Broadening the paradigm of laminin α2-related muscular dystrophy: A case of partial merosin deficiency with compound heterozygous variants

Abstract

Laminin α2-related muscular dystrophy is a rare autosomal recessive condition caused by mutations in the LAMA2 gene, with clinical presentations ranging from severe congenital forms to milder phenotypes resembling limb-girdle muscular dystrophy. We report a case of a 4-month-old girl presenting with delayed head control, axial hypotonia, and proximal muscle weakness, while cognitive and cardiac functions remained preserved. Laboratory evaluations revealed elevated serum creatine phosphokinase and lactate dehydrogenase levels. Muscle biopsy demonstrated dystrophic changes and partial merosin deficiency. Whole-exome sequencing identified two heterozygous variants in LAMA2: a known missense variant (c.6548T>G; p.L2183R) and another likely pathogenic missense variant (c.6979G>T; p.G2327). However, targeted parental testing and quantitative PCR confirmed c.6548T>G as paternally inherited and revealed a novel heterozygous frameshift deletion (c.291delC) maternally inherited, consistent with compound heterozygosity in trans. The c.6979G>T variant was not confirmed as part of the disease-causing allele combination. In silico analyses supported the pathogenicity of the novel deletion. The patient received multidisciplinary care, including individualized physical and occupational therapy, and her family received genetic counseling. This case highlights the diagnostic value of early genetic testing, the importance of confirming inheritance patterns, and the contribution of novel LAMA2 mutations to the understanding of genotype–phenotype correlations in laminin α2-related muscular dystrophy.

Introduction

Laminin α2-related muscular dystrophy (LAMA2-RD), a subtype of congenital muscular dystrophy (CMD), is an autosomal recessive disorder caused by mutations in the LAMA2 gene, which encodes the α2 chain of laminin-211 (merosin). Laminin-211 is a crucial component of the skeletal muscle extracellular matrix, providing mechanical stability and facilitating interactions between muscle cells and their surrounding environment. Mutations in LAMA2 disrupt this matrix, compromising muscle fiber integrity and leading to progressive muscle weakness and a broad clinical spectrum ranging from severe congenital forms to milder limb-girdle muscular dystrophy (LGMD)-like presentations.^1,2

This report presents a clinically atypical case of LAMA2-RD in a 4-month-old infant with compound heterozygous LAMA2 variants, including a novel frameshift deletion. By analyzing this case in the context of known phenotypic and genotypic variability, we aim to contribute new insights into the molecular and clinical spectrum of LAMA2-RD.

The global prevalence of CMD, which encompasses all subtypes, is estimated at 1–5/100,000 live births, with LAMA2-RD accounting for ~30%–40% of cases. ³ However, the prevalence of LAMA2-RD varies widely across populations due to genetic and cultural factors. For instance, a population genetics study estimated a birth prevalence of 8.3/million worldwide, with ethnic variability ranging from 1.79/million in East Asians to 10.1/million in Europeans. ⁴ In regions with high rates of consanguinity, such as the Middle East, North Africa, and parts of South Asia, the prevalence is disproportionately elevated due to an increased likelihood of homozygous pathogenic mutations. A study from Qatar reported that LAMA2-RD accounted for nearly 48% of CMD cases in the region, with a point prevalence of 0.8/100,000.^5,6

Merosin deficiency presents with considerable phenotypic heterogeneity, influenced by the nature and zygosity of LAMA2 mutations. The classic congenital form, associated with homozygous or functionally null mutations, manifests in early infancy with severe hypotonia, generalized muscle weakness, delayed motor milestones, and joint contractures. White matter abnormalities, a hallmark feature, are frequently observed on brain MRI, although these changes are typically asymptomatic. Patients with this form usually fail to achieve independent ambulation and often require ventilatory support due to progressive respiratory muscle weakness. In contrast, milder phenotypes, often associated with compound heterozygous mutations, may present in later childhood or adolescence with proximal muscle weakness, resembling LGMD. These patients are more likely to achieve ambulation and have a slower disease progression, with a generally better prognosis.^7,8

From a molecular view, LAMA2 mutations affect the structure and anchoring function of laminin-211 within the basal lamina. Disruption of laminin-α2 impairs the dystrophin-glycoprotein complex and the mechanical linkage between muscle fibers and the extracellular matrix, resulting in muscle fiber degeneration, fibrosis, and weakness. The nature of the mutation-missense, frameshift, or compound heterozygous can significantly influence the severity of the resulting phenotype.

