Clinical characteristics: 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 PEX gene defect 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 other 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.
Diagnosis/testing: The diagnosis of ZSD is established in a proband with the suggestive clinical and biochemical findings above and identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX genes.
Management: Treatment of manifestations: The focus is on symptomatic therapy and may include gastrostomy to provide adequate calories, hearing aids, cataract removal in infancy, glasses, vitamin supplementation, primary bile acid therapy, adrenal replacement, antiepileptic drugs, and possibly monitoring for hyperoxaluria. Surveillance: Annual hearing and ophthalmologic evaluations, monitoring of liver function and coagulation factors, ACTH/cortisol. A baseline brain MRI is recommended; a loss of motor and cognitive milestones could indicate a leukodystrophy.
Genetic counseling: ZSD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual 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 and prenatal diagnosis for pregnancies at increased risk are possible if both ZSD-related pathogenic variants have been identified in an affected family member. Prenatal diagnosis by biochemical testing is also possible; however, the biochemical defects in cultured fibroblasts from an affected family member must be confirmed first, since the biochemical defects present in body fluids or liver may not be detectable in cultured cells (a phenomenon called "peroxisomal mosaicism").
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