1 - Department of Paediatrics, Hospital de Cascais, Cascais, Portugal
2 - Pediatric Neurology Service, Pediatric Department, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
3 - Genetic Service, Pediatric Department, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
4 - Primary Immunodeficiency Unit, Pediatric Department, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
5 - Haematology Unit, Pediatric Department, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
6 - Neuroradiology Department, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
7 - Reference Center of Inherited Metabolic Diseases, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
- Comunicação oral em 16º Simposio Internacional da Sociedade Portuguesa de Doenças Metabólicas, Virtual, 11-13 novembro de 2020
Resumo:
Background: Mitochondrial disorders are multisystemic diseases characterized by a wide spectrum of clinical manifestations and complex molecular etiology. Contributing to its persistence as underdiagnosed disorders is the failure to recognise children with “nonclassic” phenotypes. Biochemical tests, muscle histology and enzymatic activity of the respiratory chain, although frequently performed, can be inconclusive and often misleading. The “gold standard” for a definite diagnosis are genetic studies, nowadays more accessible with gene panels.
Methods: We performed a retrospective study of the clinical, biochemical, histological, imaging and molecular features of a cohort of patients with mitochondrial disorders followed for the last 20 years at our neuro-metabolic centre in Hospital Dona Estefânia-CHLC.
Results: Thirty-seven patients from 33 unrelated families, with a median age of 10-years (min 18mo – max 22y) were included. According to consensus Mitochondrial Disease Criteria (MDC), a definite diagnosis of a mitochondrial disorder was established in 28 patients and a probable diagnosis in 9. Most patients presented in the first 2 years of life (n=24) with neurologic manifestations: encephalopathy (56%), muscular symptoms (10%) and neonatal seizures (5%). Extra-neurological manifestations at presentation were cardiac BAV, deafness and haematological (1 patient each). Classical clinical presentations were Leigh syndrome (n=4), Kearns-Sayre syndrome (n=3) and Pearson syndrome (n=1). Cerebral MRI findings were diverse but Leigh syndrome (20%) and leukoencephalopathy were the most frequent findings. Twenty-two patients (60%) had a muscle biopsy, with 82% showing abnormalities either in histological or/and RC enzyme activity. Molecular diagnosis was achieved in 23 patients, involving nuclear genes in 15 (65%): PDHc (n=4), LYRM7 (n=3) and MFN2 (n=2), and in POLG, TMEM70, SERAC1, BCS1L, COQ8A and RMND1 in one patient each. In the mtDNA, the m.8993 T>C and m.8993T>G (n=4) and large-scale deletion (n=2) were the most frequent finding.
Conclusions: This cohort although small, reflects mitochondrial disorders clinical heterogeneity, different inheritage patterns and age of first symptoms. Advances in molecular testing have improved diagnostic yield, although establishing a definite genetic diagnosis remains challenging. We stress that clinical awareness is the first crucial element of a multistep approach leading to a definite diagnosis.