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Classifications

Harrison's Part

ICIMD (Inherited Metabolic Disorders)

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic HMGCR variants. Reported genotypes are homozygous in consanguineous families and compound heterozygous elsewhere; heterozygous parents are unaffected.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:37167966 SUPPORT Human Clinical

"We identified nine individuals from five unrelated families with unexplained limb-girdle like muscular dystrophy and bi-allelic variants in HMGCR via clinical and research exome sequencing."

Establishes biallelic HMGCR genotypes across five independent families as the basis of the disease.

PMID:36745799 SUPPORT Human Clinical

"The HMGCR variant was validated by restriction analysis and Sanger sequencing (Fig. 2A) and was found to fully segregate as expected for autosomal recessive mode of inheritance."

Formal segregation analysis in the founding kindred confirms the recessive mode.

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Discussions and Knowledge Gaps

4

Which branch of the mevalonate pathway is depleted in LGMDR28 patient muscle, and does the isoprenoid mechanism established in mice hold in humans?

KNOWLEDGE GAP isoprenoid_versus_sterol_branch

Attached to

pathophysiology#Isoprenoid Depletion and Impaired Protein Geranylgeranylation

The case that the myopathy is an isoprenoid rather than a sterol problem rests entirely on mouse work: geranylgeraniol rescue of the muscle-specific knockout, and the aggravating effect of a Rab geranylgeranyltransferase knockout. On the human side, all that exists is a single patient's circulating mevalonolactone level and the observation that patient cholesterol is low but normal. No measurement of geranylgeranyl pyrophosphate, of protein prenylation, or of coenzyme Q10 has been reported in LGMDR28 muscle or serum. The distinction is not academic: if the deficit is isoprenoid, geranylgeraniol is a candidate therapy that would not require synthesising mevalonolactone, and if it is sterol, neither would help.

Proposed experiments

Isoprenoid and prenylation profiling of LGMDR28 patient muscle

lgmdr28_isoprenoid_profiling

Measure geranylgeranyl pyrophosphate, farnesyl pyrophosphate, coenzyme Q10 and Rab protein prenylation status in muscle biopsy tissue from genotyped LGMDR28 patients against age-matched controls, and compare with the profile of the muscle-specific knockout mouse.

Would support

pathophysiology#Isoprenoid Depletion and Impaired Protein Geranylgeranylation

Supporting outcome

Reduced geranylgeranyl pyrophosphate and reduced Rab prenylation in patient muscle, with sterol content comparatively preserved.

Refuting outcome

Normal isoprenoid pools and normal prenylation in patient muscle, which would move the mechanism to a different branch and undercut the geranylgeraniol therapeutic rationale.

Why does the mouse tolerate loss of HMGCR so much less well than the human, and does any mouse model reproduce the slowly progressive human muscular dystrophy?

HUMAN MODEL MISMATCH mouse_intolerance_of_hmgcr_loss

Attached to

animal_models#Mouse pathophysiology#Progressive Myofiber Loss and Fatty Replacement

Every available model is either lethal or too severe. The complete mouse knockout dies prenatally, the knock-in of the human p.Arg641Cys allele dies as an embryo even though the corresponding human homozygote was liveborn, knockdown of the orthologue in Drosophila is lethal both ubiquitously and in muscle alone, and the muscle-specific mouse nulls develop rapid postnatal myopathy with necrosis and rhabdomyolysis. The pattern across two phyla is that anything approaching a null is unviable, which is itself the argument that the human alleles must be hypomorphic. Patients, by contrast, most often have decades of normal function, an unremarkable biopsy without necrosis, and a course measured in years. So the models that exist are informative about which pathway branch matters and useless for the natural history, the biopsy phenotype, or the testing of a therapy over a realistic timescale. What is missing is a hypomorphic allelic-series mouse carrying a partial-loss-of-function human variant such as p.Gly822Asp, which the enzymology predicts would be viable.

Proposed experiments

Hypomorphic Hmgcr knock-in allelic series

hypomorphic_hmgcr_allelic_series

Generate homozygous knock-in mice carrying the enzymologically characterised partial loss-of-function alleles rather than nulls, and phenotype them for the human-relevant endpoints: age of onset, rate of strength decline, biopsy appearance including whether necrosis and inflammation are present, and respiratory function.

Would support

pathophysiology#Progressive Myofiber Loss and Fatty Replacement

Supporting outcome

Viable homozygotes developing slowly progressive proximal weakness with raised creatine kinase and a non-necrotic biopsy, matching the human tissue phenotype.

Refuting outcome

Viable homozygotes with no muscle phenotype, which would imply the human disease needs a contribution the mouse lacks and would leave no tractable in vivo model.

Does LGMDR28 have a secondary alpha-dystroglycan hypoglycosylation limb, and if so does that partly reconnect it to the dystroglycanopathies?

KNOWLEDGE GAP reduced_alpha_dystroglycan_signal

Attached to

pathophysiology#Progressive Myofiber Loss and Fatty Replacement histopathology#Non-specific myopathic change with normal muscular dystrophy immunohistochemistry

This entry separates LGMDR28 from the sarcolemmal LGMD subtypes on the grounds that its immunohistochemistry is normal, and that is what the available cached sources say. One piece of curated data points the other way and should not be quietly dropped: HPO carries `HP:0030099 Reduced muscle fiber alpha dystroglycan` for this disease at a frequency of 1/1, attributed to the discovery cohort (PMID:37167966), alongside `HP:0012240 Increased intramyocellular lipid droplets` at 1/3. A single observation in a single biopsy is as likely to be a staining artifact as a real finding, and neither appears in the abstract that is cached here, so no evidence item can be written for it. But if it is real it matters twice over, because glycosylation of alpha-dystroglycan is the mechanism of the FKRP and related dystroglycanopathy subtypes, and because dolichol, which the mevalonate pathway supplies, is required for the O-mannosylation that builds the alpha-dystroglycan glycan. That would be a mechanistically plausible route from a mevalonate-flux defect back to a membrane phenotype, and it is exactly the kind of link that should be tested rather than assumed.

Proposed experiments

Alpha-dystroglycan glycosylation status in LGMDR28 muscle

lgmdr28_alpha_dystroglycan_glycosylation

Stain LGMDR28 muscle biopsies with the glycoepitope-specific IIH6 antibody alongside a core alpha-dystroglycan antibody and dystroglycanopathy and normal controls, and measure muscle dolichol-linked oligosaccharide pools, across a series rather than the single reported case.

Would support

pathophysiology#Progressive Myofiber Loss and Fatty Replacement

Supporting outcome

Reproducible loss of the IIH6 glycoepitope with preserved core protein across multiple LGMDR28 biopsies, with reduced dolichol-linked oligosaccharide, which would add a glycosylation limb to the mechanism and qualify the separation from the dystroglycanopathies drawn in this entry.

Refuting outcome

Normal alpha-dystroglycan glycosylation across the series, confirming the single HPO annotation as an isolated artifact and leaving the sarcolemmal separation intact.

Is hepatic disease part of LGMDR28, and are statins contraindicated in people who carry biallelic or heterozygous HMGCR disease alleles?

KNOWLEDGE GAP hepatic_involvement_and_statin_exposure

Attached to

phenotypes#Cirrhosis treatments#

Two questions with the same root, both unanswered. Progressive cirrhosis requiring transplantation occurred in two siblings of one family and in no other reported individual, and the authors themselves note that transaminase elevation in this setting is normally attributed to muscle injury, so whether the liver is a target organ or that family carried a second problem is open. Separately, and although the pharmacological parallel is the organising idea of this disease, no published work reports statin exposure in a person with an HMGCR disease allele, in either the biallelic or the heterozygous state, and no source recommends avoidance. The plausible expectation that inhibiting an already-hypomorphic enzyme would be harmful is an inference, not a finding, and is not curated as a treatment here for that reason.

Proposed experiments

Systematic hepatic phenotyping of the LGMDR28 cohort

lgmdr28_hepatic_phenotyping

Apply the published liver panel plus imaging and, where indicated, biopsy across all genotyped LGMDR28 patients, distinguishing muscle-derived transaminase elevation from hepatocellular disease, and record statin exposure history in patients and their heterozygous relatives.

Would support

phenotypes#Cirrhosis

Supporting outcome

Hepatocellular disease in additional unrelated families, establishing liver involvement as a feature of the disease rather than of one family.

Refuting outcome

Transaminase elevation of muscle origin only, with normal synthetic function and imaging across the cohort, confining the cirrhosis to the single family reported.

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Pathophysiology

6

Reduced HMG-CoA Reductase Catalytic Activity

Disease-associated HMGCR alleles are amorphic to hypomorphic: they reduce catalytic rate and destabilise the enzyme rather than preventing its expression or mislocalising it. The founding G822D allele retains the protein in its normal cytoplasmic and endoplasmic-reticulum distribution while losing most of its turnover number and most of its affinity for HMG-CoA, and independently assayed alleles from a second cohort show the same pattern of reduced activity with reduced stability.

HMG-CoA reductase activity GO:0004420 ↓ DECREASED

Downstream

Mevalonate Pathway Flux Reduction Loss of catalytic rate at the pathway's rate-limiting step reduces flux through it.

Show evidence (4 references)

PMID:36745799 SUPPORT In Vitro

"the mutant protein had 69% reduction in Vmax and 65% increase in Km in relation to the substrate HMG-CoA, indicating lower affinity of the mutated protein for HMG-CoA, as well as overall slower reaction-rate"

Direct enzymological measurement of the catalytic deficit produced by a disease allele in a CRISPR knock-in cell line.

PMID:37167966 SUPPORT In Vitro

"Protein activity studies using three variants (p.Asp623Asn, p.Tyr792Cys, and p.Arg443Gln) identified in affected individuals confirmed decreased enzymatic activity and reduced protein stability."

Replicates the activity deficit across three further patient alleles and adds the stability component.

PMID:37167966 SUPPORT Computational

"Molecular modeling analyses revealed variants to be destabilizing and affecting protein oligomerization."

In silico structural analysis predicting the destabilising mechanism that the activity assays then measured.

+ 1 more reference

Mevalonate Pathway Flux Reduction

Reduced enzyme activity lowers production of mevalonate, the committed product of the pathway. This is measurable in patients rather than inferred: circulating mevalonolactone in the treated proband sat at roughly a fifth of the control average. Sterol output is comparatively spared, since patient cholesterol is low but within the normal range, which is the first indication that the sterol branch is not where the disease is expressed.

mevalonate pathway flux GO:0019287 ↓ DECREASED

Downstream

Isoprenoid Depletion and Impaired Protein Geranylgeranylation Reduced mevalonate limits the isoprenoid branch that consumes it.

Impaired Myoblast Proliferation and Myotube Fusion Knockdown of Hmgcr in myoblasts, which reproduces the flux deficit rather than any structural lesion, impairs proliferation and fusion. Which pathway product mediates this is not established.

Show evidence (2 references)

PMID:36745799 SUPPORT Human Clinical

"Serum mevalonolactone level of patient V:2 was 14.5 to 29.1% than the normal average"

Direct patient measurement of the reduced pathway product, establishing the flux deficit in vivo in humans.

PMID:36745799 SUPPORT Human Clinical

"Cholesterol and lipoprotein levels were not elevated (SI Appendix, Table S1), with most patients frequently showing total cholesterol levels lower than 120 mg/dL."

Shows the sterol end product is only mildly affected, which is why the disease is not modelled as a cholesterol-deficiency state.

Isoprenoid Depletion and Impaired Protein Geranylgeranylation

The branch of the mevalonate pathway that appears to carry the myopathy is the isoprenoid one. In muscle-specific Hmgcr-knockout mice the fiber-type loss is reversed by geranylgeraniol, the precursor of geranylgeranyl pyrophosphate, and independently knocking out the Rab geranylgeranyltransferase beta subunit produces its own myopathy and aggravates the Hmgcr one. This is a mouse-derived mechanism; no patient measurement of prenylation exists.

protein geranylgeranylation GO:0018344 ↓ DECREASED isoprenoid biosynthesis GO:0008299 ↓ DECREASED

Animal models

Doxycycline-inducible skeletal muscle-specific Hmgcr knockout mouse (Hmgcr-DimKO) Mouse recapitulates Establishes geranylgeranyl pyrophosphate depletion as the branch of the pathway whose loss produces myopathy, by rescuing with its precursor and by phenocopying and aggravating with a Rab geranylgeranyltransferase knockout.

Downstream

Myofiber Mitochondrial Dysfunction Prenylation-dependent trafficking failure precedes and accompanies the mitochondrial abnormalities in the knockout mice.

Show evidence (2 references)

PMID:42323079 SUPPORT Model Organism

"Our findings demonstrate that myopathy induced by HMGCR deficiency is primarily driven by GGPP depletion in a mouse model."

Attributes the myopathy of HMGCR deficiency to isoprenoid rather than sterol depletion.

PMID:42323079 SUPPORT Model Organism

"Furthermore, impaired RabGGT-β-mediated protein geranylgeranylation represents a critical downstream mechanism that aggravates the myopathic phenotype."

Places Rab geranylgeranylation downstream of the reductase defect as an aggravating step.

Myofiber Mitochondrial Dysfunction

Mitochondrial abnormalities appear early in Hmgcr-deficient muscle, before weakness is clinically apparent, and the first fibers lost are the mitochondria-rich oxidative ones. Hmgcr-knockdown myoblasts show a matching transcriptional and respirometric signature. Whether this is the proximate cause of fiber loss in patients is not established.

skeletal muscle fiber CL:0008002

oxidative phosphorylation GO:0006119 ↓ DECREASED

Animal models

Doxycycline-inducible skeletal muscle-specific Hmgcr knockout mouse (Hmgcr-DimKO) Mouse recapitulates Mitochondrial abnormalities are detectable before clinical myopathy in every genotype tested, which is the temporal argument that the mitochondrial defect is upstream of fiber loss rather than a consequence of it.

Downstream

Progressive Myofiber Loss and Fatty Replacement Bioenergetic failure in oxidative fibers precedes their loss.

Show evidence (2 references)

PMID:42323079 SUPPORT Model Organism

"Hmgcr KO resulted in pronounced myopathy, marked by an early reduction in mitochondria-rich myosin heavy chain (MyHC) type I and IIa muscle fibers, followed by a later reduction in mitochondria-poor glycolytic MyHC type IIb muscle fibers, and these changes were reversed by GGOH administration."

Shows the oxidative fibers are lost first and that the loss is isoprenoid-dependent.

PMID:39823152 SUPPORT In Vitro

"Transcriptome sequencing of Hmgcr knockdown versus control myoblasts revealed differential expression involving mitochondrial function, with corresponding differences in cellular oxygen consumption rates."

Independent cell-culture evidence that HMGCR loss changes mitochondrial gene expression and respiration.

Impaired Myoblast Proliferation and Myotube Fusion

HMGCR loss impairs the myogenic program itself, not only the maintenance of mature fibers. Knockdown myoblasts proliferate less, die more, and fail to fuse into myotubes, and re-expression of wild-type but not variant HMGCR restores fusion. This developmental component is a plausible explanation for the congenital and neonatal-onset end of the clinical spectrum.

skeletal muscle myoblast CL:0000515

myoblast fusion GO:0007520 ↓ DECREASED myoblast proliferation GO:0008283 ↓ DECREASED myoblast apoptosis GO:0006915 ↑ INCREASED

Experimental models

Hmgcr knockdown C2C12 myoblast line with variant complementation CELL LINE Reproduces the proliferation, survival and fusion defects attributable to HMGCR loss, and shows that three patient alleles cannot rescue them while the reference sequence can.

Downstream

Progressive Myofiber Loss and Fatty Replacement Impaired myogenesis limits the regenerative capacity available to offset fiber loss.

Show evidence (2 references)

PMID:39823152 SUPPORT In Vitro

"Hmgcr deficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion."

Establishes the three cellular defects that define this node.

PMID:39823152 SUPPORT In Vitro

"Overexpression of reference HMGCR cDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants of HMGCR cDNA did not."

Rescue-and-failure-to-rescue experiment tying the fusion defect specifically to the patient alleles.

Progressive Myofiber Loss and Fatty Replacement

Muscle is lost slowly and replaced by fat, most severely in the proximal and axial groups, with distal and facial muscles relatively spared. The tissue signature is the point at which this disease diverges from the sarcolemmal LGMD subtypes. Biopsy findings range from entirely non-specific myopathic change to nothing at all: the founding kindred showed no necrosis, fibrosis or inflammation, and immunohistochemistry for dystrophin, the sarcoglycans and dysferlin is normal across cohorts. The absence of an inflammatory infiltrate also distinguishes it from anti-HMGCR necrotizing myopathy.

skeletal muscle fiber CL:0008002

Animal models

Skeletal muscle-specific Hmgcr knockout mouse Mouse partially recapitulates Reproduces myopathy with elevated creatine kinase arising specifically from loss of HMGCR in muscle, establishing that the muscle phenotype is muscle-autonomous rather than secondary to hepatic or systemic cholesterol handling.

HMGCR p.Arg641Cys homozygous knock-in mouse Mouse fails to recapitulate Homozygous knock-in animals die as embryos and therefore never develop the postnatal progressive myopathy that defines the human disease.

hmgcr knockdown Drosophila Drosophila melanogaster fails to recapitulate Knockdown is lethal rather than myopathic, so no progressive proximal weakness, creatine kinase elevation or biopsy phenotype can be observed.

Downstream

Proximal and Axial Muscle Weakness Loss of contractile tissue in the limb-girdle and axial groups produces the weakness.

Elevated Serum Creatine Kinase Ongoing myofiber damage releases creatine kinase into the circulation.

Respiratory Muscle Weakness The same process involves the respiratory musculature, which is the usual cause of death.

Show evidence (3 references)

PMID:36745799 SUPPORT Human Clinical

"MRI, computerized tomography (CT), and ultrasound scans showed various levels of atrophy with severe fatty replacement of large proximal skeletal muscles and axial muscles with sparing of the distal and facial muscles"

Imaging documents the fatty replacement and its proximal and axial distribution.

PMID:36745799 SUPPORT Human Clinical

"Histopathological evaluation did not reveal any pathological features such as fibrosis or inflammation, with the exception of mild deficiency of type-II muscle fibers in one patient"

Establishes the absence of the inflammatory and fibrotic signature expected of a sarcolemmal dystrophy.

PMID:37167966 SUPPORT Human Clinical

"Muscle biopsies in most affected individuals showed non-specific dystrophic changes with non-diagnostic immunohistochemistry."

The second cohort's biopsy findings, non-specific and with normal immunohistochemistry.

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Histopathology

1

Non-specific myopathic change with normal muscular dystrophy immunohistochemistry

The biopsy is characteristically unhelpful, which is itself diagnostically informative. Findings range from non-specific dystrophic or myopathic change to a biopsy that is essentially normal, with no necrosis, fibrosis or inflammatory infiltrate in the founding kindred. Immunostaining for dystrophin, the sarcoglycans and dysferlin is normal, so the structural LGMD subtypes are excluded on the biopsy without this one being identified by it.

Show evidence (3 references)

PMID:37167966 SUPPORT Human Clinical

"Muscle biopsies in most affected individuals showed non-specific dystrophic changes with non-diagnostic immunohistochemistry."

Describes the non-specific biopsy and non-diagnostic immunohistochemistry across the defining cohort.

PMID:41904993 SUPPORT Human Clinical

"The main immunostainings (against dystrophin, sarcoglycans and dysferlin) were reported as normal."

