Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial disorder is an inborn error of metabolism affecting the cellular respiratory chain. Defective energy production leads to a wide variety of clinical manifestations (ataxia, epilepsy, dementia, myopathy, polyneuropathy, retinal pigment anomalies, and cardiomyopathy with conduction anomalies). Hearing loss is a regular feature and is often the first clinical symptom. Audiologic data from 26 members of a family in three generations is presented. One of these patients was examined for the biochemical error. Respiratory study of muscle biopsy revealed a mild defect in the NADH-ubiquinone oxidoreductase step of the oxidative phosphorylation (complex I). The content of cytochrome aa3 (complex IV) was also reduced. Adult onset sensorineural hearing loss starting in the high frequency region progresses with a fairly constant speed in this family. A cochlear type of hearing loss is found in the less pronounced cases. Advanced cases present features of retrocochlear affection with decreasing speech recognition, elevated acoustic reflex thresholds, and increased ABR latency with derangement of potentials. Caloric sensitivity was unaffected.
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PMID:Audiologic findings in a family with mitochondrial disorder. 180 40

A therapeutic trial with polyvitamins and dichloroacetate (DCA) in combination with thiamine in a 13-year-old girl with complex I deficiency is reported. The polyvitamin therapy included thiamine, riboflavin, ascorbate, coenzyme Q 10 and carnitine. This therapeutic regine was used over a period of 17 months without any effect. Although DCA lowered the lactate concentration in blood and CNS--measured by magnetic resonance spectroscopy--no clinical benefit was achieved. After 20 weeks of DCA therapy a distal polyneuropathy with areflexia developed although 100 mg thiamine daily as comedication was given from the beginning of DCA therapy. Nerve conduction velocity of the peroneal nerve was not detectable, sensible evoked potentials of the tibialis posterious nerve were normal. This side-effect resolved completely within 6 months after omission of DCA. Our observation suggests a direct toxic effect of DCA only on the peripheral nervous system in our patient since several cerebral MRI and magnetic resonance spectroscopy studies showed no abnormalities. CONCLUSION. DCA lowers the lactate concentration in children with complex I deficiency of the respiratory chain in a dose of 100 mg/kg body weight without clinical benefit. Reversible peripheral polyneuropathy may develop under DCA therapy despite thiamine medication.
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PMID:Therapy of complex I deficiency: peripheral neuropathy during dichloroacetate therapy. 858 9

Two sisters developed gastrointestinal malabsorption with pain and unsteady gait due to polyneuropathy at age 15. Both had ophthalmoplegia, neurogenic EMG, and COX-negative muscle fibers. One patient had low muscle complex I-IV activity, multiple mtDNA deletions, and depletion, but no thymidine phosphorylase (TP) or dNT-2 gene mutations. TP activity and brain MRI were normal. The condition resembles mitochondrial neurogastrointestinal encephalomyopathy, except for the absence of leukoencephalopathy, and is likely caused by a nuclear DNA mutation that disrupts intergenomic signaling.
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PMID:Multiple mtDNA deletions with features of MNGIE. 1229 82

Under certain conditions or at certain stages of the disease course, multiple sclerosis (MS) and mitochondrial disorder (MID) may be differential diagnoses and thus may be confused with each other. In a 30 years old female MS was diagnosed at age 16 year upon recurrent sensory disturbances of the right lower leg, an "inflammatory" cerebrospinal fluid, and a cerebral MRI with multiple non-enhancing white matter lesions. Steroids were repeatedly given but because of rapid deterioration treatment was switched to interferon and mitoxantrone, without improvement. Fourteen years after onset the patient additionally presented with a history of rhabdomyolysis, hypothyroidism, ophthalmoparesis, anarthria, tetraspasticity, tetraparesis, and joint contractures. After MID had been diagnosed in her mother she was re-evaluated and elevated resting lactate, axonal polyneuropathy, and empty sella were additionally found. Muscle biopsy revealed myophagy, fat deposition, and type-II predominance, and biochemical investigations showed a deficiency of complex I and IV of the respiratory chain. MID was diagnosed also in the index patient. It is concluded that even if CSF investigations or imaging studies suggest MS, differentials such as MIDs need to be excluded before prescribing medication possibly toxic to a MID. An "inflammatory CSF" may also occur in MIDs.
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PMID:Mimicry between mitochondrial disorder and multiple sclerosis. 2231 11

Mutations in KARS, which encodes for both mitochondrial and cytoplasmic lysyl-tRNA synthetase, have been so far associated with three different phenotypes: the recessive form of Charcot-Mary-Tooth polyneuropathy, the autosomal recessive nonsyndromic hearing loss and the last recently described condition related to congenital visual impairment and progressive microcephaly. Here we report the case of a 14-year-old girl with severe cardiomyopathy associated to mild psychomotor delay and mild myopathy; moreover, a diffuse reduction of cytochrome C oxidase (COX, complex IV) and a combined enzymatic defect of complex I (CI) and complex IV (CIV) was evident in muscle biopsy. Using the TruSight One sequencing panel we identified two novel mutations in KARS. Both mutations, never reported previously, occur in a highly conserved region of the catalytic domain and displayed a dramatic effect on KARS stability. Structural analysis confirmed the pathogenic role of the identified variants. Our findings confirm and emphasize that mt-aminoacyl-tRNA synthetases (mt-ARSs) enzymes are related to a broad clinical spectrum due to their multiple and still unknown functions.
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PMID:Novel mutations in KARS cause hypertrophic cardiomyopathy and combined mitochondrial respiratory chain defect. 2789 85