ArticlePDF Available

Mild Zellweger syndrome due to a novel PEX6 mutation: correlation between clinical phenotype and in silico prediction of variant pathogenicity

October 2017
Journal of Applied Genetics 58(4)

October 2017
58(4)

DOI:10.1007/s13353-017-0414-5

Authors:

Małgorzata Rydzanicz

Medical University of Warsaw

Teresa Joanna Stradomska

Children's Memorial Health Institute

Elzbieta Jurkiewicz

Children's Memorial Health Institute

Ewa Jamroz

Medical University of Silesia in Katowice

Show all 8 authorsHide

Zellweger syndrome (ZS) is a consequence of a peroxisome biogenesis disorder (PBD) caused by the presence of a pathogenic mutation in one of the 13 genes from the PEX family. ZS is a severe multisystem condition characterized by neonatal appearance of symptoms and a shorter life. Here, we report a case of ZS with a mild phenotype, due to a novel PEX6 gene mutation. The patient presented subtle craniofacial dysmorphic features and slightly slower psychomotor development. At the age of 2 years, he was diagnosed with adrenal insufficiency, hypoacusis, and general deterioration. Magnetic resonance imaging showed a symmetrical hyperintense signal in the frontal and parietal white matter. Biochemical tests showed elevated liver transaminases, elevated serum very long chain fatty acids, and phytanic acid. After the death of the child at the age of 6 years, molecular diagnostics were continued in order to provide genetic counseling for his parents. Next generation sequencing (NGS) analysis with the TruSight One™ Sequencing Panel revealed a novel homozygous PEX6 p.Ala94Pro mutation. In silico prediction of variant severity suggested its possible benign effect. To conclude, in the milder phenotypes, adrenal insufficiency, hypoacusis, and leukodystrophy together seem to be pathognomonic for ZS.

Content uploaded by Elzbieta Jurkiewicz

Content may be subject to copyright.

HUMAN GENETICS •ORIGINAL PAPER

Mild Zellweger syndrome due to a novel PEX6 mutation:

correlation between clinical phenotype and in silico prediction

of variant pathogenicity

Małgorzata Rydzanicz

&Teresa Joanna Stradomska

&Elżbieta Jurkiewicz

Ewa Jamroz

&Piotr Gasperowicz

&Grażyna Kostrzewa

&RafałPłoski

Anna Tylki-Szymańska

Received: 7 July 2017 /Revised: 25 September 2017 /Accepted: 27 September 2017 /Published online: 18 October 2017

#Institute of Plant Genetics, Polish Academy of Sciences, Poznan 2017

Abstract Zellweger syndrome (ZS) is a consequence of a

peroxisome biogenesis disorder (PBD) caused by the presence

of a pathogenic mutation in one of the 13 genes from the PEX

family. ZS is a severe multisystem condition characterized by

neonatal appearance of symptoms and a shorter life. Here, we

report a case of ZS with a mild phenotype, due to a novel

PEX6 gene mutation. The patient presented subtle craniofacial

dysmorphic features and slightly slower psychomotor devel-

opment. At the age of 2 years, he was diagnosed with adrenal

insufficiency, hypoacusis, and general deterioration. Magnetic

resonance imaging showed a symmetrical hyperintense signal

in the frontal and parietal white matter. Biochemical tests

showed elevated liver transaminases, elevated serum very

long chain fatty acids, and phytanic acid. After the death of

the child at the age of 6 years, molecular diagnostics were

continued in order to provide genetic counseling for his par-

ents. Next generation sequencing (NGS) analysis with the

TruSight One™Sequencing Panel revealed a novel homozy-

gous PEX6 p.Ala94Pro mutation. In silico prediction of vari-

ant severity suggested its possible benign effect. To conclude,

in the milder phenotypes, adrenal insufficiency, hypoacusis,

and leukodystrophy together seem to be pathognomonic for

ZS.

Keywords Zellweger syndrome .Mild phenotype .

Peroxisome biogenesis disorder .PEX6 p.Ala94Pro mutation

Introduction

Zellweger syndrome (ZS, OMIM # 214100) is an autosomal

recessive peroxisome biogenesis disorder (PBD) caused by

mutations in one of 13 different PEX family genes (Barth

et al. 2001;Ebberinketal.2011;Krauseetal.2013). PBD

is classified into two subtypes: Zellweger spectrum disorders

(ZSDs) and rhizomelic chondrodysplasia punctata type 1.

ZSDs include three main phenotypes: ZS, neonatal adrenoleu-

kodystrophy, and infantile Refsum disease. The majority of

the ZSDs are severe disorders, with an early, even prenatal,

appearance of symptoms. However, cases with later onset in

childhood, adolescence, or even adulthood are reported

(Ebberink et al. 2010;Mignarrietal.2012). In particular, 34

ZSDs patients with milder or unusual phenotype and

prolonged survival with mutations in PEX1,PEX2,PEX6,

PEX10,PEX12,andPEX16 have been described (Ebberink

et al. 2010;Mignarrietal.2012; Poll-The et al. 2004; Régal

et al. 2010; Sevin et al. 2011; Zeharia et al. 2007).

