Lipid storage myopathy due to FLAD1 deficiency is an autosomal recessive inborn error of metabolism that includes variable mitochondrial dysfunction. The phenoty...
Lipid storage myopathy due to FLAD1 deficiency is an autosomal recessive inborn error of metabolism that includes variable mitochondrial dysfunction. The phenotype is extremely heterogeneous: some patients have a severe disorder with onset in infancy and cardiac and respiratory insufficiency resulting in early death, whereas others have a milder course with onset of muscle weakness in adulthood. Some patients show significant improvement with riboflavin treatment (summary by Olsen et al., 2016).
▼ Clinical Features
Taylor et al. (2014) reported a Turkish boy (patient 30), born of consanguineous parents, who presented at age 4 months with respiratory insufficiency and lipid myopathy. Skeletal muscle biopsy showed global COX defect and decreased activities of mitochondrial complexes I and IV. He died at 8 months of age.
Olsen et al. (2016) reported 9 patients from 7 unrelated families, recruited from metabolic centers in 6 countries, with a metabolic myopathy variably associated with mitochondrial respiratory chain deficiencies. Seven patients had a severe disorder with onset of hypotonia, swallowing and feeding difficulties, and respiratory insufficiency in infancy. Analysis of skeletal muscle showed multiple mitochondrial respiratory chain deficiency in most patients. Muscle biopsy showed a lipid storage myopathy in most patients. Laboratory studies were variable, but tended to show elevation of multiple acylcarnitines, as well as increased urinary organic acids, including ethylmalonic acid and adipic acid. The biochemical abnormalities resembled those observed in multiple acyl-CoA dehydrogenase deficiency (MADD; 231680). Four patients died within the first year of life. In 1 consanguineous family, a boy died at age 3 days, whereas his sister was still alive at age 22 years. She had been treated for cardiomyopathy in the first year of life and had a pacing/defibrillator device; riboflavin treatment resulted in a favorable response. Two additional unrelated women had a much milder disease course, with onset of significant muscle weakness at ages 20 and 45 years, respectively. The first patient had an exacerbation of muscle weakness during pregnancy at age 30 associated with increased C8- and C10-acylcarnitine species and a lipid storage myopathy on muscle biopsy. The other woman had proximal muscle weakness of the upper and lower limbs, abnormal acylcarnitine profile, and lipid storage myopathy. Both of these patients had decreased activities of multiple respiratory chain enzymes. Riboflavin treatment in both women resulted in almost complete resolution of muscle weakness and biochemical abnormalities. None of the patients had progressive neurologic signs: there was no hearing or visual impairment and also no peripheral neuropathy. One consanguineous family experienced 4 miscarriages.
The transmission pattern of lipid-storage myopathy due to FLAD1 deficiency in the families reported by Olsen et al. (2016) was consistent with autosomal recessive inheritance.
▼ Molecular Genetics
In a Turkish boy (patient 30), born of consanguineous parents, with lipid myopathy resulting in death in infancy, Taylor et al. (2014) identified a homozygous truncating mutation in the FLAD1 gene (610595.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The patient was part of a cohort of 53 individuals with biochemical evidence of multiple respiratory chain complex defects who underwent whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In 9 patients from 7 unrelated families with lipid-storage myopathy due to FLAD1 deficiency, Olsen et al. (2016) identified homozygous or compound heterozygous mutations in the FLAD1 gene (see, e.g., 610595.0002-610595.0006). The mutations in 2 patients were found by whole-exome sequencing; mutations in other patients were found by sequencing of candidate genes associated with fatty acid oxidation and/or mitochondrial disorders, as well as genes involved in riboflavin uptake and metabolism. Fibroblasts derived from some of the patients showed residual FADS activity. Those with mutations affecting a single residue (Ser495del, 610595.0002 and R530C, 610595.0003) had a less severe phenotype than those with biallelic truncating mutations. However, even those with truncating mutations had some residual FADS activity, which Olsen et al. (2016) speculated resulted from the compensatory use of alternative isoforms encoding only the FADS domain.
Bradley et al. (1969) described the case of a 25-year-old woman, offspring of first-cousin parents, with myopathy involving the muscles of the neck and proximal limbs. Muscle biopsy showed interfibrillar and subsarcolemmal vacuoles; histochemical study showed normal type-II muscle fibers with excessive neutral fat and free fatty acids in type-I fibers; and electron microscopy showed degenerate mitochondria. The defect may reside in the pathway of free fatty acid oxidation.