The definitive diagnosis relies on a combination of genetic and histopathological analyses. Muscle biopsy typically shows absent or reduced laminin-α2 expression on immunohistochemistry, and genetic testing, particularly whole-exome sequencing (WES), can identify pathogenic LAMA2 variants with high accuracy.^9,10

Prognosis in merosin deficiency varies widely based on phenotype. In the severe congenital form, life expectancy may be significantly reduced due to complications such as respiratory failure, scoliosis, and recurrent infections. Conversely, individuals with milder forms often have prolonged ambulation and can live into adulthood with appropriate supportive care, including physiotherapy, orthopedic interventions, and noninvasive ventilation.^11,12

There are three goals in reporting this case: (1) to describe a clinically presentation of LAMA2-RD associated with a novel frameshift deletion; (2) to examine how this genetic finding contributes to the growing spectrum of LAMA2 mutations; and (3) to explore the implications for diagnostic strategies and early intervention, especially in populations with high consanguinity. By comparing this case to current literature and molecular understanding, we aim to show how single-case data can refine broader clinical and genetic paradigms.

Case presentation

A 4-month-old girl was brought to the pediatric neurology clinic by her parents due to concerns about delayed motor milestones, particularly her inability to hold her head upright. They also noted a relative thinning of her arms and legs compared to her peers. The parents reported a history of consanguinity, but no family members exhibited similar neuromuscular conditions. Her prenatal history and delivery were unremarkable.

On clinical examination, the patient was alert and displayed normal social interaction, indicating preserved cognitive function. She exhibited significant hypotonia and pronounced proximal muscle weakness. During the pull-to-sit maneuver, she showed a marked head lag, and in the prone position, she was unable to lift her head. Distal muscle strength was relatively preserved, as evidenced by spontaneous hand and foot movements and a weak but present grasp reflex. Deep tendon reflexes were absent proximally and diminished distally. There were no joint contractures, arthrogryposis, dysmorphic features, or organomegaly. Echocardiography revealed normal cardiac structure and function.

Laboratory investigations demonstrated an elevated creatine phosphokinase level of 1732 U/L, lactate dehydrogenase of 981 IU/L, and blood ammonia of 268 µg/dL. Given the neuromuscular presentation, this ammonia level prompted an initial broader metabolic evaluation to rule out primary metabolic disorders. However, subsequent liver function tests and serum amino acids were normal, and no other metabolic abnormalities were identified. The hyperammonemia was interpreted as a nonspecific finding, possibly stress-related, or secondary to muscle catabolism. A muscle biopsy was performed using an open technique from the Vastus Lateralis muscle. Histological evaluation with hematoxylin and eosin staining showed striated muscle tissue with notable variation in fiber size. Numerous atrophic fibers were observed, round in shape and dispersed throughout the sample. Round hypertrophied fibers were also present. In addition, necrotic and degenerative fibers, along with regenerating fibers, were seen, but there was no significant increase in internalized nuclei (Figure 1).

Figure 1.

Muscle biopsy revealing variation in fiber size.

Immunohistochemical staining for sarcolemmal proteins further clarified the diagnosis:

• Dystrophin (DYS1, DYS2, DYS3): normal sacrolemmal labeling of all muscle fibers.

• Sarcoglycans (alpha, beta, gamma): normal sacrolemmal labeling of all muscle fibers.

• Merosin: weak and partial sacrolemmal labeling of muscle fibers and nerve bundles.

• Beta-spectrin: normal sacrolemmal labeling of all muscle fibers.

These findings were consistent with partial merosin-deficient CMD, supported by the weak and incomplete labeling of muscle fibers and nerve bundles with merosin antibody.

Genetic testing via WES identified two heterozygous likely pathogenic variants in the LAMA2 gene: c.6548T>G (p.L2183R), a previously reported missense variant, and c.6979G>T (p.G2327), a missense variant of uncertain contribution. To further clarify the inheritance pattern, quantitative PCR was performed on whole blood samples from both parents. The father was found to be heterozygous for c.6548T>G, while the mother was homozygous normal for this variant. In parallel, targeted analysis identified a novel heterozygous frameshift variant (c.291delC) in the patient. This deletion was found to be maternally inherited, with the father testing homozygous normal. These results confirmed that the patient carries two pathogenic variants in trans—c.6548T>G from the father and c.291delC from the mother, in favor of their causative role in the disease phenotype. The role of the c.6979G>T variant remains uncertain, as it was not confirmed through inheritance analysis. (Pedigree chart is presented in Figure 2. WES findings are summarized in Table 1.)

Figure 2.

Pedigree illustrating the inheritance pattern of LAMA2 variants in the proband.

Table 1.

Detailed results of the whole-exome sequencing.

Gene and transcript	Variant	Chromosomal location (Hg38)	Associated disease	OMIM	Zygosity	CADD score a	Inheritance
LAMA2 NM_000426.4	Exon46 c.6548T>G p.L2183R	Chr6- 129774251 T>G	Muscular dystrophy, congenital merosin deficiency, or partially deficient	607855	Heterozygous	27	Autosomal recessive
	Exon49 c.6979G>T p.G2327	Chr6- 129781456 G>T	Muscular dystrophy, limb-girdle, autosomal recessive	618138	Heterozygous	29	Autosomal recessive

CADD: Combined Annotation Dependent Depletion; OMIM: Online Mendelian Inheritance in Man.

