Rhizomelic Chondrodysplasia Punctata

Background

RCDP is an ultra-rare pediatric genetic disorder with an estimated prevalence of 1 in 100,000. The disease results from a plasmalogen lipid deficiency caused by mutations in genes involved in plasmalogen biosynthesis. Plasmalogens (described further below) are unique phospholipids that form the structural building blocks of cell membranes, and are partially synthesized in a small compartment of the cell called the peroxisome. Cell membranes are structures that separate the inside contents of a cell from the surrounding environment, and are involved in a large number of functions in the body, including those related to neurological processes such as neurotransmission. 

RCDP has been clinically described for over 50 years, and was named based on characteristic X-ray observations of rhizomelia (shortening of the long bones closest to the body) and chondrodysplasia punctata (stippling pattern seen within the bones). While these features are central to the disease and often used in diagnosis, the clinical manifestations of the disease are wide-ranging and affect systems throughout the body. It is only in the last decade that physicians and researchers have begun to systematically describe and characterize the disease.  This pursuit continues in the on-going RCDP registry, which has provided critical information on the disease presentation and clinical management.  

Genetics

Classically, RCDP was described as the result of mutations in one of 3 genes, however, recently two new genes have been linked to the disease, expanding the subclasses of RCDP to include types 4 & 5. The majority of RCDP cases are type 1 and result from a mutation in the PEX7 gene. This gene codes for the PEX7 protein, which is essential for recognizing and transporting a subset of proteins into the peroxisome where they are needed for function. One of these proteins is AGPS (alkylglycerone phosphate synthase), a protein that performs one of the first steps in the plasmalogen biosynthetic pathway. Mutations in AGPS also result in RCDP and are characterized as RCDP type 3. The other peroxisomal-specific protein in the plasmalogen biosynthetic pathway is GNPAT or glycerophosphate-O-acyltransferase. Mutations in the GNPAT gene have been described and are characterized as RCDP type 2. A recent paper described mutations in the gene for fatty acid reductase 1 or FAR1, and demonstrated that this mutation results in a new type of RCDP known as type 4. FAR1 is responsible for generating fatty alcohols which are a critical starting material in the plasmalogen biosynthetic pathway. Finally, RCDP type 5 results from a specific mutation in the PEX5 gene, which like PEX7, is responsible for recognizing and shuttling proteins to the peroxisome. All of these genes directly impact the ability of cells within the body to synthesize plasmalogens, which is what results in all types being grouped together into the single disease RCDP. 

In all types of RCDP, the genetic mutations are called "autosomal recessive." The word autosomal indicates that the genes involved in this disease are not carried on the X or Y chromosome, and therefore the disease affects males and females equally. Recessive indicates that the patient must have two mutated copies of the same gene, one from each parent. That means if those parents had another child, the child would have a 25% chance of also having RCDP.

From a clinical perspective, it is impossible to determine the type of RCDP a child has from their disease presentation. The only way to know the type is to undergo genetic testing, which does occur commonly, but not always. Understanding the underlying genetic mutation does not appear to provide a clinical benefit in understanding treatment or prognosis, as the disease presentation is not linked to the mutation. What is evident is that the severity of the disease presentation is linked to the level of deficit in plasmalogen levels. Individuals with the lowest plasmalogen levels present with the most severe manifestations of the disease.  

Clinical Presentation

The inability to synthesize plasmalogens results in a number of developmental and cognitive impairments in RCDP. As discussed above, the disease is characterized by rhizomelia (shortening of the long bones) and chondrodysplasia punctata (punctate calcifications of joints). In addition to the orthopedic presentation, joint contractors are very common and cause restricted range of motion and discomfort to the patients. Cataracts are present at birth in almost all individuals with RCDP. Cardiovascular abnormalities have been described and appear to affect about half of all patients. Spinal stenosis is also a common occurrence in RCDP and should be monitored. Growth charts for RCDP have recently been published, and clearly show that growth rates are severely reduced. Feeding is challenging, with individuals having a tendency to aspirate if fed by mouth. This can result in complications often presenting as pneumonia. In addition, children with RCDP appear to have a lot of pain and discomfort which is believed to result from issues within the GI system including gas, problems stooling, reflux, and bloating. Cognitive development is severely delayed and seizures are common in patients, especially those over about 2 years of age. Clearly RCDP is a systemic disease and treatment requires addressing a wide range of symptoms and complications. 

Disease Management

There is currently no treatment for RCDP. The life expectancy has been reported as less than 5 years on average, however this range varies widely with the clinical severity of the disease. Using the RCDP registry, new analysis on life expectancy is being performed.  

Clinical management of the disease is currently based on the management of symptoms. GI tubes are commonly placed to aid with feeding challenges and prevent complications from aspirating. Surgery is performed to correct cataracts, commonly very early in life, and glasses can be used to improve vision. Medication to manage seizure activity is also regularly used to reduce seizure frequency and severity. To prevent respiratory illness, which can be devastating in these patients, many individuals have a regime of breathing treatments to control secretions. Occupational and physical therapy are also routinely incorporated into the ongoing management of the disease. The goal of all of these interventions is to improve the quality of life for individuals living with RCDP.  

See our resources page for links to more information on RCDP.