Paediatric single mitochondrial DNA deletion disorders: an overlapping spectrum of disease.

Alexander Broomfield,James V Leonard,Mary G Sweeney,Cathy E Woodward,Lara Abulhoul,Carl Fratter,Michael G Hanna,Andrew M Morris,Joanna Poulton,Shamima Rahman,Stephanie Grunewald,Peter T Clayton

doi:10.1007/s10545-014-9778-4

Abstract

BackgroundSingle large-scale mitochondrial DNA (mtDNA) deletions (SLSMDs) are amongst the most frequently diagnosed mtDNA disorders in childhood, yet their natural history remains poorly understood. We report the natural history of a large multicentre cohort of such children.MethodsWe reviewed case notes from three different UK centres to determine the clinical course of 34 patients (16 female, 18 male) with childhood-onset mitochondrial disease caused by SLSMDs. Kaplan–Meier analysis was used to compare survival of patients presenting with haematological features (Pearson syndrome) and those with nonhaematological presentations.ResultsThe most frequent initial presentation was with isolated ptosis (16/34, 47 %). Eleven (32 %) patients presented with transfusion-dependent anaemia soon after birth and were diagnosed with Pearson syndrome, whilst ten were classified as having Kearns–Sayre syndrome, three as having progressive external ophthalmoplegia (PEO) and seven as having PEO-plus. Three patients did not conform to any specific mitochondrial syndrome. The most frequently affected organ during the disease course was the kidney, with documented tubular or glomerular dysfunction in 17 of 20 (85 %) cases who had detailed investigations. SLSMDs were present in blood and/or urine cells in all cases tested, indicating that muscle biopsy is not necessary for diagnosis in the paediatric age range. Kaplan–Meier survival analysis revealed significantly worse mortality in patients with Pearson syndrome compared with the rest of the cohort.ConclusionsMitochondrial disease caused by SLSMDs is clinically heterogeneous, and not all cases conform to a classical mitochondrial syndrome. Multisystem disease is the norm, with anaemia, renal impairment and endocrine disturbance being the most frequent extraneurological features. SLSMDs should be considered in the differential diagnosis of all children presenting with ptosis.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-014-9778-4) contains supplementary material, which is available to authorized users.

Highlights

Single large-scale mitochondrial DNA deletions (SLSMDs) are amongst the most frequently diagnosed mtDNA disorders in childhood, yet their natural history remains poorly understood
Eleven (32 %) patients presented with transfusion-dependent anaemia soon after birth and were diagnosed with Pearson syndrome, whilst ten were classified as having Kearns–Sayre syndrome, three as having progressive external ophthalmoplegia (PEO) and seven as having PEO-plus
Mitochondrial disease caused by SLSMDs is clinically heterogeneous, and not all cases conform to a classical mitochondrial syndrome

Summary

Introduction

Single large-scale mitochondrial DNA (mtDNA) deletions (SLSMDs) are amongst the most frequently diagnosed mtDNA disorders in childhood, yet their natural history remains poorly understood. The overall incidence of mitochondrial disease is uncertain but has been estimated to be as frequent as 1 in 5,000 births (Skladal et al 2003; Schaefer et al 2004), with single, largescale mitochondrial DNA (mtDNA) deletions (SLSMDs) contributing to 10 % of primary mtDNA disorders (Lamont et al 1998). The term CPEO-plus was coined by Drachman in 1968 (Drachman 1968) and is used to describe patients with PEO who, whilst not fulfilling the criteria for KSS, have multisystem involvement (Di Mauro and Hirano 1993) While these clinical phenotypes have been the mainstay of recognition of SLSMD disorders, increasing experience has begun to demonstrate considerable overlap between these syndromes (Pitceathly et al 2012, Manea et al 2009; Yamashita et al 2008; Grady et al 2014)

Methods

Results

Discussion

Conclusion