RCDP Natural History Study

Rhizomelic chondrodysplasia punctata (RCDP) is a group of rare diseases that have no known cure. It is a genetic disorder characterized by mutations in the Peroxisomal Biogenesis Factor 7 (PEX7) gene (RCDP1), Glyceronephosphate O-acyltransferase (GNPAT) gene (RCDP 2), Alkylglycerone phosphate synthase (AGPS) gene (RCDP3), Fatty Acyl-CoA Reductase 1 (FAR1) gene (RCDP4) or Peroxisomal Biogenesis Factor 7 (PEX7) gene (RCDP5) all coding for peroxisomal proteins which result in defective synthesis of plasmalogens. Hence, severely decreased levels of ethanolamine plasmalogens (PlsEtn), the most common tissue plasmalogen, is both the biochemical hallmark and the primary cause of pathology for all RCDP groups. To treat RCDP, a plasmalogen replacement is under development. Before this therapeutic or any therapeutic for RCDP can be tested for efficacy in the clinic, a thorough understanding of the natural progression of the disease is required. Without this information it would be impossible to determine whether the drug was effectively improving the disease course. Classical, or severe, is the most common form of RCDP and presents in the neonatal period. It is clinically characterized by a skeletal dysplasia as seen by symmetrical rhizomelic shortening of the long bones. Chondrodysplasia is also present with premature calcification of epiphyseal cartilage (punctata), delayed calcification of vertebral bodies and mineralization of cartilaginous structures which do not normally ossify, such as the larynx, trachea and intervertebral discs. Additionally patients display dysmorphic facial features, bilateral cataracts, cognitive deficits and severe growth and psychomotor delays. Shortened life expectancy is common to RCDP patients; however survival varies widely. For the classical form, of those individuals who survive the first month of life, 50% will survive until 6 years of age with nearly all succumbing to the disease by adolescence. The majority of deaths are secondary to respiratory problems5. The chronic respiratory compromise is due to the skeletal defects, as well as the direct effect of plasmalogen deficiency on lung cellular function. Patients with less severe phenotypes can lack rhizomelia, and have less severe growth and developmental delays. The disease phenotype varies considerably and correlates directly with PlsEtn abundance.

STUDY RATIONALE Determining the appropriate measurable endpoints are as important as having a viable therapeutic strategy for a clinical trial. In a disease like RCDP, endpoints must be sensitive enough to measure subtle changes in the course of the disease and also be meaningful to the process of pathogenesis. Assessment of a RCDP treatment trial is a complex task as RCDP clinical trajectory might be influenced by the disease severity, age and care that the patient receives etc. Moreover, although measurement scales exist for such diseases as Cerebral Palsy to assess the severity of the disease, RCDP does not have such universally accepted overall set of measures that assess patient's developmental, functional, psychosocial, neurological, skeletal, and respiratory functions as a whole. Lack of such grading scales is a hindrance to evaluate the progress of a clinical trial in a complex and severe disease as RCDP. In a disease like RCDP, more than a complete cure, a functional improvement in patient's life could be considered as efficacious.

The other issue in a rare disease clinical trial design is the comparator to which the effect of treatment can be compared. Ethical considerations preclude having a placebo control and a more appropriate comparator is a non-concurrent control group. Therefore, longitudinal assessments are required to determine the inherent variability in functional measures and characterize the disease trajectory. To this end, we have designed an on-going longitudinal observational trial with assessments every 3-6 months to characterize RCDP and its disease course.

Overarching goal is to determine the longitudinal and natural trajectory of disease state in patients with RCDP by assess the quality of life, physiologic and functional measures.

Specific measurements will include:

- Medical and surgical history

- Anthropometric measurements

- Vital signs

- Physical examination

- Observational pain assessment

- Musculoskeletal system assessment

- Nerve conduction studies

- Non-invasive pulmonary function tests

- Impulse Oscillometry System

- Pneumotachography

- Respiratory Inductance Plethysmography

- 4 hour EEG

- DEXA

- Questionnaire assessment of:

- Iowa Fatigue Scale

- Pediatric Pain Scale

- NCCPC-R (Pain Scale)

- Infant Gastrointestinal Symptom Questionnaire

- Pediatric Assessment Scale for Severe Feeding Problems

- LENA

- Parental written logs (over 2 days)

- Activity

- Pain

- Seizure

- Blood Assessments

- Plasmalogen and Lipids

- Complete Blood Count

- Comprehensive Metabolic Panel

- Genetic Testing (if not available from history)

STUDY DESIGN

As described above, clinical characteristics of RCDP encompass a wide range of signs, symptoms, physiological, functional and structural abnormalities all of which must be taken in to account when assessing a patient's progress. The major systems affected are the skeletal system (severe and symmetrical shortening of proximal long bones, stippled epiphyses, dysmorphia and contractures), neurophysiological (seizures), neuromuscular and psychomotor abnormalities, respiratory, growth and developmental and daily function. Many of these symptoms can be characterized by standard tests that are in clinical or research use. Other assessments, such as the quality of life, require the development of novel tools which will be implemented once they have been validated. Assessing each domain in its own right will provide the best indication of efficacy on an individual basis.

Domain specific milestones as described here will increase the sensitivity in assessing treatment specific effects. Acute clinically evident improvements brought about by plasmalogen replacement therapy are expected to be subtle. The earliest improvements are anticipated to be improvements in membrane-related functions such as improved neurotransmission, improved neuromuscular function, improved GI function, increase growth rates and better lung health. Functionally, we anticipate that primary and immediate improvements will be evident in motor function, frequency of seizures, frequency of pulmonary infections and improved quality of life. Improvements in other systems and function are anticipated to arise later in a gradual manner. Consequently, assessment of each of these domains as well as an assessment of quality of life and measures of functionality are needed to estimate therapeutic benefits accurately.

The study is intended to be on-going, allowing for longitudinal assessment of RCDP. In- hospital assessments will be completed approximately every 6 months, based on availability of scheduling and patients' health. In home audiologic recordings will take place after each study visit along with parent completed logs. In home surveys will be distributed every 3 months to the caregiver.