^aCADD score of 20 means that a variant is among the top 1% of deleterious variants in the human genome. A CADD score of 30 means that the variant is in the top 0.1% and so forth.

The patient was referred for physical and occupational therapy to support motor development and improve head and trunk control. Genetic counseling was provided, explaining the condition, its inheritance pattern, and implications for future pregnancies. The family was also educated on disease progression and the importance of regular follow-up. Although long-term outcomes are not yet available due to the patient’s age, a structured follow-up plan includes evaluations every 3–6 months to assess motor function, respiratory status (including nocturnal oximetry), and musculoskeletal health. Brain MRI and pulmonary function tests will be considered from age two if indicated. The physiotherapy plan will be adjusted based on developmental progress, and the care team has discussed potential future needs, such as orthotic support or assisted ventilation.

This case illustrates an atypical mutation of LAMA2-RD characterized by compound heterozygosity in the LAMA2 gene and partial merosin deficiency. The absence of cognitive, cardiac, or articular involvement highlights the phenotypic heterogeneity of LAMA2-RD, expanding our understanding of its clinical spectrum and the importance of detailed genetic analysis to confirm inheritance patterns and establish a definitive diagnosis.

Discussion

This case highlights a rare and atypical mutation of the LAMA2 gene, contributing to the evolving understanding of its genetic, phenotypic, and geographic variability. ¹³ LAMA2-RD typically arises from homozygous or compound heterozygous pathogenic variants in the LAMA2 gene, which encodes the laminin-α2 chain of the laminin-211 protein complex. ¹⁴ Laminin-211 provides structural integrity and signaling cues within the extracellular matrix of skeletal muscle. Defects in this protein disrupt the basement membrane linkage to muscle fibers, ultimately compromising muscle fiber stability and contributing to the progressive weakness and dystrophic changes seen on muscle biopsy.^15,16

Pathophysiological considerations

From a molecular standpoint, laminin-α2 is integral to the formation of the dystrophin-glycoprotein complex and other molecular scaffolds, ensuring muscle fiber resilience against mechanical stress. ¹⁷ In merosin deficiency, pathogenic variants can lead to reduced or absent laminin-α2, resulting in early-onset hypotonia and muscle weakness. Without this support, muscle fibers are more prone to microtears, atrophy, and eventually fibrosis and fatty replacement. ¹⁰ These cellular-level insults translate clinically into a spectrum of disease severity. In severe congenital forms, complete or near-complete loss of laminin-α2 function manifests as profound weakness, respiratory compromise, and loss of ambulation. In milder forms, which may result from partial retention of laminin-α2 function or less destabilizing mutations, patients may have delayed milestones but attain ambulation and maintain relatively better function into childhood or beyond. ¹⁸

Genetic heterogeneity and compound heterozygosity

Traditionally, severe merosin deficiency has been linked to homozygous or functionally null mutations that virtually eliminate laminin-α2 production. ¹³ However, this case demonstrates that even two heterozygous likely pathogenic variants (each inherited from a carrier parent) can combine to produce a clinically evident myopathy. This case also presents a novel genetic finding: a previously unreported heterozygous frameshift deletion variant, c.291delC, in the LAMA2 gene. While the pathogenicity of this variant has not been previously established, null variants, including frameshift deletions, are a known mechanism of disease in LAMA2-RD.^16,19 Computational analyses using tools such as MutationTaster and CADD strongly support the deleterious impact of this variant on the LAMA2 gene and its protein product. Furthermore, its absence in large population databases, including ExAC, 1000 Genomes, and local databases, supports its rarity and potential pathogenicity. ²⁰

These findings are clinically significant because they confirm the trans inheritance pattern of two likely pathogenic variants in the patient, highlighting a complex mechanism of disease development. ²¹ By reporting this case, we aim to expand the recognized genetic architecture of merosin deficiency and emphasize the importance of detailed genetic analyses in atypical cases. This is particularly relevant in populations with high rates of consanguinity, where the likelihood of unmasking recessive or compound heterozygous variants is elevated.

