Mitochondrial disorders.

Primary mitochondrial disorders are a group of clinically variable and heterogeneous inborn errors of metabolism (IEMs), resulting from defects in cellular energy, and can affect every organ system of the body. Clinical presentations vary and may include symptoms of fatigue, skeletal muscle weakness, exercise intolerance, short stature, failure to thrive, blindness, ptosis and ophthalmoplegia, nystagmus, hearing loss, hypoglycemia, diabetes mellitus, learning difficulties, intellectual disability, seizures, stroke-like episodes, spasticity, dystonia, hypotonia, pain, neuropsychiatric symptoms, gastrointestinal reflux, dysmotility, gastrointestinal pseudo-obstruction, cardiomyopathy, cardiac conduction defects, and other endocrine, renal, cardiac, and liver problems. Most phenotypic manifestations are multi-systemic, with presentations varying at different age of onset and may show great variability within members of the same family; making these truly complex IEMs. Most primary mitochondrial diseases are autosomal recessive (AR); but maternally-inherited [from mitochondrial (mt) DNA], autosomal dominant and X-linked inheritance are also known. Mitochondria are unique energy-generating cellular organelles, geared for survival and contain their own unique genetic coding material, a circular piece of mtDNA about 16,000 base pairs in size. Additional nuclear (n)DNA encoded genes maintain mitochondrial biogenesis by supervising mtDNA replication, repair and synthesis, which is modified during increased energy demands or physiological stress. Despite our growing knowledge of the hundreds of genetic etiologies for this group of disorders, diagnosis can also remain elusive due to unique aspects of mitochondrial genetics. Though cure and FDA-approved therapies currently elude these IEMs, and current suggested therapies which include nutritional supplements and vitamins are of questionable efficacy; multi-center, international clinical trials are in progress for primary mitochondrial disorders.

Triheptanoin versus trioctanoin for long-chain fatty acid oxidation disorders: a double blinded, randomized controlled trial.

BACKGROUND: Observational reports suggest that supplementation that increases citric acid cycle intermediates via anaplerosis may have therapeutic advantages over traditional medium-chain triglyceride (MCT) treatment of long-chain fatty acid oxidation disorders (LC-FAODs) but controlled trials have not been reported. The goal of our study was to compare the effects of triheptanoin (C7), an anaplerotic seven-carbon fatty acid triglyceride, to trioctanoin (C8), an eight-carbon fatty acid triglyceride, in patients with LC-FAODs. METHODS: A double blinded, randomized controlled trial of 32 subjects with LC-FAODs (carnitine palmitoyltransferase-2, very long-chain acylCoA dehydrogenase, trifunctional protein or long-chain 3-hydroxy acylCoA dehydrogenase deficiencies) who were randomly assigned a diet containing 20% of their total daily energy from either C7 or C8 for 4 months was conducted. Primary outcomes included changes in total energy expenditure (TEE), cardiac function by echocardiogram, exercise tolerance, and phosphocreatine recovery following acute exercise. Secondary outcomes included body composition, blood biomarkers, and adverse events, including incidence of rhabdomyolysis. RESULTS: Patients in the C7 group increased left ventricular (LV) ejection fraction by 7.4% (p = 0.046) while experiencing a 20% (p = 0.041) decrease in LV wall mass on their resting echocardiogram. They also required a lower heart rate for the same amount of work during a moderate-intensity exercise stress test when compared to patients taking C8. There was no difference in TEE, phosphocreatine recovery, body composition, incidence of rhabdomyolysis, or any secondary outcome measures between the groups. CONCLUSIONS: C7 improved LV ejection fraction and reduced LV mass at rest, as well as lowering heart rate during exercise among patients with LC-FAODs. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT01379625.

Nutritional interventions in primary mitochondrial disorders: Developing an evidence base.

