Neutral Lipid Storage Myopathy

Mendelian MONDO:0012545 Pathograph 9 Show in embeddings browser Neutral Lipid Storage Disease

Neutral lipid storage disease with myopathy (NLSDM) is an autosomal recessive neutral lipid storage disorder caused by biallelic PNPLA2 variants encoding adipose triglyceride lipase (ATGL). ATGL deficiency impairs intracellular triacylglycerol hydrolysis, causing cytoplasmic triacylglycerol droplet accumulation predominantly in skeletal and cardiac muscle, producing a progressive lipid-storage myopathy (often with early, asymmetric upper-limb weakness), cardiomyopathy, and hyperCKemia, without ichthyosis. It corresponds to NLSD type M and overlaps triglyceride storage disease type 2.

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1
Mappings
1
Inheritance
2
Pathophys.
6
Phenotypes
9
Pathograph
1
Genes
1
Medical Actions
1
Differentials
1
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0012545 neutral lipid storage myopathy
skos:exactMatch MONDO
👪

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:31655616 SUPPORT Human Clinical
"Thirty-three families were carrying homozygous mutations, while seven families were carrying compound heterozygous mutations"
Biallelic (homozygous/compound heterozygous) PNPLA2 inheritance is consistent with autosomal recessive transmission.
⚙

Pathophysiology

2
PNPLA2/ATGL Deficiency
Biallelic PNPLA2 variants reduce adipose triglyceride lipase (ATGL), the rate-limiting enzyme for intracellular triacylglycerol hydrolysis.
PNPLA2 hgnc:30802
triglyceride catabolic process GO:0019433 ↓ DECREASED
Downstream
Muscle Triacylglycerol Droplet Accumulation Impaired triacylglycerol hydrolysis causes lipid-droplet accumulation in muscle.
Show evidence (1 reference)
PMID:31655616 SUPPORT Human Clinical
"Neutral lipid storage disease with myopathy (NLSDM) is a rare clinical heterogeneous disorder caused by mutations in the patatin-like phospholipase domain-containing 2 (PNPLA2) gene"
NLSDM is caused by PNPLA2 (ATGL) mutations impairing triacylglycerol hydrolysis.
Muscle Triacylglycerol Droplet Accumulation
Undegraded triacylglycerol accumulates as cytoplasmic lipid droplets in skeletal and cardiac muscle fibers (and leukocytes, producing Jordans' anomaly), driving myopathy and cardiomyopathy.
skeletal muscle fiber CL:0000188
lipid storage GO:0019915 ↑ INCREASED
Downstream
Myopathy Skeletal muscle lipid-droplet storage produces the progressive lipid-storage myopathy.
Upper limb muscle weakness Skeletal muscle lipid storage causes the early prominent upper-limb weakness pattern.
Cardiomyopathy Cardiac muscle lipid storage contributes to cardiomyopathy.
Muscle fatty infiltration Intramuscular lipid storage corresponds to fatty replacement on muscle imaging.
Generalized limb muscle atrophy Progressive muscle lipid storage and myopathy can lead to limb muscle wasting.
Easy fatigability Progressive muscle lipid storage impairs motor endurance.
Show evidence (1 reference)
PMID:31655616 SUPPORT Human Clinical
"NLSDM usually presents skeletal myopathy, cardiomyopathy and the multiple organs dysfunction"
Muscle lipid storage produces skeletal myopathy and cardiomyopathy.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Neutral Lipid Storage Myopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Cardiovascular 1
Cardiomyopathy Cardiomyopathy HP:0001638
Show evidence (2 references)
PMID:31655616 SUPPORT Human Clinical
"the combination of skeletal myopathy and cardiomyopathy (21/45)"
Cardiomyopathy, alone or combined with skeletal myopathy, is common in NLSDM.
PMID:28499397 SUPPORT Human Clinical
"one patient with NLSD-M was implanted with a cardioverter defibrillator for severe arrhythmias"
Severe arrhythmia requiring a cardioverter defibrillator illustrates the cardiac involvement of NLSDM.
Musculoskeletal 1
Myopathy Myopathy HP:0003198
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:31655616 SUPPORT Human Clinical
"NLSDM usually presents skeletal myopathy, cardiomyopathy and the multiple organs dysfunction"
Skeletal myopathy is the cardinal feature of NLSDM.
Other 4
Upper limb muscle weakness Upper limb muscle weakness HP:0003484
Show evidence (1 reference)
PMID:31655616 SUPPORT Human Clinical
"Right upper limb weakness was the early and prominent feature in 61.5% of patients"
Right upper-limb weakness is a distinctive early feature of NLSDM.
Muscle fatty infiltration Fatty replacement of skeletal muscle HP:0012548
Show evidence (1 reference)
PMID:31655616 SUPPORT Human Clinical
"Selective muscle fatty infiltration on posterior compartment of legs"
Selective muscle fatty infiltration is the characteristic muscle-MRI finding in NLSDM.
Generalized limb muscle atrophy Generalized limb muscle atrophy HP:0009055
Show evidence (1 reference)
ORPHA:98908 SUPPORT Human Clinical
"HP:0009055 | Generalized limb muscle atrophy | Occasional (29-5%)"
Orphanet reports generalized limb muscle atrophy as an occasional NLSDM phenotype.
Easy fatigability Easy fatigability HP:0003388
Show evidence (1 reference)
ORPHA:98908 SUPPORT Human Clinical
"HP:0003388 | Easy fatigability | Frequent (79-30%)"
Orphanet reports easy fatigability as a frequent NLSDM phenotype.
🧬

Genetic Associations

1
PNPLA2 pathogenic variants (Causative)
Gene: PNPLA2 hgnc:30802
Show evidence (1 reference)
PMID:31655616 SUPPORT Human Clinical
"A total of 23 mutations were identified including 11 (47.8%) point mutations, eight (34.8%) deletions"
A spectrum of PNPLA2 variant classes underlies NLSDM.
💊

