Our results show the high value of the muscle biopsy in the elucidation of mitochondrial disease. However a normal respiratory chain activity in skeletal muscle can not rule out mitochondrial disease. From our experience testing for mtDNA deletions or depletion should be the initial step. Background: Barth syndrome is an X-linked genetic disorder presenting with cardiac and skeletal myopathies and caused by inborn errors in the tafazzin gene, resulting in defects in cardiolipin (CL) metabolism. CL is a unique mitochondrial phospholipid that is essential for assembly of electron-transport chain (ETC) and multi-enzyme complexes. The objective of this study is to elucidate the involvement of CL in the interaction of fatty acid oxidation (FAO) enzymes with mitochondrial ETC complexes. Methods: We investigated the effects of CL-deficiency on mitochondrial trifunctional protein (mTFP) interaction with ETC complex I in cardiac muscle of tafazzin knockdown mice. Results: Cardiolipin deficiency resulted in cardiac dysfunction, mitochondrial abnormalities, excessive autophagy and impaired energetics in tafazzin-knockdown mice. We found that cardiolipin-deficiency destabilizes the interaction of mTFP with ETC complex I. Analysis of extracellular fluxes revealed impaired utilization of palmitate as an energy substrate for mitochondrial FAO in tafazzin-deficient cardiomyocytes. Conclusion: Cardiolipin is essential for the normal physical association of TFP with ETC Complex I in cardiac mitochondria. Dissociation of TFP from ETC Complex I adversely affects the efficiency of fatty acid oxidation and aerobic energy production in heart. Impaired FAO may be one of the many pathogenic factors in Barth syndrome patients. Background: Barth syndrome (BTHS)(OMIM302060)or 3-Methylglutaconic aciduria type II, is a rare x-linked recessive disorder. It characterized by dilated cardiomyopathy, skeletal myopathy, cyclic neutropenia and elevated 3-methylglutaconic and 3 methylglutric acide in the urine. Variable clinical phenotypes being reported. Methods: Total of 3 patients, presenting with the constellation of findings suggestive of BTHS. Two had early evaluation by fetal echocardiogram (Echo).The diagnosis in all cases confirmed at the biochemical (urine gas chromatography-mass spectrometry (GC/MS)) and molecular level (TAZ gene sequencing).Periodic complete blood count, lactic acid, and Echo were performed. Results: Two families with 3 affected children; two patients were picked up early by abnormal fetal echocardiogram. The third presented with recurrent infection in infancy and failure to thrive. Subsequently all were found to have cardiomyopathy, cyclic neutropenia and the characteristic urine organic acid changes. Molecular analysis revealed that affected patients and their mothers were having hemizygous and heterozygous changes respectively in Taz gene. Conclusions: This is the first report of Saudi patients with Barth syndrome and their genotype. Early detection of cardiomyopathy by fetal echocardiogram and high index of suspicion would prevent unnecessary investigations and aid to better management in patients with BTHS. We report a 12 year old boy, who presented at 3 months of age with intractable seizures, optic atrophy, hypertonia, hyperreflexia in the lower extremities with clonus, and areflexia in the upper extremities. Family history was normal. Progressive cystic changes of the white matter noted on sequential MRIs was classified as a neurodegenerative spongiform leukoencephalopathy of unknown etiology. MRS demonstrated a large lactate peak and low NAA. Over the next 5 years, development was static, limited to smiling responsively. Muscle biopsy was done despite the MRI changes not considered classical of mitochondrial disease. Complex I deficiency was demonstrated and sequencing for known complex 1 genes available at that time including NDUFS 3, 4, 6, 7 failed to delineate the molecular etiology. A healthy brother was born unaffected suggesting recessive rather than maternal inheritance. In 2010, molecular analysis of NDUFV1 was pursued and the patient was found to have two heterozygous mutations: one previously reported in homozygous state in two siblings with similar presentations and MRI changes. The second mutation is a novel splice site mutation. This case report illustrates the importance of considering Complex 1 disease and in particular NDUFV1 molecular analysis in children with spongiform leukoencephalopathy. We report on two siblings, born to consanguineous Pakistani parents, with Sengers syndrome. The proband presented at 15 months of age following a cardio-respiratory arrest and was found to have hypertrophic cardiomyopathy with severely impaired cardiac function requiring ECMO support. The history revealed bilateral cataract surgery at 3 months and gross motor delay noted at 12 months. After assessment for cardiac transplantation eligibility, cardio-respiratory support was withdrawn. The mother was 32 weeks pregnant at the time and delivered a newborn male, noted to have bilateral cataracts at 1 week of age, lactic acidosis and hypertrophic cardiomyopathy at 8 weeks of age. The histochemical studies in the proband showed scattered COX negative fibers (previously unreported in Sengers syndrome) and pleomorphic mitochondria with abnormal structure. Respiratory chain complex activities were atypically all severely reduced. Histochemical studies in the sibling showed normal COX staining, but an increased number of morphologically abnormal mitochondria. The sibling had reduced respiratory chain complex activities reminiscent of, but less severe than, the proband. The sibling has reached 15 months of age and has had few symptoms, although his cardiomyopathy is progressive. This case report illustrates intra-familial variability of histochemical findings for two siblings with the same clinical phenotype. year-old girl, born to nonconsanguine Chinese parents, presented with global developmental delay within the first 6 months of life. She was evaluated for sensorial-neural hearing loss, ataxia, ophthalmoplegia and muscle weakness at age 3 years. In her physical examination, her growth parameters were at 50th percentile. There was no organomegaly. Her muscle tone was decreased. Deep tendon reflexes were not elicitable. She had marked ataxia and marked restriction in all gaze directions of each eye. Peripheral nerve conduction study showed generalized sensory-motor neuropathy. Her cranial MRI and MRspectroscopy were normal. Her liver function tests were normal. She had novel compound heterozygous (c.1279 G>A; p.E427K and c.1838A>G; p.D613G) missense mutations in the TWINKLE Helicase (C10orf2) gene. Conclusion: This is a patient with early onset mitochondrial encephalomyopathy caused by mitochondrial depletion in the TWINKLE Helicase (C10orf2) gene. Background: Mitochondrial complex I assembly is an intricate process which involves incorporating 45 subunit proteins, 1 flavin mononucleotide and 8 iron-sulphur clusters into the final~980 kDa holoenzyme. Mutations in any of the 45 subunits or in an unknown number of assembly factors and chaperones may cause complex I deficiency.