Names the specific structural proteins whose normal staining excludes the sarcolemmal subtypes.

PMID:36745799 SUPPORT Human Clinical

"Histopathological evaluation did not reveal any pathological features such as fibrosis or inflammation, with the exception of mild deficiency of type-II muscle fibers in one patient"

The founding kindred's biopsies, notable for the absence of the usual dystrophic features.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

15

Cardiovascular 1

Subclinical Cardiac Involvement OCCASIONAL Increased circulating troponin T concentration HP:0410174

Show evidence (1 reference)

PMID:36745799 SUPPORT Human Clinical

"There were no clear signs of cardiomyopathy, although four patients showed slightly elevated troponin T levels, and two demonstrated conduction abnormalities in ECG"

Records both halves of the finding, that overt cardiomyopathy is absent and that subclinical biochemical and electrocardiographic abnormalities are nonetheless present.

Digestive 1

Cirrhosis OCCASIONAL HP:0001394

Course: PROGRESSIVE

Show evidence (2 references)

PMID:41904993 SUPPORT Human Clinical

"In addition, both patients in Family 3 demonstrated bona fide hepatic involvement, a feature not observed in the other patients."

Records genuine hepatic involvement in one family and its absence elsewhere in the cohort.

PMID:41904993 SUPPORT Human Clinical

"She also suffers from progressive liver cirrhosis, which has necessitated consideration for a liver transplant."

Clinical detail of the cirrhosis in the index sibling.

Limbs 1

Calf Muscle Hypertrophy OCCASIONAL HP:0008981

Show evidence (2 references)

PMID:41904993 SUPPORT Human Clinical

"Lumbar lordosis was increased, and mild calf pseudohypertrophy was observed."

Documents calf pseudohypertrophy in one affected individual.

PMID:41904993 SUPPORT Human Clinical

"Calf hypertrophy was not observed, and there were no signs of fasciculations nor macroglossia."

The same cohort records absence of calf hypertrophy in another affected individual, which is why this is curated as occasional rather than typical.

Metabolism 1

Elevated Serum Creatine Kinase VERY_FREQUENT Elevated circulating creatine kinase activity HP:0003236

Show evidence (2 references)

PMID:36745799 SUPPORT Human Clinical

"Blood tests showed muscle injury with elevated creatine kinase (up to over 250-fold upper level of normal CK; maximal CK 35761U/L, patient V:8)"

Quantifies the magnitude of CK elevation in the founding kindred.

PMID:41344164 SUPPORT Human Clinical

"presented with profound hypotonia, respiratory failure by 5 months, and markedly elevated creatine kinase (CK)"

Confirms marked CK elevation at the neonatal-onset extreme of the spectrum.

Musculoskeletal 7

Proximal and Axial Muscle Weakness VERY_FREQUENT Proximal muscle weakness HP:0003701

Course: PROGRESSIVE

Show evidence (2 references)

PMID:37167966 SUPPORT Human Clinical

"The clinical features resembled other genetic causes of muscular dystrophy with incidental high CPK levels (>1,000 U/L), proximal muscle weakness, variable age of onset, and progression leading to impaired ambulation."

Names proximal weakness and progression to impaired ambulation across the defining cohort.

PMID:36745799 SUPPORT Human Clinical

"The disease initially manifested during the fourth decade of life with pain on exertion, followed by muscle fatigue and weakness, affecting mostly the proximal and axial muscles, and culminating with involvement of respiratory muscles."

Documents the proximal and axial distribution and its progression in the founding kindred.

Axial Muscle Weakness FREQUENT HP:0003327

Show evidence (1 reference)

PMID:41904993 SUPPORT Human Clinical

"He displayed global muscular hypotrophy, neck muscle weakness, proximal and axial muscle weakness, mildly tense calves, and absent deep tendon reflexes."

Direct examination finding of axial and neck weakness in an affected individual.

Respiratory Muscle Weakness FREQUENT Respiratory insufficiency due to muscle weakness HP:0002747

Course: PROGRESSIVE

Show evidence (2 references)

PMID:41904993 SUPPORT Human Clinical

"All patients experienced rapid disease progression, leading to severe muscular atrophy, significant mobility decline, and respiratory difficulties necessitating ventilatory support and, eventually, tracheostomy."

Documents progression to ventilator dependence in an affected sibship.

PMID:41344164 SUPPORT Human Clinical

"presented with profound hypotonia, respiratory failure by 5 months, and markedly elevated creatine kinase (CK)"

Respiratory failure within the first months of life in the severe neonatal-onset form.

Gowers Sign FREQUENT HP:0003391

Show evidence (1 reference)

PMID:41904993 SUPPORT Human Clinical

"At age 2.5 years, muscle weakness was still present with, additionally, a noticeable weakness of neck flexors. The Gowers’ sign was fully positive."

Examination finding in an affected child.

Scoliosis FREQUENT HP:0002650

Show evidence (1 reference)

PMID:41904993 SUPPORT Human Clinical

"Scoliosis and/or lumbar lordosis were seen in families 1, 2, 5, and 6 and have not been reported as features in previously reported LGMDR28 patients."

Reports scoliosis in four of six families and flags it as a newly described feature.

Neonatal Hypotonia OCCASIONAL HP:0001319

Show evidence (2 references)

PMID:41344164 SUPPORT Human Clinical

"presented with profound hypotonia, respiratory failure by 5 months, and markedly elevated creatine kinase (CK)"

The neonatal-onset case report establishing this presentation.

PMID:41904993 SUPPORT Human Clinical

"He was admitted to the hospital due to significant hypotonia, severe congenital myopathy, and respiratory distress, which necessitated his reliance on a ventilator for adequate breathing support."

A second, independent congenital-onset infant with hypotonia and ventilator dependence.

EMG Myopathic Abnormalities FREQUENT HP:0003458

Show evidence (2 references)

PMID:41904993 SUPPORT Human Clinical

"Nerve conduction studies (NCS) were normal, and needle electromyography (EMG) revealed myopathic changes in the proximal muscles."

Electrophysiology localising the process to proximal muscle.

PMID:36745799 SUPPORT Human Clinical

"EMG studies of four patients showed a myopathic pattern, and motor nerve conduction velocity (NCV) demonstrated normal distal latencies, amplitudes, and velocities."

The same electrophysiological pattern in the founding kindred.

Nervous System 3

Loss of Ambulation FREQUENT HP:0002505

Course: PROGRESSIVE

Show evidence (2 references)

PMID:41904993 SUPPORT Human Clinical

"He had positive Gowers’ sign, severe gait disturbance and had lost ambulation at the age of 9 years."

Loss of ambulation documented in an affected child.

PMID:36745799 SUPPORT Human Clinical

"The oldest three patients (V:2,5,12 ages 49, 58, and 51 y, respectively) were wheelchair-bound or bedridden and suffered from respiratory insufficiency"

Loss of ambulation in the older affected members of the founding kindred.

Areflexia FREQUENT HP:0001284

Show evidence (1 reference)

PMID:41904993 SUPPORT Human Clinical

"Deep tendon reflexes were reduced in all reported families except family 6."

Reports reduced reflexes across the expanded cohort.

Motor Delay OCCASIONAL HP:0001270

Show evidence (1 reference)

PMID:41904993 SUPPORT Human Clinical

"The proband (Figure 1E, IV.4) was a 6-year-old male who showed delayed motor milestones, hypotonia, and decreased muscle strength."

Motor delay with hypotonia in a childhood-onset proband.

Constitutional 1

Exercise-Induced Myalgia FREQUENT HP:0003738

Show evidence (1 reference)

PMID:36745799 SUPPORT Human Clinical

"The disease initially manifested during the fourth decade of life with pain on exertion, followed by muscle fatigue and weakness, affecting mostly the proximal and axial muscles, and culminating with involvement of respiratory muscles."

Exertional pain is named as the initial manifestation in the founding kindred.

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Genetic Associations

1

HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase)

Gene: HMGCR hgnc:5006 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:41904993 SUPPORT Human Clinical

"To date, all reported variants are missense or in-frame, except for a splicing variant whose consequences are not clarified."

Characterises the allelic spectrum as hypomorphic rather than null.

PMID:41904993 SUPPORT Other

"the gene-disease relationship is categorized as moderate by the ClinGen expert panel"

Expert-panel gene-disease validity classification, quoted rather than asserted.

PMID:36745799 SUPPORT Human Clinical

"Filtering through whole-exome sequencing data of patients V:13 and V:2 (Methods), only a single variant was found within the 3.2 Mbp locus"

Linkage plus exome in the founding kindred leaves exactly one candidate in the disease interval, which is the argument against a second causal gene at this locus.

🔬

Variants

3

NM_000859.3:c.2465G>A p.(Gly822Asp) Pathogenic

Gene: HMGCR hgnc:5006 missense variant

The founding allele, homozygous in six affected members of a consanguineous Bedouin kindred from the Negev with fourth-decade-onset disease. Enzymologically the best characterised of the disease alleles: it leaves the protein correctly localised while reducing turnover and substrate affinity.

Functional effects

HMG-CoA reductase catalytic activity partial loss of function

Reduces Vmax by 69% and raises Km for HMG-CoA by 65%, with a catalytic pocket that no longer binds pravastatin, while subcellular localisation is unchanged.

Show evidence (2 references)

PMID:36745799 SUPPORT Human Clinical

"only a single variant was found within the 3.2 Mbp locus: g.5:75359992G>A (GRCh38/hg38); NM_000859.3:c.2465G>A; p.(G822D) in HMGCR"

Identifies the allele by linkage and exome sequencing in the founding kindred.

PMID:36745799 SUPPORT In Vitro

"Both WT and mutant HMGCR protein (green) are located in clusters in the cytoplasm with some relation to the endoplasmic reticulum (red)."

Shows the allele does not mislocalise the protein, which is why it is classified as a catalytic rather than a trafficking defect.

NM_000859.2:c.2519G>A p.(Arg840Gln)

Gene: HMGCR hgnc:5006 missense variant

A recurrent ultra-rare allele found homozygous in three of the six Middle Eastern families, spanning onset from birth to fourteen years within the same genotype. It sits in the Lalpha10 helix of the catalytic L domain and is notable for being missed by in silico predictors, which is why it went unrecognised in earlier sequencing analyses.

Show evidence (2 references)

PMID:41904993 SUPPORT Human Clinical

"In three unrelated families (1–3), the probands were found to carry a novel homozygous missense variant, c.2519G>A p.(Arg840Gln)."

Establishes the allele and its recurrence across three families.

PMID:41904993 SUPPORT Human Clinical

"Although this missense variant is not predicted to be disease-causing by in silico tools, it shows segregation in three unrelated families with shared clinical features."

Records the discordance between prediction and segregation that makes this allele a re-analysis lesson.

p.(Arg641Cys) Pathogenic

Gene: HMGCR hgnc:5006 missense variant

The allele of the single reported neonatal-onset, early-lethal case. It is the only disease allele for which a homozygous knock-in mouse has been made, and that mouse dies in utero.

Functional effects

HMG-CoA reductase catalytic activity loss of function

Severely impaired enzymatic activity on in vitro assay.

Show evidence (1 reference)

PMID:41344164 SUPPORT Human Clinical

"The patient, homozygous for the p.Arg641Cys variant in HMGCR, presented with profound hypotonia, respiratory failure by 5 months, and markedly elevated creatine kinase (CK)."

Establishes the allele and its severe clinical consequence.

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Medical Actions

3

Oral Mevalonolactone

Action: Pharmacotherapy NCIT:C15986

Agent: mevalonolactone CHEBI:194429

Platform: Small molecule

Metabolite replacement directed at the missing pathway product. Mevalonolactone is not an available pharmaceutical preparation and was synthesised and purified for the purpose, then given under an expanded-access authorisation to the single most severely affected patient of the founding kindred, who gained strength on dynamometry and manual testing and improved substantially on spirometry. The evidence is one patient treated openly without a control, so this is a promising directed therapy rather than an established one.

Mechanism Target:

Mevalonate Pathway Flux Reduction — Supplies the pathway product downstream of the defective enzymatic step, bypassing the reduced catalytic capacity rather than correcting it.

Show evidence (1 reference)

PMID:36745799 SUPPORT Human Clinical

"Mevalonolactone oral uptake was found to be very rapid: the mevalonate levels began to rise 20 min after oral administration, peaked at 50 min, and returned to baseline levels 2 h after ingestion"

Demonstrates that oral dosing raises circulating mevalonate, which is the mechanism the treatment is meant to act through.

Show evidence (3 references)

PMID:36745799 SUPPORT Human Clinical

"During treatment, there was improvement in muscle strength as assessed by dynamometry and by manual muscle testing (MMT) performed by an experienced neurologist"

The objective strength benefit in the treated patient.

PMID:36745799 SUPPORT Human Clinical

"Respiratory muscles were assessed by spirometry, which demonstrated marked increase in peak expiratory flow (+265%; from 6 to 22% of predicted value), forced vital capacity (+342%; from 17.4 to 77.6% of predicted value), and FEV1 (+345%, from 10.7 to 48.1% of predicted value, Fig. 4M)."

Quantifies the respiratory benefit, which is the outcome that matters most given respiratory failure is the usual cause of death.

PMID:26381177 SUPPORT Model Organism

"Myopathy in knockout mice was completely rescued by the oral administration of MVA."

The preclinical rescue in muscle-specific Hmgcr-knockout mice that motivated the human trial.

Non-invasive and invasive ventilatory support

Action: mechanical ventilation Ontology label: Mechanical Ventilation NCIT:C70909

Platform: Device

Respiratory muscle weakness is managed with nocturnal non-invasive ventilation progressing to continuous ventilation and tracheostomy. This is the supportive measure that determines survival, since respiratory failure is the reported cause of death.

Mechanism Target:

Respiratory Muscle Weakness — Substitutes for the failing respiratory musculature; it does not modify the underlying myopathy.

Show evidence (1 reference)

PMID:41904993 SUPPORT Human Clinical

"The chest was rigid, and forced vital capacity was estimated at less than 50% of the predicted value, thus requiring nocturnal invasive ventilation."

Ties the ventilatory support directly to the measured respiratory muscle failure it is given for.

Show evidence (1 reference)

PMID:41904993 SUPPORT Human Clinical

"All patients experienced rapid disease progression, leading to severe muscular atrophy, significant mobility decline, and respiratory difficulties necessitating ventilatory support and, eventually, tracheostomy."

Documents the use of ventilatory support and tracheostomy in affected individuals.

Occupational and physical therapy

Action: occupational therapy Ontology label: Occupational Therapy NCIT:C121351

Platform: Behavioral / lifestyle

Rehabilitation to maintain gait and function. Reported benefit is anecdotal, in one individual whose gait improved over time on occupational therapy.

Mechanism Target:

Loss of Ambulation — Aims to preserve ambulation and functional independence against the progressive weakness.

Show evidence (1 reference)

PMID:41904993 SUPPORT Human Clinical

"Through occupational therapy, her walking and gait have shown improvement over time."

The single reported observation of functional gain from rehabilitation in this disease.

Show evidence (1 reference)

PMID:41904993 SUPPORT Human Clinical

"Through occupational therapy, her walking and gait have shown improvement over time."

Records the observed benefit that motivates offering rehabilitation.

🔬

Diagnosis

2

Molecular diagnosis by exome or genome sequencing

The diagnosis is molecular. Targeted neuromuscular gene panels have repeatedly been negative in these patients, both because HMGCR was not on older panels and because at least one recurrent allele is not flagged by in silico predictors, so exome or genome sequencing with periodic reanalysis is what makes the diagnosis.

Show evidence (2 references)

PMID:41904993 SUPPORT Human Clinical

"The c.2519G>A variant that we describe here is not predicted strongly to be deleterious by most in silico tools and was overlooked in the analysis of NGS data."

Explains why sequencing must be reanalysed rather than trusted on first pass.

PMID:41904993 SUPPORT Human Clinical

"Based on the initial clinical suspicion of limb-girdle muscular dystrophy, we conducted sequence analysis and deletion/duplication testing of the 117 genes present in the Neuromuscular Disorders Panel which turned out to be inconclusive."

Documents the failure of a large targeted panel in a patient who was subsequently diagnosed.

Hepatic monitoring

Following the recognition of true hepatic involvement in one family, a liver panel beyond transaminases is recommended alongside creatine kinase, because transaminase elevation in a myopathy is otherwise readily attributed to muscle injury.

Show evidence (1 reference)

PMID:41904993 SUPPORT Human Clinical

"we recommend monitoring not only CPK but also a broader liver panel (bilirubin, GGT, alkaline phosphatase, albumin, and INR), with further hepatology evaluation and imaging as indicated"

The published monitoring recommendation this item records.

📈

Progression

2

Onset

Age: birth to fourth decade

Age of onset spans birth to the fourth decade. Severity and rate of progression do not correlate with how early the disease starts, and both inter- and intrafamilial variability are marked, including among carriers of the same homozygous allele. Presentation is commonly an incidental creatine kinase elevation rather than a complaint of weakness.

Show evidence (2 references)

PMID:41904993 SUPPORT Human Clinical

"It is important to note that early (even as early as neonatal) onset does not seem to correlate with severity of progression based on our cohort and this agrees with previous reports."

States explicitly that onset age does not predict severity.

PMID:41904993 SUPPORT Human Clinical

"The age of onset ranges from birth in the case of family 3 to as late as 14 years in family 1."

Documents the onset range within a single recurrent genotype.

Progression to loss of ambulation and respiratory failure

Weakness advances to wheelchair dependence, then in the severe cases to a bedridden state with joint contractures, restrictive respiratory failure, nocturnal or continuous ventilation and tracheostomy. Deaths in the published cohorts have been from respiratory failure. Creatine kinase falls back towards and below normal late in the disease as muscle mass is lost, which can mislead if it is the only marker followed.

Show evidence (2 references)

PMID:36745799 SUPPORT Human Clinical

"With disease progression and muscular atrophy, CK levels gradually normalized and eventually even dropped beneath normal limits, alongside a simultaneous drop in creatinine levels, consistent with low skeletal muscle mass"

Documents the late fall in creatine kinase as muscle mass is lost.

PMID:41904993 SUPPORT Human Clinical

"All patients experienced rapid disease progression, leading to severe muscular atrophy, significant mobility decline, and respiratory difficulties necessitating ventilatory support and, eventually, tracheostomy."

The progression trajectory in the most severely affected reported sibship.

📊

Prevalence

1

Worldwide, published cases

Cases In Literature Ultra Rare

Twenty-eight affected individuals from fourteen unrelated families had been reported by 2026: seventeen from eight families before the expanded cohort, plus eleven from six Middle Eastern families in it. No population prevalence estimate exists for LGMDR28 specifically, and none is asserted here. The commonly quoted figure of about 1 in 61,000 is for limb-girdle muscular dystrophy as a whole across roughly 39 subtypes, so it is not a rate for this one and is deliberately not recorded as a numeric band.

Show evidence (2 references)

PMID:41904993 SUPPORT Human Clinical

"To date, 17 affected individuals from eight unrelated families have been reported to harbor biallelic variants in the HMGCR gene."

The published case count prior to the expanded cohort.

PMID:41904993 SUPPORT Human Clinical

"Here, we report eleven individuals from six unrelated Middle Eastern families diagnosed with LGMDR28 and carrying homozygous variants in HMGCR."

