The paper described a 12yo female with multisystem mitochondrial disorder (MID) due to the compound heterozygous variants c.1963_1964dupAT and p.Ile382Met in OPA1 manifesting phenotypically with congenital nystagmus, developmental delay, visual impairment, gait ataxia, epilepsy, a stroke-like episode (SLE) with encephalopathy and vomiting, and hearing impairment.
Friedreich's ataxia is a multisystemic genetic disorder within the family of mitochondrial diseases that is characterized by reduced levels of the essential mitochondrial protein frataxin.
Homozygous and compound heterozygous variants in the LONP1 gene encoding the LonP1 protease have recently been shown to cause a diverse spectrum of human pathologies, ranging from classical mitochondrial disease phenotypes, in addition to profound neurologic impairment and multi-organ dysfunctions, some of which are uncommon to mitochondrial disorders.
These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders.
Subsequent Sanger sequencing of POLG in a further 275 unrelated probands with genetically unconfirmed mitochondrial disease revealed a third unrelated proband with a similar phenotype harboring homozygous c.1879C>T; p.R627W mutations and a fourth patient, with a milder clinical disorder, harboring compound heterozygous POLG c.1879C>T; p.R627W and c.2341G>A; p.A781T mutations.
SDH defects are associated with mitochondrial disorders and risk for various cancers; immunochemical analysis indicated loss of SDHB protein expression in the patient's tumor, compatible with SDH deficiency.
Mice lacking the mitochondrial complex I (CI) subunit Ndufs4 ( Ndufs4<sup>-/-</sup>) develop a fatal progressive encephalopathy and serve as a model for Leigh syndrome, the most common mitochondrial disease in children.
Our findings suggest that MT-ATP6-related mitochondrial DNA disease is best conceptualized as a mitochondrial disease spectrum disorder and should be routinely included in genetic ataxia and neuropathy gene panels.ANN NEUROL 2019;86:310-315.
Congenital cochlear deafness in mitochondrial diseases related to RRM2B and SERAC1 gene defects. A study of the mitochondrial patients of the CMHI hospital in Warsaw, Poland.
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a mitochondrial disorder that is commonly caused by the m.3243A > G mutation in the MT-TL1 gene encoding for mitochondrial tRNA(Leu(UUR)).
Thus, the overall positive and negative predictive values were not acceptable for these measurements to be used as diagnostic tests for mitochondrial diseases (FGF-21 positive predictive value [PPV] = 34%, negative predictive value [NPV] = 73%; GDF-15 PPV = 47%, NPV = 28%).
Among the conditions in which circulating GDF15 levels are highly elevated are mitochondrial disorders, where early skeletal muscle fatigue is a key symptom.
Thus, the overall positive and negative predictive values were not acceptable for these measurements to be used as diagnostic tests for mitochondrial diseases (FGF-21 positive predictive value [PPV] = 34%, negative predictive value [NPV] = 73%; GDF-15 PPV = 47%, NPV = 28%).
Therefore, the protocol for a future clinical study of SP therapy in this patient population needs to include plasma and lateral ventricular lactate, the L/P ratio, and serum GDF15 as diagnostic indicators, and exclude patients with end-stage mitochondrial disease.