Lucaccioni et al. BMC Medical Genetics(2020) 21:229
https://doi.org/10.1186/s12881-020-01175-y

CASE REPORTOpen Access

Overwhelming sepsis in a neonate affectedby Zellweger syndrome due to acompound heterozygosis in PEX 6 gene: acase report
Laura Lucaccioni1, Beatrice Righi2, Greta Miriam Cingolani2, Licia Lugli1, Elisa Della Casa1, Francesco Torcetta1,
Lorenzo Iughetti3* and Alberto Berardi1

Abstract
Background: Peroxisome biogenesis disorders (PBDs) are a group of metabolic diseases caused by dysfunction ofperoxisomes. Different forms of PBDs are described; the most severe one is the Zellweger syndrome (ZS). We reporton an unusual presentation of Zellweger syndrome manifesting in a newborn with severe and fulminant sepsis,
causing death during the neonatal period.
Case presentation: A term male Caucasian neonate presented at birth with hypotonia and poor feeding
associated with dysmorphic craniofacial features and skeletal abnormalities. Blood tests showed progressive
leukopenia; ultrasounds revealed cerebral and renal abnormalities. He died on the fourth day of life because of an
irreversible Gram-negative sepsis. Post-mortem tests on blood and urine samples showed biochemical alterations
suggestive of ZS confirmed by genetic test.
Conclusions: ZS is an early and severe forms of PBDs. Peroxisomes are known to be involved in lipid metabolism,
but recent studies suggest their fundamental role in modulating immune response and inflammation. In case ofclinical suspicion of ZS it is important to focus the attention on the prevention and management of infections thatcan rapidly progress to death.
Keywords: Peroxisome biogenesis disorders, Zellweger syndrome, Very long chain fatty acids, Innate immunity

Background
Peroxisome biogenesis disorders (PBDs – MIM#601539)
are rare autosomal recessive disorders, caused by mutations in any of the 14 different PEX genes which codefor peroxins, proteins involved in peroxisome assembly,
including proteins involved in the import of peroxisomal
matrix and membrane proteins [1].
* Correspondence: iughetti.lorenzo@unimore.it
3
Pediatric Unit, Department of Medical and Surgical Sciences of the Mothers,Children and Adults, University of Modena and Reggio Emilia, via del Pozzo
71, 41124 Modena, Italy
Full list of author information is available at the end of the article

PBDs are divided into two groups: Zellweger spectrum
disorder (PBD-ZSD) and rhizomelic chondrodysplasia
punctata type 1. PBD-ZSD includes three different syndromes: Zellweger syndrome (ZS - MIM# 214100), neonatal adrenoleukodystrophy (NALD - MIM# 202370)
and infantile Refsum disease (IRD - MIM# 266510) ranging from severe, intermediate and mild phenotype, respectively [2–4].
PBDs prevalence is estimated to be 1 in 50.000 births
in North America with huge differences worldwide. A
lower incidence of ZS was reported in Japan (1 in
500.000 newborns), whereas the highest incidence was© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
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Lucaccioni et al. BMC Medical Genetics(2020) 21:229

described in the Saguenay-Lac St Jean, region of Quebec(around 1 in 12.000 births) [1, 5, 6].
ZS is the most severe form of PBD-ZSD, resulting
from the complete absence of functional peroxisomes. It
is called ‘cerebrohepatorenal syndrome’ because of its
typical clinical presentation during infancy with cerebral
dysgenesis, hepatic dysfunction and evidence of renal
disease. Moreover, these patients may present with typical dysmorphic features, severe hypotonia, seizures, failure to thrive and skeletal defects [5–7].
ZS can be diagnosed biochemically, detecting elevatedvery long chain fatty acids (VLCFA) in a fasting plasma
sample, in particular elevated levels of C26:0, C26:1, ratio C24:0/C22:0, ratio C26:0/C22:0 [1, 5].
Recent reviews underline the involvement of peroxisomes in immune response and inflammation resulting
in an inadequate defense in case of infection, but further
studies are still required to improve knowledge about
the relation between peroxisomal disorders and immunity [8–10].
We present a case of ZS in a newborn dead by aGram-negative fulminant sepsis, whose diagnosis was
confirmed only post mortem.

Case presentation
The proband is the first child of unrelated healthy Caucasian parents. Prenatal ultrasound was uncomplicated,family history was silent.
The male neonate was born at 37 weeks’ gestation
after planned caesarean section (with intact membraneand no active labor) because of breech presentation.
GBS antenatal screening was negative. A placental surface culture was sterile and histological analysis of theplacenta did not show chorioamnionitis. Apgar score atbirth was 6 and 9 at 1st and 5th minute, respectively,
body weight was 2460 g (1st centile according to Italian