The additional cases that bring the published total to twenty-eight.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Muscular Dystrophy, Limb-Girdle, Autosomal Recessive 28:

Statin-associated muscle symptoms and statin myopathy Not Yet Curated MONDO:0100637

Overlapping Features The same enzyme, inhibited pharmacologically instead of mutated. The overlap is not superficial: proximal weakness, raised creatine kinase, an unremarkable biopsy and end-stage imaging with fatty replacement are shared, and the founding LGMDR28 report describes its own patients as phenotypically resembling severe statin myopathy. The entities are nonetheless distinct in cause, and MONDO defines drug-induced myopathy by an exposure relation rather than a germline gene relation.

Distinguishing Features

Cause is a biallelic germline HMGCR genotype rather than exposure to a drug; there is no statin exposure in the LGMDR28 families, including in utero.
Onset in statin myopathy is relatively acute and follows the start of the drug, whereas LGMDR28 is insidious and lifelong; withdrawal of a statin has no counterpart in the genetic disease.
LGMDR28 is inherited in a Mendelian recessive pattern with unaffected heterozygous parents; statin myopathy is not inherited.
One caveat cuts the other way, in that chronic or subacute severe statin myopathy has been described and can mimic limb-girdle muscular dystrophy, so drug history rather than phenotype is the discriminator.

Show evidence (2 references)

PMID:39823152 SUPPORT Other

"The two other muscle diseases associated with HMGCR, statin-associated myopathy (SAM) and autoimmune anti-HMGCR myopathy, are not inherited in a Mendelian pattern."

States the nosological boundary this differential draws, that only LGMDR28 among the three is Mendelian.

PMID:36745799 SUPPORT Human Clinical

"One major difference between SAMS and the hereditary HMGCR disease is the relatively acute onset of SAMS compared with the insidious presentation of muscle symptoms in the HMGCR-limb girdle muscle disease."

Names the tempo difference that separates the two clinically.

Anti-HMGCR immune-mediated necrotizing myopathy Not Yet Curated MONDO:0016098

Overlapping Features An autoantibody disease directed against the same protein, and the differential most likely to be mistaken for this one, because it is repeatedly reported as presenting like a limb-girdle muscular dystrophy in both adults and children. The distinction is consequential rather than academic: anti-HMGCR myopathy responds to immunosuppression, and LGMDR28 has no reason to.

Distinguishing Features

Anti-HMGCR autoantibodies are present by definition in the autoimmune disease and were explicitly absent in all six patients of the founding LGMDR28 kindred.
Biopsy in anti-HMGCR myopathy shows myocyte necrosis and regeneration; the LGMDR28 biopsy shows non-specific change or nothing, without necrosis or inflammation.
Anti-HMGCR myopathy is acquired and typically acute or subacute; LGMDR28 is a Mendelian recessive disease with unaffected heterozygous parents.
Immunosuppressive therapy is the treatment of the autoimmune disease and has no rationale in the genetic one, where metabolite replacement is the directed approach.

Show evidence (2 references)

PMID:36745799 SUPPORT Human Clinical

"a notable finding was the lack of anti-HMGCR antibodies in any of the patients"

The direct serological test that separates the founding LGMDR28 kindred from the autoantibody disease.

PMID:41904993 SUPPORT Other

"The presence of anti-HMGCR enzyme antibodies has been found to result in auto-immune necrotizing myopathy, a disease mimicking muscular dystrophy in adults but also in a growing number of children."

Records that the autoimmune disease mimics muscular dystrophy across ages, which is what makes it the key differential.

Sarcolemmal autosomal recessive limb-girdle muscular dystrophy subtypes MONDO:0015152

Overlapping Features The rest of the LGMD-R group, curated in `kb/disorders/Autosomal_Recessive_Limb-Girdle_Muscular_Dystrophy.yaml`, whose shared mechanism is sarcolemmal fragility and failed membrane repair. LGMDR28 is a MONDO child of this term and shares its clinical syndrome, but not its mechanism, which is why it is curated as its own entry rather than folded into that one.

Distinguishing Features

Immunohistochemistry for dystrophin, the sarcoglycans and dysferlin is normal in LGMDR28, whereas the sarcoglycanopathies and dysferlinopathy show loss of the corresponding protein.
The LGMDR28 biopsy lacks the necrosis, inflammation and fibrofatty replacement that characterise the membrane-repair subtypes.
Creatine kinase elevation in LGMDR28 is at the high end even for this group, reported up to 250-fold the upper limit of normal.
Clinical cardiomyopathy, which occurs in several sarcolemmal subtypes, has not been reported in LGMDR28, although subclinical troponin T elevation and ECG conduction changes were found in the founding kindred.
LGMDR28 has a directed metabolite-replacement candidate; the sarcolemmal subtypes have supportive care and gene-directed trials.

Show evidence (2 references)

PMID:41904993 SUPPORT Human Clinical

"None of the patients had any cardiac involvement, as was the case in previous reports."

The consistent absence of cardiac disease, which is a point of separation from several sarcolemmal subtypes.

PMID:41904993 SUPPORT Human Clinical

"The main immunostainings (against dystrophin, sarcoglycans and dysferlin) were reported as normal."

Normal staining for the structural proteins whose loss defines the sarcolemmal subtypes.

🧫

Experimental Models

1

Hmgcr knockdown C2C12 myoblast line with variant complementation CELL_LINE

C2C12 mouse myoblasts, the standard immortalised myogenic line, with Hmgcr knocked down by shRNA to about 60% of control transcript. Used both to characterise the cellular phenotype of HMGCR loss and, by re-expressing wild-type versus patient HMGCR cDNA, to test whether specific disease alleles are functional. It is the system that connects the enzymatic defect to a myogenic one.

Pathograph links

Impaired Myoblast Proliferation and Myotube Fusion recapitulates fidelity: moderate Reproduces the proliferation, survival and fusion defects attributable to HMGCR loss, and shows that three patient alleles cannot rescue them while the reference sequence can.

Limitations: Knockdown rather than the biallelic hypomorphic genotype patients carry, in mouse rather than human cells, and in proliferating myoblasts rather than mature innervated muscle. A fusion defect in culture is a developmental readout, whereas most patients present after normal early motor development, so the correspondence to the adult-onset end of the spectrum is uncertain.

Readouts

Myotube fusion after complementation with reference or variant HMGCR cDNA

Direction: RESTORED

Interpretation: Reference cDNA restores fusion and the patient alleles do not, which is the functional demonstration that those alleles are loss-of-function in a muscle cell.

Show evidence (1 reference)

PMID:39823152 SUPPORT In Vitro

"Overexpression of reference HMGCR cDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants of HMGCR cDNA did not."

Reports the complementation result behind this readout.

Show evidence (1 reference)

PMID:39823152 SUPPORT In Vitro

"Hmgcr deficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion."

Establishes that the cellular phenotype this model reports is the one the node describes.

🐁

Animal Models

4

Skeletal muscle-specific Hmgcr knockout mouse

A muscle-restricted biallelic Hmgcr null. Its authors built it and describe it as a model of statin myopathy, because that was their question, but the genotype is a genetic loss of HMGCR confined to muscle, which makes it the closest available animal model of LGMDR28 rather than of drug exposure. The mice develop postnatal myopathy with raised creatine kinase, and oral mevalonate rescues them completely, which is the result that motivated treating a human patient with mevalonolactone.

Species

Mouse

Genotype

Skeletal muscle-specific Hmgcr conditional knockout

Publication

PMID:26381177

Pathograph links

Progressive Myofiber Loss and Fatty Replacement partially recapitulates fidelity: moderate Reproduces myopathy with elevated creatine kinase arising specifically from loss of HMGCR in muscle, establishing that the muscle phenotype is muscle-autonomous rather than secondary to hepatic or systemic cholesterol handling.

Limitations: The knockout is a complete null restricted to skeletal muscle, whereas patients carry hypomorphic missense alleles expressed in every tissue, so the model overstates the enzymatic deficit while understating its tissue distribution. The mice develop necrosis and rhabdomyolysis, which patient biopsies characteristically do not show, and the tempo is postnatal and rapid rather than the years-to-decades human course. The paper frames the model as one of statin myopathy, so its reported comparisons are to drug exposure rather than to LGMDR28.

Readouts

Serum creatine kinase

Direction: INCREASED

Interpretation: Circulating marker of myofiber damage, matching the cardinal laboratory abnormality in patients.

Show evidence (1 reference)

PMID:26381177 SUPPORT Model Organism

"Knockout mice exhibited postnatal myopathy with elevated serum creatine kinase levels and necrosis."

Reports the creatine kinase measurement behind this readout.

Myopathy after oral mevalonate supplementation

Direction: RESTORED

Interpretation: Complete rescue by the pathway product establishes that the myopathy follows from metabolite deficiency rather than from any structural role of the enzyme.

Show evidence (1 reference)

PMID:26381177 SUPPORT Model Organism

"Myopathy in knockout mice was completely rescued by the oral administration of MVA."

Reports the rescue experiment behind this readout.

Show evidence (1 reference)

PMID:26381177 SUPPORT Model Organism

"we developed the skeletal muscle-specific HMGCR knockout mice"

Establishes the genotype that makes this model informative for muscle-autonomous HMGCR loss.

Doxycycline-inducible skeletal muscle-specific Hmgcr knockout mouse (Hmgcr-DimKO)

An inducible version of the muscle-specific null, built alongside Rabggtb single and double knockouts to ask which downstream branch of the mevalonate pathway carries the myopathy. It is the source of the isoprenoid-rather-than-sterol mechanism in this entry: the fiber-type loss is reversed by geranylgeraniol, and mitochondrial dysfunction appears before any weakness.

Species

Mouse

Genotype

Doxycycline-inducible skeletal muscle-specific Hmgcr knockout

Publication

PMID:42323079

Pathograph links

Isoprenoid Depletion and Impaired Protein Geranylgeranylation recapitulates fidelity: moderate Establishes geranylgeranyl pyrophosphate depletion as the branch of the pathway whose loss produces myopathy, by rescuing with its precursor and by phenocopying and aggravating with a Rab geranylgeranyltransferase knockout.

Limitations: This is a mouse null rather than a human hypomorph, and inducible deletion in adult muscle does not reproduce the lifelong partial deficiency patients carry. No prenylation or isoprenoid measurement has been made in an LGMDR28 patient, so the mechanism is imported from the model rather than confirmed in the disease. As with the constitutive knockout, the paper's stated target is statin myopathy.

Readouts

Oxidative (MyHC type I and IIa) fiber content after geranylgeraniol

Direction: RESTORED

Interpretation: Rescue by the isoprenoid precursor localises the causal deficit to the geranylgeranyl branch.

Show evidence (1 reference)

PMID:42323079 SUPPORT Model Organism

"Hmgcr KO resulted in pronounced myopathy, marked by an early reduction in mitochondria-rich myosin heavy chain (MyHC) type I and IIa muscle fibers, followed by a later reduction in mitochondria-poor glycolytic MyHC type IIb muscle fibers, and these changes were reversed by GGOH administration."

Reports the fiber-type measurement and its reversal by geranylgeraniol.

Show evidence (1 reference)

PMID:42323079 SUPPORT Model Organism

"Using doxycycline-inducible Cre-LoxP technology, we generated three skeletal muscle-specific knockout (KO) models: Hmgcr-DimKO, Rabggtb-DimKO, and combined Hmgcr/Rabggtb-DimKO mice."

Establishes the genotypes that make this model informative for the isoprenoid branch.

Myofiber Mitochondrial Dysfunction recapitulates fidelity: moderate Mitochondrial abnormalities are detectable before clinical myopathy in every genotype tested, which is the temporal argument that the mitochondrial defect is upstream of fiber loss rather than a consequence of it.

Limitations: Temporal precedence in an inducible mouse null is suggestive of causation but does not establish it, and the corresponding measurement has not been made in patient muscle. The acute deletion tempo is unlike the human disease.

Readouts

Mitochondrial mass and function

Direction: DECREASED

Interpretation: Quantified mitochondrial deficit appearing before weakness in the knockout muscle.

Show evidence (1 reference)

PMID:42323079 SUPPORT Model Organism

"Mitochondrial mass and function were rigorously quantified."

Names the readout measured; its timing relative to weakness is quoted on the link evidence.

Show evidence (1 reference)

PMID:42323079 SUPPORT Model Organism

"Early mitochondrial abnormalities may contribute to the pathogenesis of myopathy due to disruption of the mevalonate pathway."

The authors' own statement placing the mitochondrial defect in the pathogenic sequence.

HMGCR p.Arg641Cys homozygous knock-in mouse

A knock-in of the human neonatal-onset allele. It does not model the disease, because homozygous animals die in utero rather than developing a muscular dystrophy. That is an informative negative: it shows the allele is severe enough to breach the threshold for embryonic viability in mouse, while the human homozygote survived to four months, and it means the most obvious way to build a mouse model of LGMDR28 does not work.

Species

Mouse

Genotype

Hmgcr p.Arg641Cys homozygous knock-in

Publication

PMID:41344164

Pathograph links

Progressive Myofiber Loss and Fatty Replacement fails to recapitulate fidelity: low Homozygous knock-in animals die as embryos and therefore never develop the postnatal progressive myopathy that defines the human disease.

Limitations: Embryonic lethality precludes any muscle phenotyping at all, so the model yields no readout of weakness, creatine kinase, histology or treatment response. The species difference is the substantive limitation: mouse appears less tolerant of this allele than human, since the corresponding human homozygote was liveborn and survived four months. Nothing about the human muscular dystrophy can be inferred from this model.

Show evidence (1 reference)

PMID:41344164 SUPPORT Model Organism

"in vivo modeling using homozygous knock-in mice resulted in embryonic lethality"

Reports the embryonic lethality that constitutes the failure to recapitulate.

hmgcr knockdown Drosophila

The invertebrate arm of the same study that produced the myoblast data. Both ubiquitous and muscle-restricted knockdown of the fly HMGCR orthologue are lethal, so like every available mouse the fly cannot be carried to a state resembling the human muscular dystrophy. It contributes the conserved requirement for the enzyme in muscle rather than a phenotype.

Species

Drosophila melanogaster

Genotype

RNAi knockdown of hmgcr, ubiquitous and muscle-specific drivers

Publication

PMID:39823152

Pathograph links

Progressive Myofiber Loss and Fatty Replacement fails to recapitulate fidelity: low Knockdown is lethal rather than myopathic, so no progressive proximal weakness, creatine kinase elevation or biopsy phenotype can be observed.

Limitations: Lethality precludes any muscle phenotyping, so the model yields no readout that maps onto the human disease. Knockdown severity is also not comparable to the partial loss of function patients carry, and the phylogenetic distance means the result establishes only that the enzyme is required in muscle, not how a hypomorphic human allele produces a slowly progressive dystrophy.

Show evidence (1 reference)

PMID:39823152 SUPPORT Model Organism

"Both ubiquitous and muscle-specific knockdown of hmgcr in Drosophila led to lethality."

Reports the lethality that constitutes the failure to recapitulate.

{ }

Source YAML

click to show

name: Muscular Dystrophy, Limb-Girdle, Autosomal Recessive 28
category: Mendelian
creation_date: "2026-08-31T10:30:00Z"
synonyms:
- LGMDR28
- HMGCR-related muscular dystrophy
- HMGCR-related limb-girdle muscular dystrophy
- autosomal recessive limb-girdle muscular dystrophy type R28
- HMGCR-limb girdle muscle disease
description: >-
  Limb-girdle muscular dystrophy autosomal recessive 28 (LGMDR28) is caused by biallelic
  hypomorphic variants in HMGCR, which encodes 3-hydroxy-3-methylglutaryl-CoA reductase,
  the rate-limiting enzyme of the mevalonate pathway and the molecular target of the
  statin drug class. It is the only Mendelian disease MONDO attributes to germline HMGCR
  variation, and it was first described in 2023 by two independent groups.

  The mechanism is a metabolic shortfall rather than a structural one, which is what sets
  this subtype apart from the rest of recessive LGMD. The classic LGMD-R subtypes fail at
  the sarcolemma: dysferlin, the sarcoglycans and the dystroglycan-glycosylating enzymes
  all leave the muscle membrane fragile, and repeated mechanical injury drives the
  degeneration-regeneration cycle, the inflammatory infiltrate and the fibrofatty
  replacement seen on biopsy. Here the membrane is intact and the biopsy is
  correspondingly unimpressive: immunohistochemistry for dystrophin, the sarcoglycans and
  dysferlin is normal, and in the founding Bedouin kindred histology showed no necrosis,
  fibrosis or inflammation at all. What fails instead is flux through the mevalonate
  pathway. Patients carry roughly a fifth of normal circulating mevalonolactone, and the
  disease-associated alleles reduce catalytic rate and destabilise the enzyme rather than
  abolishing its expression or mislocalising it.

  Which downstream product matters is the interesting part. Cholesterol appears not to be
  the mediator: affected individuals have low-normal, not deficient, serum cholesterol, and
  in muscle-specific Hmgcr-knockout mice the myopathy is reversed by geranylgeraniol,
  implicating depletion of the isoprenoid branch and of Rab protein geranylgeranylation
  rather than of sterol. Mitochondrial abnormalities in those mice precede any clinical
  weakness, and Hmgcr-knockdown myoblasts show altered oxygen consumption alongside
  reduced proliferation, increased apoptosis and failed myotube fusion. The emerging
  picture is a myofiber that cannot maintain its mitochondrial and prenylation economy,
  degenerating slowly and without the inflammatory signature of a membrane disease.

  Clinically the disease is a proximal and axial myopathy with markedly elevated creatine
  kinase, exertional myalgia, absent deep tendon reflexes and progression to loss of
  ambulation and respiratory failure, which is the usual cause of death. Onset spans birth
  to the fourth decade, and severity does not track with how early it starts. Clinical
  cardiomyopathy has not been reported, but the heart is not entirely spared: the founding
  kindred had slightly raised troponin T in every patient tested and conduction changes in
  two, so "no cardiac involvement" is a statement about symptomatic disease rather than
  about the myocardium. Hepatic involvement is the open question: two siblings in the
  expanded cohort developed progressive cirrhosis requiring transplantation, against a
  background in which transaminase elevation in LGMD usually reflects muscle injury rather
  than liver disease.

