Muscle Involvement in a Large Cohort of Pediatric Patients with Genetic Diagnosis of Mitochondrial Disease.

Cristina Jou,Judith Armstrong,Julio Montoya,Raquel Montero,Sonia Emperador,Francesc Palau,Laura Gort,Pilar Bayona-Bafaluy,César Arjona,Alejandra Darling,Anna Codina,Frederic Tort,Rafael Artuch,A Nascimento ,Dèlia Yubero ,Plácido Navas ,Ester López‐Gallardo ,Cecilia Jiménez‐Mallebrera ,Mercédes Pineda ,María Del Mar O’callaghan ,Àngels García‐Cazorla ,Belén Pérez‐Dueñas ,Eduardo Ruiz‐Pesini ,Leticia Pías‐Peleteiro ,Antònia Ribes ,Juan Darío Ortigoza‐Escobar

doi:10.3390/jcm8010068

Abstract

Mitochondrial diseases (MD) are a group of genetic and acquired disorders which present significant diagnostic challenges. Here we report the disease characteristics of a large cohort of pediatric MD patients (n = 95) with a definitive genetic diagnosis, giving special emphasis on clinical muscle involvement, biochemical and histopathological features. Of the whole cohort, 51 patients harbored mutations in nuclear DNA (nDNA) genes and 44 patients had mutations in mitochondrial DNA (mtDNA) genes. The nDNA patients were more likely to have a reduction in muscle fiber succinate dehydrogenase (SDH) stains and in SDH-positive blood vessels, while a higher frequency of mtDNA patients had ragged red (RRF) and blue fibers. The presence of positive histopathological features was associated with ophthalmoplegia, myopathic facies, weakness and exercise intolerance. In 17 patients younger than two years of age, RRF and blue fibers were observed only in one case, six cases presented cytochrome c oxidase (COX) reduction/COX-fibers, SDH reduction was observed in five and all except one presented SDH-positive blood vessels. In conclusion, muscle involvement was a frequent finding in our series of MD patients, especially in those harboring mutations in mtDNA genes.

Highlights

Of all inherited metabolic diseases, mitochondrial diseases (MD) occur at the highest frequency [1]
Biochemical and histopathological data for the whole patient cohort and for the mitochondrial DNA (mtDNA) and number of of genetic genetic diagnoses diagnoses (nDNA) subgroups are presented in Table 1 and Figure 1
We classified the 95 patients according to their clinical features and to histopathological features (RRF, blue or c oxidase (COX)-fibers, positive or negative) (Table 2)

Summary

Introduction

Of all inherited metabolic diseases, mitochondrial diseases (MD) occur at the highest frequency (incidence around 1/5000 births) [1]. The intricate and fundamental metabolic pathways occurring in mitochondria leads to, amongst other problems, a remarkable difficulty reaching an etiological diagnosis of MD [2]. Genetic disturbances in other non-mitochondrial pathways may mimic MD or even cause a secondary mitochondrial dysfunction [3]. From a clinical point of view, there are classical and well-recognized mitochondrial syndromes that have been extensively reported [1,4]. In these cohorts of patients, mutations either in nDNA or mtDNA genes are the cause of the disease. Clinical pictures may be incomplete and unspecific, especially at pediatric age, increasing diagnostic difficulties [1,4]. High-energy demanding tissues are affected first, with neuromuscular involvement being one of the cardinal features of MD [5,6]

Methods

Results

Conclusion