Dataset Information

A homozygous mutation in LYRM7/MZM1L associated with early onset encephalopathy, lactic acidosis, and severe reduction of mitochondrial complex III activity.

ABSTRACT: Mutations in nuclear genes associated with defective complex III (cIII) of the mitochondrial respiratory chain are rare, having been found in only two cIII assembly factors and, as private changes in single families, three cIII structural subunits. Recently, human LYRM7/MZM1L, the ortholog of yeast MZM1, has been identified as a new assembly factor for cIII. In a baby patient with early onset, severe encephalopathy, lactic acidosis and profound, isolated cIII deficiency in skeletal muscle, we identified a disease-segregating homozygous mutation (c.73G>A) in LYRM7/MZM1L, predicting a drastic change in a highly conserved amino-acid residue (p.Asp25Asn). In a mzm1? yeast strain, the expression of a mzm1(D25N) mutant allele caused temperature-sensitive respiratory growth defect, decreased oxygen consumption, impaired maturation/stabilization of the Rieske Fe-S protein, and reduced complex III activity and amount. LYRM7/MZM1L is a novel disease gene, causing cIII-defective, early onset, severe mitochondrial encephalopathy.

SUBMITTER: Invernizzi F

PROVIDER: S-EPMC4028993 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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A homozygous mutation in LYRM7/MZM1L associated with early onset encephalopathy, lactic acidosis, and severe reduction of mitochondrial complex III activity.

Invernizzi Federica F Tigano Marco M Dallabona Cristina C Donnini Claudia C Ferrero Ileana I Cremonte Maurizio M Ghezzi Daniele D Lamperti Costanza C Zeviani Massimo M

Human mutation 20130923 12

Mutations in nuclear genes associated with defective complex III (cIII) of the mitochondrial respiratory chain are rare, having been found in only two cIII assembly factors and, as private changes in single families, three cIII structural subunits. Recently, human LYRM7/MZM1L, the ortholog of yeast MZM1, has been identified as a new assembly factor for cIII. In a baby patient with early onset, severe encephalopathy, lactic acidosis and profound, isolated cIII deficiency in skeletal muscle, we id ...[more]

PMID: 24014394

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Project description:Background and objectivesStroke management in the context of primary mitochondrial disease is clinically challenging, and the best treatment options for patients with stroke-like episodes remain uncertain. We sought to perform a systematic review of the safety and efficacy of l-arginine use in the acute and prophylactic management of stroke-like episodes in patients with mitochondrial disease.MethodsThe systematic review was registered in PROSPERO (CRD42020181230). We searched 6 databases from inception to January 15, 2021: MEDLINE, Embase, Scopus, Web of Science, CINAHL, and ClinicalTrials.gov. Original articles and registered trials available, in English, reporting l-arginine use in the acute or prophylactic management of stroke-like episodes in patients with genetically confirmed mitochondrial disease were eligible for inclusion. Data on safety and treatment response were extracted and summarized by multiple observers. Risk of bias was assessed by the methodologic quality of case reports, case series, and a risk-of-bias checklist for nonrandomized studies. Quality of evidence was synthesized with the Oxford Centre for Evidence-Based Medicine Levels of Evidence and Grade of Recommendations. The predetermined main outcome measures were clinical response to l-arginine treatment, adverse events, withdrawals, and deaths (on treatment and/or during follow-up), as defined by the author.ResultsThirty-seven articles met inclusion criteria (0 randomized controlled trials; 3 open-label; 1 retrospective cohort; 33 case reports/case series) (N = 91 patients; 86% m.3243A>G). In the case reports, 54% of patients reported a positive clinical response to acute l-arginine, of which 40% were concomitantly treated with antiepileptic drugs. Improved headache at 24 hours was the greatest reported benefit in response to IV l-arginine in the open-label trials (31 of 39, 79%). In 15 of 48 patients (31%) who positively responded to prophylactic l-arginine, antiepileptic drugs were either used (7 of 15) or unreported (8 of 15). Moderate adverse events were reported in the follow-up of both IV and oral l-arginine treatment, and 11 patients (12%) died during follow-up or while on prophylactic treatment.DiscussionThe available evidence is of poor methodologic quality and classified as Level 5. IV and oral l-arginine confers no demonstrable clinical benefit in either the acute or prophylactic treatment of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, with more robust controlled trials required to assess its efficacy and safety profile.

Dataset Information

A homozygous mutation in LYRM7/MZM1L associated with early onset encephalopathy, lactic acidosis, and severe reduction of mitochondrial complex III activity.

Publications

A homozygous mutation in LYRM7/MZM1L associated with early onset encephalopathy, lactic acidosis, and severe reduction of mitochondrial complex III activity.

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