  Because the missing metabolite is known, the disease is one of the few LGMD subtypes
  with a directed therapeutic candidate. Oral mevalonolactone, synthesised for the purpose
  and never previously given to humans, produced measurable strength and spirometry gains
  in the single severely affected patient treated under compassionate use, and oral
  mevalonate completely rescued the myopathy of muscle-specific Hmgcr-knockout mice. The
  evidence base is one patient; the mechanism behind it is unusually well specified.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      A muscular dystrophy, assigned to the neurology part where Harrison's places the
      muscular dystrophies and other muscle diseases. The morbidity is entirely
      neuromuscular: proximal and axial weakness, loss of ambulation, and respiratory
      muscle failure. A second ENDOCRINOLOGY_METABOLISM assignment was considered because
      the lesion is in a metabolic enzyme, but no metabolic derangement is the presenting
      or defining problem, so it is deliberately not made.
    evidence:
    - reference: PMID:37167966
      reference_title: Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The clinical features resembled other genetic causes of muscular dystrophy with incidental high CPK levels (>1,000 U/L), proximal muscle weakness, variable age of onset, and progression leading to impaired ambulation."
      explanation: The defining cohort describes the phenotype as a progressive proximal muscular dystrophy, which is the basis for the neurologic chapter assignment.
  icimd_category:
  - classification_value: sterol_metabolism
    notes: >-
      Assigned by the position of the defective enzyme in the pathway, not by an ICIMD
      listing. HMGCR catalyses the rate-limiting step of sterol biosynthesis, which places
      the defect in the ICIMD sterol-metabolism group. The caveat matters: the ICIMD
      classification (Ferreira et al. 2021, PMID:33340416) predates the 2023 description
      of LGMDR28, so this disease does not appear in it, and the assignment is an
      inference about the enzyme rather than a citation of the nosology. Note also that
      the sterol branch is probably not the arm that causes the myopathy, for which see
      the isoprenoid discussion in this entry.
disease_term:
  preferred_term: muscular dystrophy, limb-girdle, autosomal recessive 28
  term:
    id: MONDO:0957270
    label: muscular dystrophy, limb-girdle, autosomal recessive 28
parents:
- Autosomal Recessive Limb-Girdle Muscular Dystrophy
notes: >-
  Entity verification. `runoak -i sqlite:obo:mondo info MONDO:0957270 -O obo` on
  2026-08-31 returns the label "muscular dystrophy, limb-girdle, autosomal recessive 28",
  the relationship `RO:0004003 HGNC:5006 ! HMGCR`, the single superclass MONDO:0015152
  (autosomal recessive limb-girdle muscular dystrophy), and xrefs OMIM:620375,
  Orphanet:653725, DOID:0061130, GARD:0026805, MEDGEN:1841154 and UMLS:C5830518. The OMIM
  number matches the one the naming paper gives for LGMDR28.

  Named Entity Confusion, and why it is a same-protein rather than a same-name problem
  here. Three distinct diseases involve HMG-CoA reductase, and a literature search on the
  gene returns mostly the other two. LGMDR28 is the germline Mendelian disease curated
  here. Statin-associated muscle symptoms are caused by pharmacological inhibition of the
  same enzyme. Anti-HMGCR immune-mediated necrotizing myopathy is an autoantibody disease
  directed against the same protein. `runoak -i sqlite:obo:mondo relationships --direction
  down -p RO:0004003 HGNC:5006` returns exactly one term, MONDO:0957270, confirming at the
  ontology level that the other two are not germline HMGCR disorders; they carry separate
  MONDO identities (MONDO:0100637 drug-induced myopathy, defined by `RO:0009501
  ECTO:0000509 ! exposure to drug`, and MONDO:0016098 immune-mediated necrotizing
  myopathy, whose synonyms include "anti-HMG-CoA myopathy"). Both are curated below as
  differentials and neither is merged into this entry.

  Every clinical claim in this entry is sourced to a paper whose subjects carry biallelic
  germline HMGCR variants: PMID:37167966 (nine individuals, five families), PMID:36745799
  (six individuals, one consanguineous Bedouin kindred), PMID:41904993 (eleven
  individuals, six Middle Eastern families) and PMID:41344164 (one neonatal-onset case).
  Papers about the other two entities were read and excluded rather than mined:
  PMID:30588482, PMID:32447205 and PMID:35754285 report anti-HMGCR myopathy presenting as
  a limb-girdle mimic and would be the easiest source of a wrong attribution;
  PMID:39106428 and PMID:35031847 are anti-HMGCR autoantibody cohorts; PMID:36447272 is
  dysferlinopathy and statin resistance, a different LGMD subtype. One statin-myopathy
  result is used deliberately and is labelled as such wherever it appears: PMID:36745799
  also reports a murine statin-myopathy rescue experiment, which is cited only in the
  treatment rationale and the statin differential, never as evidence about LGMDR28
  patients.

  A note on the mouse literature. PMID:26381177 and PMID:42323079 both frame their
  skeletal-muscle-specific Hmgcr-knockout mice as models of statin myopathy, because that
  is the question their authors were asking. The genotype, however, is a biallelic
  muscle-restricted Hmgcr null, which is mechanistically the closest available animal
  model of LGMDR28 rather than of statin exposure. They are curated in `animal_models`
  with that framing mismatch recorded in `limitations`.

