Clinical, biochemical and molecular characterization of mild (nonclassic) Rhizomelic Chondrodysplasia Punctata

Fallatah W, Schouten M, Yergeau C, Di Pietro E, Engelen M, Waterham HR, Poll-The BT, and Braverman N. (2020) Clinical, biochemical and molecular characterization of mild (nonclassic) Rhizomelic Chondrodysplasia Punctata. Journal of Inherited Metabolic Disease

Rhizomelic chondrodysplasia punctata (RCDP) is a class of recessive genetic disorders that results from the inability to synthesize plasmalogens, a class of lipids that contain a vinyl-ether bond. This inability is typically due to mutations in the early enzymes in the biosynthetic pathway. Most patients diagnosed with RCDP present with severe symptoms including congenital cataracts, skeletal dysplasia, chondrodysplasia punctata in the cartilages of large joints, cardiac malformations, recurrent respiratory infections, and seizure disorders. There is however a range of phenotypic presentation, which has led many clinicians to adopt the term “classic RCDP” to describe individuals which present with this severe phenotype. Patients with classic RCDP typically do not live past 10 years of age and death is often caused by respiratory complications. Although classic RCDP is the most common, there are some individuals with nonclassic RCDP and they experience milder symptoms of the disorder with more variable rhizomelia, better growth and development, cataracts, and a longer lifespan. These patients also have an intermediate level of plasmalogens compared to the patients with classic RCDP. As there is little clinical data about nonclassic RCDP, Fallatah et al analyzed the clinical, biochemical, and molecular characteristics of 16 people with a mild case of RCDP.

Of the 16 patients, 14 were found to have bilateral cataracts in the neonatal period, eight lacked the ability to fully extend their limbs, seven individuals had hip deformities, and only three had mild rhizomelia involving the humeri. Five of the 16 had cardiac abnormalities and four had asthma. Seven of the 16 patients developed a seizure disorder with the onset occurring between four and 24 years. In addition, half had normal MRIs while the others showed some signal abnormalities (3/16), brain atrophy (1/16), or other abnormal brain structures. Behaviorally, abnormalities were very common across most of the patients. Four had anxiety symptoms, two patients had obsessive compulsive disorder, two were diagnosed with autism spectrum disorder, repetitive behavior occurred in three patients, and four patients had difficulties falling asleep and waking at night.

Although classic RCDP results in severe cognitive deficits, the 16 nonclassic patients were split into three tiers based on the age of walking independently. Group A consisted of two patients who were able to walk independently by 15 months of age and received standard education with support for learning difficulty. Eight patients fell into Group B for walking by three years of age, also experienced delays in gross motor and cognitive skills, and required special education. The final group, C, was four patients who walked independently and two that walked with support after 3 years. Only one member of this group had full bladder control, and all required special education.

During the biochemical analyses it was found that in erythrocytes the C16:0 plasmalogen levels were reduced to 34% and the C18:0 plasmalogens were 39% of that in healthy controls. As well, plasma phytanic acid, a branched chain fatty acid, were increased in 10 patients. Molecularly, the specific mutation and resultant RCDP type of each patient was determined. Fourteen patients were diagnosed with RCDP 1; 12 were heterozygous for a PEX7, peroxisomal protein in the plasmalogen biosynthetic pathway, allele known to cause the severe phenotype and a PEX7 allele probably responsible for the mild phenotype. Two patients were found to have RCDP 2; one patient was compound heterozygous for GNPAT and Arg163Ter and the other patient was homozygous for Arg163Ter.

As most cases of RCDP are classic and experience more severe symptoms and deficits, it is very interesting to uncover the differences between classic and nonclassic presentations, especially in RCDP types that typically result in a more severe phenotype. Where most individuals with classic RCDP experience severe developmental defects and cognitive deficits, the symptoms observed in this study were only found in 25-50% of the patients. This is not to say these individuals do not have challenges ahead of them in their lives, but a greater quality of life may be experienced by patients with fewer symptoms. Aside from genetic differences that would be present in those with classic RCDP, the intermediate plasmalogen levels seen in this study provides hope for severe RCDP and the chance to improve pathology through increasing plasmalogens levels. As well, there are likely many more individuals with mild RCDP but have not been correctly diagnosed due to a lack of understanding about this less typical version of the disease. Further research about how mild RCDP presents will allow patients to be properly diagnosed.