Medical Actions

1
Supportive Care
Action: Supportive Care NCIT:C15747
Supportive management of myopathy with cardiac surveillance and management.
🔬

Biochemical Markers

1
HyperCKemia (INCREASED)
Context: Elevated serum creatine kinase (hyperCKemia) is a common biochemical finding, sometimes the only manifestation (asymptomatic hyperCKemia).
Show evidence (1 reference)
PMID:31655616 SUPPORT Human Clinical
"asymptomatic hyperCKemia (2/45)"
HyperCKemia can be the sole presentation of NLSDM.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Neutral Lipid Storage Myopathy:

Triglyceride storage disease type 2 (NLSD type M) MONDO:0008602
Overlapping Features Triglyceride storage disease type 2 is the same PNPLA2-related NLSD type M; the entries are essentially synonymous.
Show evidence (1 reference)
PMID:31655616 SUPPORT Human Clinical
"Neutral lipid storage disease with myopathy (NLSDM) is a rare clinical heterogeneous disorder caused by mutations in the patatin-like phospholipase domain-containing 2 (PNPLA2) gene"
Both denote the PNPLA2-related neutral lipid storage disease with myopathy.
{ }

Source YAML

click to show 
name: Neutral Lipid Storage Myopathy
creation_date: "2026-06-13T00:00:00Z"
description: >-
  Neutral lipid storage disease with myopathy (NLSDM) is an autosomal recessive neutral lipid
  storage disorder caused by biallelic PNPLA2 variants encoding adipose triglyceride lipase
  (ATGL). ATGL deficiency impairs intracellular triacylglycerol hydrolysis, causing cytoplasmic
  triacylglycerol droplet accumulation predominantly in skeletal and cardiac muscle, producing
  a progressive lipid-storage myopathy (often with early, asymmetric upper-limb weakness),
  cardiomyopathy, and hyperCKemia, without ichthyosis. It corresponds to NLSD type M and
  overlaps triglyceride storage disease type 2.
synonyms:
- NLSDM
- NLSD type M
- ATGL deficiency myopathy
- Jordans' anomaly with myopathy
category: Mendelian
disease_term:
  preferred_term: neutral lipid storage myopathy
  term:
    id: MONDO:0012545
    label: neutral lipid storage myopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0012545
      label: neutral lipid storage myopathy
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- Neutral Lipid Storage Disease
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:31655616
    reference_title: "Neutral lipid storage disease with myopathy in China: a large multicentric cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty-three families were carrying homozygous mutations, while\nseven families were carrying compound heterozygous mutations"
    explanation: Biallelic (homozygous/compound heterozygous) PNPLA2 inheritance is consistent with autosomal recessive transmission.
pathophysiology:
- name: PNPLA2/ATGL Deficiency
  description: >-
    Biallelic PNPLA2 variants reduce adipose triglyceride lipase (ATGL), the rate-limiting
    enzyme for intracellular triacylglycerol hydrolysis.
  gene:
    preferred_term: PNPLA2
    term:
      id: hgnc:30802
      label: PNPLA2
  biological_processes:
  - preferred_term: triglyceride catabolic process
    term:
      id: GO:0019433
      label: triglyceride catabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:31655616
    reference_title: "Neutral lipid storage disease with myopathy in China: a large multicentric cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neutral lipid storage disease with myopathy (NLSDM) is a rare\nclinical heterogeneous disorder caused by mutations in the patatin-like\nphospholipase domain-containing 2 (PNPLA2) gene"
    explanation: NLSDM is caused by PNPLA2 (ATGL) mutations impairing triacylglycerol hydrolysis.
  downstream:
  - target: Muscle Triacylglycerol Droplet Accumulation
    description: Impaired triacylglycerol hydrolysis causes lipid-droplet accumulation in muscle.
- name: Muscle Triacylglycerol Droplet Accumulation
  description: >-
    Undegraded triacylglycerol accumulates as cytoplasmic lipid droplets in skeletal and
    cardiac muscle fibers (and leukocytes, producing Jordans' anomaly), driving myopathy and
    cardiomyopathy.
  biological_processes:
  - preferred_term: lipid storage
    term:
      id: GO:0019915
      label: lipid storage
    modifier: INCREASED
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  evidence:
  - reference: PMID:31655616
    reference_title: "Neutral lipid storage disease with myopathy in China: a large multicentric cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NLSDM usually presents skeletal\nmyopathy, cardiomyopathy and the multiple organs dysfunction"
    explanation: Muscle lipid storage produces skeletal myopathy and cardiomyopathy.
  downstream:
  - target: Myopathy
    description: Skeletal muscle lipid-droplet storage produces the progressive lipid-storage myopathy.
    causal_link_type: DIRECT
  - target: Upper limb muscle weakness
    description: Skeletal muscle lipid storage causes the early prominent upper-limb weakness pattern.
    causal_link_type: DIRECT
  - target: Cardiomyopathy
    description: Cardiac muscle lipid storage contributes to cardiomyopathy.
    causal_link_type: DIRECT
  - target: Muscle fatty infiltration
    description: Intramuscular lipid storage corresponds to fatty replacement on muscle imaging.
    causal_link_type: DIRECT
  - target: Generalized limb muscle atrophy
    description: Progressive muscle lipid storage and myopathy can lead to limb muscle wasting.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Easy fatigability
    description: Progressive muscle lipid storage impairs motor endurance.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
phenotypes:
- name: Myopathy
  description: >-
    Progressive lipid-storage skeletal myopathy; right upper-limb weakness is often the early
    and prominent feature.
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:31655616
    reference_title: "Neutral lipid storage disease with myopathy in China: a large multicentric cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NLSDM usually presents skeletal\nmyopathy, cardiomyopathy and the multiple organs dysfunction"