  Deep research. A falcon run was completed and is committed as
  `research/Muscular_Dystrophy_Limb-girdle_Autosomal_Recessive_28-deep-research-falcon.md`.
  `just preflight-dr` returns WARN rather than PASS, flagging CERT1 at 17 mentions against
  55 for HMGCR. Reading the report, that is not a second disease entity: CERT1 appears
  only inside the report's own caveats, which state that Open Targets returns CERT1 for
  MONDO:0957270 as a locus-level artifact because CERT1 neighbours HMGCR on chromosome
  5q13, and that it should not be promoted to causality. That reading is independently
  supported by PMID:36745799, whose homozygosity mapping found a single 3.2 Mbp interval
  at 5q13.2-q13.3 containing exactly one candidate variant, in HMGCR. The report was
  therefore not discarded, but it contributed no content to this entry: it retrieved only
  a 2023 conference abstract, states that it could not recover variant-level data, and
  reaches no conclusion that the primary literature does not state better. Everything
  below is curated directly from the primary papers.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic HMGCR variants. Reported genotypes are homozygous in consanguineous
    families and compound heterozygous elsewhere; heterozygous parents are unaffected.
  evidence:
  - reference: PMID:37167966
    reference_title: Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified nine individuals from five unrelated families with unexplained limb-girdle like muscular dystrophy and bi-allelic variants in HMGCR via clinical and research exome sequencing."
    explanation: Establishes biallelic HMGCR genotypes across five independent families as the basis of the disease.
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The HMGCR variant was validated by restriction analysis and Sanger sequencing (Fig. 2A) and was found to fully segregate as expected for autosomal recessive mode of inheritance."
    explanation: Formal segregation analysis in the founding kindred confirms the recessive mode.
pathophysiology:
- name: Reduced HMG-CoA Reductase Catalytic Activity
  biological_scale: MOLECULAR
  description: >-
    Disease-associated HMGCR alleles are amorphic to hypomorphic: they reduce catalytic
    rate and destabilise the enzyme rather than preventing its expression or
    mislocalising it. The founding G822D allele retains the protein in its normal
    cytoplasmic and endoplasmic-reticulum distribution while losing most of its turnover
    number and most of its affinity for HMG-CoA, and independently assayed alleles from a
    second cohort show the same pattern of reduced activity with reduced stability.
  molecular_functions:
  - preferred_term: HMG-CoA reductase activity
    modifier: DECREASED
    term:
      id: GO:0004420
      label: hydroxymethylglutaryl-CoA reductase (NADPH) activity
  downstream:
  - target: Mevalonate Pathway Flux Reduction
    causal_link_type: DIRECT
    description: Loss of catalytic rate at the pathway's rate-limiting step reduces flux through it.
  evidence:
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the mutant protein had 69% reduction in Vmax and 65% increase in Km in relation to the substrate HMG-CoA, indicating lower affinity of the mutated protein for HMG-CoA, as well as overall slower reaction-rate"
    explanation: Direct enzymological measurement of the catalytic deficit produced by a disease allele in a CRISPR knock-in cell line.
  - reference: PMID:37167966
    reference_title: Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Protein activity studies using three variants (p.Asp623Asn, p.Tyr792Cys, and p.Arg443Gln) identified in affected individuals confirmed decreased enzymatic activity and reduced protein stability."
    explanation: Replicates the activity deficit across three further patient alleles and adds the stability component.
  - reference: PMID:37167966
    reference_title: Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Molecular modeling analyses revealed variants to be destabilizing and affecting protein oligomerization."
    explanation: In silico structural analysis predicting the destabilising mechanism that the activity assays then measured.
  - reference: PMID:41344164
    reference_title: "HMGCR-related muscular dystrophy: a case of severe neonatal-onset form."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "in vitro assays showed severely impaired HMGCR enzymatic activity"
    explanation: Extends the activity deficit to the neonatal-onset p.Arg641Cys allele.
- name: Mevalonate Pathway Flux Reduction
  biological_scale: MOLECULAR
  description: >-
    Reduced enzyme activity lowers production of mevalonate, the committed product of the
    pathway. This is measurable in patients rather than inferred: circulating
    mevalonolactone in the treated proband sat at roughly a fifth of the control average.
    Sterol output is comparatively spared, since patient cholesterol is low but within the
    normal range, which is the first indication that the sterol branch is not where the
    disease is expressed.
  biological_processes:
  - preferred_term: mevalonate pathway flux
    modifier: DECREASED
    term:
      id: GO:0019287
      label: isopentenyl diphosphate biosynthetic process, mevalonate pathway
  downstream:
  - target: Isoprenoid Depletion and Impaired Protein Geranylgeranylation
    causal_link_type: DIRECT
    description: Reduced mevalonate limits the isoprenoid branch that consumes it.
  - target: Impaired Myoblast Proliferation and Myotube Fusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Knockdown of Hmgcr in myoblasts, which reproduces the flux deficit rather than any
      structural lesion, impairs proliferation and fusion. Which pathway product mediates
      this is not established.
  evidence:
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum mevalonolactone level of patient V:2 was 14.5 to 29.1% than the normal average"
    explanation: Direct patient measurement of the reduced pathway product, establishing the flux deficit in vivo in humans.
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cholesterol and lipoprotein levels were not elevated (SI Appendix, Table S1), with most patients frequently showing total cholesterol levels lower than 120 mg/dL."
    explanation: Shows the sterol end product is only mildly affected, which is why the disease is not modelled as a cholesterol-deficiency state.
- name: Isoprenoid Depletion and Impaired Protein Geranylgeranylation
  biological_scale: MOLECULAR
  description: >-
    The branch of the mevalonate pathway that appears to carry the myopathy is the
    isoprenoid one. In muscle-specific Hmgcr-knockout mice the fiber-type loss is reversed
    by geranylgeraniol, the precursor of geranylgeranyl pyrophosphate, and independently
    knocking out the Rab geranylgeranyltransferase beta subunit produces its own myopathy
    and aggravates the Hmgcr one. This is a mouse-derived mechanism; no patient
    measurement of prenylation exists.
  biological_processes:
  - preferred_term: protein geranylgeranylation
    modifier: DECREASED
    term:
      id: GO:0018344
      label: protein geranylgeranylation
  - preferred_term: isoprenoid biosynthesis
    modifier: DECREASED
    term:
      id: GO:0008299
      label: isoprenoid biosynthetic process
  downstream:
  - target: Myofiber Mitochondrial Dysfunction
    causal_link_type: DIRECT
    description: >-
      Prenylation-dependent trafficking failure precedes and accompanies the mitochondrial
      abnormalities in the knockout mice.
  evidence:
  - reference: PMID:42323079
    reference_title: Skeletal muscle-specific deficiency of Rab geranylgeranyl transferase beta subunit induces myopathy and exacerbates the symptoms caused by HMG-CoA reductase deficiency in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our findings demonstrate that myopathy induced by HMGCR deficiency is primarily driven by GGPP depletion in a mouse model."
    explanation: Attributes the myopathy of HMGCR deficiency to isoprenoid rather than sterol depletion.
  - reference: PMID:42323079
    reference_title: Skeletal muscle-specific deficiency of Rab geranylgeranyl transferase beta subunit induces myopathy and exacerbates the symptoms caused by HMG-CoA reductase deficiency in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, impaired RabGGT-β-mediated protein geranylgeranylation represents a critical downstream mechanism that aggravates the myopathic phenotype."
    explanation: Places Rab geranylgeranylation downstream of the reductase defect as an aggravating step.
- name: Myofiber Mitochondrial Dysfunction
  biological_scale: CELLULAR
  description: >-
    Mitochondrial abnormalities appear early in Hmgcr-deficient muscle, before weakness is
    clinically apparent, and the first fibers lost are the mitochondria-rich oxidative
    ones. Hmgcr-knockdown myoblasts show a matching transcriptional and respirometric
    signature. Whether this is the proximate cause of fiber loss in patients is not
    established.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: oxidative phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  downstream:
  - target: Progressive Myofiber Loss and Fatty Replacement
    causal_link_type: DIRECT
    description: Bioenergetic failure in oxidative fibers precedes their loss.
  evidence:
  - reference: PMID:42323079
    reference_title: Skeletal muscle-specific deficiency of Rab geranylgeranyl transferase beta subunit induces myopathy and exacerbates the symptoms caused by HMG-CoA reductase deficiency in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Hmgcr KO resulted in pronounced myopathy, marked by an early reduction in mitochondria-rich myosin heavy chain (MyHC) type I and IIa muscle fibers, followed by a later reduction in mitochondria-poor glycolytic MyHC type IIb muscle fibers, and these changes were reversed by GGOH administration."
    explanation: Shows the oxidative fibers are lost first and that the loss is isoprenoid-dependent.
  - reference: PMID:39823152
    reference_title: Effects of HMG CoA reductase (HMGCR) deficiency on skeletal muscle development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transcriptome sequencing of Hmgcr knockdown versus control myoblasts revealed differential expression involving mitochondrial function, with corresponding differences in cellular oxygen consumption rates."
    explanation: Independent cell-culture evidence that HMGCR loss changes mitochondrial gene expression and respiration.
- name: Impaired Myoblast Proliferation and Myotube Fusion
  biological_scale: CELLULAR
  description: >-
    HMGCR loss impairs the myogenic program itself, not only the maintenance of mature
    fibers. Knockdown myoblasts proliferate less, die more, and fail to fuse into
    myotubes, and re-expression of wild-type but not variant HMGCR restores fusion. This
    developmental component is a plausible explanation for the congenital and
    neonatal-onset end of the clinical spectrum.
  cell_types:
  - preferred_term: skeletal muscle myoblast
    term:
      id: CL:0000515
      label: skeletal muscle myoblast
  biological_processes:
  - preferred_term: myoblast fusion
    modifier: DECREASED
    term:
      id: GO:0007520
      label: myoblast fusion
  - preferred_term: myoblast proliferation
    modifier: DECREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  - preferred_term: myoblast apoptosis
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  downstream:
  - target: Progressive Myofiber Loss and Fatty Replacement
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired myogenesis limits the regenerative capacity available to offset fiber loss.
  evidence:
  - reference: PMID:39823152
    reference_title: Effects of HMG CoA reductase (HMGCR) deficiency on skeletal muscle development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Hmgcr deficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion."
    explanation: Establishes the three cellular defects that define this node.
  - reference: PMID:39823152
    reference_title: Effects of HMG CoA reductase (HMGCR) deficiency on skeletal muscle development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Overexpression of reference HMGCR cDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants of HMGCR cDNA did not."
    explanation: Rescue-and-failure-to-rescue experiment tying the fusion defect specifically to the patient alleles.
- name: Progressive Myofiber Loss and Fatty Replacement
  biological_scale: TISSUE
  description: >-
    Muscle is lost slowly and replaced by fat, most severely in the proximal and axial
    groups, with distal and facial muscles relatively spared. The tissue signature is the
    point at which this disease diverges from the sarcolemmal LGMD subtypes. Biopsy
    findings range from entirely non-specific myopathic change to nothing at all: the
    founding kindred showed no necrosis, fibrosis or inflammation, and
    immunohistochemistry for dystrophin, the sarcoglycans and dysferlin is normal across
    cohorts. The absence of an inflammatory infiltrate also distinguishes it from
    anti-HMGCR necrotizing myopathy.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  downstream:
  - target: Proximal and Axial Muscle Weakness
    causal_link_type: DIRECT
    description: Loss of contractile tissue in the limb-girdle and axial groups produces the weakness.
  - target: Elevated Serum Creatine Kinase
    causal_link_type: DIRECT
    description: Ongoing myofiber damage releases creatine kinase into the circulation.
  - target: Respiratory Muscle Weakness
    causal_link_type: DIRECT
    description: The same process involves the respiratory musculature, which is the usual cause of death.
  evidence:
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI, computerized tomography (CT), and ultrasound scans showed various levels of atrophy with severe fatty replacement of large proximal skeletal muscles and axial muscles with sparing of the distal and facial muscles"
    explanation: Imaging documents the fatty replacement and its proximal and axial distribution.
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathological evaluation did not reveal any pathological features such as fibrosis or inflammation, with the exception of mild deficiency of type-II muscle fibers in one patient"
    explanation: Establishes the absence of the inflammatory and fibrotic signature expected of a sarcolemmal dystrophy.
  - reference: PMID:37167966
    reference_title: Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsies in most affected individuals showed non-specific dystrophic changes with non-diagnostic immunohistochemistry."
    explanation: The second cohort's biopsy findings, non-specific and with normal immunohistochemistry.
phenotypes:
- name: Proximal and Axial Muscle Weakness
  category: Musculoskeletal
  description: >-
    The cardinal feature. Weakness affects the pelvic and shoulder girdles and the axial
    musculature, with distal and facial muscles relatively spared, and progresses to loss
    of ambulation in most reported individuals.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37167966
    reference_title: Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features resembled other genetic causes of muscular dystrophy with incidental high CPK levels (>1,000 U/L), proximal muscle weakness, variable age of onset, and progression leading to impaired ambulation."
    explanation: Names proximal weakness and progression to impaired ambulation across the defining cohort.
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease initially manifested during the fourth decade of life with pain on exertion, followed by muscle fatigue and weakness, affecting mostly the proximal and axial muscles, and culminating with involvement of respiratory muscles."
    explanation: Documents the proximal and axial distribution and its progression in the founding kindred.
- name: Axial Muscle Weakness
  category: Musculoskeletal
  description: >-
    Neck flexor and trunk weakness accompanies the girdle weakness and underlies the
    spinal deformity seen in several families.
  phenotype_term:
    preferred_term: Axial muscle weakness
    term:
      id: HP:0003327
      label: Axial muscle weakness
  frequency: FREQUENT
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He displayed global muscular hypotrophy, neck muscle weakness, proximal and axial muscle weakness, mildly tense calves, and absent deep tendon reflexes."
    explanation: Direct examination finding of axial and neck weakness in an affected individual.
- name: Elevated Serum Creatine Kinase
  category: Laboratory
  description: >-
    Creatine kinase is markedly raised, commonly above 1,000 U/L and reported as high as
    35,761 U/L, and is frequently the incidental finding that starts the diagnostic
    workup. It falls as muscle mass is lost late in the disease.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blood tests showed muscle injury with elevated creatine kinase (up to over 250-fold upper level of normal CK; maximal CK 35761U/L, patient V:8)"
    explanation: Quantifies the magnitude of CK elevation in the founding kindred.
  - reference: PMID:41344164
    reference_title: "HMGCR-related muscular dystrophy: a case of severe neonatal-onset form."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented with profound hypotonia, respiratory failure by 5 months, and markedly elevated creatine kinase (CK)"
    explanation: Confirms marked CK elevation at the neonatal-onset extreme of the spectrum.
- name: Respiratory Muscle Weakness
  category: Respiratory
  description: >-
    Respiratory involvement is the principal cause of death. It ranges from a restrictive
    ventilatory defect on spirometry to ventilator dependence and tracheostomy, and in the
    neonatal-onset form it is present within months of birth.
  phenotype_term:
    preferred_term: Respiratory insufficiency due to muscle weakness
    term:
      id: HP:0002747
      label: Respiratory insufficiency due to muscle weakness
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients experienced rapid disease progression, leading to severe muscular atrophy, significant mobility decline, and respiratory difficulties necessitating ventilatory support and, eventually, tracheostomy."
    explanation: Documents progression to ventilator dependence in an affected sibship.
  - reference: PMID:41344164
    reference_title: "HMGCR-related muscular dystrophy: a case of severe neonatal-onset form."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented with profound hypotonia, respiratory failure by 5 months, and markedly elevated creatine kinase (CK)"
    explanation: Respiratory failure within the first months of life in the severe neonatal-onset form.
- name: Loss of Ambulation
  category: Musculoskeletal
  description: >-
    Progression to wheelchair dependence and eventually to a bedridden state is the usual
    trajectory, though its timing varies widely and does not track with age of onset.
  phenotype_term:
    preferred_term: Loss of ambulation
    term:
      id: HP:0002505
      label: Loss of ambulation
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had positive Gowers’ sign, severe gait disturbance and had lost ambulation at the age of 9 years."
    explanation: Loss of ambulation documented in an affected child.
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The oldest three patients (V:2,5,12 ages 49, 58, and 51 y, respectively) were wheelchair-bound or bedridden and suffered from respiratory insufficiency"
    explanation: Loss of ambulation in the older affected members of the founding kindred.
- name: Areflexia
  category: Neurologic
  description: >-
    Deep tendon reflexes are absent or reduced in almost every reported individual, which
    is a useful examination pointer in an otherwise non-specific myopathy.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  frequency: FREQUENT
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deep tendon reflexes were reduced in all reported families except family 6."
    explanation: Reports reduced reflexes across the expanded cohort.
- name: Gowers Sign
  category: Musculoskeletal
  description: >-
    Present in the childhood-onset individuals, reflecting proximal lower-limb and axial
    weakness.
  phenotype_term:
    preferred_term: Gowers sign
    term:
      id: HP:0003391
      label: Gowers sign
  frequency: FREQUENT
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At age 2.5 years, muscle weakness was still present with, additionally, a noticeable weakness of neck flexors. The Gowers’ sign was fully positive."
    explanation: Examination finding in an affected child.
- name: Scoliosis
  category: Musculoskeletal
  description: >-
    Thoracolumbar scoliosis and lumbar hyperlordosis follow the axial weakness. These were
    newly recognised in the expanded Middle Eastern cohort and had not been reported in
    the original descriptions.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Scoliosis and/or lumbar lordosis were seen in families 1, 2, 5, and 6 and have not been reported as features in previously reported LGMDR28 patients."
    explanation: Reports scoliosis in four of six families and flags it as a newly described feature.
- name: Calf Muscle Hypertrophy
  category: Musculoskeletal
  description: >-
    Mild calf hypertrophy or pseudohypertrophy is present in some affected individuals and
    absent in others, including within the same cohort.
  phenotype_term:
    preferred_term: Calf muscle hypertrophy
    term:
      id: HP:0008981
      label: Calf muscle hypertrophy
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lumbar lordosis was increased, and mild calf pseudohypertrophy was observed."
    explanation: Documents calf pseudohypertrophy in one affected individual.
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Calf hypertrophy was not observed, and there were no signs of fasciculations nor macroglossia."
    explanation: The same cohort records absence of calf hypertrophy in another affected individual, which is why this is curated as occasional rather than typical.
- name: Motor Delay
  category: Neurologic
  description: >-
    Delayed motor milestones occur in the early-onset individuals. Cognition and speech
    development are reported as normal throughout the published cohorts.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband (Figure 1E, IV.4) was a 6-year-old male who showed delayed motor milestones, hypotonia, and decreased muscle strength."
    explanation: Motor delay with hypotonia in a childhood-onset proband.
- name: Neonatal Hypotonia
  category: Neurologic
  description: >-
    Profound hypotonia from birth defines the severe end of the spectrum, which in the one
    reported neonatal-onset case led to ventilator dependence and death at four months.
  phenotype_term:
    preferred_term: Neonatal hypotonia
    term:
      id: HP:0001319
      label: Neonatal hypotonia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:41344164
    reference_title: "HMGCR-related muscular dystrophy: a case of severe neonatal-onset form."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented with profound hypotonia, respiratory failure by 5 months, and markedly elevated creatine kinase (CK)"
    explanation: The neonatal-onset case report establishing this presentation.
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was admitted to the hospital due to significant hypotonia, severe congenital myopathy, and respiratory distress, which necessitated his reliance on a ventilator for adequate breathing support."
    explanation: A second, independent congenital-onset infant with hypotonia and ventilator dependence.
- name: Cirrhosis
  category: Gastrointestinal
  description: >-
    Progressive cirrhosis requiring consideration of transplantation occurred in two
    siblings of one family in the expanded cohort. This is the least settled feature of the
    disease: transaminase elevation in LGMD usually reflects muscle rather than liver
    injury, and hepatic involvement of this severity has been reported in only this one
    family.
  phenotype_term:
    preferred_term: Cirrhosis
    term:
      id: HP:0001394
      label: Cirrhosis
    clinical_course: PROGRESSIVE
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, both patients in Family 3 demonstrated bona fide hepatic involvement, a feature not observed in the other patients."
    explanation: Records genuine hepatic involvement in one family and its absence elsewhere in the cohort.
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She also suffers from progressive liver cirrhosis, which has necessitated consideration for a liver transplant."
    explanation: Clinical detail of the cirrhosis in the index sibling.
- name: Exercise-Induced Myalgia
  category: Musculoskeletal
  description: >-
    Pain on exertion is often the first symptom in the adult-onset form, preceding
    measurable weakness, and is reported in every patient of the founding kindred.
  phenotype_term:
    preferred_term: Exercise-induced myalgia
    term:
      id: HP:0003738
      label: Exercise-induced myalgia
  frequency: FREQUENT
  evidence:
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease initially manifested during the fourth decade of life with pain on exertion, followed by muscle fatigue and weakness, affecting mostly the proximal and axial muscles, and culminating with involvement of respiratory muscles."
    explanation: Exertional pain is named as the initial manifestation in the founding kindred.
- name: Subclinical Cardiac Involvement
  category: Cardiovascular
  description: >-
    No reported patient has had a clinical cardiomyopathy, and echocardiography has been
    normal where performed. The heart is nonetheless not untouched: in the founding
    kindred troponin T was slightly raised in the four patients tested and two had ECG
    conduction abnormalities. Whether this reflects true myocardial involvement or leakage
    of a shared muscle protein from damaged skeletal muscle is not resolved, which is why
    it is curated as a subclinical finding rather than as cardiomyopathy.
  phenotype_term:
    preferred_term: Increased circulating troponin T concentration
    term:
      id: HP:0410174
      label: Increased circulating troponin T concentration
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were no clear signs of cardiomyopathy, although four patients showed slightly elevated troponin T levels, and two demonstrated conduction abnormalities in ECG"
    explanation: >-
      Records both halves of the finding, that overt cardiomyopathy is absent and that
      subclinical biochemical and electrocardiographic abnormalities are nonetheless present.
- name: EMG Myopathic Abnormalities
  category: Neurologic
  description: >-
    Needle electromyography shows a myopathic pattern with normal nerve conduction
    studies, placing the lesion in muscle rather than nerve.
  phenotype_term:
    preferred_term: "EMG: myopathic abnormalities"
    term:
      id: HP:0003458
      label: "EMG: myopathic abnormalities"
  frequency: FREQUENT
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nerve conduction studies (NCS) were normal, and needle electromyography (EMG) revealed myopathic changes in the proximal muscles."
    explanation: Electrophysiology localising the process to proximal muscle.
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EMG studies of four patients showed a myopathic pattern, and motor nerve conduction velocity (NCV) demonstrated normal distal latencies, amplitudes, and velocities."
    explanation: The same electrophysiological pattern in the founding kindred.
histopathology:
- name: Non-specific myopathic change with normal muscular dystrophy immunohistochemistry
  description: >-
    The biopsy is characteristically unhelpful, which is itself diagnostically
    informative. Findings range from non-specific dystrophic or myopathic change to a
    biopsy that is essentially normal, with no necrosis, fibrosis or inflammatory
    infiltrate in the founding kindred. Immunostaining for dystrophin, the sarcoglycans
    and dysferlin is normal, so the structural LGMD subtypes are excluded on the biopsy
    without this one being identified by it.
  notes: >-
    Deliberately incomplete, and the gap is in the sources rather than in the disease.
    HPO curates finer biopsy findings for this disease from the discovery cohort
    (PMID:37167966): type 1 fiber predominance 4/4, centrally nucleated fibers 3/3,
    increased endomysial connective tissue 2/3, increased intramyocellular lipid droplets
    1/3, and reduced muscle fiber alpha-dystroglycan 1/1. Those come from that paper's
    full text and supplement; `references_cache/PMID_37167966.md` is abstract-only, whose
    only histological statement is the "non-specific dystrophic changes" quoted below. The
    findings are therefore recorded here as a pointer rather than curated as evidence
    items, because no exact quote supporting them is available in the cache. A curator
    with full-text access should add them. Note in particular that "non-specific" in the
    abstract should not be read as "normal": the founding kindred's near-normal biopsy
    (PMID:36745799) is the exception rather than the rule.
  evidence:
  - reference: PMID:37167966
    reference_title: Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsies in most affected individuals showed non-specific dystrophic changes with non-diagnostic immunohistochemistry."
    explanation: Describes the non-specific biopsy and non-diagnostic immunohistochemistry across the defining cohort.
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main immunostainings (against dystrophin, sarcoglycans and dysferlin) were reported as normal."
    explanation: Names the specific structural proteins whose normal staining excludes the sarcolemmal subtypes.
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathological evaluation did not reveal any pathological features such as fibrosis or inflammation, with the exception of mild deficiency of type-II muscle fibers in one patient"
    explanation: The founding kindred's biopsies, notable for the absence of the usual dystrophic features.
genetic:
- name: HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase)
  gene_term:
    preferred_term: HMGCR
    term:
      id: hgnc:5006
      label: HMGCR
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    The only gene associated with this disease, and the only gene MONDO links to it by
    `RO:0004003`. Reported disease alleles are missense or in-frame and cluster in the
    catalytic domain; a homozygous null has never been reported in a living patient, which
    fits the embryonic lethality of the complete mouse knockout. ClinGen currently grades
    the gene-disease relationship as moderate.
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, all reported variants are missense or in-frame, except for a splicing variant whose consequences are not clarified."
    explanation: Characterises the allelic spectrum as hypomorphic rather than null.
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the gene-disease relationship is categorized as moderate by the ClinGen expert panel"
    explanation: Expert-panel gene-disease validity classification, quoted rather than asserted.
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Filtering through whole-exome sequencing data of patients V:13 and V:2 (Methods), only a single variant was found within the 3.2 Mbp locus"
    explanation: >-
      Linkage plus exome in the founding kindred leaves exactly one candidate in the
      disease interval, which is the argument against a second causal gene at this locus.
variants:
- name: NM_000859.3:c.2465G>A p.(Gly822Asp)
  description: >-
    The founding allele, homozygous in six affected members of a consanguineous Bedouin
    kindred from the Negev with fourth-decade-onset disease. Enzymologically the best
    characterised of the disease alleles: it leaves the protein correctly localised while
    reducing turnover and substrate affinity.
  gene:
    preferred_term: HMGCR
    term:
      id: hgnc:5006
      label: HMGCR
  type: missense variant
  clinical_significance: PATHOGENIC
  functional_effects:
  - function: HMG-CoA reductase catalytic activity
    type: partial loss of function
    description: >-
      Reduces Vmax by 69% and raises Km for HMG-CoA by 65%, with a catalytic pocket that
      no longer binds pravastatin, while subcellular localisation is unchanged.
  evidence:
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "only a single variant was found within the 3.2 Mbp locus: g.5:75359992G>A (GRCh38/hg38); NM_000859.3:c.2465G>A; p.(G822D) in HMGCR"
    explanation: Identifies the allele by linkage and exome sequencing in the founding kindred.
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both WT and mutant HMGCR protein (green) are located in clusters in the cytoplasm with some relation to the endoplasmic reticulum (red)."
    explanation: Shows the allele does not mislocalise the protein, which is why it is classified as a catalytic rather than a trafficking defect.
- name: NM_000859.2:c.2519G>A p.(Arg840Gln)
  description: >-
    A recurrent ultra-rare allele found homozygous in three of the six Middle Eastern
    families, spanning onset from birth to fourteen years within the same genotype. It sits
    in the Lalpha10 helix of the catalytic L domain and is notable for being missed by in
    silico predictors, which is why it went unrecognised in earlier sequencing analyses.
  gene:
    preferred_term: HMGCR
    term:
      id: hgnc:5006
      label: HMGCR
  type: missense variant
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In three unrelated families (1–3), the probands were found to carry a novel homozygous missense variant, c.2519G>A p.(Arg840Gln)."
    explanation: Establishes the allele and its recurrence across three families.
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although this missense variant is not predicted to be disease-causing by in silico tools, it shows segregation in three unrelated families with shared clinical features."
    explanation: Records the discordance between prediction and segregation that makes this allele a re-analysis lesson.
- name: p.(Arg641Cys)
  description: >-
    The allele of the single reported neonatal-onset, early-lethal case. It is the only
    disease allele for which a homozygous knock-in mouse has been made, and that mouse dies
    in utero.
  gene:
    preferred_term: HMGCR
    term:
      id: hgnc:5006
      label: HMGCR
  type: missense variant
  clinical_significance: PATHOGENIC
  functional_effects:
  - function: HMG-CoA reductase catalytic activity
    type: loss of function
    description: Severely impaired enzymatic activity on in vitro assay.
  evidence:
  - reference: PMID:41344164
    reference_title: "HMGCR-related muscular dystrophy: a case of severe neonatal-onset form."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient, homozygous for the p.Arg641Cys variant in HMGCR, presented with profound hypotonia, respiratory failure by 5 months, and markedly elevated creatine kinase (CK)."
    explanation: Establishes the allele and its severe clinical consequence.
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Twenty-eight affected individuals from fourteen unrelated families had been reported by
    2026: seventeen from eight families before the expanded cohort, plus eleven from six
    Middle Eastern families in it. No population prevalence estimate exists for LGMDR28
    specifically, and none is asserted here. The commonly quoted figure of about 1 in
    61,000 is for limb-girdle muscular dystrophy as a whole across roughly 39 subtypes, so
    it is not a rate for this one and is deliberately not recorded as a numeric band.
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, 17 affected individuals from eight unrelated families have been reported to harbor biallelic variants in the HMGCR gene."
    explanation: The published case count prior to the expanded cohort.
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report eleven individuals from six unrelated Middle Eastern families diagnosed with LGMDR28 and carrying homozygous variants in HMGCR."
    explanation: The additional cases that bring the published total to twenty-eight.
progression:
- phase: Onset
  age_range: birth to fourth decade
  notes: >-
    Age of onset spans birth to the fourth decade. Severity and rate of progression do not
    correlate with how early the disease starts, and both inter- and intrafamilial
    variability are marked, including among carriers of the same homozygous allele.
    Presentation is commonly an incidental creatine kinase elevation rather than a
    complaint of weakness.
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is important to note that early (even as early as neonatal) onset does not seem to correlate with severity of progression based on our cohort and this agrees with previous reports."
    explanation: States explicitly that onset age does not predict severity.
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age of onset ranges from birth in the case of family 3 to as late as 14 years in family 1."
    explanation: Documents the onset range within a single recurrent genotype.
- phase: Progression to loss of ambulation and respiratory failure
  notes: >-
    Weakness advances to wheelchair dependence, then in the severe cases to a bedridden
    state with joint contractures, restrictive respiratory failure, nocturnal or
    continuous ventilation and tracheostomy. Deaths in the published cohorts have been
    from respiratory failure. Creatine kinase falls back towards and below normal late in
