Clinical features
Human disease phenotypes linked to either dominant or recessive LAMA5 mutations were unknown until 2016 (Napolitano et al. 2016) therefore data on prevalence are not available.
Early symptoms of LAMA5 dominant phenotype in the infancy may be episodes of loss of consciousness associated with hypoglycaemia, with inter-ictal electroencephalography (EEG) inconsistent for epilepsy, and inter-ictal plasma glucose and insulin levels usually normal. The growth charts measures remain in the lower reference percentile in the early infancy. In addition to reduced head circumference, platybasia, dental abnormalities (tooth germ alterations and dental crowding) may occur, together with delaying in cranial sutures closure. General growth parameters achieve normality during puberty. Mild alopecia with dry and brittle hair and lack of eyebrows occur since puberty (Sampaolo S et al. 2017). Coagulation factors VII and VIII deficiency is a common trait, which disappears during adolescence. Joints pain as well as daytime sleepiness are referred since school age. For this reason, diagnosis of serum-negative osteoarthritis is common and intra-articular hip effusions is frequently detected. Therapy with steroids and immunosuppressive drugs leads to amelioration of symptoms but are not decisive. Muscle pain and fatigability together with persistent mild hyperCKemia are common in adult individuals. Electrophysiological registration is normal. Muscle biopsy demonstrates a mild primitive myopathy with variability of fibers calibre and a degeneration/regeneration pattern involving both types 1 and 2 fibers in a similar degree. Delayed wound healing and atrophic scars are typical in adult females while males disclose only atrophic scars. Malabsorption symptoms are usually present since childhood. Joint ligaments and visceral laxity are a common trait with different degree of severity (Liguori et al. 2018). Vitreous abnormalities, including Posterior Precortical Vitreous Pocket and Posterior Vitreous Detachment, were also reported (Napolitano et al. 2018).
Homozygous phenotype has been described in one adult consanguineous female (Maselli et al. 2017; Maselli et al. 2018). She was born hypotonic with weak sucking and crying and restrictive ventilatory failure requiring mechanical ventilation. One older brother died of muscle weakness and respiratory failure. Physical examination shows minor dysmorphic features including elongated face, elevated harch palate, and mild facial and body hirsutism. Gastric tube feeding is needed because of impaired swallowing. Severe scoliosis is present and chronic inflammatory bowel disease is reported. A further trait is myopia without retinal abnormalities. The neuromuscular clinical picture is dominated by inability to ambulate with bilateral knee flexion contractures, facial muscle twitches and tics, ptosis and weakness of extraocular, facial, tongue, and soft palate muscles. Furthermore, moderate weakness of neck flexors and proximal limb muscles is observed, together with depressed deep tendon reflexes. Serum CPK is normal and antibodies against the acetylcholine receptor (AChR) and the muscle specific kinase (MuSK) are negative. Magnetic resonance imaging shows mild volume loss of the brain despite the normal cognitive function. Repetitive nerve stimulation at 2 Hz shows anomalies similar to those seen in Lambert–Eaton myasthenic syndrome. Electron microscopy of neuromuscular junctions shows endplates alterations which explain the severe neuromuscular transmission failure.