 Our body ’s nucleated cells contain mitochondria  In the cone cell photoreceptors of the eye, mitochondria make up 80% of the intracellular volume  In extraocular muscles like the lateral rectus :60%  In heart muscle :40%  In the liver, mitochondria are specialized to detoxify ammonia in the urea cycle  Mitochondria are also required, for neurotransmitter metabolism,

 The first mitochondrial disorder was recognized in 1962; since then, mitochondrial disorders have emerged as major clinical entities  Organs such as the brain, heart, and skeletal muscle are highly energy dependent and vulnerable to defects in energy metabolism  Mitochondrial encephalomyopathies are a genetically, biochemically, and clinically heterogeneous group of disorders associated with abnormalities of oxidative phosphorylation  The final diagnosis relied on clinical and molecular criteria  There is no absolute gold standard to establish a diagnosis of mitochondrial encephalomyopathy

 Lethal infantile mitochondrial disease :  Fulminant neonatal onset (death within 6 months of life)  Classic Mitochondrial syndrome  (mtDNA deletion/duplication and point mutation):  MELAS – A3243G and T3271C  MERRF _ A8344G and T8356C  NARP _ T8993G and T8993C  Cardiomyopathy _ G8363A  LHON _ G11778A, G3460A, T1448C, G14459A  Kern Sayre Syndrome

 MNGIE  Severe gastrointestinal dysmotility ( Vomiting and pseudo-obstruction)  Cachexia  Ptosis  External ophtalmoplegia  Peripheral neuropathy  Leukoencephalopathy

 Cardiomyopathy and myopathy :  clinical subtype dominated by cardiac and myopathic symptoms (within this group) :  - Sengers syndrome :  congenital cataracts, hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis  -Barth syndrome diagnosed with : left ventricular noncompaction (LVNC), skeletal myopathy, 3- methylglutaconic aciduria, and short stature  The group of nonspecific encephalomyopathy included all patients who would not fit into any of the other subtypes

 Developmental delay  Abnormality of tone  Movement disorder  Seizure  Cardiomyopathy  Arrythmia  Ophthalmologic disease  Hearing loss

 Lactic acidosis  Neuroimaging  Histopathologic finding  Enzyme histochemistry  Ultrastructural abnormalities of mitochondria  Quantitative biochemical analysis (RC defects)

 Diagnostic criteria for pediatric mitochondrial disorders have been modified from an adult classification system  The modified Walker criteria  Because the natural history of this heterogeneous group of disorders remains largely unknown, the modified Walker criteria is useful to assess the frequency of major clinical manifestations in a population of infants and children with definite diagnosis of mitochondrial disease  By using the modified Walker criteria,  we are able to gather a large group of pediatric patients with a definite diagnosis of a mitochondrial disorder and study their clinical histories

Modified Walker Criteria Applied to Children of Mitochondrial Disease 2 major criteria or 1 major plus 2 minor = Mitochondrial D. Major CriteriaMinor Criteria Clinical Clinically complete Respiratory chain encephalomyopathy or a mitochondrial cytopathy defined as fulfilling all 3 of the following Symptoms compatible with a Respiratory Chain defect Histology >2% ragged red fibers in skeletal muscleSmaller numbers of RRF, Sub sarcolemal Accumulation of Mitochondria or widespread electron microscopy abnormalities of mitochondria Enzymology Cytochrome c oxidase negative fibers or residual activity of a RC complex <20% in a tissue; <30% in a cell line, or <30% in 2 or more tissues Antibody-based demonstration of an RC defect or residual activity of an RC complex 20%–30% in a tissue, 30%–40% in a cell line, or 30%–40% in 2 or more tissues Functional Fibroblast ATP synthesis rates >3 SD below mean Fibroblast ATP synthesis rates 2–3 SD below mean, or fibroblasts unable to grow in galactose media Molecular Nuclear or mtDNA mutation of undisputed pathogenicity Nuclear or mtDNA mutation of probable pathogenicity Metabolic One or more metabolic indicators of impaired metabolic function

 1-Unexplained combination of multisystemic symptoms that is essentially pathogonomic for RC defects  2-Progressive clinical course with episodes of exacerbations or a family history strongly indicative of mtDNA mutation  3-Other possible neurometabolic disorders have been excluded

 RC defect,Pediatric features :  Stillbirth associated with a paucity of intrauterine movement, neonatal death, movement disorder, severe FTT, neonatal hypotonia, neonatal hypertonia are minor criteria