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neonatal anthropometric charts) length was 47 cm (4thcentile), while head circumference was within the normal range (33 cm, 10th centile) [11].
At birth the newborn presented with hypotonia, bilateral club feet and dysmorphic features (flattened facies,
broad nasal bridge, micrognathia, thin lips). The baby
was unable to suck but breast milk was given via orogastric tube. Glucose infusion was administered for transient hypoglycemia. Neutrophil count was at the lower
limit for age (3242/mm3), whereas total white cell count(5.810/mm3), C reactive protein (0.8 mg/dl) and blood
gas analysis were within a normal range [12]. Cerebral
ultrasound showed mild dilated lateral ventricles with bilateral ventricular pseudocysts, hypoplasia of corpus callosum, poor insular gyration, hyperechoic subcorticalwhite matter, and hyperechoic linear spots in the basal
ganglia (Fig. 1). Abdominal ultrasound revealed bilateralrenal cysts. Ophthalmologic evaluation was unremarkable. The newborn was well-appearing, except for hypotonia. At 70 h of life clinical conditions worsened
rapidly. The newborn presented with respiratory failure,
low blood pressure, severe metabolic acidosis, low total
white cell (2400/mm3) and neutrophil (480/mm3)
counts; E. coli was yielded from blood culture. Broad
spectrum antibiotics (penicillin and gentamicin) were
promptly administered. The neonate underwent mechanical ventilation and was treated with intravenous
fluids, catecholamine support (dobutamine 6 μg/Kg/min;dopamine 4 μg/kg/min; adrenaline 0.02 μg/Kg/min andbolus of 0.09 mg) and i.v. sodium bicarbonate (8.4%, 11ml). Despite intensive care, the baby died after 5 h.
On the basis of clinical phenotype the hypothesis of
PBDs was considered. Very long chain fatty acid analysis
showed C26:0 high blood levels (5.3 μmol/l; normal
range 0.2–0.9 μmol/l) with elevated C24:0/C22:0 ratio (2;normal range 0.6–1.2).

Fig. 1 Cerebral Ultrasound images A: coronal posterior scan shows hyperechoic subcortical white matter; B: lateral sagittal scan shows ventricularpseudocysts and linear hyperechoic striae in basal ganglia

Lucaccioni et al. BMC Medical Genetics(2020) 21:229

A compound heterozygous mutation of PEX6 gene
was found confirming the diagnosis of Zellweger Syndrome: c.1958C > G (p.Ser653*) variant was inherited by
the mother and c.2440C > T (p.Arg814*) variant wasinherited by the father.

Discussion and conclusions
Peroxisomes are small cellular organelles bound by asingle membrane, containing variable compositions ofproteins with detoxify functions The PEX genes encode
for several proteins called peroxins that are involved invarious stages of peroxisomal protein import and/or in
the biogenesis of peroxisomes. In particular, peroxins
are part of the formation of peroxisomal membranes,
peroxisomal growth, fission and proliferation, and import of matrix proteins [13]. All of the approximately 46
proteins contained in peroxisomal matrix, in fact, areimported from the cytosol by a unique mechanism that
does not require the imported proteins to be unfolded asthey cross the membrane. In particular, PEX6 gene, theone found mutated in our patient, encode for a 104 kDa
peroxin that is a cytosolic AAA protein (ATPase associated with diverse cellular activities), part of PEX1–
PEX6–PEX26 export complex [13]. The AAA family proteins are a group of proteins that use the energy of ATPhydrolysis to remodel molecular complexes. PEX6 andPEX1 form a hetero-hexameric ring, best described as atrimer of PEX1/PEX6 dimers fundamental to import peroxisomal matrix proteins and/or vesicles fusion [14, 15].
So far, 77 different mutations in PEX6 gene have been
identified, being the second most recurrent PEX gene involved in PBD-ZSD genesis [16].
We describe an unusual presentation of Zellweger syndrome manifesting in a newborn with an overwhelming
sepsis. Zellweger syndrome was confirmed by two pathogenic PEX6 gene mutations, inherited from parents andcombined in an compound heterozygosis previously
unreported.
Although symptoms developed close to 72 h of life(that is the usual cut-off to define early- and late-onset
sepsis) many data strongly support a horizontal transmission of E coli (i.e. the delivery after planned cesarean
section, the negative maternal prenatal screening, thesterile placental surface cultures, the lack of evidence ofchorioamnionitis at placental histological analysis, and avery long [70 h] interval free of evident symptoms ofsepsis).
Moreover, poor feeding and hypotonia (2 symptoms
that could be consistent with sepsis) may be more easily
explained by the underlying Zellweger disease.
Zellweger disease was likely responsible for the overwhelming course of sepsis and death within a few hours.
Indeed, a pivotal role of peroxisomes in regulating inflammation and antimicrobial responses has been