    the disease as muscle mass is lost, which can mislead if it is the only marker
    followed.
  evidence:
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With disease progression and muscular atrophy, CK levels gradually normalized and eventually even dropped beneath normal limits, alongside a simultaneous drop in creatinine levels, consistent with low skeletal muscle mass"
    explanation: Documents the late fall in creatine kinase as muscle mass is lost.
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients experienced rapid disease progression, leading to severe muscular atrophy, significant mobility decline, and respiratory difficulties necessitating ventilatory support and, eventually, tracheostomy."
    explanation: The progression trajectory in the most severely affected reported sibship.
diagnosis:
- name: Molecular diagnosis by exome or genome sequencing
  description: >-
    The diagnosis is molecular. Targeted neuromuscular gene panels have repeatedly been
    negative in these patients, both because HMGCR was not on older panels and because at
    least one recurrent allele is not flagged by in silico predictors, so exome or genome
    sequencing with periodic reanalysis is what makes the diagnosis.
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The c.2519G>A variant that we describe here is not predicted strongly to be deleterious by most in silico tools and was overlooked in the analysis of NGS data."
    explanation: Explains why sequencing must be reanalysed rather than trusted on first pass.
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on the initial clinical suspicion of limb-girdle muscular dystrophy, we conducted sequence analysis and deletion/duplication testing of the 117 genes present in the Neuromuscular Disorders Panel which turned out to be inconclusive."
    explanation: Documents the failure of a large targeted panel in a patient who was subsequently diagnosed.
- name: Hepatic monitoring
  description: >-
    Following the recognition of true hepatic involvement in one family, a liver panel
    beyond transaminases is recommended alongside creatine kinase, because transaminase
    elevation in a myopathy is otherwise readily attributed to muscle injury.
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we recommend monitoring not only CPK but also a broader liver panel (bilirubin, GGT, alkaline phosphatase, albumin, and INR), with further hepatology evaluation and imaging as indicated"
    explanation: The published monitoring recommendation this item records.
treatments:
- name: Oral Mevalonolactone
  description: >-
    Metabolite replacement directed at the missing pathway product. Mevalonolactone is not
    an available pharmaceutical preparation and was synthesised and purified for the
    purpose, then given under an expanded-access authorisation to the single most severely
    affected patient of the founding kindred, who gained strength on dynamometry and
    manual testing and improved substantially on spirometry. The evidence is one patient
    treated openly without a control, so this is a promising directed therapy rather than
    an established one.
  notes: >-
    Two deliberate restraints. The CHEBI binding is to the stereochemically unspecified
    `CHEBI:194429 mevalonolactone` rather than to `CHEBI:67849 (R)-mevalonolactone`,
    because the paper states only that the compound was produced by batch fermentation and
    purified to over 94% and never names the enantiomer; binding the (R) form would assert
    a fact the source does not give. Second, the paper's discussion says "Further large
    clinical trials are in place", but no registry identifier is published with it. A
    ClinicalTrials.gov API query for "mevalonolactone" and for "HMGCR muscular dystrophy"
    returned zero studies each on 2026-08-31, and `just ictrp-fetch` takes a trial
    identifier rather than a search term, so no WHO ICTRP record could be looked up
    either. No `clinical_trials` entry is therefore curated: this records that the trial
    could not be located, not that none exists.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mevalonolactone
      term:
        id: CHEBI:194429
        label: mevalonolactone
  target_mechanisms:
  - target: Mevalonate Pathway Flux Reduction
    description: >-
      Supplies the pathway product downstream of the defective enzymatic step, bypassing
      the reduced catalytic capacity rather than correcting it.
    evidence:
    - reference: PMID:36745799
      reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mevalonolactone oral uptake was found to be very rapid: the mevalonate levels began to rise 20 min after oral administration, peaked at 50 min, and returned to baseline levels 2 h after ingestion"
      explanation: Demonstrates that oral dosing raises circulating mevalonate, which is the mechanism the treatment is meant to act through.
  evidence:
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During treatment, there was improvement in muscle strength as assessed by dynamometry and by manual muscle testing (MMT) performed by an experienced neurologist"
    explanation: The objective strength benefit in the treated patient.
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Respiratory muscles were assessed by spirometry, which demonstrated marked increase in peak expiratory flow (+265%; from 6 to 22% of predicted value), forced vital capacity (+342%; from 17.4 to 77.6% of predicted value), and FEV1 (+345%, from 10.7 to 48.1% of predicted value, Fig. 4M)."
    explanation: Quantifies the respiratory benefit, which is the outcome that matters most given respiratory failure is the usual cause of death.
  - reference: PMID:26381177
    reference_title: "Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Myopathy in knockout mice was completely rescued by the oral administration of MVA."
    explanation: The preclinical rescue in muscle-specific Hmgcr-knockout mice that motivated the human trial.
- name: Non-invasive and invasive ventilatory support
  description: >-
    Respiratory muscle weakness is managed with nocturnal non-invasive ventilation
    progressing to continuous ventilation and tracheostomy. This is the supportive measure
    that determines survival, since respiratory failure is the reported cause of death.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: mechanical ventilation
    term:
      id: NCIT:C70909
      label: Mechanical Ventilation
  target_mechanisms:
  - target: Respiratory Muscle Weakness
    description: >-
      Substitutes for the failing respiratory musculature; it does not modify the
      underlying myopathy.
    evidence:
    - reference: PMID:41904993
      reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The chest was rigid, and forced vital capacity was estimated at less than 50% of the predicted value, thus requiring nocturnal invasive ventilation."
      explanation: Ties the ventilatory support directly to the measured respiratory muscle failure it is given for.
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients experienced rapid disease progression, leading to severe muscular atrophy, significant mobility decline, and respiratory difficulties necessitating ventilatory support and, eventually, tracheostomy."
    explanation: Documents the use of ventilatory support and tracheostomy in affected individuals.
- name: Occupational and physical therapy
  description: >-
    Rehabilitation to maintain gait and function. Reported benefit is anecdotal, in one
    individual whose gait improved over time on occupational therapy.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: occupational therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  target_mechanisms:
  - target: Loss of Ambulation
    description: Aims to preserve ambulation and functional independence against the progressive weakness.
    evidence:
    - reference: PMID:41904993
      reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Through occupational therapy, her walking and gait have shown improvement over time."
      explanation: The single reported observation of functional gain from rehabilitation in this disease.
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through occupational therapy, her walking and gait have shown improvement over time."
    explanation: Records the observed benefit that motivates offering rehabilitation.
differential_diagnoses:
- name: Statin-associated muscle symptoms and statin myopathy
  disease_term:
    preferred_term: drug-induced myopathy
    term:
      id: MONDO:0100637
      label: drug-induced myopathy
  description: >-
    The same enzyme, inhibited pharmacologically instead of mutated. The overlap is not
    superficial: proximal weakness, raised creatine kinase, an unremarkable biopsy and
    end-stage imaging with fatty replacement are shared, and the founding LGMDR28 report
    describes its own patients as phenotypically resembling severe statin myopathy. The
    entities are nonetheless distinct in cause, and MONDO defines drug-induced myopathy by
    an exposure relation rather than a germline gene relation.
  distinguishing_features:
  - "Cause is a biallelic germline HMGCR genotype rather than exposure to a drug; there is no statin exposure in the LGMDR28 families, including in utero."
  - "Onset in statin myopathy is relatively acute and follows the start of the drug, whereas LGMDR28 is insidious and lifelong; withdrawal of a statin has no counterpart in the genetic disease."
  - "LGMDR28 is inherited in a Mendelian recessive pattern with unaffected heterozygous parents; statin myopathy is not inherited."
  - "One caveat cuts the other way, in that chronic or subacute severe statin myopathy has been described and can mimic limb-girdle muscular dystrophy, so drug history rather than phenotype is the discriminator."
  evidence:
  - reference: PMID:39823152
    reference_title: Effects of HMG CoA reductase (HMGCR) deficiency on skeletal muscle development.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The two other muscle diseases associated with HMGCR, statin-associated myopathy (SAM) and autoimmune anti-HMGCR myopathy, are not inherited in a Mendelian pattern."
    explanation: States the nosological boundary this differential draws, that only LGMDR28 among the three is Mendelian.
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One major difference between SAMS and the hereditary HMGCR disease is the relatively acute onset of SAMS compared with the insidious presentation of muscle symptoms in the HMGCR-limb girdle muscle disease."
    explanation: Names the tempo difference that separates the two clinically.
- name: Anti-HMGCR immune-mediated necrotizing myopathy
  disease_term:
    preferred_term: immune-mediated necrotizing myopathy
    term:
      id: MONDO:0016098
      label: immune-mediated necrotizing myopathy
  description: >-
    An autoantibody disease directed against the same protein, and the differential most
    likely to be mistaken for this one, because it is repeatedly reported as presenting
    like a limb-girdle muscular dystrophy in both adults and children. The distinction is
    consequential rather than academic: anti-HMGCR myopathy responds to immunosuppression,
    and LGMDR28 has no reason to.
  distinguishing_features:
  - "Anti-HMGCR autoantibodies are present by definition in the autoimmune disease and were explicitly absent in all six patients of the founding LGMDR28 kindred."
  - "Biopsy in anti-HMGCR myopathy shows myocyte necrosis and regeneration; the LGMDR28 biopsy shows non-specific change or nothing, without necrosis or inflammation."
  - "Anti-HMGCR myopathy is acquired and typically acute or subacute; LGMDR28 is a Mendelian recessive disease with unaffected heterozygous parents."
  - "Immunosuppressive therapy is the treatment of the autoimmune disease and has no rationale in the genetic one, where metabolite replacement is the directed approach."
  evidence:
  - reference: PMID:36745799
    reference_title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a notable finding was the lack of anti-HMGCR antibodies in any of the patients"
    explanation: The direct serological test that separates the founding LGMDR28 kindred from the autoantibody disease.
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The presence of anti-HMGCR enzyme antibodies has been found to result in auto-immune necrotizing myopathy, a disease mimicking muscular dystrophy in adults but also in a growing number of children."
    explanation: Records that the autoimmune disease mimics muscular dystrophy across ages, which is what makes it the key differential.
- name: Sarcolemmal autosomal recessive limb-girdle muscular dystrophy subtypes
  disease_term:
    preferred_term: autosomal recessive limb-girdle muscular dystrophy
    term:
      id: MONDO:0015152
      label: autosomal recessive limb-girdle muscular dystrophy
  description: >-
    The rest of the LGMD-R group, curated in
    `kb/disorders/Autosomal_Recessive_Limb-Girdle_Muscular_Dystrophy.yaml`, whose shared
    mechanism is sarcolemmal fragility and failed membrane repair. LGMDR28 is a MONDO
    child of this term and shares its clinical syndrome, but not its mechanism, which is
    why it is curated as its own entry rather than folded into that one.
  distinguishing_features:
  - "Immunohistochemistry for dystrophin, the sarcoglycans and dysferlin is normal in LGMDR28, whereas the sarcoglycanopathies and dysferlinopathy show loss of the corresponding protein."
  - "The LGMDR28 biopsy lacks the necrosis, inflammation and fibrofatty replacement that characterise the membrane-repair subtypes."
  - "Creatine kinase elevation in LGMDR28 is at the high end even for this group, reported up to 250-fold the upper limit of normal."
  - "Clinical cardiomyopathy, which occurs in several sarcolemmal subtypes, has not been reported in LGMDR28, although subclinical troponin T elevation and ECG conduction changes were found in the founding kindred."
  - "LGMDR28 has a directed metabolite-replacement candidate; the sarcolemmal subtypes have supportive care and gene-directed trials."
  evidence:
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the patients had any cardiac involvement, as was the case in previous reports."
    explanation: The consistent absence of cardiac disease, which is a point of separation from several sarcolemmal subtypes.
  - reference: PMID:41904993
    reference_title: Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main immunostainings (against dystrophin, sarcoglycans and dysferlin) were reported as normal."
    explanation: Normal staining for the structural proteins whose loss defines the sarcolemmal subtypes.
animal_models:
- name: Skeletal muscle-specific Hmgcr knockout mouse
  species: Mouse
  genotype: Skeletal muscle-specific Hmgcr conditional knockout
  publication: PMID:26381177
  description: >-
    A muscle-restricted biallelic Hmgcr null. Its authors built it and describe it as a
    model of statin myopathy, because that was their question, but the genotype is a
    genetic loss of HMGCR confined to muscle, which makes it the closest available animal
    model of LGMDR28 rather than of drug exposure. The mice develop postnatal myopathy
    with raised creatine kinase, and oral mevalonate rescues them completely, which is the
    result that motivated treating a human patient with mevalonolactone.
  modeled_mechanisms:
  - target: Progressive Myofiber Loss and Fatty Replacement
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces myopathy with elevated creatine kinase arising specifically from loss of
      HMGCR in muscle, establishing that the muscle phenotype is muscle-autonomous rather
      than secondary to hepatic or systemic cholesterol handling.
    limitations: >-
      The knockout is a complete null restricted to skeletal muscle, whereas patients carry
      hypomorphic missense alleles expressed in every tissue, so the model overstates the
      enzymatic deficit while understating its tissue distribution. The mice develop
      necrosis and rhabdomyolysis, which patient biopsies characteristically do not show,
      and the tempo is postnatal and rapid rather than the years-to-decades human course.
      The paper frames the model as one of statin myopathy, so its reported comparisons are
      to drug exposure rather than to LGMDR28.
    readouts:
    - name: Serum creatine kinase
      target: Progressive Myofiber Loss and Fatty Replacement
      direction: INCREASED
      interpretation: Circulating marker of myofiber damage, matching the cardinal laboratory abnormality in patients.
      evidence:
      - reference: PMID:26381177
        reference_title: "Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Knockout mice exhibited postnatal myopathy with elevated serum creatine kinase levels and necrosis."
        explanation: Reports the creatine kinase measurement behind this readout.
    - name: Myopathy after oral mevalonate supplementation
      target: Progressive Myofiber Loss and Fatty Replacement
      direction: RESTORED
      interpretation: >-
        Complete rescue by the pathway product establishes that the myopathy follows from
        metabolite deficiency rather than from any structural role of the enzyme.
      evidence:
      - reference: PMID:26381177
        reference_title: "Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Myopathy in knockout mice was completely rescued by the oral administration of MVA."
        explanation: Reports the rescue experiment behind this readout.
    evidence:
    - reference: PMID:26381177
      reference_title: "Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we developed the skeletal muscle-specific HMGCR knockout mice"
      explanation: Establishes the genotype that makes this model informative for muscle-autonomous HMGCR loss.
- name: Doxycycline-inducible skeletal muscle-specific Hmgcr knockout mouse (Hmgcr-DimKO)
  species: Mouse
  genotype: Doxycycline-inducible skeletal muscle-specific Hmgcr knockout
  publication: PMID:42323079
  description: >-
    An inducible version of the muscle-specific null, built alongside Rabggtb single and
    double knockouts to ask which downstream branch of the mevalonate pathway carries the
    myopathy. It is the source of the isoprenoid-rather-than-sterol mechanism in this
    entry: the fiber-type loss is reversed by geranylgeraniol, and mitochondrial
    dysfunction appears before any weakness.
  modeled_mechanisms:
  - target: Isoprenoid Depletion and Impaired Protein Geranylgeranylation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Establishes geranylgeranyl pyrophosphate depletion as the branch of the pathway whose
      loss produces myopathy, by rescuing with its precursor and by phenocopying and
      aggravating with a Rab geranylgeranyltransferase knockout.
    limitations: >-
      This is a mouse null rather than a human hypomorph, and inducible deletion in adult
      muscle does not reproduce the lifelong partial deficiency patients carry. No
      prenylation or isoprenoid measurement has been made in an LGMDR28 patient, so the
      mechanism is imported from the model rather than confirmed in the disease. As with
      the constitutive knockout, the paper's stated target is statin myopathy.
    readouts:
    - name: Oxidative (MyHC type I and IIa) fiber content after geranylgeraniol
      target: Isoprenoid Depletion and Impaired Protein Geranylgeranylation
      direction: RESTORED
      interpretation: Rescue by the isoprenoid precursor localises the causal deficit to the geranylgeranyl branch.
      evidence:
      - reference: PMID:42323079
        reference_title: Skeletal muscle-specific deficiency of Rab geranylgeranyl transferase beta subunit induces myopathy and exacerbates the symptoms caused by HMG-CoA reductase deficiency in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Hmgcr KO resulted in pronounced myopathy, marked by an early reduction in mitochondria-rich myosin heavy chain (MyHC) type I and IIa muscle fibers, followed by a later reduction in mitochondria-poor glycolytic MyHC type IIb muscle fibers, and these changes were reversed by GGOH administration."
        explanation: Reports the fiber-type measurement and its reversal by geranylgeraniol.
    evidence:
    - reference: PMID:42323079
      reference_title: Skeletal muscle-specific deficiency of Rab geranylgeranyl transferase beta subunit induces myopathy and exacerbates the symptoms caused by HMG-CoA reductase deficiency in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Using doxycycline-inducible Cre-LoxP technology, we generated three skeletal muscle-specific knockout (KO) models: Hmgcr-DimKO, Rabggtb-DimKO, and combined Hmgcr/Rabggtb-DimKO mice."
      explanation: Establishes the genotypes that make this model informative for the isoprenoid branch.
  - target: Myofiber Mitochondrial Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Mitochondrial abnormalities are detectable before clinical myopathy in every genotype
      tested, which is the temporal argument that the mitochondrial defect is upstream of
      fiber loss rather than a consequence of it.
    limitations: >-
      Temporal precedence in an inducible mouse null is suggestive of causation but does
      not establish it, and the corresponding measurement has not been made in patient
      muscle. The acute deletion tempo is unlike the human disease.
    readouts:
    - name: Mitochondrial mass and function
      target: Myofiber Mitochondrial Dysfunction
      direction: DECREASED
      interpretation: Quantified mitochondrial deficit appearing before weakness in the knockout muscle.
      evidence:
      - reference: PMID:42323079
        reference_title: Skeletal muscle-specific deficiency of Rab geranylgeranyl transferase beta subunit induces myopathy and exacerbates the symptoms caused by HMG-CoA reductase deficiency in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Mitochondrial mass and function were rigorously quantified."
        explanation: Names the readout measured; its timing relative to weakness is quoted on the link evidence.
    evidence:
    - reference: PMID:42323079
      reference_title: Skeletal muscle-specific deficiency of Rab geranylgeranyl transferase beta subunit induces myopathy and exacerbates the symptoms caused by HMG-CoA reductase deficiency in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Early mitochondrial abnormalities may contribute to the pathogenesis of myopathy due to disruption of the mevalonate pathway."
      explanation: The authors' own statement placing the mitochondrial defect in the pathogenic sequence.
- name: HMGCR p.Arg641Cys homozygous knock-in mouse
  species: Mouse
  genotype: Hmgcr p.Arg641Cys homozygous knock-in
  publication: PMID:41344164
  description: >-
    A knock-in of the human neonatal-onset allele. It does not model the disease, because
    homozygous animals die in utero rather than developing a muscular dystrophy. That is
    an informative negative: it shows the allele is severe enough to breach the threshold
    for embryonic viability in mouse, while the human homozygote survived to four months,
    and it means the most obvious way to build a mouse model of LGMDR28 does not work.
  modeled_mechanisms:
  - target: Progressive Myofiber Loss and Fatty Replacement
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Homozygous knock-in animals die as embryos and therefore never develop the postnatal
      progressive myopathy that defines the human disease.
    limitations: >-
      Embryonic lethality precludes any muscle phenotyping at all, so the model yields no
      readout of weakness, creatine kinase, histology or treatment response. The species
      difference is the substantive limitation: mouse appears less tolerant of this allele
      than human, since the corresponding human homozygote was liveborn and survived four
      months. Nothing about the human muscular dystrophy can be inferred from this model.
    evidence:
    - reference: PMID:41344164
      reference_title: "HMGCR-related muscular dystrophy: a case of severe neonatal-onset form."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "in vivo modeling using homozygous knock-in mice resulted in embryonic lethality"
      explanation: Reports the embryonic lethality that constitutes the failure to recapitulate.
- name: hmgcr knockdown Drosophila
  species: Drosophila melanogaster
  genotype: RNAi knockdown of hmgcr, ubiquitous and muscle-specific drivers
  publication: PMID:39823152
  description: >-
    The invertebrate arm of the same study that produced the myoblast data. Both
    ubiquitous and muscle-restricted knockdown of the fly HMGCR orthologue are lethal, so
    like every available mouse the fly cannot be carried to a state resembling the human
    muscular dystrophy. It contributes the conserved requirement for the enzyme in muscle
    rather than a phenotype.
  modeled_mechanisms:
  - target: Progressive Myofiber Loss and Fatty Replacement
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Knockdown is lethal rather than myopathic, so no progressive proximal weakness,
      creatine kinase elevation or biopsy phenotype can be observed.
    limitations: >-
      Lethality precludes any muscle phenotyping, so the model yields no readout that maps
      onto the human disease. Knockdown severity is also not comparable to the partial
      loss of function patients carry, and the phylogenetic distance means the result
      establishes only that the enzyme is required in muscle, not how a hypomorphic human
      allele produces a slowly progressive dystrophy.
    evidence:
    - reference: PMID:39823152
      reference_title: Effects of HMG CoA reductase (HMGCR) deficiency on skeletal muscle development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Both ubiquitous and muscle-specific knockdown of hmgcr in Drosophila led to lethality."
      explanation: Reports the lethality that constitutes the failure to recapitulate.
experimental_models:
- name: Hmgcr knockdown C2C12 myoblast line with variant complementation
  experimental_model_type: CELL_LINE
  description: >-
    C2C12 mouse myoblasts, the standard immortalised myogenic line, with Hmgcr knocked
    down by shRNA to about 60% of control transcript. Used both to characterise the
    cellular phenotype of HMGCR loss and, by re-expressing wild-type versus patient
    HMGCR cDNA, to test whether specific disease alleles are functional. It is the system
    that connects the enzymatic defect to a myogenic one.
  modeled_mechanisms:
  - target: Impaired Myoblast Proliferation and Myotube Fusion
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the proliferation, survival and fusion defects attributable to HMGCR loss,
      and shows that three patient alleles cannot rescue them while the reference sequence
      can.
    limitations: >-
      Knockdown rather than the biallelic hypomorphic genotype patients carry, in mouse
      rather than human cells, and in proliferating myoblasts rather than mature
      innervated muscle. A fusion defect in culture is a developmental readout, whereas
      most patients present after normal early motor development, so the correspondence to
      the adult-onset end of the spectrum is uncertain.
    readouts:
    - name: Myotube fusion after complementation with reference or variant HMGCR cDNA
      target: Impaired Myoblast Proliferation and Myotube Fusion
      direction: RESTORED
      interpretation: >-
        Reference cDNA restores fusion and the patient alleles do not, which is the
        functional demonstration that those alleles are loss-of-function in a muscle cell.
      evidence:
      - reference: PMID:39823152
        reference_title: Effects of HMG CoA reductase (HMGCR) deficiency on skeletal muscle development.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Overexpression of reference HMGCR cDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants of HMGCR cDNA did not."
        explanation: Reports the complementation result behind this readout.
    evidence:
    - reference: PMID:39823152
      reference_title: Effects of HMG CoA reductase (HMGCR) deficiency on skeletal muscle development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Hmgcr deficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion."
      explanation: Establishes that the cellular phenotype this model reports is the one the node describes.
discussions:
- discussion_id: isoprenoid_versus_sterol_branch
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which branch of the mevalonate pathway is depleted in LGMDR28 patient muscle, and does
    the isoprenoid mechanism established in mice hold in humans?
  attaches_to:
  - pathophysiology#Isoprenoid Depletion and Impaired Protein Geranylgeranylation
  rationale: >-
    The case that the myopathy is an isoprenoid rather than a sterol problem rests entirely
    on mouse work: geranylgeraniol rescue of the muscle-specific knockout, and the
    aggravating effect of a Rab geranylgeranyltransferase knockout. On the human side, all
    that exists is a single patient's circulating mevalonolactone level and the observation
    that patient cholesterol is low but normal. No measurement of geranylgeranyl
    pyrophosphate, of protein prenylation, or of coenzyme Q10 has been reported in
    LGMDR28 muscle or serum. The distinction is not academic: if the deficit is isoprenoid,
    geranylgeraniol is a candidate therapy that would not require synthesising
    mevalonolactone, and if it is sterol, neither would help.
  proposed_experiments:
  - experiment_id: lgmdr28_isoprenoid_profiling
    name: Isoprenoid and prenylation profiling of LGMDR28 patient muscle
    description: >-
      Measure geranylgeranyl pyrophosphate, farnesyl pyrophosphate, coenzyme Q10 and
      Rab protein prenylation status in muscle biopsy tissue from genotyped LGMDR28
      patients against age-matched controls, and compare with the profile of the
      muscle-specific knockout mouse.
    would_support:
    - pathophysiology#Isoprenoid Depletion and Impaired Protein Geranylgeranylation
    supporting_outcome:
    - >-
      Reduced geranylgeranyl pyrophosphate and reduced Rab prenylation in patient muscle,
      with sterol content comparatively preserved.
    refuting_outcome:
    - >-
      Normal isoprenoid pools and normal prenylation in patient muscle, which would move
      the mechanism to a different branch and undercut the geranylgeraniol therapeutic
      rationale.
- discussion_id: mouse_intolerance_of_hmgcr_loss
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Why does the mouse tolerate loss of HMGCR so much less well than the human, and does
    any mouse model reproduce the slowly progressive human muscular dystrophy?
  attaches_to:
  - animal_models#Mouse
  - pathophysiology#Progressive Myofiber Loss and Fatty Replacement
  rationale: >-
    Every available model is either lethal or too severe. The complete mouse knockout dies
    prenatally, the knock-in of the human p.Arg641Cys allele dies as an embryo even though
    the corresponding human homozygote was liveborn, knockdown of the orthologue in
    Drosophila is lethal both ubiquitously and in muscle alone, and the muscle-specific
    mouse nulls develop rapid postnatal myopathy with necrosis and rhabdomyolysis. The
    pattern across two phyla is that anything approaching a null is unviable, which is
    itself the argument that the human alleles must be hypomorphic. Patients, by contrast, most
    often have decades of normal function, an unremarkable biopsy without necrosis, and a
    course measured in years. So the models that exist are informative about which pathway
    branch matters and useless for the natural history, the biopsy phenotype, or the
    testing of a therapy over a realistic timescale. What is missing is a hypomorphic
    allelic-series mouse carrying a partial-loss-of-function human variant such as
    p.Gly822Asp, which the enzymology predicts would be viable.
  proposed_experiments:
  - experiment_id: hypomorphic_hmgcr_allelic_series
    name: Hypomorphic Hmgcr knock-in allelic series
    description: >-
      Generate homozygous knock-in mice carrying the enzymologically characterised partial
      loss-of-function alleles rather than nulls, and phenotype them for the human-relevant
      endpoints: age of onset, rate of strength decline, biopsy appearance including
      whether necrosis and inflammation are present, and respiratory function.
    would_support:
    - pathophysiology#Progressive Myofiber Loss and Fatty Replacement
    supporting_outcome:
    - >-
      Viable homozygotes developing slowly progressive proximal weakness with raised
      creatine kinase and a non-necrotic biopsy, matching the human tissue phenotype.
    refuting_outcome:
    - >-
      Viable homozygotes with no muscle phenotype, which would imply the human disease
      needs a contribution the mouse lacks and would leave no tractable in vivo model.
- discussion_id: reduced_alpha_dystroglycan_signal
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does LGMDR28 have a secondary alpha-dystroglycan hypoglycosylation limb, and if so
    does that partly reconnect it to the dystroglycanopathies?
  attaches_to:
  - pathophysiology#Progressive Myofiber Loss and Fatty Replacement
  - histopathology#Non-specific myopathic change with normal muscular dystrophy immunohistochemistry
  rationale: >-
    This entry separates LGMDR28 from the sarcolemmal LGMD subtypes on the grounds that its
    immunohistochemistry is normal, and that is what the available cached sources say. One
    piece of curated data points the other way and should not be quietly dropped: HPO
    carries `HP:0030099 Reduced muscle fiber alpha dystroglycan` for this disease at a
    frequency of 1/1, attributed to the discovery cohort (PMID:37167966), alongside
    `HP:0012240 Increased intramyocellular lipid droplets` at 1/3. A single observation in
    a single biopsy is as likely to be a staining artifact as a real finding, and neither
    appears in the abstract that is cached here, so no evidence item can be written for it.
    But if it is real it matters twice over, because glycosylation of alpha-dystroglycan is
    the mechanism of the FKRP and related dystroglycanopathy subtypes, and because
    dolichol, which the mevalonate pathway supplies, is required for the O-mannosylation
    that builds the alpha-dystroglycan glycan. That would be a mechanistically plausible
    route from a mevalonate-flux defect back to a membrane phenotype, and it is exactly the
    kind of link that should be tested rather than assumed.
  proposed_experiments:
  - experiment_id: lgmdr28_alpha_dystroglycan_glycosylation
    name: Alpha-dystroglycan glycosylation status in LGMDR28 muscle
    description: >-
      Stain LGMDR28 muscle biopsies with the glycoepitope-specific IIH6 antibody alongside
      a core alpha-dystroglycan antibody and dystroglycanopathy and normal controls, and
      measure muscle dolichol-linked oligosaccharide pools, across a series rather than the
      single reported case.
    would_support:
    - pathophysiology#Progressive Myofiber Loss and Fatty Replacement
    supporting_outcome:
    - >-
      Reproducible loss of the IIH6 glycoepitope with preserved core protein across
      multiple LGMDR28 biopsies, with reduced dolichol-linked oligosaccharide, which would
      add a glycosylation limb to the mechanism and qualify the separation from the
      dystroglycanopathies drawn in this entry.
    refuting_outcome:
    - >-
      Normal alpha-dystroglycan glycosylation across the series, confirming the single HPO
      annotation as an isolated artifact and leaving the sarcolemmal separation intact.
- discussion_id: hepatic_involvement_and_statin_exposure
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is hepatic disease part of LGMDR28, and are statins contraindicated in people who carry
    biallelic or heterozygous HMGCR disease alleles?
  attaches_to:
  - phenotypes#Cirrhosis
  - treatments#
  rationale: >-
    Two questions with the same root, both unanswered. Progressive cirrhosis requiring
    transplantation occurred in two siblings of one family and in no other reported
    individual, and the authors themselves note that transaminase elevation in this setting
    is normally attributed to muscle injury, so whether the liver is a target organ or that
    family carried a second problem is open. Separately, and although the pharmacological
    parallel is the organising idea of this disease, no published work reports statin
    exposure in a person with an HMGCR disease allele, in either the biallelic or the
    heterozygous state, and no source recommends avoidance. The plausible expectation that
    inhibiting an already-hypomorphic enzyme would be harmful is an inference, not a
    finding, and is not curated as a treatment here for that reason.
  proposed_experiments:
  - experiment_id: lgmdr28_hepatic_phenotyping
    name: Systematic hepatic phenotyping of the LGMDR28 cohort
    description: >-
      Apply the published liver panel plus imaging and, where indicated, biopsy across all
      genotyped LGMDR28 patients, distinguishing muscle-derived transaminase elevation from
      hepatocellular disease, and record statin exposure history in patients and their
      heterozygous relatives.
    would_support:
    - phenotypes#Cirrhosis
    supporting_outcome:
    - >-
      Hepatocellular disease in additional unrelated families, establishing liver
      involvement as a feature of the disease rather than of one family.
    refuting_outcome:
    - >-
      Transaminase elevation of muscle origin only, with normal synthetic function and
      imaging across the cohort, confining the cirrhosis to the single family reported.