    explanation: Skeletal myopathy is the cardinal feature of NLSDM.
- name: Upper limb muscle weakness
  description: Asymmetric, often right-predominant upper-limb weakness as an early prominent feature.
  phenotype_term:
    preferred_term: Upper limb muscle weakness
    term:
      id: HP:0003484
      label: Upper limb muscle weakness
  evidence:
  - reference: PMID:31655616
    reference_title: "Neutral lipid storage disease with myopathy in China: a large multicentric cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Right upper limb weakness was the early and\nprominent feature in 61.5% of patients"
    explanation: Right upper-limb weakness is a distinctive early feature of NLSDM.
- name: Cardiomyopathy
  description: Cardiac muscle involvement; pure or combined cardiomyopathy occurs in many patients.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:31655616
    reference_title: "Neutral lipid storage disease with myopathy in China: a large multicentric cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the combination of skeletal myopathy and cardiomyopathy (21/45)"
    explanation: Cardiomyopathy, alone or combined with skeletal myopathy, is common in NLSDM.
  - reference: PMID:28499397
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one patient with NLSD-M was\nimplanted with a cardioverter defibrillator for severe arrhythmias"
    explanation: Severe arrhythmia requiring a cardioverter defibrillator illustrates the cardiac involvement of NLSDM.
- name: Muscle fatty infiltration
  description: >-
    Selective fatty infiltration of muscle (posterior compartment of the legs) is a
    characteristic muscle-imaging finding.
  phenotype_term:
    preferred_term: Fatty replacement of skeletal muscle
    term:
      id: HP:0012548
      label: Fatty replacement of skeletal muscle
  evidence:
  - reference: PMID:31655616
    reference_title: "Neutral lipid storage disease with myopathy in China: a large multicentric cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Selective muscle fatty infiltration on posterior compartment of\nlegs"
    explanation: Selective muscle fatty infiltration is the characteristic muscle-MRI finding in NLSDM.
- name: Generalized limb muscle atrophy
  description: >-
    Limb muscle wasting accompanies the progressive lipid-storage myopathy in a subset of
    patients.
  phenotype_term:
    preferred_term: Generalized limb muscle atrophy
    term:
      id: HP:0009055
      label: Generalized limb muscle atrophy
  evidence:
  - reference: ORPHA:98908
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0009055 | Generalized limb muscle atrophy | Occasional (29-5%)"
    explanation: Orphanet reports generalized limb muscle atrophy as an occasional NLSDM phenotype.
- name: Easy fatigability
  description: >-
    Increased susceptibility to fatigue is a frequent motor manifestation of NLSDM.
  phenotype_term:
    preferred_term: Easy fatigability
    term:
      id: HP:0003388
      label: Easy fatigability
  evidence:
  - reference: ORPHA:98908
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0003388 | Easy fatigability | Frequent (79-30%)"
    explanation: Orphanet reports easy fatigability as a frequent NLSDM phenotype.
biochemical:
- name: HyperCKemia
  presence: INCREASED
  context: >-
    Elevated serum creatine kinase (hyperCKemia) is a common biochemical finding, sometimes
    the only manifestation (asymptomatic hyperCKemia).
  evidence:
  - reference: PMID:31655616
    reference_title: "Neutral lipid storage disease with myopathy in China: a large multicentric cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "asymptomatic hyperCKemia (2/45)"
    explanation: HyperCKemia can be the sole presentation of NLSDM.
genetic:
- name: PNPLA2 pathogenic variants
  gene_term:
    preferred_term: PNPLA2
    term:
      id: hgnc:30802
      label: PNPLA2
  association: Causative
  notes: >-
    Biallelic PNPLA2 variants cause NLSDM; point mutations, deletions, and other variant
    classes have been reported across large cohorts.
  evidence:
  - reference: PMID:31655616
    reference_title: "Neutral lipid storage disease with myopathy in China: a large multicentric cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 23\nmutations were identified including 11 (47.8%) point mutations, eight (34.8%)\ndeletions"
    explanation: A spectrum of PNPLA2 variant classes underlies NLSDM.
differential_diagnoses:
- name: Triglyceride storage disease type 2 (NLSD type M)
  description: >-
    Triglyceride storage disease type 2 is the same PNPLA2-related NLSD type M; the entries
    are essentially synonymous.
  disease_term:
    preferred_term: triglyceride storage disease, type 2
    term:
      id: MONDO:0008602
      label: triglyceride storage disease, type 2
  evidence:
  - reference: PMID:31655616
    reference_title: "Neutral lipid storage disease with myopathy in China: a large multicentric cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neutral lipid storage disease with myopathy (NLSDM) is a rare\nclinical heterogeneous disorder caused by mutations in the patatin-like\nphospholipase domain-containing 2 (PNPLA2) gene"
    explanation: Both denote the PNPLA2-related neutral lipid storage disease with myopathy.
treatments:
- name: Supportive Care
  description: Supportive management of myopathy with cardiac surveillance and management.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
references:
- reference: PMID:28499397
  title: "Neutral Lipid Storage Diseases: clinical/genetic features and natural history in a large cohort of Italian patients."
📚

References & Deep Research

References

1
PMID:28499397
Neutral Lipid Storage Diseases: clinical/genetic features and natural history in a large cohort of Italian patients.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Neutral Lipid Storage Myopathy (NLSM / NLSDM) — Comprehensive Disease Characteristics Report
Edison Scientific Literature 34 citations 2026-06-13T17:42:19.570158

Neutral Lipid Storage Myopathy (NLSM / NLSDM) — Comprehensive Disease Characteristics Report

