It's Never Too Late for a Diagnosis

Zellweger spectrum disorder (ZSD) (OMIM#214100) is a phenotypic continuum ranging from severe to mild presentations. ZSD is now used in all individuals with a defect in one of the 13 ZSD-PEX genes, regardless of phenotype. Diagnosis can be suggested by abnormal levels of very long-chain fatty acids, phytanic acid, pristanic acid, plasmalogens, pipecolic acid, or bile acids. However, false negatives are frequent, mostly in older patients. Definite diagnosis is established in a proband with suggestive clinical findings by identification of biallelic pathogenic variants in one of the 13 ZSD-PEX genes.

A 39-year-old female patient had a global development delay since her first year of life. Never developed oral language but had sphincter control and was able to walk and laugh. At 8 years old, she had her first seizure and lost sphincter control when she was 20 years old. At 28 years old, she had an episode of status epilepticus, with severe prostration and became bedridden. She is currently mute, without capacity for communication or motor control. She has no consanguineous parents, has a 35 year old brother with global developmental delay and their mother had a history of an abortion, without other relevant family history. Brain MRI of the patient revealed severe leukodystrophy mainly periventricular, bilateral and symmetric, and less prominent in the cerebellar white matter, with severe cerebral and corpus callosum atrophy. Molecular study with a leukodystrophy gene panela identified a homozygotic pathogenic variant on PEX 1 gene (NM_000466.3) - c.2528G>A (p.(Gly843Asp)), confirming the diagnosis of ZSD.

Homozygosity for PEX1 p.Gly843Asp seems to be associated with an intermediate/milder ZSD phenotype,with survival until adulthood. Some patients develop progressive degeneration of CNS myelin, a leukodystrophy pattern, like this patient, which may lead to regression. This girl with ZSD had a rapid and severe loss of previous skills after a seizure. Even though there is no specific treatment for this disease, a correct diagnosiswas very important for the parents and for family genetic counselling.