RHIZOMELIC CHONDRODYSPLASIA PUNCTATA (RCDP)
Rhizomelic Chondrodysplasia Punctata
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.
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.
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.
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.
Plasmalogens and the Peroxisome
The body is made up of millions of cells. Cells are discrete, structural units of living organisms that are separated from the extracellular environment by the lipid (also called plasma) membrane. This membrane is actually made up to two layers of lipids called phospholipids, which form what is called a lipid bilayer. There are multiple classes of phospholipids that pack together to form the lipid membrane bilayer. The membrane not only holds the contents of the cell together, but serves a number of other functions including nutrient transport, cell-cell communication, vesicular fusion, neurotransmission, and houses special microdomain regions required for the activity of various membrane-anchored protein receptors.
Plasmalogens are a unique family of cell membrane glycerophospholipids that contain a vinyl-ether bond. A glycerophospholipid is built by the body through the attachment of fatty acids to a three-carbon glycerol backbone. Examples of fatty acids include those from the diet such as the 18-carbon linoleic and linolenic acids, DHA (a 22-carbon fatty acid), and many others. Fatty acids are joined to two carbons of the glycerol backbone (often referred to as the sn-1 and sn-2 positions) through specific chemical bonds. When the chemical bond connecting the fatty acid to the sn-1 position is a vinyl-ether bond, the lipid is referred to as a plasmalogen.
Within each cell there are a number of smaller organelles that serve various functions. The nucleus, for example, contains the DNA. The peroxisome is another tiny organelle that contains enzymes specifically involved in long-chain fatty acid metabolism, metabolism of catalase, and plasmalogen biosynthesis.
There are two specific enzymes (proteins that carry out chemical reactions in the body) located in the peroxisome that make a critical ether-bond required for a plasmalogen. This ether bond is then converted to a vinyl-ether bond, which is the defining bond of a plasmalogen, by enzymes that are located outside of the peroxisome in another part of the cell called the endoplasmic reticulum (ER). As described above under GENETICS, all of the RCDP subtypes ultimately result from mutations in genes that in one way or another affect the peroxisome's ability to synthesize chemical reactions critical for the synthesis of plasmalogens.
key Plasmalogen functions
In-depth details of plasmalogen functions can be found in several excellent reviews on our Resources Page. In the context of RCDP, precisely how reduced plasmalogen levels cause all of the symptoms of RCDP is still not clear, although there are a number of groups worldwide researching this.
One of the main functions of plasmalogens is their effect on the physical structure of the cell membrane. Cell membranes containing plasmalogens have a different structure, being more highly-ordered and rigid. This is because the fatty acid side-chains are located more closely together due to the vinyl-ether bond, resulting in a more tightly-packed structure. One cell function, in particular, that is highly sensitive to the amount of plasmalogen in the membrane, is a process called vesicular fusion. Vesicular fusion occurs when small vesicles, located inside a cell, move contents to the outside of the cell by "fusing" its membrane with the cell membrane. The short video to the right really is worth a thousand words!
The less plasmalogen in a cell membrane, the less likely it is that the vesicle will fuse to the cell membrane. One critical physiological function that is completely dependent on vesicular fusion is neurotransmission. Neurotransmission is the process whereby electrical signals, called action potentials, are relayed from the end of one neuron to the beginning of adjacent neurons. In simple terms, vesicles inside of neurons hold chemicals called neurotransmitters. When an action potential travels through a neuron and reaches the end-terminal, called the pre-synaptic terminal, it signals the vesicles containing neurotransmitters to fuse to the membrane, and in doing so, release their contents into the extracellular space (referred to as the synaptic cleft) between the ends of the neurons. The neurotransmitters then move through the presynaptic cleft and bind to receptors on the next neuron (called the post-synaptic terminal), resulting in the creation of a new action potential that propagates along the length of the neuron, and the process repeats. This process is also much easier to grasp through visualization as shown in the Chemical Synapse Animation above.
Obviously, many physiological processes, both in the central and peripheral nervous systems, including muscle contractions, pain and discomfort, awareness, cognition, vision, and many others, rely on vesicular fusion-mediated neurotransmitter release. If membranes don't contain healthy amounts of plasmalogens, some of these functions will undoubtedly be compromised.
An added complexity with RCDP is that because it is an inborn genetic condition, plasmalogens are deficient during embryonic and fetal development. How a plasmalogen deficiency leads to the developmental issues associated with RCDP is poorly understood. Certain aspects of the disease, such as the skeletal abnormalities, will likely not be reversible by any treatment, however, other aspects such as growth, discomfort, overall health, attention and awareness, quality of life, and lifespan, might be. The correlation between the severity of the disease and plasmalogen level provides hope that by augmenting plasmalogens therapeutically, improvement in at least some of these endpoints can be achievable.
There are several other roles that plasmalogens play in the body. These include protection against oxidative stress, regulation of cholesterol levels, and formation of optimal cell membrane microdomains, which is another membrane structural phenomenon that is required for the function of many membrane-anchored proteins. More information on these functions can be found in the papers included on the Resources page. In addition we will expand in more detail on some of these functions in future posts.