Pietrusz, Aleksandra; (2025) A natural history study of adults with Duchenne Muscular Dystrophy living in the UK. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Duchenne Muscular Dystrophy (DMD) is a progressive inherited disorder affecting skeletal, smooth, and cardiac muscles and extra muscular systems (the brain). It causes muscle degeneration, weakness, loss of ambulation (LOA) in early teens, cardiopulmonary complications, and premature death due to cardiac and respiratory failure. Corticosteroid (CS) treatment has shown to delay LOA, preserve respiratory and upper limb (UL) function, and reduce the need for scoliosis surgery and has become the international standard of care. However, evidence for benefit comes mainly from paediatric cohorts and evidence to evaluate the effect of continuing CS in adults is limited, leading to inconsistent clinical practice. Additionally, with increased survival, data on gastrointestinal (GI) and genitourinary (GU) symptoms and renal dysfunction in the older population has been emerging. However, the frequency and CS effect on smooth muscle remains unclear. The aim of this thesis was to evaluate the effect of CS on cardiorespiratory function and assess the GI and GU symptoms and renal function in the adult population aged 16 years and above. This project included: a retrospective multicentre clinical audit of respiratory function, a retrospective single centre clinical audit of cardiac function, and a prospective data collection using a bowel symptoms screening tool and a GU symptoms and renal function questionnaire. Respiratory function data from 209 subjects (age 15.92y–40.5y) from 3 UK centres and cardiac function data from 149 subjects (age 17.08y–40.5y) from Queen Square Institute of Neurology, London, was completed. A prospective bowel symptoms screening tool was completed by 42 patients and urinary symptoms and renal function questionnaire by 26 patients. Results demonstrated that continuing CS treatment in adults was beneficial for preservation of respiratory function over the third decade of life, demonstrated by delayed time to non-invasive ventilation (NIV) start (p=0.0031) and all clinically meaningful pulmonary function milestones (forced vital capacity (FVC)<1L (p<0.0001), forced vital capacity percent predicted for height (FVC%)<60% (p=0.0222), FVC%<50% (p=0.0031), and FVC%<30% (p<0.0001)). Additionally, findings were consistent with the preservation of longitudinal measures of respiratory function (defined as changes over time in FVC (p≤0.001), FVC% (p≤0.001), forced expiratory volume in 1 second (FEV1) (p≤0.001), forced expiratory volume in 1 second percent predicted for height FEV1% (p=0.004), peak expiratory 5 flow (PEF) (p=0.007), and peak cough flow (PCF) (p=0.011)). Whereas stopping CS led to a steeper decline over the second and third decade and appeared to have worse outcomes than CS naïve group as evidenced by an average younger age at reaching all clinically significant milestones described above. No effect was observed on cardiac function. Furthermore, adult population was characterised by a high occurrence of GI and GU symptoms. The results of this project should contribute to future refinement of an ongoing longitudinal data collection and clinical trials design, as well as provide valuable insights for natural history of the disease in the adult population. Additionally, these findings should help with the development of consensus guidelines for GI and GU symptoms and renal function management in adults with DMD.

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