Height as a Clinical Biomarker of Disease Burden in Adult Mitochondrial Disease

Abstract

Context Abnormal growth and short stature are observed in patients with mitochondrial disease, but it is unclear whether there is a relationship between final adult height and disease severity. Objective To determine whether patients with genetically confirmed mitochondrial disease are shorter than their peers and whether stature is related to disease severity. Design Analysis of final adult height in relation to disease severity as determined by the Newcastle Mitochondrial Disease Adult Scale (NMDAS). Setting UK Mitochondrial Disease Patient Cohort (Mito Cohort). Patients 575 patients were identified with recorded height, weight, and molecular genetic diagnosis of mitochondrial disease within the Mito Cohort. Main Outcome Measures Adult height, body mass index (BMI), and their association with genetic subgroup and disease severity. Results Adults with mitochondrial disease were short, with a mean height of −0.49 SD (95% CI, −0.58 to −0.39; n = 575) compared with UK reference data. Patients were overweight, with a BMI SD of 0.52 (95% CI, 0.37 to 0.67; n = 472). The most common genetic subgroup (m.3243A>G mutation) had a height SD of −0.70 (95% CI, −0.85 to −0.54; n = 234) and a BMI SD of 0.12 (95% CI, −0.10 to 0.34; n = 212). NMDAS scores were negatively correlated with height SD ( r = −0.25; 95% CI, −0.33 to −0.17; P < 0.001, n = 533). Rate of disease progression also correlated negatively with adult height ( P < 0.001). Conclusion Final height in mitochondrial disease reflects disease severity and rate of disease progression. Mitochondrial dysfunction and associated subclinical comorbidities affect growth plate physiology.

Height as a clinical biomarker of disease burden in adult mitochondrial disease

“…It was interesting to note that patients with short stature were more likely to have diabetes and cardiovascular involvement, whereas patients with a low BMI had more severe symptoms such as seizures, encephalopathy, and strokelike episodes, as noted previously (16). Both short stature and low BMI were associated with hearing impairment and gastrointestinal disturbances.…”

“…The mechanism is believed to be dysfunctional involvement of smooth muscle, peripheral nerves, and central nervous system in swallowing. Gastroparesis, delayed gastric emptying, bacterial overgrowth, and intestinal pseudo-obstruction have also been noted in this population (16). Malabsorption is commonly experienced by patients, and mtDNA defects have been shown to impair human colonic epithelial function (29).…”

An atlas of mitochondrial DNA genotype–phenotype associations in the UK Biobank

“…The effect size of these associations are comparable to the top 10% of effects reported for the nuclear genome 24 . Short stature is a well-recognized feature of inherited mitochondrial diseases 25 . In some patients this has a neuroendocrine basis, but this is not the case in most, where impaired cartilage-mediated growth has been implicated 25 , 26 .…”

Body Mass Index and Height in the Friedreich Ataxia Clinical Outcome Measures Study

“…In adults, but not in children, genetic severity of disease (GAA1 repeat length) was associated with shorter stature, analogous to a different study in adults with other genetic mitochondrial disorders that showed height was a biomarker of disease burden. 41 The authors posited that primary mitochondrial disorders had subtle effects on growth even before clinical diagnosis. Similarly, the bioenergetic changes related to FRDA may antedate more overt symptoms; therefore, even individuals with adult-onset FRDA may have experienced subclinical effects on growth earlier in life.…”