Early versus late diagnosis of LAMA2 congenital muscular dystrophy: a distinct consequence

Laminins are a family of glycoproteins that serve as major components of all basement membranes. Laminin-211, previously known as merosin, is a laminin isoform and cell adhesion molecule that is strongly expressed in the basement membrane of skeletal muscle [1]. Mutations in the laminin subunit alpha 2 gene (LAMA2) can lead to laminin α2 chain deficiencies, causing skeletal muscle dysfunction, resulting in LAMA2-related muscular dystrophy (LAMA2 MD), which is also known as merosin-deficient congenital muscular dystrophy [2, 3].

LAMA2 MD is characterized by generalized hypotonia and muscle weakness at birth. Patients typically develop motor delays, proximal joint contractures, the inability to walk, and high levels of creatine phosphokinase (CPK). Brain magnetic resonance imaging (MRI) may also reveal clinically asymptomatic abnormalities of the central white matter [4, 5].

Cardiomyopathy, respiratory insufficiency, demyelinating sensory and motor neuropathy, and (late) external ophthalmoplegia have also been reported as symptoms in LAMA2 MD patients in the literature [3, 5]. The present study reports two cases of LAMA2 MD, diagnosed at different stages of life, resulting in different trajectories. The patients’ genetic features, phenotypes, clinical presentations, and outcomes are described here.

Patient 1 A 7-year-old girl (P1, twin A born to a G1P1 mother at the gestational age of 37 weeks, with a body weight of 2440 g at birth) exhibited poor sucking strength and hypotonia from early infancy. When the patient arrived at the China Medical University Hospital’s Neurological Outpatient Department at three months old, her physical and neurological examination revealed no specific findings except hypotonia and spinal muscular atrophy, which was initially suspected but later excluded through genetic testing. Her parents had no consanguinity; her family pedigree is shown in Fig. 1A. The patient’s CPK level was 2217 IU/L (normal range: 38–234 IU/L). Respiratory insufficiency and sleep apnea episodes were evident starting at 6 months of age. Significant axial and proximal muscle weakness were observed, causing feeding difficulties and choking episodes. Therefore, the patient received a nasojejunal tube insertion for nutritional support, and intensive respiratory care was administered using biphasic positive airway pressure during sleep. Periodic pulmonary function testing and pulmonary follow-ups were conducted. A genetic study revealed a compound heterozygous mutation in LAMA2 at the age of 8 months, confirming a diagnosis of LAMA2 MD. Brain MRI at 8 months exhibited extensive white matter abnormalities (Fig. 2A). Cardiac echocardiography revealed normal cardiac function but multiple aortopulmonary collateral arteries and mild aortic regurgitation. Motor nerve conduction velocity (NCV) showed normal amplitude but mild to moderate decreases in conduction velocity in the upper extremities. Sensory NCV showed a mild to moderate decrease in conduction velocity. F response showed borderline abnormal latency and conduction velocity over both lower extremities.

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The patient is currently 7 years old; ambulation has not been achieved, active rehabilitation is ongoing, and mental development is normal.

Patient 2 A male infant (P2) died suddenly, ostensibly of pneumonia and respiratory failure, at the age of 1 year and 2 months. His parents had no consanguinity; his family pedigree is shown in Fig. 1B. A blood sample was sent to China Medical University Hospital for the genetic investigation of a possible neuromuscular disorder. The patient’s genetic history revealed a healthy mother (the patient was born at gestational age 39 + 2 weeks, with a body weight of 3675 g at birth). The patient exhibited hypotonia, decreased deep tendon reflex, and a weak cry soon after birth. During the first 6 months of life, frequent respiratory infections and dyspnea were reported, in addition to substantial motor delay and a slight delay in cognitive and language development. His cardiac echocardiography showed mild mitral valve collapse and mild tricuspid regurgitation. A series of biochemical and molecular tests (including for SMN1) were negative, except for the observation of mildly elevated CPK levels at 548 IU/L.

