Peroxisome biogenesis disorders (PBDs) are a genetically heterogeneous group of metabolic diseases caused by impaired peroxisome assembly and function. PBDs exhibit striking clinical variability, ranging from lethal neonatal forms (e.g., Zellweger spectrum disorders) to milder childhood-onset presentations such as rhizomelic chondrodysplasia punctata. While elevated levels of very-long-chain fatty acids (VLCFAs) remain a key diagnostic feature, the existence of unusual cases with normal plasma VLCFA levels highlight the limitations of relying solely on this biochemical marker for diagnosis. Genetic variations in PEX6, an important peroxisome biogenesis factor, contribute significantly to this phenotypic diversity, with missense variants often associated with less severe disease compared to truncating mutations. Recent studies further implicate dysregulated pexophagy-a targeted autophagic degradation of peroxisomes-in the underlying disease mechanisms. This review underscores the necessity for a multifaceted diagnostic approach that, thorough clinical assessment, detailed biochemical evaluation, and advanced molecular genetic testing, seeks to improve diagnostic accuracy and patient care, particularly in pediatric populations. Advancements in identifying novel biomarkers and targeted therapies offer promise for tailored interventions, underscoring the importance of precision medicine in optimizing outcomes for pediatric PBD patients.

Rhizomelic chondrodysplasia punctata (RCDP) is a rare genetic disorder characterized by symptoms such as respiratory dysfunction, seizures, orthopedic issues, and neurodevelopmental delay. Potential therapeutics for RCDP warrant the development of clinical outcome assessments to assess the efficacy of treatment and the well-being of patients. Our study aimed to develop a valid quality-of-life (QOL) caregiver-reported survey instrument, RhizoQOL, to be used as a supportive endpoint in RCDP clinical trials. Development of the RhizoQOL survey tool included three RCDP caregiver focus groups to elicit concepts to serve as potential domains in a QOL survey instrument for RCDP, pilot survey development and initial testing, cognitive interviewing of revised survey drafts to determine content validity, as well as a three-month longitudinal study for reliability and internal consistency of the survey instrument. Twenty-eight caregivers participated in the focus groups, reporting that concepts that could be appropriate domains of QOL in RCDP include psychosocial behavior, feeding symptoms, mobility symptoms, respiratory symptoms, seizures and related activity, and impact of treatment. Following pilot survey testing (n = 22) and stakeholder feedback, a revised pilot survey instrument was administered to five caregivers for cognitive interviewing. This resulted in a revised survey instrument with 31 question items, six domains, and a 1-5 Likert scale item response assessing frequency or severity of event in the question item. Longitudinal testing (n = 18) of the revised survey instrument found the average response score was 1.98 ± 0.97 for all question items, and a Cronbach's alpha value of 0.856, suggesting strong intra-survey question reliability. Using individual question item results from reliability testing, linear regression modeling, and testing for required magnitude of significant treatment effects, eight question items were removed from the survey instrument, resulting in a total of 23 question items within 6 discrete domains. The final RhizoQOL survey instrument, consisting of 23 questions, assesses the symptoms and experiences of RCDP patients as observed by caregivers and serves as a novel clinical outcome assessment for RCDP therapeutic clinical trials to assess the impacts of RCDP and support the overall effectiveness of treatments.

PPI-1011 is a synthetic plasmalogen precursor designed to augment plasmalogen levels in patients with Rhizomelic chondrodysplasia punctata (RCDP), an ultra-rare genetic disorder caused by a plasmalogen deficiency that results in significant physical and mental delays. We report here a Phase I, randomized, double-blind, placebo-controlled study that evaluated the safety, tolerability, and pharmacokinetics (PK) of single (10-100 mg/kg) and multiple (75 and 100 mg/kg/day) ascending doses of PPI-1011 in healthy adults. All treatment-emergent adverse events (TEAEs) were mild, monitorable, and resolved without intervention, suggesting no significant safety concerns. The most common TEAEs were gastrointestinal in both the placebo and PPI-1011 groups, suggesting they were likely related to the oil-based nature of the formulation. PK analysis confirmed that both single (25, 50, 75 and 100 mg/kg) and multiple-dose (75 and 100 mg/kg, once daily) administration of PPI-1011 significantly increased serum levels of the target plasmalogen (PlsEtn 16:0/22:6). With a once-daily regimen, PPI-1011 administration resulted in a sustained increase of PlsEtn 16:0/22:6 serum concentrations in healthy participants over a duration of 14 days and beyond.

Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a peroxisomal disorder characterized by skeletal shortening, intellectual disability, seizures, cataracts, and reduced lifespans. RCDP1 is caused by biallelic loss-of-function variants in PEX7, which encodes a protein required for importing select enzymes into the peroxisome matrix, including those essential for ether lipid synthesis (e.g., plasmalogens) and the branched-chain fatty acid catabolism. Plasmalogen deficiency is a hallmark of RCDP1 and other peroxisomal disorders, including RCDP types 2-5 (RCDP2-5) and Zellweger spectrum disorders (ZSD). Here, we performed comprehensive metabolomic profiling of clinical samples from RCDP patients and Pex7-deficient mouse models. We identified profound neurometabolic disturbances in the cerebral cortex and cerebellum of Pex7-deficient mice involving multiple lipid classes, including phosphatidylethanolamines (PEs), phosphatidylcholines (PCs), acylcarnitines, and sphingomyelins. Notably, many of these neurometabolic alterations were absent in patient and Pex7-deficient mouse plasma, indicating that plasma-based profiling can underrepresent the extent of CNS lipid remodeling. Overall, these findings reveal novel insights into neurometabolic adaptations to plasmalogen deficiency and suggest the potential involvement of additional pathways that may contribute to neurological dysfunction in RCDP.

Rhizomelic chondrodysplasia punctata (RCDP) is one of the rare inherited peroxisomal disorders that belongs to the heterogeneous group of chondrodysplasias presenting with proximal shortening of the limbs and distinctive punctate calcifications of bones and cartilages. This disorder occurs due to mutations in the genes responsible for peroxisomal biosynthesis inherited commonly as autosomal recessive, though a few are reported as x-linked dominant and recessive. The diagnosis can be made on clinical findings along with a skeletal survey; however, sonography and genetic analysis are crucial for a definitive prenatal diagnosis in cases where RCDP is inherited within a family as there is no definitive cure for RCDP and the treatment revolves around the management of its manifestations and complications. We hereby report the case of a neonate with features of RCDP. Significant respiratory involvement in RCDP babies is linked with high mortality which was also observed in this case. PEX7-related rhizomelic chondrodysplasia punctata (PEX7-RCDP), a peroxisome biogenesis disorder (PBD), has a classic (severe) form and a nonclassic (mild) form. Classic (severe) PEX7-RCDP is characterized by proximal shortening of the humerus (rhizomelia) and to a lesser degree the femur, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata, or CDP), coronal clefts of the vertebral bodies, and cataracts that are usually present at birth or appear in the first few months of life. Birth weight, length, and head circumference are often at the lower range of normal; postnatal growth deficiency is profound. Intellectual disability is severe, and most children develop seizures. Most affected children do not survive the first decade of life; a proportion die in the neonatal period. Nonclassic (mild) PEX7-RCDP is characterized by congenital or childhood cataracts, CDP or, infrequently, chondrodysplasia manifesting only as mild epiphyseal changes, joint contractures, neurobehavioral abnormalities, and milder intellectual disability and growth restriction than classic PEX7-RCDP. The diagnosis of PEX7-RCDP is established in a proband with suggestive clinical, radiographic, and laboratory findings and biallelic pathogenic variants in PEX7 identified on molecular genetic testing. Treatment of manifestations: In those with classic (severe) PEX7-RCDP, management is supportive and limited by the severe health issues present at birth and poor outcome. Dietary restriction of phytanic acid to avoid the consequences of phytanic acid accumulation over time may benefit individuals with mild PEX7-RCDP. Physical therapy to improve contractures; orthopedic procedures may improve function in some individuals; consider need for positioning and mobility devices; spinal decompression with or without fusion depending on region of compression and myelopathic signs; cataract extraction may restore and/or preserve vision; community vision services through early intervention or school district; poor feeding and recurrent aspiration may necessitate placement of a gastrostomy tube; developmental and educational support; standard treatment of seizures by an experienced neurologist; good pulmonary clearance and attention to respiratory function; influenza vaccine, RSV monoclonal antibody, and other interventions to prevent lung disease; management of congenital heart disease per cardiologist; dermatologist management of skin manifestations; management of kidney and urinary tract anomalies per nephrologist and/or urologist; social work and care coordination as needed. Surveillance: Annual measurement of phytanic acid levels in children with non-classic (mild) PEX7-RCDP; musculoskeletal assessment, assessment for kyphosis and scoliosis, and neurologic exam with assessment for seizures at each visit; vision assessment every three months until cataracts are detected and then as recommended by ophthalmologist; assessment of growth, nutritional status, safety of oral intake, development, behavior, and respiratory function at each visit; cardiac exam, echocardiogram, and EKG with frequency per treating cardiologist; urine and imaging studies to assess for kidney stones as needed; assessment for skin issues and family needs at each visit. PEX7-RCDP is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PEX7 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the PEX7 pathogenic variants have been identified in an affected family member, molecular genetic carrier testing of at-risk relatives and prenatal/preimplantation genetic testing are possible.