Executive Summary

Neutral lipid storage myopathy (commonly referred to as neutral lipid storage disease with myopathy; NLSDM/NLSD‑M) is a rare autosomal recessive lipid droplet disorder caused by biallelic PNPLA2 (ATGL) loss-of-function leading to impaired intracellular triglyceride hydrolysis, accumulation of neutral lipids in multiple tissues, and progressive skeletal myopathy frequently complicated by cardiomyopathy. Cohort studies show marked phenotypic heterogeneity, long diagnostic delays, and a spectrum ranging from isolated hyperCKemia to severe cardiomyopathy. (pennisi2017neutrallipidstorage pages 1-2, zhang2019neutrallipidstorage pages 1-2, missaglia2019neutrallipidstorage pages 3-6, pennisi2017neutrallipidstorage pages 2-3)

A compact curation-ready summary table is provided below.

Knowledge-base field Summary Best supporting citations
Disease name / synonyms Neutral lipid storage myopathy; neutral lipid storage disease with myopathy; NLSDM; NLSD-M; NLSM (pennisi2017neutrallipidstorage pages 1-2, wang2024dilatedcardiomyopathycaused pages 1-2, landim2023neutrallipidstorage pages 1-2)
Key identifiers MONDO: MONDO_0012545; OMIM/MIM: #610717 (OpenTargets Search: Neutral lipid storage myopathy, wang2024dilatedcardiomyopathycaused pages 1-2)
Causal gene PNPLA2 encodes adipose triglyceride lipase (ATGL), the rate-limiting intracellular triglyceride lipase (missaglia2019neutrallipidstorage pages 3-6, wang2024dilatedcardiomyopathycaused pages 2-4)
Inheritance Autosomal recessive; affected individuals typically have biallelic PNPLA2 variants, while heterozygous relatives may be unaffected (landim2023neutrallipidstorage pages 1-2, wang2024dilatedcardiomyopathycaused pages 2-4)
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 (kanti2022adiposetriglyceridelipase–mediated pages 1-2, wang2024dilatedcardiomyopathycaused pages 2-4, missaglia2019neutrallipidstorage pages 1-3)
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 (landim2023neutrallipidstorage pages 1-2, zhang2019neutrallipidstorage pages 1-2, pennisi2017neutrallipidstorage pages 2-3)
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 (pennisi2017neutrallipidstorage pages 2-3, pennisi2017neutrallipidstorage pages 5-7)
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%) (missaglia2019neutrallipidstorage pages 3-6, wang2024dilatedcardiomyopathycaused pages 1-2, zhang2019neutrallipidstorage pages 1-2)
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 (missaglia2019neutrallipidstorage pages 3-6, pennisi2017neutrallipidstorage pages 2-3, faedo2026casereporta pages 1-2)
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%) (zhang2019neutrallipidstorage pages 1-2)
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 (landim2023neutrallipidstorage pages 1-2, pennisi2017neutrallipidstorage pages 2-3, pennisi2017neutrallipidstorage pages 5-7)
Serum CK Usually elevated; Italian cohort range 300–5700 U/L with average ~1000 U/L; hyperCKemia may be isolated early (pennisi2017neutrallipidstorage pages 2-3, zhang2019neutrallipidstorage pages 1-2)
Electrophysiology EMG commonly shows myogenic changes; myotonic discharges were seen in 5/15 NLSD-M patients in the Italian cohort (pennisi2017neutrallipidstorage pages 7-8, luan2025clinicopathologicalgeneticfeaturesof pages 1-2)
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%) (zhang2019neutrallipidstorage pages 1-2, zhang2019neutrallipidstorage pages 6-9)
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 (pennisi2017neutrallipidstorage pages 7-8, zhang2019neutrallipidstorage pages 6-9, luan2025clinicopathologicalgeneticfeaturesof pages 1-2)
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 (missaglia2019neutrallipidstorage pages 3-6, wang2024dilatedcardiomyopathycaused pages 5-6)
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 (zhang2019neutrallipidstorage pages 1-2, wang2024dilatedcardiomyopathycaused pages 5-6, zhang2019neutrallipidstorage pages 6-9)
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 (missaglia2019neutrallipidstorage pages 3-6, wang2024dilatedcardiomyopathycaused pages 1-2, faedo2026casereporta pages 1-2)
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 (pennisi2017neutrallipidstorage pages 2-3, missaglia2022neutrallipidstorage pages 1-2)
Standard management No established curative therapy; supportive care plus low-fat diet and medium-chain triglyceride (MCT) supplementation are commonly used; benefit appears variable (risi2025primarylipidmyopathiesa pages 16-18, missaglia2022neutrallipidstorage pages 1-2)
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 (missaglia2022neutrallipidstorage pages 1-2, NCT01527318 chunk 1)
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 (kanti2022adiposetriglyceridelipase–mediated pages 1-2, NCT01527318 chunk 1)
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 (NCT01527318 chunk 1)

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.

