| Domain | Curated finding | Key ontology/identifier |
|---|---|---|
| Disease entity | Severe congenital end of the LAMA2-related muscular-dystrophy spectrum, usually associated with complete or near-complete merosin/laminin-α2 deficiency; also called MDC1A or LAMA2-related congenital muscular dystrophy. (pqac-00000000, pqac-00000001) | MONDO:0011925; OMIM phenotype: 607855 |
| Causal gene/protein | Biallelic pathogenic variants in **LAMA2** impair laminin-α2, a component of extracellular-matrix laminin-211 (α2β1γ1). (pqac-00000000, pqac-00000015) | LAMA2; OMIM gene: 156225; chromosome 6q22.33 |
| Inheritance | Autosomal recessive, germline Mendelian disease; each pregnancy of two confirmed heterozygous carriers has a 25% affected, 50% carrier and 25% unaffected/non-carrier probability. (pqac-00000000, pqac-00000001) | HP:0000007 Autosomal recessive inheritance |
| Variant spectrum | Nonsense, frameshift, canonical/noncanonical splice and exon-level deletion/CNV alleles predominate in severe disease; complete loss-of-function usually causes absent laminin-α2, although genotype–phenotype exceptions occur. One 2024 cohort review estimated 60–80% single-nucleotide variants and 20–40% exon deletions. (pqac-00000003, pqac-00000004, pqac-00000005) | ClinVar classification: pathogenic/likely pathogenic under ACMG/AMP; germline |
| Molecular mechanism | Loss of laminin-211 linkage to α-dystroglycan and integrin α7β1 weakens the basement-membrane–sarcolemma–cytoskeleton axis, leading to contraction-associated injury, degeneration and secondary inflammation, fibrosis and defective regeneration. (pqac-00000005, pqac-00000015, pqac-00000020) | GO:0005604 basement membrane; GO:0031589 cell–substrate adhesion; GO:0007519 skeletal-muscle tissue development |
| Core neuromuscular phenotype | Congenital/early-infantile hypotonia, severe axial and proximal weakness, delayed motor development, reduced spontaneous movement and muscle atrophy; independent walking is uncommon. (pqac-00000001, pqac-00000003) | HP:0001252 Hypotonia; HP:0003701 Proximal muscle weakness; HP:0001270 Motor delay; HP:0003202 Skeletal muscle atrophy |
| Orthopedic phenotype | Progressive large-joint contractures, spinal rigidity, scoliosis and hyperlordosis substantially impair positioning, transfers and mobility. (pqac-00000001, pqac-00000003, pqac-00000013) | HP:0001371 Flexion contracture; HP:0002650 Scoliosis; HP:0003306 Spinal rigidity; HP:0003307 Hyperlordosis |
| Respiratory phenotype | Restrictive respiratory weakness, sleep-related hypoventilation, ineffective cough and recurrent infections may begin in childhood and progress to ventilatory dependence. (pqac-00000011, pqac-00000013, pqac-00000014) | HP:0002093 Respiratory insufficiency; HP:0002104 Apnea/sleep-related hypoventilation—broader mapping; HP:0002205 Recurrent respiratory infections |
| Feeding/growth phenotype | Feeding and swallowing difficulty, silent aspiration, poor weight gain or failure to thrive may require nutritional supplementation or gastrostomy. (pqac-00000003, pqac-00000013, pqac-00000014) | HP:0011968 Feeding difficulties; HP:0002015 Dysphagia; HP:0001508 Failure to thrive |
| Nervous-system phenotype | Diffuse cerebral white-matter MRI signal abnormalities are characteristic. A minority have cortical malformations, epilepsy or intellectual disability; demyelinating peripheral neuropathy is also recognized. (pqac-00000008, pqac-00000009, pqac-00000020) | HP:0002500 Abnormal cerebral white matter morphology; HP:0001250 Seizure; HP:0001249 Intellectual disability; HP:0007108 Demyelinating peripheral neuropathy |
| Cardiac/bone phenotype | Cardiomyopathy or conduction abnormalities are less dominant than skeletal/respiratory disease but warrant surveillance; reduced bone quality and fragility fractures are important secondary morbidity. (pqac-00000011, pqac-00000012, pqac-00000013) | HP:0001638 Cardiomyopathy—broader; HP:0011675 Arrhythmia—broader; HP:0000938 Osteopenia; HP:0002756 Pathologic fracture |
| Diagnostic evaluation | Confirm with biallelic LAMA2 variants using a neuromuscular panel or exome/genome sequencing with deletion/duplication analysis. RNA studies can resolve suspected splice/deep-intronic variants. (pqac-00000004, pqac-00000009, pqac-00000010) | LAMA2 molecular genetic testing; ACMG/AMP variant interpretation |
