ESPE Abstracts (2018) 89 FC2.6

Final Height is Negatively Related to Disease Burden in Mitochondrial Disease

Rachel Boala, Yi Shiau Ngb, Robert McFarlandb & Tim Cheethama,c

aDepartment of Paediatric Endocrinology, Great North Children’s Hospital, Royal Victoria Infirmary, Newcastle Upon Tyne, UK; bWellcome Centre for Mitochondrial Research, Institute of Neuroscience, 4th Floor Cookson Building, Medical School, Framlington Place, Newcastle University, Newcastle Upon Tyne, UK; cInstitute of Genetic Medicine, Newcastle University c/o Office Block 1. Floor 3, Royal Victoria Infirmary, Newcastle Upon Tyne, UK

Context: Abnormal growth and short stature are observed in patients with mitochondrial disease but it is unclear whether there is a relationship between growth, stature and muscle phenotype.

Objectives: To examine growth and final height in patients with genetically confirmed mitochondrial disease, to describe growth patterns in the principle underlying genetic subgroups and to establish whether stature is related to disease severity.

Method: Patients were identified from the United Kingdom Mitochondrial Disease Patient Cohort from inception to January 2017. A retrospective analysis of the association between final adult height and most recent body mass index (BMI) within the key genetic subgroups of patients with mitochondrial disease and a comparison with clinical disease severity was then performed. Diseases severity was determined by a validated assessment tool, the Newcastle Mitochondrial Disease Adult Scale (NMDAS).

Results: Five hundred and eighty five patients aged 19–89 years of age were identified with documented height, weight and a molecular genetic diagnosis of mitochondrial disease. Patients with mitochondrial disease were short, with a mean height standard deviation (S.D.) of −0.48 (CI 95%; −0.57 to −0.39) when compared to UK reference data. Patients with the m.3243A>G genotype, were particularly short with a mean height S.D. of −0.70 (±1.20) compared to the single large scale mitochondrial deletions sub-group (−0.27±1.18; P=0.01) or the nuclear DNA groups (0.41± 1.12; P=0.06). Patients were not thin overall although the m.3243A>G sub-group demonstrated a significantly lower mean BMI S.D., 0.12 (± 1.64) when compared to the single large scale deletions (0.68± 1.55; P=0.03) and the nuclear DNA sub-group (1.13±1.73; P=<0.00). NMDAS scores were negatively correlated with the height S.D. (r=−0.265, P=< 0.00). This association was most pronounced in the m.3243A>G group (r=−0.31, P=<0.00). An analysis of the association between NMDAS score and height in older patients (> 25 years) was similar to the data as a whole confirming that the association was not simply due to delayed pubertal development and growth. Age corrected blood heteroplasmy levels in the m.3243A>G sub-group were positively correlated with NMDAS score (r=0.361, P=<0.00).

Conclusion: Multiple mechanisms may contribute to short stature in mitochondrial disease including the impact of impaired muscle function on the growth plate and suboptimal nutrition. However we suspect that abnormal growth also reflects abnormal adenosine triphosphate (ATP) generation and higher heteroplasmy levels in growth plate chondrocytes. Further in-vitro and in-vivo studies are required to confirm this.

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