1. Disease Information

1.1 Definition and overview

NLSDM/NLSM is part of the broader group “neutral lipid storage diseases” and is characterized by excessive, non‑lysosomal accumulation of neutral lipids (primarily triacylglycerol) in multiple tissues, with prominent skeletal muscle involvement and common cardiac involvement. (pennisi2017neutrallipidstorage pages 1-2, missaglia2019neutrallipidstorage pages 3-6)

A key diagnostic hallmark is Jordan anomaly (lipid vacuoles/droplets in leukocytes). (pennisi2017neutrallipidstorage pages 1-2, pennisi2017neutrallipidstorage pages 2-3)

1.2 Key identifiers

  • MONDO: MONDO_0012545 (“neutral lipid storage myopathy”) (OpenTargets Search: Neutral lipid storage myopathy)
  • OMIM/MIM: #610717 (zhang2019neutrallipidstorage pages 1-2, wang2024dilatedcardiomyopathycaused pages 1-2)

Not found in retrieved full-text evidence: Orphanet code, MeSH ID, ICD‑10/ICD‑11 code (no explicit codes were present in the retrieved articles/trial records). (pennisi2017neutrallipidstorage pages 1-2, zhang2019neutrallipidstorage pages 1-2)

1.3 Synonyms / alternative names

  • Neutral lipid storage disease with myopathy (NLSDM; NLSD‑M) (pennisi2017neutrallipidstorage pages 1-2, landim2023neutrallipidstorage pages 1-2)
  • Neutral lipid storage myopathy (NLSM; sometimes used interchangeably) (astrea2013clinicalmolecularand pages 58-64)

1.4 Evidence source type

The evidence base is largely aggregated disease-level resources (reviews; multicenter cohorts) plus individual case reports/series. (zhang2019neutrallipidstorage pages 1-2, missaglia2019neutrallipidstorage pages 3-6, pennisi2017neutrallipidstorage pages 2-3)

2. Etiology

2.1 Disease causal factors

Genetic cause (primary): biallelic pathogenic variants in PNPLA2, encoding adipose triglyceride lipase (ATGL), causing deficient ATGL activity and impaired triglyceride hydrolysis. (wang2024dilatedcardiomyopathycaused pages 1-2, missaglia2019neutrallipidstorage pages 3-6)

Related condition (important distinction): ABHD5/CGI‑58 variants cause the related neutral lipid storage disease with ichthyosis (Chanarin–Dorfman syndrome), not NLSDM. (pennisi2017neutrallipidstorage pages 1-2, missaglia2019neutrallipidstorage pages 6-8)

2.2 Risk factors

  • Genetic: autosomal recessive inheritance; consanguinity can increase the chance of homozygosity (13/45 in a Chinese cohort had consanguineous parents). (zhang2019neutrallipidstorage pages 1-2)
  • Potential modifiers: A large Chinese cohort found phenotype not strongly predicted by PNPLA2 mutation type and suggested “multiple environmental risk factors” may contribute to phenotype variability, but specific environmental modifiers were not defined. (zhang2019neutrallipidstorage pages 1-2, zhang2019neutrallipidstorage pages 6-9)

2.3 Protective factors

No specific protective genetic variants or environmental protective factors were identified in the retrieved evidence.

2.4 Gene–environment interaction

Direct gene–environment interaction evidence was not identified in the retrieved texts; however, genotype–phenotype variability suggests modifier effects (genetic/epigenetic and/or environmental). (zhang2019neutrallipidstorage pages 1-2, pennisi2017neutrallipidstorage pages 1-2)

3. Phenotypes

3.1 Core skeletal muscle phenotypes

Phenotype type: symptoms/signs + lab abnormalities.

  • Progressive myopathy: proximal and axial weakness/atrophy; distal muscles involved in advanced stages. (pennisi2017neutrallipidstorage pages 2-3)
  • Fatigue: 100% in an Italian cohort of NLSD‑M. (pennisi2017neutrallipidstorage pages 2-3)
  • Myalgia/cramps: 50% in the same cohort. (pennisi2017neutrallipidstorage pages 2-3)
  • Muscle atrophy: 8/15 in the same cohort. (pennisi2017neutrallipidstorage pages 2-3)

Suggested HPO terms (examples): - Proximal muscle weakness (HP:0003701) - Muscle atrophy (HP:0003202) - Fatigue (HP:0012378) - Myalgia (HP:0003326)

3.2 Laboratory abnormalities

  • HyperCKemia: CK elevated in all NLSD‑M in the Italian cohort (300–5700 U/L; ~1000 average). (pennisi2017neutrallipidstorage pages 2-3)

Suggested HPO term: Elevated creatine kinase (HP:0003236)

3.3 Cardiac involvement

  • Cardiac involvement is frequent but variable. In a review summarizing reported cases, cardiac dysfunction occurred in ~40% (22/55). (missaglia2019neutrallipidstorage pages 3-6)
  • A 2024 review/case report notes cardiac involvement 40–50% and that cardiomyopathy can mimic dilated or hypertrophic cardiomyopathy. (wang2024dilatedcardiomyopathycaused pages 1-2)
  • In the 45-patient Chinese cohort, phenotypes included pure cardiomyopathy 4/45 and combined skeletal + cardiomyopathy 21/45. (zhang2019neutrallipidstorage pages 1-2)

Suggested HPO terms: Cardiomyopathy (HP:0001638), Dilated cardiomyopathy (HP:0001644), Hypertrophic cardiomyopathy (HP:0001639), Arrhythmia (HP:0011675)

3.4 Liver/metabolic and other features

  • Liver involvement in NLSDM was reported in ~20% (mainly hepatomegaly) in one review. (missaglia2019neutrallipidstorage pages 3-6)
  • In an Italian NLSD‑M cohort: mild hyperglycaemia in 4/15 and triglyceride abnormalities in 2/15. (pennisi2017neutrallipidstorage pages 2-3)
  • Hearing loss, cataract, diabetes appear in subsets (e.g., reported in cohort/case descriptions). (pennisi2017neutrallipidstorage pages 7-8, faedo2026casereporta pages 1-2)

Suggested HPO terms: Hepatomegaly (HP:0002240), Diabetes mellitus (HP:0000819), Sensorineural hearing impairment (HP:0000407), Cataract (HP:0000518)

3.5 Phenotype distributions (cohort-based)

A multicenter Chinese cohort classified phenotypes (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%) (zhang2019neutrallipidstorage pages 1-2)