| Supporting tests | Serum CK is commonly elevated, often above 1,000 IU/L; brain MRI typically shows diffuse T2/FLAIR white-matter abnormalities; muscle biopsy shows dystrophic change and absent/reduced laminin-α2 immunoreactivity. (pqac-00000001, pqac-00000003) | HP:0003236 Elevated serum creatine kinase; brain MRI; laminin-α2 immunohistochemistry |
| Motor cohort data | In 116 Chinese LAMA2-CMD patients, 76.3% achieved head control, 92.6% independent sitting and 18.4% walking; median attainment ages were 6, 11 and 27 months, respectively. (pqac-00000010) | Motor milestones; MFM-20/32 and CHOP INTEND are broader outcome instruments |
| Multisystem cohort data | In a 2023 cohort of 27 genetically confirmed patients, 85% had respiratory impairment, 37% required ventilation, 62% had fragmented QRS, 25% abnormal LV strain and 14% reduced LVEF; mean MFM-20/32 was 42.0% ± 29.4%. (pqac-00000011) | Spirometry/sleep assessment; ECG; echocardiography; MFM-20/32 |
| CNS cohort data | Among 52 Brazilian patients, cortical malformations and epilepsy each occurred in 19.2%, and intellectual disability in 15.4%; LG-domain and null variants correlated with greater CNS involvement. (pqac-00000008) | Brain MRI; EEG when clinically indicated; HP terms above |
| Longitudinal morbidity | In a pediatric cohort dominated by complete deficiency, 22 patients began nocturnal noninvasive ventilation at median age 11.7 years, FVC declined 2.9 percentage points/year, 20 underwent gastrostomy at median age 10.9 years and seven died at median age 12 years. (pqac-00000013) | Forced vital capacity; noninvasive ventilation; gastrostomy |
| Management | No approved disease-modifying therapy is established. Care is multidisciplinary: respiratory surveillance and cough/NIV support, swallowing and nutritional management, physiotherapy and contracture prevention, mobility/assistive technology, scoliosis management, cardiac monitoring, and bone-health optimization. (pqac-00000012, pqac-00000014, pqac-00000025) | NCIT mappings are broader/non-specific: Physical Therapy, Noninvasive Ventilation, Gastrostomy, Spinal Fusion, Genetic Counseling |
| Trials and readiness | Current registered work is predominantly observational: completed infant/toddler retrospective study, 75 participants (NCT04299321); completed LAST STRONG study, 38 participants (NCT04478981); and five-year Extended LAST STRONG study, planned 40 participants (NCT06132750). A seven-adult ex-vivo genetic-correction study was observational rather than therapeutic. (pqac-00000024, pqac-00000025, pqac-00000026, pqac-00000028) | NCT04299321; NCT04478981; NCT06132750; NCT06582537 |
| Experimental strategies | Preclinical approaches include mini-agrin/linker proteins, laminin-α1 substitution or activation, LAMA2 correction/exon skipping, CRISPR-based editing and modulation of apoptosis, fibrosis or inflammation; clinical efficacy remains unproven. (pqac-00000005, pqac-00000015, pqac-00000022) | NCIT: Gene Therapy, CRISPR-Cas9 Gene Editing, Antisense Oligonucleotide Therapy—broader/non-specific |
| Mouse models | **Lama2** dy/dy, dy2J/dy2J, dyW/dyW and dy3K/dy3K mice reproduce combinations of muscular dystrophy, weakness, fibrosis and peripheral dysmyelination. Severe dy3K/dy3K and dyW/dyW animals have shortened survival; dy2J/dy2J is milder and useful for longer therapeutic studies. (pqac-00000020, pqac-00000021) | Mus musculus, NCBI Taxon:10090; MGI/IMSR resources |
| Zebrafish/cellular models | Lama2-deficient zebrafish show myofiber detachment with a transient rescue window and laminin-responsive regeneration. CRISPR Lama2-null myoblasts and dyW fetal muscle reveal impaired proliferation/differentiation, oxidative stress, DNA damage and broad transcriptional downregulation; the latter 2024 evidence was a non-peer-reviewed preprint. (pqac-00000016, pqac-00000017, pqac-00000019) | Danio rerio, NCBI Taxon:7955; C2C12 myoblast model; ZFIN/Cellosaurus resources |


*Table: Compact curation of MDC1A identifiers, genetics, phenotypes, quantitative human evidence, diagnostics, management, trials, and experimental models. Ontology mappings labeled “broader/non-specific” should be validated against the target knowledge-base release.*