A number sign (#) is used with this entry because of evidence that infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12) is caused by homozygous or compound heterozygous mutation in the MYL2 gene (160781) on chromosome 12q23.

Infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12) is a severe autosomal recessive disorder affecting both skeletal and cardiac muscle tissue that is apparent in the first weeks of life. Affected infants show tremor or clonus at birth, followed by onset of rapidly progressive generalized muscle weakness and dilated cardiomyopathy and cardiac failure, usually resulting in death by 6 months of age. Skeletal and cardiac muscle tissues show hypotrophy of type I muscle fibers and evidence of myofibrillar disorganization (summary by Weterman et al., 2013).

For a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).

Barth et al. (1998) reported 5 infants from 3 unrelated Dutch families with a similar fatal disorder affecting skeletal and cardiac muscle. The affected infants had neonatal onset of tremor that gradually became less pronounced and was followed by progressive generalized muscle weakness with head lag, ptosis, and failure of antigravity movements. All patients developed dilated cardiomyopathy with progressive cardiac decompensation, eventually resulting in cardiac failure and death by 6 months of age. Skeletal muscle biopsy showed hypotrophy of type I muscle fibers, consistent with congenital fiber-type disproportion (CTFD), as well as variable Z-band streaming and myofibrillar lysis on electron microscopy. Examination of heart muscle tissue from 1 patient showed loss of myocardial myofibrillar structures and subendocardial foci of fibrinoid necrosis. The brain and spinal cord were normal. Although the authors postulated a metabolic defect, possibly due to mitochondrial dysfunction, analysis of mitochondrial respiratory chain function was normal.

Weterman et al. (2013) reported 11 infants from 8 different Dutch families and 2 infants from an Italian family with MFM12. Three of the Dutch families had previously been reported by Barth et al. (1998). The patients had a normal birth with no obvious signs of malformation, although they had a characteristic generalized high-amplitude coarse clonus/tremor resembling an infantile hyperexcitation syndrome. Within a few weeks of birth, the patients developed rapidly progressive generalized muscle weakness, often with facial muscle weakness and a tented mouth. All died of progressive failure due to cardiomyopathy by 6 months of age. The cardiomyopathy was mainly dilated, although some had hypertrophic, restrictive, or noncompaction cardiomyopathy. Skeletal muscle biopsy showed fiber-type disproportion with small type I fibers. Electron microscopy showed myofibrillar disorganization, loss of myofibrils, disarray of normal sarcomeric structures, and abnormal Z-discs. Plasma creatine kinase was increased.

Manivannan et al. (2020) reported 4 infants, born of consanguineous parents, who died of cardiac failure by 1 year of age. All patients also had hypotonia, suggesting generalized muscle weakness, and hepatomegaly. Two patients studied in more detail had dilated cardiomyopathy with ventricular hypertrophy and mitral valve regurgitation. Postmortem examination of the proband confirmed severe biatrial dilatation, biventricular hypertrophy, and severe mitral valve dysplasia. The parents were asymptomatic from a cardiac standpoint.

The transmission pattern of MFM12 in the families reported by Weterman et al. (2013) was consistent with autosomal recessive inheritance.

In 11 infants from 5 unrelated Dutch families and 2 sibs from an Italian family with MFM12, Weterman et al. (2013) identified homozygous or compound heterozygous mutations in the MYL2 gene (160781.0006-160781.0008) that segregated with the disorder in the families. The mutations, 1 splice site and 2 frameshifts, all occurred in the last exon of the gene and were predicted to result in the production of C-terminally truncated proteins with disruption of the second EF-hand domain, which is important for calcium signaling. The mutations, which were found by a combination of homozygosity mapping and candidate gene sequencing or whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The heterozygous parents were unaffected. Analysis of patient tissue from the Dutch patients showed absence of the full-length MYL2 protein and decreased expression of mutant protein with an altered C-terminal tail. The authors postulated a partial loss-of-function effect. Three of the families had previously been reported by Barth et al. (1998). Haplotype analysis indicated a founder effect for the Dutch mutation (160781.0006).

In a male infant, born of consanguineous parents, with MFM12, Manivannan et al. (2020) identified a homozygous frameshift mutation in the last exon of the MYL2 gene (160781.0009). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the gnomAD database. The carrier parents were clinically unaffected; 3 additional sibs of the proband died of a similar disorder in infancy. Cardiac muscle tissue from the proband showed decreased protein levels of MYL2 compared to controls, although mRNA levels were similar. In vitro cellular studies showed that the mutant MYL2 variant is degraded by the proteasomal machinery, suggesting instability of the mutant protein. Expression of the mutation failed to rescue developmental lethality and cardiac muscle defects in Myl2-null Drosophila, consistent with a loss-of-function effect.