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LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency
  1. François-Guillaume Debray1,
  2. Charles Morin2,
  3. Annie Janvier3,
  4. Josée Villeneuve2,
  5. Bruno Maranda4,
  6. Rachel Laframboise4,
  7. Jacques Lacroix5,
  8. Jean-Claude Decarie6,
  9. Yves Robitaille7,
  10. Marie Lambert8,
  11. Brian H Robinson9,
  12. Grant A Mitchell8
  1. 1Metabolic Unit, Department of Human Genetics, University of Liège, CHU Sart-Tilman, Liège, Belgium
  2. 2Department of Pediatrics and Clinical Research Unit, Chicoutimi Hospital, University of Québec at Chicoutimi, Chicoutimi, Québec, Canada
  3. 3Neonatology, Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Côte Sainte Catherine, Montreal, Canada
  4. 4Division of Medical Genetics, Department of Pediatrics, Laval University, CHU Laval, boulevard Laurier, Sainte-Foy, Québec, Canada
  5. 5Intensive Care Unit, Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Côte Sainte Catherine, Montreal, Canada
  6. 6Department of Medical Imaging, University of Montreal, CHU Sainte-Justine, Côte Sainte-Catherine, Montreal, Canada
  7. 7Department of Pathology, University of Montreal, CHU Sainte-Justine, Côte Sainte-Catherine, Montreal, Canada
  8. 8Division of Medical Genetics, Department of Pediatrics, University of Montreal, CHU Sainte-Justine, Côte Sainte-Catherine, Montreal, Canada
  9. 9Metabolism Research Program, Research Institute, Departments of Pediatrics and Biochemistry, Hospital for Sick Children, University of Toronto, University Avenue, Toronto, Ontario, Canada
  1. Correspondence to Dr Grant A Mitchell, Division of Medical Genetics, CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, Québec H3T 1C5, Canada; grant.mitchell{at}recherche-ste-justine.qc.ca

Abstract

Background The natural history of all known patients with French-Canadian Leigh disease (Saguenay-Lac-St-Jean cytochrome c oxidase deficiency, MIM220111, SLSJ-COX), the largest known cohort of patients with a genetically homogeneous, nuclear encoded congenital lactic acidosis, was studied.

Results 55 of 56 patients were homozygous for the A354V mutation in LRPPRC. One was a genetic compound (A354V/C1277Xdel8). Clinical features included developmental delay, failure to thrive, characteristic facial appearance and, in 90% of patients, acute crises that have not previously been detailed, either metabolic (fulminant lactic acidosis) and/or neurological (Leigh syndrome and/or stroke-like episodes). Survival ranged from 5 days to >30 years. 46/56 patients (82%) died, at a median age of 1.6 years. Of 73 crises, 38 (52%) were fatal. The immediate causes of death were multiple organ failure and/or Leigh disease. Major predictors of mortality during crises (p<0.005) were hyperglycaemia, hepatic cytolysis, and altered consciousness at admission. Compared to a group of SURF1-deficient Leigh syndrome patients assembled from the literature, SLSJ-COX is distinct by the occurrence of metabolic crises, leading to earlier and higher mortality (p=0.001).

Conclusion SLSJ-COX is clinically distinct, with acute fatal acidotic crises on a backdrop of chronic moderate developmental delay and hyperlactataemia. Leigh syndrome is common. Stroke-like episodes can occur. The Leigh syndrome of SLSJ-COX differs from that of SURF1-related COX deficiency. SLSJ-COX has a different spectrum of associated abnormalities, acidotic crises being particularly suggestive of LRPPRC related Leigh syndrome. Even among A354V homozygotes, pronounced differences in survival and severity occur, showing that other genetic and/or environmental factors can influence outcome.

  • Metabolic diseases
  • mitochondrial disorders
  • COX deficiency
  • lactic acidosis
  • Leigh syndrome
  • metabolic disorders
  • clinical genetics
  • neurology

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Footnotes

  • Funding F-GD was financed in part by L'Association de l'Acidose Lactique du Saguenay-Lac Saint-Jean, Québec, Canada for his contribution to the design and conductance of the study.

  • Competing interests None to declare.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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