3.6 Quality of life impact

Long diagnostic delays (mean ~16.75 years) and progressive loss of ambulation in a subset imply substantial functional impact; formal QoL instruments (e.g., SF‑36/EQ‑5D) were not identified in retrieved evidence. (pennisi2017neutrallipidstorage pages 2-3)

4. Genetic / Molecular Information

4.1 Causal gene(s)

  • PNPLA2 (ATGL) is the causal gene for NLSDM. (missaglia2019neutrallipidstorage pages 3-6)

Related gene in differential context: ABHD5/CGI‑58 is a co-activator of ATGL and is causal for NLSD with ichthyosis (not NLSDM). (missaglia2019neutrallipidstorage pages 6-8)

4.2 Pathogenic variant spectrum

  • In a 2019 review of genetically characterized cases: 39 distinct PNPLA2 (ATGL) mutations among 55 patients; 25/39 (64%) truncating, 13/39 (33%) missense, and 1 predicted to abrogate expression. (missaglia2019neutrallipidstorage pages 3-6)
  • A large Chinese cohort identified 23 mutations: 11 point mutations, 8 deletions, 4 insertions. (zhang2019neutrallipidstorage pages 1-2)

Recurrent/hotspot variant in cohorts: - c.757+1G>T: in the Chinese cohort, 24/80 alleles (30.0%); also highlighted as recurrent in cardiomyopathy-focused literature synthesis. (wang2024dilatedcardiomyopathycaused pages 5-6, zhang2019neutrallipidstorage pages 6-9)

Variant classes: missense, frameshift, splice, insertions/deletions are all reported. (wang2024dilatedcardiomyopathycaused pages 5-6)

Somatic vs germline: evidence supports germline inheritance (AR); somatic involvement not reported. (wang2024dilatedcardiomyopathycaused pages 2-4)

4.3 Modifier genes / epigenetics

Direct modifier genes were not identified in the retrieved evidence; multiple sources emphasize genotype–phenotype heterogeneity consistent with modifier influences. (zhang2019neutrallipidstorage pages 1-2, pennisi2017neutrallipidstorage pages 1-2)

5. Environmental Information

No specific toxins, lifestyle triggers, or infectious agents were identified as causal in the retrieved NLSDM-focused sources. The literature suggests environmental/modifying factors may influence phenotype but does not specify actionable exposures. (zhang2019neutrallipidstorage pages 1-2)

6. Mechanism / Pathophysiology

6.1 Key concepts: lipid droplet lipolysis machinery

ATGL (PNPLA2) catalyzes the first (rate-limiting) step of TAG hydrolysis on lipid droplets and is activated by ABHD5/CGI‑58; downstream lipases (HSL, MGL) complete lipolysis. (missaglia2019neutrallipidstorage pages 6-8)

Visual evidence: A lipid droplet schematic showing ATGL activation by ABHD5 and key regulators/inhibitors is available (Missaglia et al., 2019, Figure 4). (missaglia2019neutrallipidstorage media 37b46157)

6.2 Causal chain (upstream → downstream)

  1. PNPLA2 loss-of-function → ATGL deficiency (upstream genetic trigger). (wang2024dilatedcardiomyopathycaused pages 1-2, missaglia2019neutrallipidstorage pages 3-6)
  2. Impaired intracellular TAG hydrolysis → lipid droplet accumulation in myocytes/cardiomyocytes and other tissues. (wang2024dilatedcardiomyopathycaused pages 2-4, missaglia2019neutrallipidstorage pages 1-3)
  3. Reduced FA release and lipid signaling: ATGL-derived fatty acids act as ligands/agonists for PPARα; ATGL loss produces dysfunctional PPARα signaling and altered mitochondrial programs. (kanti2022adiposetriglyceridelipase–mediated pages 1-2, wang2024dilatedcardiomyopathycaused pages 2-4)
  4. Mitochondrial dysfunction: patient-derived myotubes with defective ATGL show reduced mitochondrial respiration and abnormal mitochondrial morphology/dynamics (fragmentation, reduced membrane potential), despite preserved or increased mitochondrial content markers. (gemmink2024atglmediatedlipolysisis pages 5-8)
  5. Organ dysfunction: progressive skeletal myopathy and cardiomyopathy (lipotoxicity-associated). (wang2024dilatedcardiomyopathycaused pages 2-4)

6.3 Cellular processes and pathways (ontology suggestions)

  • GO biological processes: triglyceride catabolic process (GO:0019433); lipid droplet organization (GO:0034389); fatty acid beta-oxidation (GO:0006635); mitochondrial organization (GO:0007005); regulation of PPAR signaling (broadly captured under regulation of transcription by nuclear receptor; context-dependent). (kanti2022adiposetriglyceridelipase–mediated pages 1-2, missaglia2019neutrallipidstorage pages 6-8)
  • GO cellular components: lipid droplet (GO:0005811); mitochondrion (GO:0005739). (missaglia2019neutrallipidstorage pages 6-8)

6.4 Model systems / experimental evidence

  • Mouse genetic evidence: ATGL (Pnpla2) deletion produces triglyceride accumulation and mitochondrial/functional defects in multiple tissues; in bronchiolar regeneration experiments, a PPARα agonist (WY14643) rescued ultrastructure and function, illustrating the ATGL→PPARα→mitochondria axis. (kanti2022adiposetriglyceridelipase–mediated pages 1-2)
  • Human cell models: NLSDM patient muscle-derived myotubes show lipid accumulation, impaired myogenic differentiation, and intrinsic mitochondrial dysfunction. (gemmink2024atglmediatedlipolysisis pages 5-8)

6.5 Molecular profiling / multi-omics

The strongest molecular profiling signal in retrieved evidence is mitochondrial functional phenotyping (respirometry/EM) in patient myotubes; extensive transcriptomics/proteomics/lipidomics specific to NLSDM were not captured in the retrieved full-text snippets. (gemmink2024atglmediatedlipolysisis pages 5-8)

7. Anatomical Structures Affected

7.1 Primary organs

  • Skeletal muscle (UBERON:0001134) and heart (UBERON:0000948) are primary target tissues. (wang2024dilatedcardiomyopathycaused pages 1-2, pennisi2017neutrallipidstorage pages 2-3)

7.2 Tissue/cell level

  • Skeletal muscle fibers (particularly type 1 fiber–predominant lipid accumulation) with type 1 atrophy and type 2 hypertrophy patterns in some series. (luan2025clinicopathologicalgeneticfeaturesof pages 4-5, luan2025clinicopathologicalgeneticfeaturesof pages 1-2)

Suggested Cell Ontology terms: skeletal muscle cell (CL:0000197); cardiomyocyte (CL:0000746).

