Peroxisome biogenesis disorders (PBDs) encompass a group of diseases marked by clinical and genetic heterogeneity. Phenotypes linked to PBDs include Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease (IRD), rhizomelic chondrodysplasia punctata type 1, and Heimler syndrome. PBD phenotypes manifest through hypotonia, developmental delay, facial dysmorphism, seizures, liver dysfunction, sensorineural hearing loss, and retinal dystrophy. The proband underwent comprehensive clinical evaluation, followed by whole-exome sequencing (WES) coupled with copy number analysis (CNV), aimed at identifying potential disease-causing variants aligning with the observed phenotype. Our findings detail an individual exhibiting developmental delay, hearing loss, visual impairment, hepatomegaly, and splenomegaly, attributed to a biallelic deletion of exon 4 in the PEX26 gene. The WES analysis of the index case did not uncover any pathogenic/likely pathogenic single-nucleotide variations that could account for the observed clinical findings. However, the CNV data derived from WES revealed a homozygous deletion in exon 4 of the PEX26 gene (NM_001127649.3), providing a plausible explanation for the patient's clinical features. The exon 4 region of PEX26 encodes the transmembrane domain of the protein. The transmembrane domain plays a crucial role in anchoring the protein within lipid bilayers, and its absence can disrupt proper localization and functioning. As a result, this structural alteration may impact the protein's ability to facilitate essential cellular processes related to peroxisome biogenesis and function. The index patient, which presented with hearing loss, retinal involvement and hepatic dysfunction in adolescence age, has atypical clinical course that can be considered unusual for Zellweger syndrome (ZS) and IRD phenotypes, and its rare genotypic data (in-frame single exon deletion) expands the PBD disease spectrum. This study revealed for the first time that PEX26 protein transmembrane domain loss exhibits an unusual course with clinical findings of IRD and ZS phenotypes. WES studies, incorporating CNV analyses, empower the identification of novel genetic alterations in genes seldom associated with gross deletion/duplication variations, such as those in the PEX26 gene. This not only enhances diagnostic rates in rare diseases but also contributes to broadening the spectrum of causal mutations. What is now known as Refsum disease was initially described by Sigvald Refsum as heredoataxia hemeralopica polyneuritiformis in 1945, but its name was changed to heredopathia atactica polyneuritiformis the following year. Today, Refsum disease is synonymous with "adult Refsum disease" and "classic Refsum disease." The Online Catalog of Human Genes and Genetic Disorders (OMIM) records adult Refsum disease as phenotype MIM number #266500. The condition is rare, autosomal recessive, and classified as a disorder of peroxisomal function.  Peroxisomes are single membrane-bound intracellular organelles that generate peroxide for use in metabolic functions. Their functions are far-reaching and include a vast complement of lipid catabolism and biogenesis functions; the dysfunction in lipid catabolism is responsible for Refsum disease. The fundamental characteristic of disorders of peroxisome function is that they are due to a deficiency in the function of a single enzyme. This produces specific metabolic abnormalities. Refsum disease is caused by a deficiency of the phytanoyl-CoA hydroxylase, which results in deficient catabolism of phytanic acid and an excess. The core of Refsum disease's clinical characteristics is due to the effects of phytanic acid buildup on the nervous system. Since the terminology surrounding Refsum disease can be confusing, it is worth emphasizing that Refsum disease is distinct from infantile Refsum disease, which falls within the Zellweger spectrum disorders. These are classified as disorders of peroxisomal biogenesis and assembly. For more information on infantile Refsum disease, see StatPearls' companion topic, "Zellweger Spectrum Disorder."

Zellweger spectrum disorders (ZSDs) are known to present with variable hepatic manifestations ranging from benign hepatosplenomegaly and elevated liver enzymes to advanced liver cirrhosis with hepatocellular carcinoma. However, the progression of liver disease in ZSD patients over time is poorly characterized due to scarcity of the disease. Herein, we report a case of newly diagnosed liver cirrhosis in a ZSD patient with rapid progression and fatal outcome to demonstrate key clinical learning points.

