Challenges and strategies for clinical trials in propionic and methylmalonic acidemias.

Clinical trial development in rare diseases poses significant study design and methodology challenges, such as disease heterogeneity and appropriate patient selection, identification and selection of key endpoints, decisions on study duration, choice of control groups, selection of appropriate statistical analyses, and patient recruitment. Therapeutic development in organic acidemias (OAs) shares many challenges with other inborn errors of metabolism, such as incomplete understanding of natural history, heterogenous disease presentations, requirement for sensitive outcome measures and difficulties recruiting a small sample of participants. Here, we review strategies for the successful development of a clinical trial to evaluate treatment response in propionic and methylmalonic acidemias.

Lifelong impact of ENPP1 Deficiency and the early onset form of ABCC6 Deficiency from patient or caregiver perspective.

The ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1) and ATP-binding cassette subfamily C member 6 (ABCC6) proteins play a prominent role in inhibiting ectopic calcification and arterial stenosis. Patients with ENPP1 Deficiency or infant onset ABCC6 Deficiency often present with pathological calcification, narrowed blood vessels, multiorgan dysfunction and high infant mortality. The heterogenous presentation and progression is well documented.

Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome): defining and measuring functional impacts in pediatric patients.

Background: Research about pediatric patients' perspective on mucopolysaccharidosis type VI (MPS VI) and its impact on daily life is limited. We aimed to identify the disease concepts of interest that most impact function and day-to-day life of pediatric patients with MPS VI, and to consider clinical outcome assessments (COAs) that may potentially measure meaningful improvements in these concepts.

Methods: Potential focus group participants were identified by the National MPS Society (USA) and invited to participate if they self-reported a clinician-provided diagnosis of MPS VI and were 4 to 18 years, receiving enzyme replacement therapy (ERT), and available to attend a 1-day focus group with their caregiver in Dallas, TX, USA.

Clinical Outcome Assessments: Use of Normative Data in a Pediatric Rare Disease.

Pediatric rare diseases present unique challenges in clinical trial design and in selection of clinical outcome assessments (COAs) used to support claims in medical product labeling. COAs that discriminate level of function relative to a normative sample are particularly important in the pediatric rare disease setting because the literature is often void of natural history data. Pediatric rare disease clinical trials will often include a wide age distribution.

Physical therapy management of infants and children with hypophosphatasia.

Hypophosphatasia (HPP) is a rare inborn error of metabolism resulting in undermineralization of bone and subsequent skeletal abnormalities. The natural history of HPP is characterized by rickets and osteomalacia, increased propensity for bone fracture, early loss of teeth in childhood, and muscle weakness. There is a wide heterogeneity in disease presentation, and the functional impact of the disease can vary from perinatal death to gait abnormalities.