness and atrophy; fatigue in 100% and myalgia/cramps in 50% in one Italian cohort; distal muscles often involved later | (pqac-00000024, pqac-00000021) |
| Cardiac involvement | Cardiomyopathy in ~40% of 55 reported patients in one review; 40%–50% cited in recent review; Chinese cohort: pure cardiomyopathy 4/45 (8.9%), combined skeletal + cardiomyopathy 21/45 (46.7%) | (pqac-00000010, pqac-00000004, pqac-00000019) |
| Other systemic features | Hepatomegaly/liver involvement ~20% in one review; mild hyperglycemia 4/15 and triglyceride abnormalities 2/15 in Italian cohort; hearing loss, cataract, diabetes can occur in subsets | (pqac-00000010, pqac-00000024, pqac-00000017) |
| Typical phenotype distribution | Chinese multicenter cohort (n=45): asymptomatic hyperCKemia 2/45 (4.4%), pure skeletal myopathy 18/45 (40.0%), pure cardiomyopathy 4/45 (8.9%), combined skeletal + cardiomyopathy 21/45 (46.7%) | (pqac-00000019) |
| Hallmark laboratory clue | Jordan anomaly (lipid vacuoles/droplets in leukocytes) is a hallmark and was present in 100% of tested patients in the Italian cohort | (pqac-00000008, pqac-00000024, pqac-00000036) |
| Serum CK | Usually elevated; Italian cohort range 300–5700 U/L with average ~1000 U/L; hyperCKemia may be isolated early | (pqac-00000024, pqac-00000019) |
| Electrophysiology | EMG commonly shows myogenic changes; myotonic discharges were seen in 5/15 NLSD-M patients in the Italian cohort | (pqac-00000018, pqac-00000039) |
| Imaging pattern | Muscle MRI often shows asymmetric fatty infiltration, especially posterior thigh/calf muscles; severe involvement of long head of biceps femoris, semimembranosus, adductor magnus, soleus, medial gastrocnemius; right upper limb weakness can be an early clue (61.5%) | (pqac-00000019, pqac-00000023) |
| Biopsy / pathology | Lipid-droplet accumulation in myofibers (Oil Red O positive), often with rimmed vacuoles; 93% of NLSD-M muscle biopsies showed lipid droplets in one cohort; preferential type 1 fiber involvement reported | (pqac-00000018, pqac-00000023, pqac-00000039) |
| Common variant classes | Truncating, frameshift, nonsense, splice-site, insertions/deletions, and missense variants; among 39 reported variants, 25/39 (64%) were truncating and 13/39 (33%) missense in one review | (pqac-00000010, pqac-00000011) |
| Recurrent / hotspot variants | Recurrent hotspot **c.757+1G>T**; Chinese cohort allele frequencies: c.757+1G>T 24/80 (30.0%), c.245G>A 9/80 (11.3%), c.187+1G>A 8/80 (10.0%); variants often cluster in exons 4–7 / C-terminal region | (pqac-00000009, pqac-00000011, pqac-00000023) |
| Reported case burden | Literature estimates have risen over time: ~55 genetically characterized patients (2019 review), nearly 130 reported patients / >60 PNPLA2 mutations (2024 review), and 132 patients with 72 PNPLA2 variants in a 2026 case review | (pqac-00000010, pqac-00000004, pqac-00000012) |
| Natural history / prognosis | Chronic progressive disease with long diagnostic delay (mean 16.75 years in Italian cohort); after median 30.6 years of disease, 5/21 lost independent ambulation; some patients remain without cardiac disease while others develop severe cardiomyopathy | (pqac-00000024, pqac-00000035) |
| Standard management | No established curative therapy; supportive care plus low-fat diet and medium-chain triglyceride (MCT) supplementation are commonly used; benefit appears variable | (pqac-00000034, pqac-00000035) |
| Reported dietary response | In one 10-year follow-up, low-fat + MCT reduced CPK but did not halt progression; a 2024 case report abstract reported improved limb strength and resolution of dysarthria after a medium-chain fatty acids diet | (pqac-00000035, pqac-00000040) |
| Targeted / experimental therapy | PPAR agonist strategy: bezafibrate explored based on ATGL/PPAR biology; tricaprin/CNT-01 and CNT-02 studied mainly in TGCV/ATGL-defect spectrum rather than routine NLSDM care | (pqac-00000026, pqac-00000040) |
| Key clinical trials / registries | **NCT01527318**: bezafibrate in NLSDM, completed, phase 4, planned enrollment 6; **NCT02830763**: CNT-02 safety for TGCV and NLSD-M, terminated, enrollment 2; **NCT02918032**: international NLSD/TGCV registry, recruiting, target 120 | (pqac-00000040) |


*Table: This table condenses the main knowledge-base fields for Neutral Lipid Storage Myopathy, including identifiers, genetics, hallmark phenotypes, diagnostics, variant hotspots, and current management/trial information. It is useful as a quick-reference scaffold for structured disease curation.*