Clinical RCDP discoveries in the last decade
Rhizomelic chondrodysplasia punctata (RCDP) is a class of rare genetic recessive disorders caused by an inability to synthesize plasmalogens, a class of lipids that contain a vinyl-ether bond at sn-1. The predicted incidence is ~1 in 100 000 live births, with under 100 known cases in North America. Plasmalogens are involved in membrane structure, vesicular fusion, and act as strong antioxidants, therefore it is unsurprising that inadequate levels result in significant pathologies. RCDP is characterized by proximal shortening of bones, punctate calcifications of epiphyseal cartilage, and cognitive impairment. Other common symptoms include recurrent respiratory illnesses, spinal stenosis, and cardiac abnormalities. The exact mechanism that causes a plasmalogen deficiency to result in these symptoms is still not fully understood, but great strides have been made in the RCDP field in recent years. Looking at publications from 2011 to 2021, a simple “rhizomelic chondrodysplasia punctata” PubMed search produces over 78 articles where RCDP is mentioned, with over 60 having RCDP and its pathology as the primary topic. This post will highlight some of the key findings of these papers described in the last decade.
One of the most significant recent findings in the RCDP field is an update to the survival rate for patients with RCDP. In 2003, White et al (1) examined 35 individuals with RCDP that had been a part of a clinical assessment or a questionnaire and found that 90% lived to 1.5-2 years of age and 50% lived to ~6 years. This was a vast improvement from the 1990 paper by Wardinsky et al (2) which stated that most infants with RCDP would not survive the first year of life; however more recent work by Duker et al (3) demonstrated a 90% probability of survival in the first year, and a 75% probability of surviving to school age. It was also shown that survival was not impacted by geography, sex, or RCDP type. However, it was reported that those with “non-classic” presentation of RCDP, which correlated with higher plasmalogen levels, lived longer including some patients that were over 20 years of age at the time of the study.
Until recently there was also a poor understanding of the prevalence of cardiac conditions and seizures in the RCDP population. In 2003, White et al (1) presented a 6% risk of cardiac complications, but this was updated by Huffnagel et al (4) in 2013 to a 52% risk and Duker et al (5) found a 64% risk in 2015. Understanding and awareness of the risk for cardiac complications in RCDP is essential for ensuring that RCDP patients receive proper and complete clinical care. Similarly, by studying 16 individuals with RCDP, 12 of which had the severe phenotype and 4 had the mild phenotype, Bams-Mengerink et al (6) found that only two (one from each group) did not develop epilepsy. As well, the severe group developed seizures earlier between 4 months and 11 years of age, while the mild group did not begin to experience seizures until 7 years of age. They also found a difference in the type of seizures in each group. The severe group typically had myoclonic jerks and the mild group would have periods of staring with a frozen expression without the 3 Hz spike and slow wave discharges seen with an EEG.
Mild RCDP types have also been described in more detail in recent years. Compared to “classic” RCDP, individuals with a “nonclassic” presentation usually lack rhizomelia and chondrodysplasia punctata, two of the hallmark physical characteristics, and therefore may get misdiagnosed with another peroxisomal disorder. In addition, RCDP 4 and 5 were only discovered in the last decade. RCDP 4 is the result of mutations in fatty acyl-CoA reductase 1 (FAR1; more information can be found here) and RCDP 5 is caused by a mutation in the long variant of peroxisome biogenesis factor 5 (PEX5; more information can be found here).
With an increased awareness of RCDP comes a greater understanding of the disorder. In the last decade the scientific community has made incredible progress in describing details of RCDP pathology, as well as identifying new genetic mutations that cause this class of disorders. These clinical descriptions provide a more accurate understanding of the cardiac complications and neurological symptoms of the disease. In addition, the community benefits from understanding the current survival rate of individuals with RCDP, and what factors do and do not impact survival. Continuing this work will be critical for designing potential therapeutics, and ensuring that patients receive the correct diagnosis and clinical management of their symptoms.
References:
1) White AL, Modaff P, Holland-Morris F, and Pauli RM. (2003) Natural history of rhizomelic chondrodysplasia punctata. American Journal of Medical Genetic, 118A:332-342
2) Wardinsky TD, Pagon RA, Powell BR, McGillivray B, Stephan M, Zonana J, and Moser A. (1990) Rhizomelic chondrodysplasia punctata and survival beyond one year: a review of the literature and five case reports. Clinical Genetics
3) Duker AL, Niiler T, Kinderman D, Schouten M, Poll-The BT, Braverman N, and Bober MB. (2019) Rhizomelic chondrodysplasia punctata morbidity and mortality, an update. American Journal of Medial Genetics, 1-5
4) Huffnagel IC, Clur SB, Bams-Mengerink AM, Blom NA, Wanders RJA, Waterham HR, and Poll-The BT. (2013) Rhizomelic chondrodysplasia punctata and cardiac pathology. Journal of Medical Genetics
5) Duker AL, Eldridge G, Braverman NE, and Bober MB. (2015) Congentical heart defects common in rhizomelic chondrodysplasia punctata. American Journal of Medical Genetics, 9999A:1-3
6) Bams-Mengerink AM, Koelman JHTM, Waterham H, Barth PG, and Poll-The BT. (2013) The neurology of rhizomelic chondrodysplasia punctata. Orphanet Journal of Rare Diseases