7.3 Subcellular localization

  • Cytosolic lipid droplets and mitochondria are key compartments. (missaglia2019neutrallipidstorage pages 6-8, gemmink2024atglmediatedlipolysisis pages 5-8)

8. Temporal Development

8.1 Onset

  • Typical onset around early 30s / 3rd–4th decade in many reports, but can range from childhood to advanced age. (landim2023neutrallipidstorage pages 1-2, zhang2019neutrallipidstorage pages 6-9, pennisi2017neutrallipidstorage pages 2-3)

8.2 Progression

  • Chronic progressive course with variable rate; long subclinical period with isolated hyperCKemia is common. (luan2025clinicopathologicalgeneticfeaturesof pages 1-2, pennisi2017neutrallipidstorage pages 2-3)

9. Inheritance and Population

9.1 Inheritance

Autosomal recessive. (wang2024dilatedcardiomyopathycaused pages 1-2, wang2024dilatedcardiomyopathycaused pages 2-4)

9.2 Epidemiology and burden statistics

True prevalence/incidence are not defined in the retrieved texts. Published case counts vary by time and review scope: - 55 genetically characterized patients in a 2019 review. (missaglia2019neutrallipidstorage pages 3-6) - Nearly 130 reported NLSDM patients with >60 PNPLA2 mutations described in a 2024 literature review. (wang2024dilatedcardiomyopathycaused pages 1-2) - “Fewer than 150 cases” and 132 patients/72 variants in a 2026 case review. (faedo2026casereporta pages 1-2)

9.3 Founder effects / geographic distribution

A large Chinese cohort identified recurrent variants (c.757+1G>T; c.245G>A; c.187+1G>A) and described them as relatively frequent in that population; detailed founder-effect analysis was not captured in retrieved snippets. (zhang2019neutrallipidstorage pages 6-9)

10. Diagnostics

10.1 Clinical tests and biomarkers

  • Serum CK: elevated; can be isolated early (hyperCKemia). (pennisi2017neutrallipidstorage pages 2-3)
  • Peripheral smear: Jordan anomaly (Oil Red O/Wright stain). (zhang2019neutrallipidstorage pages 1-2)

10.2 Imaging

  • Skeletal muscle MRI: asymmetric and posterior-compartment predominant fatty infiltration; characteristic muscle selectivity described in the Chinese cohort. (zhang2019neutrallipidstorage pages 6-9)
  • Cardiac imaging: echocardiography and cardiac MRI can identify cardiomyopathy with lipid infiltration in affected individuals. (pennisi2017neutrallipidstorage pages 5-7)

10.3 Electrophysiology

  • EMG frequently myogenic; myotonic discharges reported in a subset (5/15 in one cohort). (pennisi2017neutrallipidstorage pages 7-8, luan2025clinicopathologicalgeneticfeaturesof pages 1-2)

10.4 Biopsy findings

  • Muscle biopsy often shows Oil Red O–positive lipid droplets, sometimes with rimmed vacuoles; lipid droplets detected in 93% of NLSD‑M biopsies in one cohort. (pennisi2017neutrallipidstorage pages 5-7)

10.5 Genetic testing

  • PNPLA2 testing via targeted sequencing or NGS panels is used for confirmation; compound heterozygous and homozygous states reported. (luan2025clinicopathologicalgeneticfeaturesof pages 1-2)

10.6 Differential diagnosis (selected)

The retrieved evidence emphasizes that NLSDM can mimic inflammatory myopathy (e.g., misdiagnosis and ineffective prednisone in a case report) and cardiomyopathy of other causes; thus lipid storage myopathies and inherited cardiomyopathies are key differentials. (shi2021casereportpnpla2 pages 1-2, wang2024dilatedcardiomyopathycaused pages 1-2)

11. Outcome / Prognosis

  • In an Italian cohort (21 NLSD total; 15 NLSD‑M), mean follow-up 17.8 years and mean diagnostic delay ~16.75 years for NLSD‑M; after median 30.6 years of disease, 5/21 lost independent ambulation (4 NLSD‑M, 1 NLSD‑I); no mechanical ventilation was required in this series. (pennisi2017neutrallipidstorage pages 1-2, pennisi2017neutrallipidstorage pages 2-3)
  • Cardiac disease is a major morbidity determinant; some patients have severe cardiomyopathy while others may remain without cardiac involvement (10‑year follow-up case report described severe skeletal myopathy without cardiac involvement). (missaglia2022neutrallipidstorage pages 1-2)

12. Treatment

12.1 Standard of care (supportive/dietary)

There is no established curative therapy; commonly used management includes supportive care and dietary interventions such as low-fat diet with medium-chain triglyceride (MCT) supplementation (and sometimes carnitine). (risi2025primarylipidmyopathiesa pages 16-18, missaglia2022neutrallipidstorage pages 1-2)

Real-world implementation evidence: a 10‑year follow-up case used low-fat + MCT; CK decreased but weakness progressed. (missaglia2022neutrallipidstorage pages 1-2)

MAXO suggestions: dietary fat restriction (MAXO: dietary modification—term selection may require ontology lookup); medium-chain triglyceride supplementation (MAXO: nutritional supplementation).