Page 3 of 4

recently hypothesized. Three main reasons support thisassumption: 1) peroxisomes can contribute and modulate the cellular redox status, fundamental for the antiviral interferon-mediated cellular response, bothproducing and cleaning up reactive oxygen (ROS) andreactive nitrogen species (RNS) [17]; 2) peroxisomes are
involved in the degradation of prostaglandins and leukotrienes, key modulators of inflammation [18, 19]; 3) peroxisomes are involved in polyunsaturated fatty acidmetabolism, the backbone of a series of mediators forthe resolution of inflammation such as resolvins, maresins, and protectins [20]. Peroxisomes are involved in
multiple processes, such as the signaling between cells
and the immune pathways, and may influence the production of inflammatory regulators as cytokines andantimicrobial peptides [7]. Finally, peroxisomes are involved in phagocytic processes, participating in tissue remodeling and maintenance of overall homeostasis. The
effect of their impairment can be particularly dangerous
in the central nervous system, where cells phagocytosis
is essential for the elimination of excessive unwanted
synapses and for the removal of overproduced apoptotic
neurons and oligodendrocyte progenitor. Peroxisomes
closely cooperate with mitochondria, influencing energy
metabolism and lipid catabolism [7].
Thus, it is not surprising that considerable experimental evidence has recently emerged to support the conceptthat peroxisomes are pivotal organelles in coordinating
cellular and systemic immune response strategies byserving as signaling platforms to initiate immune pathways, and by controlling the synthesis and breakdown of
immune bioactive metabolites [8].
Patients with ZS have poor prognosis (often within thefirst year of life) due to infectious respiratory morbidity,
or to severe epilepsy [1].
Increased susceptibility to infections has been also recently reported in one case of ZS. Cardoso et al. described a 2-month-old infant admitted for severe failure
to thrive, with several recurrent opportunistic infections
during the hospital stay, lymphopenia and thymic atrophy. Diagnosis of ZS was confirmed and a primary immunodeficiency was suspected, but subsequently it was
not confirmed [21].
Due to the fulminant course of sepsis, we were unable
to study the immune function, although an increased
susceptibility to infections is common in many metabolic
diseases. Sepsis is a life threatening condition resulting
from a dysregulated response to infections. Classically,
the acute phase of sepsis is characterized by an initialstrong pro-inflammatory and innate immune status
aimed to eliminate the pathogen, while in the later phaseof sepsis there is a shift toward an anti-inflammatory
and immunosuppressive status, resulting in diminishedinflammation and initiation of tissue repair. Sepsis has

Lucaccioni et al. BMC Medical Genetics(2020) 21:229

always been considered as an inflammatory disease but
recent research suggests an important contribution ofother mechanisms such as coagulation, complement activation, microbiome composition, thermoregulation,
circadian rhythm and metabolism. The pathogenesis ofsepsis is characterized by profound changes in metabolic
homeostasis and energy balance, (especially due to thefailure of mitochondrial activity) [21, 22]. Therefore sepsis can overlap to metabolic disorders, worsening theirclinical course.
In conclusion, ZS is a severe form of PBDs with poor
prognosis. Peroxisomes are organelles involved in metabolic processes, and their role in modulating immune response and inflammation is increasingly recognized. In
the clinical suspicion of ZS it is important to address
promptly the diagnosis and to provide supportive therapy, particularly for preventing severe and potentiallyfatal neonatal infections. On the other hand, we recommend to investigate for an underlying metabolic diseasein every neonate with multiple dysmorphic features andrapid worsening of suspected sepsis.
Abbreviations
AAA: ATPases Associated with diverse cellular Activities; IRD: Infantile Refsum
disease; NALD: Neonatal adrenoleukodystrophy; PBDs: Peroxisome biogenesis
disorders; PBD-ZSD: Zellweger spectrum disorder;
PMN: Polymorphonucleates; ROS: Reactive oxygen species; RNS: Reactive
nitrogen species; VLCFA: Very long chain fatty acids; ZS: Zellweger syndrome
Acknowledgements
We would like to thank Dr. Elisabetta Garetti and Dr. Paola Torelli who
worked hardly on the clinical assistance of this patient.
Authors’ contributions
Study conception and design – LL1. Drafted the work– BR, GC and EDC.
Analysis and interpretation of data – LL1, LI, and FT. Substantial and criticalrevision of the manuscript –LL2, LI, AB. All authors have read and approved
the manuscript.
Funding
The authors declare that they did not receive any funding.
Availability of data and materials
All data generated or analyzed during this study are included in thispublished article. The data supporting this clinical case description are frompreviously reported studies and datasets, which have been cited. The
processed data are available from the corresponding author upon request.
Ethics approval and consent to participate
Written informed consent to participate was obtained from proband’sparents.
Consent for publication
The parents gave informed written consent to publish the clinical case.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Neonatal Intensive Care Unit, Department of Medical and Surgical Sciencesof the Mothers, Children and Adults, University of Modena and Reggio
Emilia, via del Pozzo 71, 41124 Modena, Italy. 2Post Graduate School ofPaediatrics, Department of Medical and Surgical Sciences of the Mothers,Children and Adults, University of Modena and Reggio Emilia, via del Pozzo
71, 41124 Modena, Italy. 3Pediatric Unit, Department of Medical and SurgicalPage 4 of 4

Sciences of the Mothers, Children and Adults, University of Modena andReggio Emilia, via del Pozzo 71, 41124 Modena, Italy.
Received: 10 June 2020 Accepted: 12 November 2020

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