Dataset Information

Genetic epidemiology approach to estimating birth incidence and current disease prevalence for rhizomelic chondrodysplasia punctata.

ABSTRACT:

Background

Rhizomelic chondrodysplasia punctata (RCDP) is an inherited ultra-rare disease which results in severely impaired physical and mental development. Mutations in one of five genes involved in plasmalogen biosynthesis have been reported to drive disease pathology. Estimates of disease incidence have been extremely challenging due to the rarity of the disorder, preventing an understanding of the unmet medical need. To address this, we have prepared a disease incidence and prevalence model based on genetic epidemiology approaches to estimate the total number of RCDP patients affected, and their demographic characteristics.

Results

Extraction of allelic frequencies for known and predicted pathogenic variants in PEX7, GNPAT, AGPS, FAR1, PEX5 (limited to the PTS2 domain encoding region) genes, from large-scale human genetic diversity datasets (TopMed and gnomAD) revealed the mutational landscape contributing to the RCDP patient population in the US and Europe. We computed genetic prevalence to derive birth incidence for RCDP and modeled the impact to life expectancy to obtain high confidence estimates of disease prevalence. Our population genetics-based model indicates PEX7 variants are expected to contribute to the majority of RCDP cases in both the US and Europe; closely aligning with clinical reports. Furthermore, this model provides estimates for RCDP subtypes due to mutations in other genes, including exceedingly rare subtypes.

Conclusion

In total, the estimated number of RCDP patients in the US and the five largest European countries (UK, Germany, France, Italy and Spain) is between 516 and 847 patients, all under the age of 35 years old. This model provides a quantitative framework for better understanding the unmet medical need in RCDP, to help guide disease awareness and diagnosis efforts for this specific patient group.

SUBMITTER: Luisman T

PROVIDER: S-EPMC8258949 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: To describe the neurologic profiles of Rhizomelic chondrodysplasia punctata (RCDP); a peroxisomal disorder clinically characterized by skeletal abnormalities, congenital cataracts, severe growth and developmental impairments and immobility of joints. Defective plasmalogen biosynthesis is the main biochemical feature. METHODS: Observational study including review of clinical and biochemical abnormalities, genotype, presence of seizures and neurophysiological studies of a cohort of 16 patients with RCDP. RESULTS: Patients with the severe phenotype nearly failed to achieve any motor or cognitive skills, whereas patients with the milder phenotype had profound intellectual disability but were able to walk and had verbal communication skills. Eighty-eight percent of patients developed epileptic seizures. The age of onset paralleled the severity of the clinical and biochemical phenotype. Myoclonic jerks, followed by atypical absences were most frequently observed. All patients with clinical seizures had interictal encephalographic evidence of epilepsy. Visual evoked (VEP) and brain auditory potential (BAEP) studies showed initial normal latency times in 93% of patients. Deterioration of VEP occurred in a minority in both the severe and the milder phenotype. BAEP and somatosensory evoked potentials (SSEP) were more likely to become abnormal in the severe phenotype. Plasmalogens were deficient in all patients. In the milder phenotype levels of plasmalogens were significantly higher in erythrocytes than in the severe phenotype. Phytanic acid levels ranged from normal to severely increased, but had no relation with the neurological phenotype. CONCLUSION: Neurodevelopmental deficits and age-related occurrence of seizures are characteristic of RCDP and are related to the rest-activity in plasmalogen biosynthesis. Evoked potential studies are more likely to become abnormal in the severe phenotype, but are of no predictive value in single cases of RCDP.

Project description:Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a peroxisome biogenesis disorder caused by defects in PEX7 leading to impairment in plasmalogen (Pls) biosynthesis and phytanic acid (PA) oxidation. Pls deficiency is the main pathogenic factor that determines the severity of RCDP. Severe (classic) RCDP patients have negligible Pls levels, congenital cataracts, skeletal dysplasia, growth and neurodevelopmental deficits, and cerebral hypomyelination and cerebellar atrophy on brain MRI. Individuals with milder or nonclassic RCDP have higher Pls levels, better growth and cognitive outcomes. To better understand the pathophysiology of RCDP disorders, we generated an allelic series of Pex7 mice either homozygous for the hypomorphic allele, compound heterozygous for the hypomorphic and null alleles or homozygous for the null allele. Pex7 transcript and protein were almost undetectable in the hypomorphic model, and negligible in the compound heterozygous and null mice. Pex7 deficient mice showed a graded reduction in Pls and increases in C26:0-LPC and PA in plasma and brain according to genotype. Neuropathological evaluation showed significant loss of cerebellar Purkinje cells over time and a decrease in brain myelin basic protein (MBP) content in Pex7 deficient models, with more severe effects correlating with Pex7 genotype. All Pex7 deficient mice exhibited a hyperactive behavior in the open field environment. Brain neurotransmitters analysis of Pex7 deficient mice showed a significant reduction in levels of dopamine, norepinephrine, serotonin and GABA. Also, a significant correlation was found between brain neurotransmitter levels, the hyperactivity phenotype, Pls level and the severity of Pex7 genotype. In conclusion, our study showed evidence of a genotype-phenotype correlation between the severity of Pex7 deficiency and several clinical and neurobiochemical phenotypes in RCDP1 mouse models. We propose that PA accumulation may underlie the cerebellar atrophy seen in older RCDP1 patients, as even relatively low tissue levels were strongly associated with Purkinje cells loss over time in the murine models. Also, our data demonstrate the interrelation between Pls, brain neurotransmitter deficiencies and the neurobehavioral phenotype, which could be further used as a valuable clinical endpoint for therapeutic interventions. Finally, these models show that incremental increases in Pex7 levels result in dramatic improvements in phenotype.