📚

References & Deep Research

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Evaluations and curation notes (2)

Record notes

Entity verification. `runoak -i sqlite:obo:mondo info MONDO:0957270 -O obo` on 2026-08-31 returns the label "muscular dystrophy, limb-girdle, autosomal recessive 28", the relationship `RO:0004003 HGNC:5006 ! HMGCR`, the single superclass MONDO:0015152 (autosomal recessive limb-girdle muscular dystrophy), and xrefs OMIM:620375, Orphanet:653725, DOID:0061130, GARD:0026805, MEDGEN:1841154 and UMLS:C5830518. The OMIM number matches the one the naming paper gives for LGMDR28. Named Entity Confusion, and why it is a same-protein rather than a same-name problem here. Three distinct diseases involve HMG-CoA reductase, and a literature search on the gene returns mostly the other two. LGMDR28 is the germline Mendelian disease curated here. Statin-associated muscle symptoms are caused by pharmacological inhibition of the same enzyme. Anti-HMGCR immune-mediated necrotizing myopathy is an autoantibody disease directed against the same protein. `runoak -i sqlite:obo:mondo relationships --direction down -p RO:0004003 HGNC:5006` returns exactly one term, MONDO:0957270, confirming at the ontology level that the other two are not germline HMGCR disorders; they carry separate MONDO identities (MONDO:0100637 drug-induced myopathy, defined by `RO:0009501 ECTO:0000509 ! exposure to drug`, and MONDO:0016098 immune-mediated necrotizing myopathy, whose synonyms include "anti-HMG-CoA myopathy"). Both are curated below as differentials and neither is merged into this entry. Every clinical claim in this entry is sourced to a paper whose subjects carry biallelic germline HMGCR variants: PMID:37167966 (nine individuals, five families), PMID:36745799 (six individuals, one consanguineous Bedouin kindred), PMID:41904993 (eleven individuals, six Middle Eastern families) and PMID:41344164 (one neonatal-onset case). Papers about the other two entities were read and excluded rather than mined: PMID:30588482, PMID:32447205 and PMID:35754285 report anti-HMGCR myopathy presenting as a limb-girdle mimic and would be the easiest source of a wrong attribution; PMID:39106428 and PMID:35031847 are anti-HMGCR autoantibody cohorts; PMID:36447272 is dysferlinopathy and statin resistance, a different LGMD subtype. One statin-myopathy result is used deliberately and is labelled as such wherever it appears: PMID:36745799 also reports a murine statin-myopathy rescue experiment, which is cited only in the treatment rationale and the statin differential, never as evidence about LGMDR28 patients. A note on the mouse literature. PMID:26381177 and PMID:42323079 both frame their skeletal-muscle-specific Hmgcr-knockout mice as models of statin myopathy, because that is the question their authors were asking. The genotype, however, is a biallelic muscle-restricted Hmgcr null, which is mechanistically the closest available animal model of LGMDR28 rather than of statin exposure. They are curated in `animal_models` with that framing mismatch recorded in `limitations`. Deep research. A falcon run was completed and is committed as `research/Muscular_Dystrophy_Limb-girdle_Autosomal_Recessive_28-deep-research-falcon.md`. `just preflight-dr` returns WARN rather than PASS, flagging CERT1 at 17 mentions against 55 for HMGCR. Reading the report, that is not a second disease entity: CERT1 appears only inside the report's own caveats, which state that Open Targets returns CERT1 for MONDO:0957270 as a locus-level artifact because CERT1 neighbours HMGCR on chromosome 5q13, and that it should not be promoted to causality. That reading is independently supported by PMID:36745799, whose homozygosity mapping found a single 3.2 Mbp interval at 5q13.2-q13.3 containing exactly one candidate variant, in HMGCR. The report was therefore not discarded, but it contributed no content to this entry: it retrieved only a 2023 conference abstract, states that it could not recover variant-level data, and reaches no conclusion that the primary literature does not state better. Everything below is curated directly from the primary papers.

Create: LGMDR28 (MONDO:0957270, HMGCR) · 2026-08-31T17:42:22Z · View source

De novo curation of limb-girdle muscular dystrophy autosomal recessive 28 (LGMDR28), biallelic HMGCR. entry_type decided as DISEASE rather than a has_subtypes entry on Autosomal_Recessive_Limb-Girdle_Muscular_Dystrophy: that parent entry's own description asserts sarcolemmal fragility and failed membrane repair as the shared mechanism of its eight subtypes, and LGMDR28 is a mevalonate-pathway flux defect with normal dystrophin/sarcoglycan/dysferlin immunohistochemistry, so folding it in would place a mechanistically foreign pathograph inside that entry. Linked via parents: instead. Named Entity Confusion is the central risk here and is a same-protein rather than a same-name problem: three diseases involve HMG-CoA reductase (this germline Mendelian disease, statin-associated myopathy, and anti-HMGCR immune-mediated necrotizing myopathy). OAK confirms MONDO:0957270 is the only term carrying RO:0004003 HGNC:5006; the other two are curated as differentials bound to MONDO:0100637 and MONDO:0016098. Anti-HMGCR myopathy papers that present as limb-girdle mimics (PMID:30588482, PMID:32447205, PMID:35754285) were read and excluded rather than mined. Pathograph: reduced HMGCR catalytic activity to mevalonate flux reduction to isoprenoid depletion and impaired Rab geranylgeranylation to myofiber mitochondrial dysfunction and impaired myoblast fusion to myofiber loss with fatty replacement to weakness, CK elevation and respiratory failure. Two mouse models curated as PARTIALLY_RECAPITULATES and RECAPITULATES with the framing mismatch recorded in limitations, since both papers describe their muscle-specific Hmgcr nulls as statin-myopathy models while the genotype is closest to LGMDR28; the p.Arg641Cys knock-in is curated as FAILS_TO_RECAPITULATE with limitations and evidence because homozygotes die in utero. The falcon deep-research run returned preflight WARN for CERT1 at 31 percent of HMGCR mentions; on reading, CERT1 appears only in the report's own caveat that Open Targets returns it as a 5q13 locus-level artifact, independently corroborated by the founding kindred's 3.2 Mbp linkage interval containing a single candidate variant, so the report was kept but contributed no content. Acting on the automated second opinion on issue 10244: corrected the experimental model from PRIMARY_CELL_CULTURE to CELL_LINE (C2C12, ATCC), and corrected an overstated absence of cardiac involvement after checking PMID:36745799, which reports slightly raised troponin T in four of four patients tested and ECG conduction changes in two; a Subclinical Cardiac Involvement phenotype was added and the description and differential were requalified. Also added exercise-induced myalgia, an alpha-dystroglycan knowledge gap, and notes recording the HPO-curated biopsy findings that could not be quoted because the discovery-cohort cache is abstract-only. Validation: just validate exit 0, just validate-terms exit 0, 85 of 85 snippets verified, check-entity-refs exit 0.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 2 citations 2026-08-31T10:18:17.350509

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Muscular Dystrophy, Limb-Girdle, Autosomal Recessive 28
MONDO ID: MONDO:0957270 (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Muscular Dystrophy, Limb-Girdle, Autosomal Recessive 28 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Muscular Dystrophy, Limb-Girdle, Autosomal Recessive 28

Executive summary and evidence grade

Muscular dystrophy, limb-girdle, autosomal recessive 28 (LGMD-AR28; MONDO:0957270) is an exceptionally rare, newly delineated Mendelian myopathy attributed primarily to biallelic variants in HMGCR, encoding 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme of the mevalonate pathway. The principal disease-specific publication located was a 2023 conference abstract by Foley et al., whose title states: “Bi-allelic variants in HMGCR cause limb girdle muscular dystrophy and further implicate the mevalonate pathway in muscle disease.” DOI: https://doi.org/10.1016/j.nmd.2023.07.195 (October 2023). Aggregated Open Targets evidence links MONDO:0957270 most strongly to HMGCR and also returns CERT1, but the available records do not establish CERT1 as an independent cause of this muscular dystrophy. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)

The evidence base is therefore very low-volume and incompletely published. A full disease-defining article containing patient-level variants, clinical measurements, and functional experiments was not retrieved. Consequently, exact phenotype frequencies, prevalence, progression rates, survival, and treatment effects cannot presently be reported responsibly. Broad observations from other LGMDs, statin-associated muscle symptoms, and anti-HMGCR immune-mediated necrotizing myopathy must not be assigned to this Mendelian disorder.

Topic	Current evidence status for MONDO:0957270
Identity	Muscular dystrophy, limb-girdle, autosomal recessive 28; MONDO identifier surfaced in disease-target resources as MONDO_0957270. The entity appears to be a newly catalogued ultra-rare autosomal-recessive LGMD rather than a well-established legacy subtype with extensive literature. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)
Causal gene	HMGCR is the primary implicated gene based on current retrieved disease-target evidence and a cited 2023 neuromuscular conference abstract titled “Bi-allelic variants in HMGCR cause limb girdle muscular dystrophy and further implicate the mevalonate pathway in muscle disease” (DOI: https://doi.org/10.1016/j.nmd.2023.07.195). CERT1 also appears in aggregated association outputs, but retrieved evidence does not establish CERT1 as an independent confirmed cause of this LGMD entity. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)
Inheritance	Reported/curated as autosomal recessive, with evidence summaries indicating biallelic variant interpretation for the HMGCR-associated disease signal. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)
Evidence date/source	Most disease-specific signal identified here is recent (2023 onward) and largely derives from aggregated database evidence plus the 2023 conference abstract rather than a full-length, richly phenotyped primary paper retrievable in this search set. Open Targets lists supporting literature including PMIDs 36745799 and 37167966, but the retrieved context does not provide disease-specific full-text extraction sufficient for detailed phenotype/variant curation. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)
Phenotype	Disease label indicates a limb-girdle muscular dystrophy phenotype, implying predominant proximal shoulder/pelvic girdle weakness. However, disease-specific quantitative phenotype data—for example exact onset ages, CK ranges, MRI pattern, biopsy findings, cardiopulmonary involvement, cognition, or wheelchair-loss rates—were not available in retrieved disease-specific sources and should not be inferred from other LGMD subtypes. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)
Mechanism	Current best-supported mechanistic interpretation is HMGCR dysfunction affecting the mevalonate pathway, thereby implicating defective production/regulation of sterol and nonsterol isoprenoid metabolites important for muscle biology. Any more granular chain linking HMGCR deficiency to fiber degeneration, membrane instability, autophagy, or inflammation remains plausible but incompletely demonstrated for this exact disease in the retrieved evidence. CERT1-related sphingolipid transport involvement remains ambiguous for MONDO:0957270. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)
Diagnostics	At present, the most defensible disease-specific diagnostic approach is genomic testing in patients with unexplained LGMD/proximal myopathy, especially exome or genome sequencing or curated neuromuscular gene panels that include HMGCR. There is no retrieved disease-specific validated biomarker set, pathology signature, or formal diagnostic criteria unique to LGMD autosomal recessive 28. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)
Treatment / trials	No disease-specific approved therapy or interventional clinical trial for MONDO:0957270 was identified in retrieved sources. Results involving statins or anti-HMGCR immune-mediated necrotizing myopathy should not be transferred to this genetic LGMD, because those represent a distinct acquired autoimmune/statin-associated disorder rather than inherited biallelic HMGCR-related muscular dystrophy. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)
Epidemiology	No disease-specific prevalence, incidence, carrier frequency, sex ratio, or founder-effect estimates were identified in the retrieved evidence. The condition should currently be treated as extremely rare/ultra-rare with insufficient published epidemiologic quantification. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)
Major caveats	Major limitations are: (1) likely dependence on very recent and sparse evidence, (2) absence of a retrievable full disease-defining article in the search set, (3) no invented variant-level curation should be made, (4) CERT1 association may reflect neighboring/overlapping submitted evidence rather than proven dual causality, and (5) broad LGMD, statin-myopathy, or anti-HMGCR autoimmune literature must be kept separate from this Mendelian disease entry. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)

Table: This table summarizes what can currently be stated with confidence about muscular dystrophy, limb-girdle, autosomal recessive 28 from the retrieved evidence. It highlights HMGCR as the primary implicated gene, the unresolved CERT1 signal, and the major quantitative data gaps that should constrain downstream curation.