In December 2014, a workshop entitled "Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base" was convened at the NIH with the goals of exploring the use of nutritional interventions in primary mitochondrial disorders (PMD) and identifying knowledge gaps regarding their safety and efficacy; identifying research opportunities; and forging collaborations among researchers, clinicians, patient advocacy groups, and federal partners. Sponsors included the NIH, the Wellcome Trust, and the United Mitochondrial Diseases Foundation. Dietary supplements have historically been used in the management of PMD due to their potential benefits and perceived low risk, even though little evidence exists regarding their effectiveness. PMD are rare and clinically, phenotypically, and genetically heterogeneous. Thus patient recruitment for randomized controlled trials (RCTs) has proven to be challenging. Only a few RCTs examining dietary supplements, singly or in combination with other vitamins and cofactors, are reported in the literature. Regulatory issues pertaining to the use of dietary supplements as treatment modalities further complicate the research and patient access landscape. As a preface to exploring a research agenda, the workshop included presentations and discussions on what PMD are; how nutritional interventions are used in PMD; challenges and barriers to their use; new technologies and approaches to diagnosis and treatment; research opportunities and resources; and perspectives from patient advocacy, industry, and professional organizations. Seven key areas were identified during the workshop. These areas were: 1) defining the disease, 2) clinical trial design, 3) biomarker selection, 4) mechanistic approaches, 5) challenges in using dietary supplements, 6) standards of clinical care, and 7) collaboration issues. Short- and long-term goals within each of these areas were identified. An example of an overarching goal is the enrollment of all individuals with PMD in a natural history study and a patient registry to enhance research capability. The workshop demonstrates an effective model for fostering and enhancing collaborations among NIH and basic research, clinical, patient, pharmaceutical industry, and regulatory stakeholders in the mitochondrial disease community to address research challenges on the use of dietary supplements in PMD.

Bilateral symmetrical basal ganglia and thalamic lesions in children: an update (2015).

INTRODUCTION: In children, many inherited or acquired neurological disorders may cause bilateral symmetrical signal intensity alterations in the basal ganglia and thalami. METHODS: A literature review was aimed at assisting neuroradiologists, neurologists, infectious diseases specialists, and pediatricians to provide further understanding into the clinical and neuroimaging features in pediatric patients presenting with bilateral symmetrical basal ganglia and thalamic lesions on magnetic resonance imaging (MRI). RESULTS: We discuss hypoxic-ischemic, toxic, infectious, immune-mediated, mitochondrial, metabolic, and neurodegenerative disorders affecting the basal ganglia and thalami. CONCLUSION: Recognition and correct evaluation of basal ganglia abnormalities, together with a proper neurological examination and laboratory findings, may enable the identification of each of these clinical entities and lead to earlier diagnosis.

Infantile hypophosphatasia secondary to a novel compound heterozygous mutation presenting with pyridoxine-responsive seizures.

Hypophosphatasia (HPP) is a rare metabolic disease with the hallmark finding of deficient serum tissue nonspecific alkaline phosphatase (TNSALP) activity. TNSALP is primarily known for its role in mineralization; hence, HPP is characterized by defective mineralization of bone and/or teeth. TNSALP is also necessary for proper vitamin B6 metabolism and its participation as a cofactor for neurotransmitters in the central nervous system. Defective TNSALP activity in the brain can result in intractable seizures responsive to pyridoxine. The pathophysiology of pyridoxine-responsive seizures (PRS) in severe HPP remains to be clearly defined. We review the case of a 2-month-old Caucasian boy presenting with seizures refractory to conventional antiepileptic medications. Empiric treatment with favorable response to pyridoxine in conjunction with severe metabolic bone disease, extremely low serum alkaline phosphatase, elevated phosphoethanolamine, hypercalcemia, hypercalciuria, and nephrocalcinosis led to a clinical diagnosis of infantile HPP. Sequence analysis revealed compound heterozygosity of the TNSALP gene with a novel mutation in exon 9 and a previously reported mutation in exon 12. This case reminds the physician that severe infantile HPP can present with PRS as its major initial manifestation and should alert clinicians to consider HPP in their differential of PRS. In addition, despite this severe genotype, the clinical diagnosis of our patient was delayed because of minimal phenotypic features initially. This highlights that the phenotype-genotype correlation could be variable even in severe disease. This case also demonstrates that HPP should be classified as PRS and not a form of pyridoxine-dependent epilepsy (PDE) as our patient was able to stop the pyridoxine supplementation without seizure recurrence once enzyme replacement was initiated. With the advent of enzyme replacement therapy, this once fatal disease may have improved morbidity and mortality.