Despite an intensive rehabilitation course, neither a pulmonary function test nor respiratory assistance was administered in the patient’s medical setting. At 10 months, the patient experienced sudden-onset respiratory distress, requiring cardiopulmonary resuscitation in an emergency room. Brain MRI at that time disclosed mild ventricular dilatation and myelination delay (Fig. 2B). After another 2 months, the patient experienced a second, longer asphyxia event, and the brain MRI performed during hospital admission revealed extensive cystic cavities in the bilateral parietal, frontal, and temporal lobes and insular cortex with marked neuronal loss. Abnormal signal intensity was present within the bilateral basal ganglia and white matter (Fig. 2C). Therefore, brain damage due to asphyxia was diagnosed, and the patient exhibited a persistent vegetative state. Following a third respiratory distress event at 1 year and 2 months, the patient died because the family requested no further resuscitation.

In P1, a muscular dystrophy/myopathy gene panel comprising 77 genes revealed compound heterozygous variants in trans in LAMA2. One variant was maternally inherited (NM_000426.3:c.7525_7528dupCTCA/ p.Ser2510ThrfsTer3), and one variant was paternally inherited (c.112 + 2 T > C). In P2, we conducted WES and Sanger sequencing to validate the results of WES on DNA samples from the proband and his parents, leading to the identification of the following compound heterozygote mutations in LAMA2: (1) c.1583dupA(p.S529Efs*18) in exon 11, inherited from the father; and (2) c.A6931T:p.K2311X in exon 49, inherited from the mother. The four variants in our patients were extremely rare and were not listed among known Genome Aggregation Database exomes; all of the identified mutations were expected to be damaging to the protein structure, resulting in the premature termination of translation.

We present two cases of LAMA2 MD, one in which the patient was diagnosed early and achieved a good prognosis, and another in which the patient died before diagnosis. The clinical presentations and prognoses of these two patients are compared in Table 1. The early diagnosis of LAMA2 MD and disease management by a multidisciplinary team can improve the quality of life and prolong the life span of a patient. Although spinal muscular atrophy is a commonly considered diagnosis among infants presenting with hypotonia and motor delays, many cases of congenital muscular dystrophy involve genetically determined conditions that are evident at birth (such as mutations in LAMA2, SEPN1, COL6A1, COL6A2, COL6A3, LMNA, POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE, ISPD, GTDC2, TMEM5, B3GALNT2, POMK, B3GNT1, or GMPPB) [6, 7]. This clinical report underlines the importance of early diagnosis in cases of LAMA2 MD, which may lead to more favorable results, as was observed in these two patients.

Most patients with LAMA2 MD display periventricular white matter abnormalities on brain imaging, but mental retardation and seizures are rare occurrences [8‐10]. However, the case of P2 raises two questions. (1) What changes occur on brain MRI in patients with LAMA2 MD who experience concurrent hypoxic/ischemic events? (2) Can the typical clinical manifestation of LAMA2 MD be masked or distorted by hypoxic events? P2 entered a vegetative state after two prolonged asphyxia events, resulting in a delayed diagnosis due to a distorted clinical presentation [11, 12].

The diagnostic algorithm for early-onset congenital muscular dystrophy has recently undergone considerable change [13, 14], and many currently available molecular diagnostic tools, such as WES, whole-genome sequencing, and targeted panel sequencing for myopathy diseases, can facilitate the early diagnosis of muscular diseases [10]. All cases of hypotonia in infants without determined causes should proceed to comprehensive genetic screening, and WES should be considered as a first choice for cases with clear causal indications. These less invasive techniques have partially replaced muscle biopsies as the first diagnostic step [15].

In addition to being clinically significant, the four variants identified in these two patients are novel LAMA2 mutations. In particular, the c.7525_7528dupCTCA(p.Ser2510ThrfsTer3), c.112 + 2 T > C, c.1583dupA(p.S529Efs*18), and c.A6931T(p.K2311X) mutations enrich the genetic spectrum of LAMA2 MD.

In summary, we report two cases of LAMA2 MD diagnosed that were diagnosed at different stages of life, resulting in opposite outcomes. We suggest that a comprehensive genetic investigation for patients with suspected muscular dystrophy be performed as early as possible to facilitate correct diagnosis and the provision of appropriate treatment. Moreover, four novel mutations in LAMA2 were discovered, enriching the genetic spectrum of LAMA2 MD.