Case Report: Spanish Male Newborn with Zellweger Syndrome Detected by X-ALD Newborn Screening

Background
Zellweger syndrome (ZS) is the most severe peroxisome biogenesis disorder (PBD). ZS is a rare genetic disorder that affects about 1 in 50000 to 1 in 75000 newborns as the result of a mutation in any of the 13 PEX genes. The presence of increased levels of very long-chain fatty acids (VLCFAs), specially C26:0-lysophosphatidylcholine (C26:0-LPC) during newborn screening (NBS), requires follow-up testing.

Case study

A nine-day-old male newborn was diagnosed at the Regional University Hospital of Malaga with ZS. He was born by vaginal delivery at 37 weeks gestation and weighed 2570 g. He presented with dysmorphic features including a large anterior fontanelle, hypertelorism, low-set ears and open sutures. He was admitted to the intensive care unit with severe axial hypotonia and convulsive syndrome. MRI, abdomen ultrasounds, blood analytics and karyotype analysis were performed, with C24:0-LPC and C26:0-LPC concentrations measured by HPLC-MS/MS in dried blood spots (DBS). In addition, C26:0, C24:0, and C22:0 plasmalogens were analysed and molecular genetic testing was performed including a 29 multigene panel for peroxisome disorders.

Results

The brain MRI showed 1–2 mm bilateral subependymal cysts in the caudothalamic grove and the abdominal ultrasound revealed numerous bilateral renal subcortical cysts. ACTH was increased (54 pg/mL vs. control: 5−50) and VLCFAs were elevated in the blood (mg/mL). The C24:0-LPC level was 0.35 (control ≤ 0.1) and C26:0-LPC 1.07 (control ≤ 0.145). Plasma C26:0, C24:0 and C22:0 remained elevated. Plasmalogens were decreased, C16* 0,003 (control: 0,052 ± 0,002) and C18* 0,005 (control: 0,135 ± 0,013), where * is the ratio between C16 or C18 dimethyl acetal and its methyl ester. Genetic testing identified found two heterozygous PEX6 variants, c.531delA, p.Pro179fs and c.402delC, p.Gly135fs.

Conclusion

X-ALD NBS allows the early diagnosis, follow-up, healthcare and genetic counselling of newborns affected with peroxisomal disorders.