12.2 Pharmacotherapy / targeted approaches

  • Bezafibrate (PPAR agonist strategy): ClinicalTrials.gov NCT01527318 tested bezafibrate 400 mg/day for 28 weeks in NLSDM (completed; planned enrollment 6). The trial protocol included muscle biopsy lipid quantification, in vivo 1H‑MRS, and respirometry-based mitochondrial assessment. (NCT01527318 chunk 1)

12.3 Experimental programs / registries (TGCV/NLSD spectrum)

  • NCT02830763: “Safety of CNT‑02 for TGCV and NLSD‑M” (terminated; enrollment 2). (NCT01527318 chunk 1)
  • NCT02918032: “International registry of NLSD/TGCV and related diseases” (recruiting; target 120). (NCT01527318 chunk 1)

12.4 Treatment response data and gaps

Robust, generalizable efficacy data for dietary or pharmacologic interventions remain limited; response may depend on whether residual ATGL function is present (complete loss of expression may predict limited benefit from MCT diet in some cases). (missaglia2022neutrallipidstorage pages 1-2)

13. Prevention

No primary prevention is currently available beyond genetic counseling/carrier testing in at-risk families. Avoidance of factors that precipitate metabolic stress (e.g., prolonged fasting/exertion in metabolic myopathy care paradigms) is suggested in lipid myopathy management reviews but was not specifically quantified for NLSDM in retrieved evidence. (risi2025primarylipidmyopathiesa pages 16-18)

14. Other Species / Natural Disease

No naturally occurring NLSDM orthologous disease in non-human species was identified in the retrieved evidence.

15. Model Organisms

  • Mouse ATGL/Pnpla2 knockout models show severe tissue triglyceride accumulation and impaired mitochondrial function in multiple tissues; the ATGL→PPARα axis has been experimentally manipulated (PPARα agonist rescue in airway regeneration model). (kanti2022adiposetriglyceridelipase–mediated pages 1-2)
  • Human patient-derived myotubes serve as a translational cellular model for mitochondrial dysfunction and lipid droplet accumulation in NLSDM. (gemmink2024atglmediatedlipolysisis pages 5-8)

Recent Developments (2023–2024 prioritized)

  1. 2024 cardiomyopathy-focused synthesis: A 2024 Frontiers in Genetics case report + literature review emphasized NLSDM as a cause of cardiomyopathy (40–50% cardiac involvement; cardiomyopathy may mimic DCM/HCM; recurrent splice variant c.757+1G>T described). Publication date: Jul 2024; URL: https://doi.org/10.3389/fgene.2024.1415156 (wang2024dilatedcardiomyopathycaused pages 1-2, wang2024dilatedcardiomyopathycaused pages 5-6)
  2. 2024 mechanistic advance in human muscle cells (preprint): Patient-derived NLSDM myotubes show intrinsic mitochondrial respiration defects and altered mitochondrial dynamics linked to ATGL dysfunction. Publication date: Nov 2024; URL: https://doi.org/10.1101/2024.10.31.621255 (gemmink2024atglmediatedlipolysisis pages 5-8)
  3. 2023 diagnostic/phenotype expansion (case report): 2023 BMC Neurology case report documented Jordan anomaly and coexisting PNPLA2 + CLCN1 pathogenic variants with myotonia features. Publication date: Apr 2023; URL: https://doi.org/10.1186/s12883-023-03195-6 (landim2023neutrallipidstorage pages 1-2)

Authoritative expert interpretation (evidence-based)

Multiple cohort and review sources converge on the concept that NLSDM is best understood as a lipid droplet lipolysis disorder rather than a primary inflammatory myopathy, and that its multisystem manifestations reflect the dependence of high-energy tissues (skeletal muscle and myocardium) on regulated intracellular lipolysis for mitochondrial energy supply and lipid signaling (PPAR axis). (gemmink2024atglmediatedlipolysisis pages 5-8, kanti2022adiposetriglyceridelipase–mediated pages 1-2, shi2021casereportpnpla2 pages 1-2)

Key Data Points (for knowledge base ingestion)

  • Cardiac dysfunction frequency: ~40% (22/55) (review) (missaglia2019neutrallipidstorage pages 3-6)
  • Chinese cohort phenotype distribution (n=45): hyperCKemia 2; pure skeletal 18; pure cardiac 4; combined 21 (zhang2019neutrallipidstorage pages 1-2)
  • Italian cohort: CK 300–5700 U/L; fatigue 100%; myalgia/cramps 50%; muscle atrophy 8/15; Jordan anomaly 100%; myotonic discharges 5/15; lipid droplets in muscle biopsy 93%; diagnostic delay ~16.75 years; loss of independent ambulation 5/21 after median 30.6 years disease duration. (pennisi2017neutrallipidstorage pages 7-8, pennisi2017neutrallipidstorage pages 5-7, pennisi2017neutrallipidstorage pages 2-3)

Limitations of this report (evidence availability)

  • No Orphanet/ICD/MeSH identifiers were explicitly present in the retrieved full texts.
  • Incidence/prevalence rates (population denominators) were not found in the retrieved evidence; available epidemiology is largely case-count based.
  • Some 2023–2024 Neuromuscular Disorders cohort papers relevant to NLSDM were flagged as unobtainable in this run; therefore, the report emphasizes accessible cohort/review evidence plus 2023–2024 accessible sources. (wang2024dilatedcardiomyopathycaused pages 1-2, gemmink2024atglmediatedlipolysisis pages 5-8)

References

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