Zellweger syndrome, also known as Zellweger spectrum disorder (ZSD), is a rare genetic disorder that falls within a group of conditions known as peroxisome biogenesis disorders (PBD). These disorders are characterized by the impaired formation and function of peroxisomes, which are cellular organelles involved in various metabolic processes. This syndrome is caused by mutations in one of the 13 PEX genes encoding peroxin proteins. Pathogenic variants in the PEX genes can lead to alterations in peroxisome formation and peroxisomal dysfunction that can be more or less pronounced depending on the effect of the mutations. The incidence of Zellweger's syndrome in the general population is 1 case per 50.000 individuals. It is highest in the Saguenay-Lac St-Jean region of Quebec (Canada), with about 1 case per 12.000 inhabitants.
Zellweger syndrome genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
The key features and aspects of Zellweger syndrome include:
- Genetic Basis: Zellweger syndrome is caused by gene mutations, including PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, and PEX16. These genes are involved in peroxisome biogenesis.
- Peroxisome Dysfunction: The primary defect in Zellweger syndrome is the absence or malfunction of peroxisomes, leading to the impairment of various metabolic pathways. Peroxisomes play a crucial role in lipid metabolism, bile acid synthesis, and the detoxification of certain substances.
- Clinical Features: Zellweger syndrome is associated with symptoms that typically become apparent in infancy. These may include severe hypotonia (weak muscle tone), feeding difficulties, hearing and vision impairment, seizures, and developmental delays.
- Facial Characteristics: Infants with Zellweger syndrome may have distinctive facial features, including a high forehead, large fontanel (soft spot), widely spaced eyes, and a flattened midface.
- Liver Dysfunction: Liver dysfunction is joint in Zellweger syndrome, and affected individuals may have hepatomegaly (enlarged liver) and liver failure.
- Neurological Involvement: Neurological symptoms are prominent and may include white matter abnormalities and structural brain abnormalities. Severe intellectual disability is a standard feature.
- Vision and Hearing Impairment: Vision impairment is often due to abnormalities in the retina and optic nerve development. Hearing loss is also common and can be profound.
- Prognosis: Zellweger syndrome is a severe and life-limiting disorder. The prognosis is generally poor, with many affected individuals not surviving beyond the first year of life.
- Diagnosis: Diagnosis is typically based on clinical features, imaging studies, and biochemical testing. Genetic testing can confirm the presence of mutations in the relevant genes associated with peroxisome biogenesis.
- Supportive Care: Zellweger syndrome has no cure, and treatment is primarily supportive. Management addresses symptoms, provides nutritional support, and addresses complications such as liver dysfunction.
It's important to note that Zellweger syndrome is part of a spectrum of disorders, and the severity of symptoms can vary.
Mutations in the PEX1 gene account for approximately 63% of all alleles in individuals with Zellweger syndrome. This gene encodes for peroxisome biogenesis factor 1. The most frequent mutations in PEX1 are c.2528G>A (p.Gly843Asp) and c.2097dup (p.Ile700fs). Both have been observed in patients, with symptoms ranging from mild to moderate in both homozygosis and compound heterozygosis (in combination with other mutations in PEX1).
The c.2528G>A (p.Gly843Asp) variant has been linked to peroxisome biogenesis disorders. It is the most frequent variant associated with the syndrome and produces a non-conservative amino acid substitution affecting the structure and functionality of the protein.
Zellweger syndrome genetic testing analyzes the 8 most frequent pathogenic mutations of the PEX1 gene.
The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).