Bile acid intermediates, 3α,7α,12α-trihydroxycholestanoic acid (THCA) and 3α,7α-dihydroxycholestanoic acid (DHCA), are metabolized in peroxisomes. Some peroxisomal disorders (PDs), such as Zellweger spectrum disorder (ZSD), show an accumulation of bile acid intermediates. In particular, ABCD3 deficiency and acyl-CoA-oxidase 2 deficiency are characterized by these metabolite abnormalities. In patients with ZSD, levels of bile acid intermediates can be lowered by a primary bile acid supplementation treatment; therefore, measuring their levels could help evaluate treatment effectiveness. Here, we established a method for the quantitative determination of bile acid intermediates (THCA/DHCA) for differentiating PDs and assessing bile acid treatment. Serum samples, obtained from patients with several forms of ZSD as well as peroxisomal β-oxidation enzyme deficiencies, were deproteinized and analyzed using liquid chromatography-mass spectrometry. Levels of the bile acid intermediates increased significantly in patients with Zellweger syndrome (ZS) and slightly in patients with neonatal adrenoleukodystrophy and infantile Refsum disease (IRD), reflecting the severity of these diseases. One patient with ZS treated with primary bile acids for 6 months showed slightly decreased serum DHCA levels but significantly increased serum THCA levels. One patient with IRD who underwent living-donor liver transplantation showed a rapid decrease in serum THCA and DHCA levels, which remained undetected for 6 years. In all controls, THCA and DHCA levels were below the detection limit. The analytical method developed in this study is useful for diagnosing various PD and validating bile acid treatment. Additionally, it can help predict the prognosis of patients with PD and support treatment strategies.

The aim of this paper is to describe the temporal progression and clinical picture of a 2-year-old child with infantile Refsum disease, as well as the diagnostic procedures performed; this case presented multiple hematologic, metabolic, and developmental complications and progressive disabilities. Genetic testing revealed a mutation of the PEX6 (Peroxisomal Biogenesis Factor 6) gene, and the metabolic profile was consistent with the diagnosis. Particularly, the child also presented altered coagulation factors and developed a spontaneous brain hemorrhage. The clinical picture includes several neurological, ophthalmological, digestive, cutaneous, and endocrine disorders as a result of the very long chain fatty acid accumulation as well as secondary oxidative anomalies. The study of metabolic disorders occurring because of genetic mutations is a subject of core importance in the pathology of children today. The PEX mutations, difficult to identify antepartum, are linked to an array of cell anomalies with severe consequences on the patient's status, afflicting multiple organs and systems. This is the reason for which our case history may be relevant, including a vast number of symptoms, as well as modified biological parameters.

Zellweger spectrum disorder (ZSD) is a heterogeneous group of autosomal recessive disorders characterized by a defect in peroxisome formation and attributable to mutations in the PEX gene family. Patients with ZSD have profound neurologic impairments, including seizures, severe retardation, and dysmorphic features, and poor prognosis. Currently, there is no specific, effective treatment. Here, we investigated the effects of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on PEX1-related ZSD. The suspected clinical proband was first diagnosed at the Department of Neurology of our hospital. The proband died soon after diagnosis, and his family was studied. We found that a brother had the same genetic alterations, and he was diagnosed with Infantile Refsum disease (IRD) as the mildest form of ZSD. We implemented treatment with allo-HSCT, at the request of the child's parents. After transplantation, we observed significant improvements in the clinical manifestations, very-long-chain fatty acids, and brain MRI. The patient has recovered well and not showed any abnormal clinical manifestations after 2 years of follow-up. We have achieved satisfactory short-term results in the treatment of ZSD-IRD with allo-HSCT. Long-term follow-up and observation will be performed to determine the long-term prognosis. Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term "ZSD" is now used to refer to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and the long bones), and liver disease that can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth. The diagnosis of ZSD is established in a proband with the suggestive clinical and biochemical findings above by identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX genes. One PEX6 variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state due to allelic expression imbalance dependent on allelic background. Treatment of manifestations: The focus is on symptomatic therapy and may include gastrostomy to provide adequate calories, hearing aids, cataract removal, glasses to correct refractive errors, supplementation of fat-soluble vitamins, and cholic acid supplementation; varices can be treated with sclerosing therapies; anti-seizure medication, early intervention services for developmental delay and intellectual disability; adrenal replacement therapy; vitamin D supplementation and consideration of bisphosphonates for osteopenia; treatment as per dentist for ameliogenesis imperfecta. Supportive treatment for renal oxalate stones has included hydration, lithotripsy, and surgical intervention. Annual influenza and respiratory syncytial virus vaccines should be provided. Surveillance: Growth and nutrition should be assessed at each visit. Annual audiology and ophthalmologic evaluations; annual monitoring of liver function and coagulation factors, and ultrasound and/or fibroscan to evaluate liver architecture; monitor for changes in seizure activity; head MRI to evaluate for white matter changes that may explain changes in cognitive and/or motor ability; monitor developmental progress and educational needs; ACTH and cortisol levels by age one year and annually thereafter. Dental examinations every six months. Annual urine oxalate-to-creatinine ratio with consideration of kidney imaging when performing liver imaging. Assessment of family needs at each visit. ZSD is typically inherited in an autosomal recessive manner (one PEX6 variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state). At conception, each sib of an individual with biallelic ZSD-causing pathogenic variants has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible if the pathogenic variants have been identified in an affected family member. Prenatal testing for a pregnancy at increased risk is possible by DNA testing if both ZSD-related pathogenic variants have been identified in an affected family member, or by biochemical testing if the biochemical defects have been confirmed in cultured fibroblasts from an affected family member.