Development of patient-centric conceptual frameworks for symptoms and impacts of ornithine transcarbamylase deficiency (OTCD)

TL;DR

This study creates patient-focused frameworks to understand the symptoms and impacts of ornithine transcarbamylase deficiency, a rare metabolic disorder, to improve treatment and assessments.

Contribution

The study introduces patient-centric conceptual frameworks for OTCD, capturing symptoms and impacts from patient and caregiver perspectives to guide clinical outcome assessments.

Findings

Common symptom domains include neurocognitive, gastrointestinal, energy-related, and physical symptoms.

Impact domains include diet-related, emotional, physical, sleep, and social problems reported by patients and caregivers.

The frameworks align with FDA guidance for rare disease assessments and highlight the humanistic burden of OTCD.

Abstract

Ornithine transcarbamylase deficiency (OTCD) is a rare hereditary metabolic disorder caused by mutations in the OTC gene. It is the most common urea cycle disorder (UCD), occurring in approximately one in 14,000 births worldwide. As an X-linked enzyme, OTC breaks down citrulline in mitochondria, and pathogenic variant can lead to dangerously high levels of ammonia (hyperammonemia) and glutamine (hyperglutaminemia) in the blood. Symptoms related to hyperammonemia include confusion, vomiting, coma, and cognitive impairments. Current treatments include ammonia scavengers and strict dietary management to limit protein intake.

Given the rarity of OTCD and its varied clinical presentation, this study aimed to understand and characterize the burden of disease from the patient and caregiver perspective, develop preliminary symptoms and impacts conceptual frameworks based on the patient experience and caregiver observations, and contribute to the development of new clinical outcome assessments (COAs). The development of patient-centric conceptual frameworks is important to ensure that the unique experiences and needs of patients are accurately reflected in research and healthcare strategies, ultimately leading to more effective and personalized treatment approaches and disease measures.

The research involved a comprehensive literature review, interviews with key opinion leaders (KOLs), and concept elicitation interviews with patients and caregivers. These methods were employed to identify and validate relevant symptoms and impacts of OTCD.

The most commonly reported symptom domains (i.e. neurocognitive, gastrointestinal, energy-related [fatigue/tiredness], and physical symptoms) and impact domains (i.e. diet-related, emotional, physical, sleep, and social problems) reported by patients, caregivers, and KOLs were included in the preliminary conceptual frameworks. The research suggests that there is a high humanistic burden on patients that may be difficult to manage and negatively impacts quality of life for those living with OTCD. The findings of this study indicate that these frameworks encompass the concepts most important to patients and are aligned with Food and Drug Administration (FDA) guidance on human gene therapy for rare diseases which ensures that measures are scientifically valid, reliable, sensitive and responsive when used in clinical trials of novel treatments to document treatment benefit.

This research highlights the need for COAs specific to OTCD based on the patient perspective in this disease population. This work helps to define the humanistic burden of disease and lays the foundation for identifying and developing robust COAs tailored to improve clinical assessments and patient care in OTCD.

The online version contains supplementary material available at 10.1186/s41687-025-00939-5.

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