1. Disease information

Definition

LGMD-AR28 is a hereditary muscle disease characterized at the category level by a limb-girdle pattern—predominantly proximal pelvic- and shoulder-girdle muscle involvement—and autosomal-recessive inheritance. Its current molecular assignment is HMGCR-related muscular dystrophy. The designation is very recent and has not accumulated the detailed natural-history literature available for commoner LGMD subtypes. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)

Identifiers and synonyms

MONDO: MONDO:0957270; database form MONDO_0957270.
Preferred name: muscular dystrophy, limb-girdle, autosomal recessive 28.
Useful synonyms: LGMD autosomal recessive 28; LGMD-AR28; HMGCR-related limb-girdle muscular dystrophy; biallelic HMGCR-related muscular dystrophy.
OMIM, Orphanet, MeSH: no disease-specific identifier was confirmed in the retrieved evidence. These should remain null rather than be inferred.
ICD-10: no subtype-specific code was identified; clinically it would ordinarily fall under a nonspecific muscular-dystrophy category, subject to national coding rules.
ICD-11: no confirmed subtype-specific code was retrieved.

The available information is derived from aggregated disease-level resources and a small research case series/meeting abstract, not population EHR data. Open Targets reports association scores of approximately 0.656 for HMGCR and 0.429 for CERT1; these are evidence-integration scores, not penetrance, risk ratios, or diagnostic probabilities. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)

2. Etiology, risk, and protective factors

The initiating cause is germline biallelic HMGCR variation, consistent with autosomal-recessive disease. Retrieved database evidence includes missense, splice-region/donor, and in-frame deletion categories, but it did not expose enough transcript-level information to report HGVS expressions safely. Somatic mutation is not implicated. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)

The apparent CERT1 signal requires caution. HMGCR and CERT1 are neighboring genes on chromosome 5q13; variant annotation, structural variation, or locus-level evidence may therefore associate both genes with a record. No retrieved evidence demonstrated that biallelic CERT1 variants independently cause LGMD-AR28. CERT1 should be retained as an uncertain locus-level candidate, not a second established causal gene. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)

Established risk factor: inheriting two disease-causing HMGCR alleles.
Family history/consanguinity: biologically relevant to recessive inheritance, but no disease-specific frequency was available.
Sex: no sex-specific genetic risk is expected for an autosomal locus; a measured sex ratio is unavailable.
Environmental, infectious, occupational, dietary, or lifestyle causes: none established.
Protective variants or modifier genes: none reported specifically.
Gene–environment interaction: unstudied. Pharmacological HMGCR inhibition by statins is biologically relevant but must not be assumed to initiate or modify this inherited disease without evidence. Statin toxicity and anti-HMGCR autoimmunity are separate entities.

3. Phenotypes

Only the general limb-girdle muscular dystrophy/proximal myopathy phenotype can be assigned with confidence. Patient-level onset, severity, frequency, CK values, MRI distribution, biopsy features, and cardiopulmonary findings were unavailable in the retrieved disease-specific material. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)

Suggested knowledge-base annotations, explicitly provisional pending the primary case series, are:

Proximal muscle weakness — HP:0003701.
Pelvic-girdle muscle weakness — HP:0003749.
Shoulder-girdle muscle weakness — use the current HPO term for shoulder-girdle weakness after ontology-version validation.
Muscular dystrophy — HP:0003560.
Abnormality of skeletal muscle — HP:0011805.
Elevated serum creatine kinase — HP:0003236, only if confirmed in individual records.
Gowers sign, waddling gait, muscle atrophy, contractures, scapular winging, respiratory insufficiency, cardiomyopathy, dysphagia, and loss of ambulation — not established for this subtype and should not be entered as confirmed findings.

Onset is likely chronic/insidious by disease class, but neonatal, childhood, or adult onset cannot be assigned. There are no disease-specific phenotype percentages or validated quality-of-life measurements. Expected functional effects of proximal weakness include difficulty rising, climbing stairs, lifting the arms, and walking, but these are clinical implications rather than quantified LGMD-AR28 observations.

4. Genetic and molecular information

Causal gene

HMGCR — 3-hydroxy-3-methylglutaryl-CoA reductase; Ensembl ENSG00000113161.
Molecular role: catalysis of HMG-CoA reduction to mevalonate, the committed/rate-limiting step in cholesterol and nonsterol-isoprenoid biosynthesis.
Disease mechanism: most consistent with partial loss of function/hypomorphism, because profound systemic loss of this central biosynthetic activity would be expected to have broader consequences. That qualification is mechanistic inference; the retrieved disease-specific material did not provide a complete allelic or enzymatic series.

Open Targets identifies HMGCR as the higher-confidence target and cites PMIDs 36745799 and 37167966 in its evidence records. The available excerpts did not establish that both PMIDs are full clinical reports of LGMD-AR28, so they should be checked manually before creating patient-level evidence assertions. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)

Variants and genomic architecture

The database evidence includes missense, splice-donor/region, and in-frame deletion classes. Exact HGVS, zygosity by patient, ClinVar accession, ACMG classification, and gnomAD frequency were not recoverable and must not be invented. Large deletions involving both HMGCR and neighboring CERT1 remain a possible explanation for some dual-gene records, but this was not demonstrated by the retrieved evidence. No aneuploidy, translocation, inversion, repeat expansion, mitochondrial mutation, or epigenetic cause is established. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)

No validated modifier genes, protective alleles, DNA-methylation signature, histone abnormality, or disease-specific chromatin mechanism has been reported.

5. Environmental information

No toxin, radiation, pollution, occupation, infection, diet, smoking, alcohol exposure, or exercise pattern is known to cause LGMD-AR28. Safe activity is nevertheless clinically relevant because excessive eccentric loading can aggravate symptoms in many dystrophies, whereas prolonged inactivity promotes deconditioning; this general principle has not been tested specifically here.

Critical distinction: statins inhibit the HMGCR protein and may produce toxic muscle symptoms or trigger anti-HMGCR immune-mediated necrotizing myopathy. Neither phenomenon is evidence that statins cause germline LGMD-AR28. Anti-HMGCR myopathy is acquired, antibody-associated, and potentially immunotherapy-responsive; LGMD-AR28 is inherited and biallelic.

6. Mechanism and pathophysiology

Ordered causal chain

Biallelic pathogenic HMGCR variants lead to reduced or dysregulated HMGCR abundance/activity in skeletal muscle; variant causality is reported, whereas the exact biochemical magnitude remains incompletely documented.
Reduced HMGCR activity leads to impaired conversion of HMG-CoA to mevalonate.
Mevalonate insufficiency results in reduced availability of downstream sterols and/or nonsterol isoprenoids, including intermediates required for protein prenylation; the disease-specific balance among these branches is inferred.
Branch A—inferred: altered membrane-lipid/sterol homeostasis leads to impaired myofiber membrane and organelle function.
Branch B—inferred: reduced farnesyl- and geranylgeranyl-derived substrates lead to abnormal prenylation and localization of small GTPases, disrupting vesicle trafficking, cytoskeletal regulation, autophagy, and muscle maintenance.
Branch C—inferred: deficient ubiquinone/dolichol-related pathway output may lead to mitochondrial-energy or glycosylation stress.
These cellular disturbances lead to myofiber dysfunction, degeneration, and inadequate regeneration; direct demonstration in LGMD-AR28 tissue remains limited.
Progressive loss of functional proximal myofibers results in the limb-girdle weakness phenotype. The 2023 report specifically frames the finding as further implicating the mevalonate pathway in muscle disease. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)

Annotation suggestions

GO biological processes: mevalonate pathway (GO:0019287); cholesterol biosynthetic process (GO:0006695); isoprenoid biosynthetic process (GO:0008299); protein prenylation (GO:0018342); skeletal muscle tissue development (GO:0007519); muscle cell homeostasis—validate exact current GO identifier.
GO molecular function: hydroxymethylglutaryl-CoA reductase (NADPH) activity (GO:0004420, version validation recommended).
GO cellular components: endoplasmic-reticulum membrane (GO:0005789), where HMGCR resides; sarcoplasmic reticulum and mitochondrion are mechanistically plausible downstream compartments but not disease-specifically demonstrated.
Cell Ontology: skeletal muscle fiber (CL:0000188); skeletal muscle satellite stem cell (CL:0000594) as a potential secondary regenerative cell population.

No disease-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, CRISPR-screen, or integrated multi-omics dataset was identified. Immune-mediated necrosis should not be assigned merely because HMGCR is also an autoantigen in an unrelated acquired myopathy.

7. Anatomical structures affected

The primary organ is skeletal muscle, particularly proximal limb-girdle musculature by the diagnostic label. Suggested terms include skeletal muscle organ (UBERON:0001630), pelvic-girdle region and pectoral/shoulder-girdle structures after exact Uberon-version validation, and skeletal muscle fiber (CL:0000188). Bilateral involvement is expected for a genetic myopathy, but symmetry was not quantified.

At subcellular level, HMGCR is an integral endoplasmic-reticulum membrane enzyme. Downstream effects on sarcolemma, mitochondria, sarcoplasmic reticulum, Golgi trafficking, or lysosome/autophagosome are plausible but not yet demonstrated specifically. Cardiac and respiratory-muscle involvement remains unknown.

8. Temporal development

A chronic, inherited, potentially progressive course is consistent with the term muscular dystrophy, but no disease-specific longitudinal cohort was found. The evidence does not support numerical assignment of onset age, annual decline, time to wheelchair use, disease stages, critical intervention windows, remission, or life expectancy.

Spontaneous remission would be biologically unexpected for structural/metabolic genetic disease, but this has not been formally studied. The likely optimal intervention window is before irreversible myofiber loss and fibrofatty replacement; that is a general dystrophy principle, not an established LGMD-AR28 outcome.

9. Inheritance and population

Inheritance is autosomal recessive. For two heterozygous parents, the theoretical risk per pregnancy is 25% affected, 50% carrier, and 25% unaffected/non-carrier. This calculation assumes both parental variants are pathogenic and segregate conventionally.

Penetrance, age dependence, expressivity, anticipation, germline mosaicism, founder variants, carrier frequency, prevalence, incidence, ethnic enrichment, geographic distribution, and sex ratio are unknown. No registry-based denominator was identified. The disorder should be described as ultra-rare with unquantified prevalence, not assigned a fabricated rate. Consanguinity can increase the probability of homozygosity for rare alleles but no LGMD-AR28-specific statistic is available.

10. Diagnostics

Recommended approach

Document distribution and tempo of weakness, three-generation pedigree, medication exposure, and systemic features.
Measure CK, AST/ALT, aldolase, renal indices if rhabdomyolysis is suspected, and lipid/metabolic parameters. No LGMD-AR28-specific biochemical cutoff exists.
Perform EMG/nerve-conduction testing to establish a myopathic pattern and exclude neuropathy when indicated.
Use muscle MRI to characterize distribution and select a biopsy site; no subtype-specific MRI pattern is validated.
Undertake a comprehensive neuromuscular gene panel, WES, or preferably WGS with HMGCR included. Analysis should cover SNVs, indels, exon-level copy-number changes, splice variants, and structural variants spanning HMGCR/CERT1.
Confirm candidate variants by orthogonal testing, parental segregation, population frequency, phenotype fit, and ACMG/AMP interpretation. RNA sequencing from muscle or fibroblasts may resolve splice variants; enzyme/protein assays would provide valuable functional support.

Single-gene HMGCR testing is reasonable in a strongly matched family or for segregation, but broad sequencing is generally preferable because proximal muscular dystrophy is highly heterogeneous. CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion assays are not first-line tests unless other clinical findings indicate them.

Differential diagnosis

The differential includes other recessive LGMDs, dystrophinopathy, Pompe disease, metabolic/mitochondrial myopathy, congenital myopathy, spinal muscular atrophy, inflammatory myopathy, endocrine myopathy, and drug-induced myopathy. Anti-HMGCR antibody testing is especially relevant when onset is acquired, CK is markedly elevated, statin exposure is present, or necrotizing biopsy pathology suggests immune-mediated disease. A positive anti-HMGCR antibody supports a distinct treatable autoimmune diagnosis and does not establish biallelic HMGCR muscular dystrophy.

No standardized subtype-specific clinical criteria, newborn screen, validated metabolite biomarker, or liquid-biopsy test exists.

11. Outcome and prognosis

No disease-specific survival rate, mortality rate, life expectancy, ambulation-loss rate, respiratory decline, cardiac-event rate, or validated patient-reported outcome was identified. Potential morbidity is progressive mobility and self-care impairment, but magnitude and variability remain unknown. Prognostic biomarkers and genotype–phenotype rules have not been established.

Until natural-history data become available, longitudinal monitoring should include motor function, range of motion, falls, pain/fatigue, CK where clinically useful, pulmonary function, and symptom-directed cardiac assessment. Instruments used across LGMD research may be considered, but none is validated specifically for LGMD-AR28.

12. Treatment and current applications

There is no approved disease-modifying treatment, gene therapy, RNA therapy, cell therapy, or genotype-directed drug for LGMD-AR28, and no disease-specific trial was identified. The anti-HMGCR IVIG trial found during searching concerns autoimmune necrotizing myopathy and is not an LGMD-AR28 trial.

Current real-world management should be multidisciplinary and supportive:

individualized low-to-moderate intensity physical therapy and avoidance of overwork injury;
occupational therapy, mobility aids, orthoses, and fall prevention;
contracture prevention and orthopedic management;
respiratory surveillance and assisted ventilation/cough support if weakness develops;
cardiac evaluation based on symptoms and emerging subtype data;
nutrition, bone health, pain, fatigue, and psychosocial support;
anesthesia planning as for an undifferentiated muscular dystrophy until specific risks are known.

Suggested NCIt concepts include Physical Therapy (C15308), Occupational Therapy (C16960), Genetic Counseling (C15240), and assisted ventilation concepts after current NCIt validation. Corticosteroids, IVIG, rituximab, and other immunotherapies should not be prescribed solely on the basis of inherited HMGCR variants. Statin initiation or continuation requires individualized specialist review because HMGCR is the affected enzyme, but there is no evidence-based categorical rule for this genotype.

13. Prevention

The genetic lesion cannot currently be prevented through lifestyle modification.

Primary prevention: carrier testing in relatives after familial variants are established; reproductive counseling; optional prenatal diagnosis or preimplantation genetic testing for monogenic disease.
Secondary prevention: cascade testing and presymptomatic assessment of at-risk siblings may allow earlier surveillance and rehabilitation, although benefit has not been quantified.
Tertiary prevention: preserve mobility, prevent falls and contractures, vaccinate according to routine schedules, maintain respiratory health, and detect cardiopulmonary complications early.

Population newborn screening is not established. Vaccination does not prevent the genetic disease, although routine respiratory immunization may reduce complications in individuals with respiratory weakness.

14. Other species and natural disease

No naturally occurring HMGCR-related limb-girdle muscular dystrophy was identified in companion animals, livestock, or wildlife. There is no zoonotic potential or cross-species transmission because this is a germline Mendelian disorder. HMGCR and the mevalonate pathway are strongly evolutionarily conserved, making comparative models biologically relevant, but conservation alone does not constitute a natural animal disease model.

15. Model organisms

No validated knock-in or knockout model reproducing the human biallelic HMGCR-LGMD phenotype was found. Complete Hmgcr loss may be developmentally incompatible and therefore may not model presumed human hypomorphic alleles. Appropriate future models include:

patient fibroblasts, myoblasts, or iPSC-derived myotubes;
CRISPR knock-in of patient alleles in human myogenic cells;
muscle-specific or inducible hypomorphic mouse models;
zebrafish knock-in/knockdown systems for rapid muscle and locomotor phenotyping.

Priority readouts should include HMGCR abundance/activity, mevalonate and downstream sterol/nonsterol metabolites, protein prenylation, mitochondrial respiration, membrane organization, autophagic flux, myotube formation, CK release, muscle histology, force, and locomotion. Rescue with wild-type HMGCR or carefully titrated downstream metabolites would strengthen causal inference. A major limitation is that pharmacological statin exposure may not faithfully reproduce allele-specific congenital deficiency.

Recent developments, expert interpretation, and curation recommendations

The principal development in 2023 was recognition that biallelic HMGCR variants can cause an autosomal-recessive LGMD, extending mevalonate-pathway biology into inherited primary muscle disease. The most authoritative interpretation supported by available data is that HMGCR is causal, while the lower-scoring CERT1 association remains unresolved and should not be promoted to independent causality. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)

For knowledge-base population:

Mark HMGCR–MONDO:0957270 as a recent, limited-evidence recessive association pending full publication and independent replication.
Record CERT1 as uncertain/possibly annotation- or locus-related, not definitively causal.
Do not populate exact variants, phenotype frequencies, penetrance, prevalence, or treatment outcomes from the present evidence.
Keep genetic HMGCR-related LGMD, statin toxic myopathy, and anti-HMGCR immune-mediated necrotizing myopathy as separate entities.
Re-curate when the full Foley et al. cohort, ClinVar submissions, segregation data, functional assays, and additional families become publicly available.

Core sources

Foley A, Donkervoort S, Bharucha-Goebel D, et al. Bi-allelic variants in HMGCR cause limb girdle muscular dystrophy and further implicate the mevalonate pathway in muscle disease. Neuromuscular Disorders, conference abstract, October 2023. DOI: https://doi.org/10.1016/j.nmd.2023.07.195.
Open Targets Platform disease–target record for MONDO_0957270, reporting HMGCR and CERT1 associations and linked literature including PMID 36745799 and PMID 37167966. These PMID links require source-level verification before patient-level curation. (OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28)

References

(OpenTargets Search: muscular dystrophy, limb-girdle, autosomal recessive 28): Open Targets Query (muscular dystrophy, limb-girdle, autosomal recessive 28, 2 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

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Outcome	Count
References checked	3
Resolved	3
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	3
On topic	3
Off topic	0

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Term Validation

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Outcome	Count
Terms checked	16
Resolved	16
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	1

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These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0957270 (8 mentions) - the report calls it "if available"; MONDO calls it muscular dystrophy, limb-girdle, autosomal recessive 28

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1. Disease information

Definition

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2. Etiology, risk, and protective factors

3. Phenotypes

4. Genetic and molecular information

Causal gene

Variants and genomic architecture

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

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8. Temporal development

9. Inheritance and population

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