Lim et al. (2013) reported a 20-year-old man, from a consanguineous family of Lebanese and Syrian ancestry, with a mitochondrial disorder characterized by respiratory distress, hypotonia, and severe lactic acidosis in the newborn period. Other features included gastroesophageal ... Lim et al. (2013) reported a 20-year-old man, from a consanguineous family of Lebanese and Syrian ancestry, with a mitochondrial disorder characterized by respiratory distress, hypotonia, and severe lactic acidosis in the newborn period. Other features included gastroesophageal reflux and elevated liver enzymes with normal synthetic function. He slowly improved with supportive therapy over the following weeks. At age 20 years, he showed normal psychomotor development and had no residual muscular or neurologic defects. A double first cousin of this patient showed a more severe phenotype. She had respiratory distress and lactic acidosis as a neonate, and showed persistent poor growth, hepatomegaly, and weakness. EEG showed epileptiform changes. She died at 2 months of age. Postmortem examination showed widened fiber size in skeletal muscle, increased lipid in muscle and liver, and abnormal mitochondria on electron microscopy. Laboratory studies on patient liver and muscle samples showed decreased activities of mitochondrial respiratory complexes I, II, and III. Lim et al. (2013) postulated that the differences in clinical outcome between these patients may have resulted from differences in the dietary neonatal availability of cysteine, requirement of which is highest at birth and later decreases.
In 2 members of a consanguineous family of Lebanese and Syrian ancestry with combined oxidative phosphorylation deficiency, Lim et al. (2013) identified a homozygous missense mutation in the LYRM4 gene (R68L; 613311.0001). The mutation, which was found by ... In 2 members of a consanguineous family of Lebanese and Syrian ancestry with combined oxidative phosphorylation deficiency, Lim et al. (2013) identified a homozygous missense mutation in the LYRM4 gene (R68L; 613311.0001). The mutation, which was found by massively parallel sequencing of mitochondrial proteins and confirmed by Sanger sequencing, was not present in the dbSNP (build 132), 1000 Genomes Project, or Exome Variant Server databases, or in 172 ethnically matched control chromosomes. The LYRM4 protein was not detected in skeletal muscle from 1 patient or in liver tissue from either patient. Liver and muscle tissue from both patients showed decreased levels and activities of multiple mitochondrial oxidative enzymes, including complexes I, II, and III, as well as decreased amounts of FeS-containing proteins. Patient fibroblasts showed normal OXPHOS enzyme activity. The mutant yeast ortholog R71L failed to rescue the growth of a LYRM4-null yeast strain, consistent with a loss of function. In vitro cellular expression studies showed that mutant LYRM4 could form a normal complex with NFS1 (603485), but the desulfurase enzymatic activity of this complex was severely decreased compared to control. The findings indicated a defect in the early step of FeS assembly affecting multiple proteins.