It's Never Too Late for a Diagnosis.

Area of Science:

• Genetics
• Neurology
• Biochemistry

Background:

• Zellweger spectrum disorder (ZSD) is a group of genetic conditions caused by defects in PEX genes, presenting a wide range of clinical severity.
• Diagnosis relies on biochemical markers and genetic testing, but challenges like false negatives in older patients exist.
• Definitive diagnosis requires identifying biallelic pathogenic variants in one of the 13 ZSD-PEX genes.

Purpose of the Study:

• To report a case of Zellweger spectrum disorder (ZSD) diagnosed through molecular genetic testing.
• To investigate the clinical presentation and genetic basis of a specific PEX1 gene variant associated with ZSD.
• To highlight the importance of accurate genetic diagnosis for patient management and family counseling.

Main Methods:

• Clinical evaluation of a 39-year-old female with global developmental delay and neurological regression.
• Brain MRI to assess leukodystrophy and cerebral atrophy.
• Molecular genetic analysis using a leukodystrophy gene panel to identify pathogenic variants.

Main Results:

• The patient exhibited global developmental delay, seizures, and progressive neurological decline.
• Brain MRI revealed severe leukodystrophy and cerebral atrophy.
• Homozygosity for a pathogenic variant in the PEX1 gene (c.2528G>A; p.(Gly843Asp)) was identified, confirming ZSD.

Conclusions:

• Homozygosity for the PEX1 p.Gly843Asp variant is associated with an intermediate or milder ZSD phenotype, compatible with survival into adulthood.
• The identified PEX1 variant can lead to progressive leukodystrophy and neurological regression, as observed in this patient.
• Accurate genetic diagnosis of ZSD is crucial for prognosis, management, and genetic counseling, despite the absence of specific treatments.