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Teresa Painho1; Andreia Pereira1,2; Diana Antunes3; Ana Ferreira4; Laura Vilarinho5; Sandra Jacinto1

1- Serviço de Neurologia Pediátrica, Área da Mulher, Adolescente e Criança, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa
2- Centro de Neurodesenvolvimento, Centro Hospitalar e Universitário do Algarve - Unidade de Faro, Faro
3- Serviço de Genética, Área da Mulher, Adolescente e Criança, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa
4- Centro de Referência de Doenças Hereditárias do Metabolismo, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa
5- Unidade de Rastreio Neonatal, Metabolismo e Genética, Instituto Nacional de Saúde Dr. Ricardo Jorge, Porto

- Poster 15th International Symposium SPDM
- 14-16 Março 2019, Coimbra

Background: LYRM7 (LYR motif containing 7) gene mutations are a cause of mitochondrial complex III deficiency, which relates to a highly variable phenotype. Few patients were described so far. Recently a distinct MRI pattern of progressive leukoencephalopathy with multifocal cavitations in the periventricular and deep cerebral white matter was described related with LYRM7 mutations.
Case Report: An eleven month-old girl, born to consanguineous parents, was referred for investigation of global developmental delay, sensorineural deafness and low visual acuity. At 2-month of age she was admitted with respiratory distress and an unexpected metabolic acidosis with raised lactic acid was noticed. Initial metabolic investigation revealed abnormal redox imbalance, markedly raised urinary lactic acid and a minor elevation of alanine. Ammonia was normal. Biotinidase deficiency and pyruvate dehydrogenase deficiency were excluded. With 7 months she started having seizures. CT scan showed discrete hypodensities in the right corona radiata and bilateral pontocerebellar hypodensity. Brain MRI revealed a bilateral restricted diffusion from the cervical spinal cord until the posterior subependymal areas, suggesting a mitochondrial disorder. The biochemical analysis of mitochondrial respiratory chain in muscle biopsy revealed an increased activity of citrate synthetase and complex II associated with diminished activity of II-III complex. Complex III activity was reported as normal. Muscle morphology was normal. Mitochondrial DNA copy number was 30%, suggesting a secondary depletion. Mitochondrial DNA sequencing revealed two mutations in heteroplasmy in MT-TD and MT-CYB genes. Next generation sequencing gene panel for nuclear genes associated with mitochondrial disorders revealed the variant c.73G> in LYRM7 gene in homozygosity, not previously reported in healthy controls. This variant appears to be located in a functional domain, and was previously described in two non-consanguineous portuguese patients. She started thiamine, biotin and CoQ with no significant improvement. The child died with 14-months with respiratory failure and irreversible lactic acidosis.
Conclusion: Here we described the third patient in Portugal with LYRM7 mutation. We discuss the unexpected MRI pattern since it lacks the major stigmata associated with this gene. We hypothesize that additional mitochondrial DNA mutations of MT-TD and MT-CYB genes could explain the diversity of phenotype.

Keywords: Leukoencephalopathy; LYRM7; Mitochondrial disorders; MRI