Ethnic and geographical variations in prevalence

The prevalence of merosin deficiency is influenced by genetic drift, founder effects, and cultural practices. ²² Studies have reported worldwide birth prevalence estimates of up to ~8.3/million, but these averages mask considerable variation by ethnicity and region. In populations characterized by high rates of consanguinity—such as parts of the Middle East, North Africa, and certain South Asian communities—the incidence of recessive disorders, including merosin deficiency, is markedly increased.^{23 –25} For instance, reported prevalence rates in certain Middle Eastern countries may surpass those in regions with less frequent consanguineous marriages.^26,27 This elevated prevalence is partly due to the greater probability of unmasking rare recessive variants when both parents share common ancestral lineages.^28,29 In such settings, not only homozygous but also compound heterozygous configurations become more prevalent, increasing the phenotypic diversity of merosin deficiency. ³⁰ Identifying and cataloging local variants through population-specific genetic databases can improve diagnostic accuracy and genetic counseling in these high-risk regions. ³¹

Spectrum of clinical presentations

Merosin deficiency encompasses a broad clinical spectrum, ranging from severe “congenital” presentations to milder, LGMD-like phenotypes. ¹⁰ Severe cases typically present in infancy with profound hypotonia, delayed motor milestones, and an inability to achieve independent ambulation. Respiratory involvement and orthopedic complications (e.g. scoliosis and joint contractures) are common. ¹⁹ Patients with milder phenotypes may attain ambulation, display less pronounced weakness, and show slower progression of disease. ³² The case reported here, demonstrating early proximal weakness without arthrogryposis, cognitive impairment, or cardiac involvement, further enriches our understanding that not all patients follow the classic, severe congenital pattern. Instead, the genotype–phenotype correlation in merosin deficiency is nuanced, with even compound heterozygous variants capable of producing an intermediate or atypical clinical picture. ¹⁹

Current and future therapeutic strategies

At present, management of merosin deficiency is largely supportive and multidisciplinary. Physical and occupational therapies are fundamental to maintain or improve function, delay contracture formation, and optimize activities of daily living. ³³ Orthopedic interventions may be employed to correct spinal deformities and improve mobility. ³⁴ Respiratory support, including non-invasive ventilation, can enhance quality of life and longevity in patients with significant respiratory muscle involvement. ³⁵ Although no current pharmacological agents specifically target the underlying molecular defect in merosin deficiency, several potential therapeutic avenues are under exploration. ³⁶

Gene therapy and gene editing

Advances in viral vectors, CRISPR/Cas9-mediated genome editing, and antisense oligonucleotides offer hope for restoring partial laminin-α2 function or compensating for its deficiency. ³⁷ While these techniques are still in preclinical or early clinical trial phases, they may in the future provide disease-modifying or even curative therapies. ³⁸

Protein replacement or stabilization approaches

Experimental strategies aimed at enhancing residual laminin-α2 expression or stabilizing the extracellular matrix structure may mitigate disease severity. ¹⁴ Pharmacological chaperones or small molecules to improve the function or half-life of mutated laminin-α2 are potential targets, though development in this area remains nascent. ³⁹

Stem cell and regenerative medicine

Skeletal muscle regeneration and repair using stem cells or induced pluripotent stem cells (iPSCs) could theoretically replace damaged muscle fibers with healthier ones. ⁴⁰ While technically challenging, this field continues to advance, bringing the possibility of cell-based therapies into the realm of future potential treatments. ⁴¹

Metabolic and nutritional interventions

Although not disease-modifying, nutritional support and certain supplements (e.g. creatine monohydrate and coenzyme Q10) may transiently improve energy metabolism and muscle strength. ⁴² Ensuring adequate caloric intake, balancing macronutrients, and preventing malnutrition are standard supportive measures. ⁴³ Robust evidence for supplements remains limited, underscoring the need for well-designed clinical trials.

While this case provides valuable insights into the genetic and clinical variability of LAMA2-related muscular dystrophy, several limitations must be acknowledged. First, the absence of long-term follow-up data limits our ability to assess disease progression, functional outcomes, and the potential development of complications such as scoliosis or respiratory insufficiency. Second, functional assessments such as electromyography, standardized motor function scales, and longitudinal imaging were not performed or reported, limiting the phenotypic characterization. Third, although computational analyses and inheritance studies support the pathogenicity of the novel frameshift variant, functional validation at the protein or transcript level was not conducted. These limitations highlight the need for longitudinal studies and broader functional investigations to better understand the correlations between genotype and phenotype in LAMA2-RD.

Conclusion

This case report illustrates an atypical merosin deficiency mutation of two heterozygous likely pathogenic variants, broadening the classical genetic paradigm and underscoring the phenotypic heterogeneity of this disorder. It emphasizes the influence of consanguinity and local genetic pools on disease prevalence, particularly in Middle Eastern populations. While no definitive therapies currently exist, emerging molecular technologies hold promise for the future. Until then, early recognition, genetic confirmation, and comprehensive supportive care remain the cornerstone of improving outcomes for patients with merosin deficiency.

By taking into consideration that early intervention and supportive management are crucial in shaping the long-term functional outcomes for infants with merosin deficiency, the patient was promptly referred for physical and occupational therapy to optimize motor development, strengthen proximal musculature, and improve head control.