Conditions with Nuclear DNA Defects  Substrate Transport defect  carnitine transporter  carnitine palmitoyltransferase I  the carnitine–acylcarnitine translocase  carnitine palmitoyltransferase II  Defects of Substrate Utilization  Pyruvate carboxylase deficiency,  pyruvate dehydrogenase complex deficiency  defects of beta oxidation  Defects of Oxidation–Phosphorylation Coupling  Defects of the Krebs Cycle  Defects of the Respiratory Chain  Defects of Protein Importation  Defects of Intergenomic Signaling  Defects of the Lipid of the Inner Mitochondrial Membrane  Defects of Mitochondrial Motility, Fusion, and Fission Inherited Conditions Associated with Mitochondrial DNA Defects  Sporadic Large-Scale Rearrangements  Point Mutations Deffects  Protein-Coding Genes  Point Mutations Affecting Synthetic Genes Acquired Conditions Associated with Mitochondrial Dysfunction

 Muscle weakness (proximal > distal and upper > lower extremities)  Hypotonia  Peripheral neuropathy  Ataxia  Ptosis  Ophthalmoplegia  Bulbar signs  Spasticity Stroke-like episodes  Migraine  Headaches  Tremor, chorea, ballismus  Dystonia  Seizures  Myoclonus

 CPEO :Chronic progressive external ophthalmoplegia  LHON :Leber hereditary optic neuropathy  MELAS :Mitochondrial encephalopathy, lactic acidosis, and stroke  MERRF :Myoclonic epilepsy with ragged red fibers  MNGIE :Mitochondrial myopathy,  peripheral neuropathy, and gastrointestinal encephalopathy  NARP :Neuropathy, ataxia, and retinitis pigmentosa  KSS :Kearns-Sayre syndrome

 With congenital anomalies :  Are premature,24-48 hours of life :severe hypoglycemia,hypotonia, hepatomegaly, metabolic acidosis, sweaty feet odor  Abnormal feature, high forehead, low set ear, hypertelorism, hypoplastic mid facial and anomaly of kidney  Most of them die in first weeks of life  Without congenital anomalies,  hypotonia, tachypnea, metabolic acidosis, hepatomegaly, hypoglycemia, and a peculiar odor reminiscent of isovaleric acidemia  Adult phenotype or late onset :  Vomiting, hypoglycemia, hepatomegaly, and limb weakness  Milder form of multiple acyl coenzyme A dehydrogenase deficiency respond to riboflavin

 Extremely different in age and presentation  Asymptomatic during childhood  Presented in juvenile and adult life with episodic vomiting, hypoglycemia, hepatomegaly or proximal weakness  Some patients have had progressive lipid storage myopathy with carnitine deficiency  Caused by mutation in ETF dehydrogenase gene and can be treated with coQ10 and Riboflavin  These patients present with exercise intolerance, fatigue, proximal myopathy and high serum CPK

 Due to defect of the electron transfer flavoprotein (ETF) or ETF ubiquinone oxidoreductase which are nuclear encoded proteins through which electrons from flavoprotein acyl-coA dehydrogenase enter the respiratory chain  High dose Riboflavin

 Described by Denis Leigh, British physician, in 1951  One of the more deadly mitochondrial D.  Bilaterally symmetrical MRI abnormalities in the brain stem, cerebellum, and basal ganglia,  Accompanied by elevated lactic acid in the blood and cerebrospinal fluid and Urine

 Belongs to a group of neurodevelopmental disorders known as ASD and is characterized by impaired social interactions, deficits in language and communication, repetitive as well as restricted behaviors  usually observed in the first three years of life  males are affected 4 times more than females  Symptoms include hyperactivity, inattention, irritability (including severe tantrums, aggression, and self-injurious behavior), intellectual impairment, sleep disturbances, sensory hypersensitivity, and seizures  Exact cause of autism remain unknown but it considered to be a result of various genetic, environmental, and immunological factors along with increased vulnerability to oxidative stress.  No biomarkers exist to diagnose therefore diagnosis is based on observed behaviors  No known cures exist for autism

 Significantly lower levels of:  complexes III and V in the cerebellum  complex I in the frontal cortex  complexes II, III, and V in the temporal cortex  No defects in the parietal and occipital cortices have been observed as of yet  This can lead to abnormal energy metabolism