Detection of FLAD1 mutations and lipid storage myopathy in a 5-year-old boy: a case report study

**Background:** Lipid storage myopathy due to FLAD1 deficiency is a rare autosomal recessive disorder caused by mutations in the FLAD1 gene, which encodes FAD synthetase. This enzyme is essential for the synthesis of flavin adenine dinucleotide (FAD), a cofactor for multiple mitochondrial dehydrogenases. Deficiency leads to multiple acyl-CoA dehydrogenase deficiency (MADD) and variable clinical phenotypes, ranging from severe early-onset disease with cardiac and respiratory failure to milder adult-onset muscle weakness. Riboflavin supplementation can improve symptoms in some patients, but response depends on the genotype.

**Methods:** This is a case report of a 5-year-old boy from Iran, born full-term to consanguineous parents. At age 3, he presented with difficulty climbing stairs and Gower's sign. Initial workup included routine blood tests, MLPA for Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), muscle biopsy, and whole-exome sequencing (WES).

**Key Results:** Routine blood tests showed mild anemia (Hb 12.3 g/dL, MCV 76.5 fL) and elevated alkaline phosphatase (672 U/L). MLPA for DMD and SMA were normal. Muscle biopsy revealed striated muscle with bimodal fiber size, atrophic fibers in groups, round hypertrophied fibers, some necrosis/regeneration with myophagocytosis, and no lipid excess on Oil Red O stain. Gomori trichrome, Congo red, PAS, NADH-TR, SDH, and COX stains were unremarkable. Severe atrophy of mainly type 2 fibers was noted. WES identified a homozygous pathogenic variant in FLAD1: Chr1:154960762:A>T, c.A554T:p.D185V in exon 2. The patient was treated with high-dose vitamins B1, B6, and Q10 and followed every 3 months.

**Clinical Implications:** This case confirms that exon 2 mutations in FLAD1 are associated with severe, early-onset lipid storage myopathy that is less responsive to riboflavin. The patient showed only partial biochemical response to riboflavin. The authors recommend FLAD1 genetic testing in all patients with MADD and suggest that riboflavin therapy should be considered even if the diagnosis is suspected, but may not be sufficient for survival in severe cases. This report expands the clinical spectrum of FAD synthase deficiency and underscores the need for further research on prenatal or postnatal high-dose riboflavin treatment.