A Novel Homozygous PEX5 Variant in a Newborn with Severe Zellweger Spectrum Disorder: A Case Report

    

    

    Figure 3: Brian MRI Images.
Axial T2WIs for the brain (figures a and b) and inverted axial T2WIs for the
brain (figure c). Both cerebral hemispheres showed diffuse lack of normal
sulcation with multinodular surface, more evident at the frontal and perisylvian
regions on both sides (white arrows). Findings are consistent with
congenital cortical malformation (Lissencephaly-pachygyria spectrum). In
addition, cluster of periventricular / subependymal small cysts centered
at the caudothalamic grooves on both sides (black arrows), suggestive of
germinolysis / germinolytic cysts.
    

However, lab investigations were repeated during follow up and revealed that liver function tests became high: ALT 175 U\L, AST:271U\L, total bilirubin 65Umol\L, direct bilirubin 54 mmo\L, with total urea became 3.1 umol\L and creatinine 23.8 umol\L. He experienced recurrent chest infection and recurrent uncontrollable seizures. Elevated levels of VLCFAs in blood sample were evident. Chromosome analysis from blood lymphocytes was done showing normal male karyotype (46, XY) with no apparent numerical or structural chromosome anomalies.

Peripheral blood sample was collected on EDTA tube and sent for whole exome sequencing (WES) by which homozygous missense variant was identified in the PEX5 gene (c.1073T>C, p.Phe358Ser).

During the hospital stay; the infant continued supportive care in the form of oxygen therapy, tube feeding, anticonvulsants, despite aggressive supportive management, the patient exhibited poor growth. When the condition of the infant becomes stable, he was referred to higher centre for proper management and genetic counselling for the family.

Discussion

Zellweger Spectrum Disorder (ZSD) is a heterogenous genetic disorder caused by a defect in one of the ZSD-PEX genes transmitted from carrier parents through autosomal recessive mode. Severe ZWD is presented early in neonatal period with unusual facial features, poor feeding, neurological and multiorgan dysfunction. Infants with severe ZSD die early during the first year of life. On the other hand, Individuals with intermediate or mild ZSD have progressive course manifested by sensorineural hearing loss, hypotonia, developmental delays, adrenal insufficiency, and liver/renal dysfunction, however intellectual function can be normal [3,9,10].

Here is a case highlights a severe clinical presentation of ZSD in an infant during the neonatal period, our case has dysmorphic features, hypotonia, difficulty in feeding and recurrent episodes of seizures which matches with severe ZSD presentation. In addition to recurrent pneumonia and chest infection. A role of peroxisomes in modulating host–pathogen interactions was suggested [11]. Fazi et al 2022 [12] hypothesized the existence of a link between ZS and humoral immunodeficiencies. However, the exact pathway and regulations of peroxisomes in relation to humoral and innate immunity is not well understood.

The associated laboratory and radiological findings in conjunction with the presence of parental consanguinity and family history of neurodegenerative disease is going classically with severe Zellweger spectrum disorders which was further supported by high level of VLCFAs as a gold standard test with the clinical picture to diagnose such cases [11], and MRI finding of lissencephaly, pachygyria and germinolytic cysts observed on MRI further support the diagnosis, as they are strongly indicative of severe ZSD when correlated with the clinical findings [13]. Alshenaifi et al 2018 [14] reported the prevalence of peroxisomal disorders among Arabs is around 1:30 000, which is much higher than the worldwide prevalence estimates [1]. The diagnosis of ZWS is based mainly on the clinical, biochemical and molecular findings in the suspected cases. Although the main biochemical marker for screening of ZWS is VLCFAs assay, the new era of molecular genetics revealed many pathogenic and likely pathogenic variants in one or more of PEX genes that are known to be involved in ZWD especially PEX1 and PEX6 gene variants [15].

Many gene variants of PEX5 gene are reported in ZWS. Based on data published before; PEX 5 gene variants were relevant in the Arabs in which peroxisomal disorders appear to be more common than in other populations (14). WES analysis of the DNA sample of the patient revealed a homozygous missense variant in the PEX5 NM_001351132.2: c.1073T>C (p.Phe358Ser). To the best of our knowledge, this novel variant has not been previously reported in the literature and not listed in CLIN Var database. According to the ACMG guidelines, this variant is classified as a variant of uncertain significance (VUS). However; based on the evident clinical manifestations of severe ZWS including dysmorphism, seizures, neurodegenerative and hepatorenal dysfunction with biochemical clues in the form of elevated VLCFAs in plasma supported by the radiological findings in the brain and kidney mentioned above in details and in addition to the family history of previous neonatal death and parental consanguinity which are further supported by the homogeneity of such gene variant in the affected proband; we can suggest that this novel PEX5 gene variant may contribute to the early neonatal mortality observed in this family and could be reclassified to likely pathogenic or pathogenic and its pathogenicity might be confirmed by further research.

Conclusion

This case emphasizes the importance of considering peroxisomal disorders in neonates with dysmorphic features, hypotonia, seizures, and characteristic brain MRI findings. Biochemical and Genetic testing plays a crucial role in early diagnosis of severe ZSD aiming to facilitate tailored management and informed family counseling.

Abbreviations

ZDS: Zellweger spectrum disorder; PEX: peroxisome biogenesis factor; VLCFAs: very long chain fatty acids; PPV: positive pressure ventilation; NICU: neonatal intensive care unit; CBC: complete blood count; ALT: alanine transaminase; WES: whole exome; ZWD: Zellweger disease; MRI: magnetic resonance imaging; ZWS: Zellweger syndrome; VUS: variant of unknown significant.

Declarations

Ethics Approval and Consent to Participate

Ethics approval was not required for this case report

Consent for Publication

Written informed consent was obtained from the patient for publication of this case report

Availability of Data and Materials

Available in Armed Forces Hospitals Southern Region, Najran

Competing interests

All financial and non-financial competing interests must be declared in this section.

Authors' Contributions

Dr. Asmaa Abdulla Mohamed Osman: Recognize case that is unusual, has valuable clinical insights, Critical analysing case highlights its unique features, Draft manuscript, Respond to peer review

Dr. Lama M. El -Attar: Drafting manuscript, clearly explaining the significance of the case from genetic side of view, Review literature, place the case in context and compare it to similar cases or known knowledge, review manuscript, respond to peer review

Dr. Sally Ibrahim Hafez Sadaka: Collecting the data and accurate clinical information, ensuring data has history, physical examination diagnostic tests interventions, and outcomes

Dr. Mohamed Talaat Ali Abdallatif: Draft manuscript, Explain radiological importance of baby findings, Collaboration with coauthors

Dr. Wegdan Mawlana: Ensure ethical standards, respond to peer review, making revisions to improve the manuscript, Promotion knowledge sharing.

Acknowledgements

Authors thank parents for their co-operation.

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