Małgorzata Rydzanicz and Teresa Joanna Stradomska contributed

equally to this work.

Communicated by: Michal Witt

*RafałPłoski

rploski@wp.pl

Department of Medical Genetics, Medical University of Warsaw,

Pawinskiego 3c, 02-106 Warsaw, Poland

Department of Biochemistry, Radioimmunology and Experimental

Medicine, The Children’s Memorial Health Institute, Dzieci Polskich

20, 04-730 Warsaw, Poland

Department of Diagnostic Imaging, The Children’s Memorial Health

Institute, Dzieci Polskich 20, 04-730 Warsaw, Poland

Department of Child Neurology, Medical University of Silesia,

Medykow 16, 40-752 Katowice, Poland

Department of Forensic Medicine, Medical University of Warsaw, W.

Oczki 1, 02-007 Warsaw, Poland

Department of Pediatric, Nutrition and Metabolic Diseases, The

Children’s Memorial Health Institute, Dzieci Polskich 20,

04-730 Warsaw, Poland

J Appl Genetics (2017) 58:475–480

https://doi.org/10.1007/s13353-017-0414-5

ZS is the most serious of ZSDs, with its phenotype charac-

terized by severe psychomotor retardation, craniofacial abnor-

malities, and liver dysfunction. The biochemical markers for

the defect of peroxisomes function are plasma accumulation

of very long chain fatty acids (VLCFAs), phytanic and

pristanic acid, C27-bile acid intermediates, and a deficiency

of erythrocyte plasmalogens.

Among ZSDs patients, mutations in PEX1 and PEX6 are

the most often found (60% and 16%, respectively) (Waterham

and Ebberink 2012). The PEX6 gene encodes a 104-kD

peroxin protein, which belongs to the AAA ATPase family

protein. PEX6 participates in the recycling of PEX5 cytosolic

receptor for PTS1-targeted matrix proteins in the process of

peroxisomal translocation (Grou et al. 2009). Patients with

ZSDs caused by PEX6 mutations present a milder clinical

phenotype; however, about 20% have been reported as severe

(Ebberink et al. 2011; Krause et al. 2006; Levesque et al.

2012; Zhang et al. 1999).

Here, we report a case of a male patient with mild ZS pheno-

type, due to a novel missense homozygous p.Ala94Pro mutation

in the PEX6 gene.

Patient and methods

Case report

The patient was the only child of nonconsanguineous parents

of Polish origin, born at term from an uncomplicated pregnan-

cy. His birth body mass was 2650 g. In infancy, his psycho-

motor development was slightly slower; at the age of

9 months, he was able to sit alone, at 20 months, he stood

independently, and at the age of 2 years, he began to walk

alone. He displayed subtle dysmorphic features (Fig. 1), mi-

crocephaly, hypoplastic optic disks, nystagmus, and strabis-

mus. From the age of 8 months, he received a hearing aid

because of hypoacusis.

At the age of 2 years, he was diagnosed with adrenal insuf-

ficiency; from this age, general deterioration became evident.

The magnetic resonance imaging (MRI) examination per-

formed at the age of 3 years showed symmetrical hyperintense

signal of the posterior parts of the frontal and parietal white

matter. High signal intensity of both posterior limbs of the

internal capsules was also seen. There was an abnormally high

signal in pyramidal tracts, midbrain, medial lemniscus, supe-

rior and middle cerebellar peduncles, and hilus of the dentate

nuclei. After contrast injection, little enhancement of the py-

ramidal tract at the level of the left cerebral peduncle was seen

(Fig. 2a–c).

From the age of 3 years, his clinical status declined quickly

and refractory seizures occurred. The computed tomography

(CT) examination at the age of 5 years revealed severe brain

atrophy, symmetrical subcortical and periventricular intensive

calcification, and symmetrical calcification of the pyramidal

tracts. A small intraparenchymal cyst was found in the right

frontal lobe (Fig. 2d–f). From the age of 4 years, he was

nourished by gastrostomy and received respiratory support;

he died at the age of 6 years.

Biochemical examination performed as described else-

where (Stradomska and Tylki-Szymańska 1996; Takemoto

et al. 2003) showed elevated serum liver transaminases, ele-

vated serum VLCFAs, and phytanic acid (Table 1). The

plasmalogen was within the normal range. The patient’s

mother’s serum VLCFAs level was normal.

Genetic analysis

After the child’s death, molecular diagnostics was continued

to provide genetic counseling for the parents. We performed

next generation sequencing (NGS) using the TruSight One™

Sequencing Panel Kit (Illumina, San Diego, CA, USA),

allowing us to study the coding sequence and splice sites of

4813 loci (including all 13 PEX genes) associated with known

clinical phenotypes. Library preparation was performed ac-

cording to the manufacturer’s recommendations and the sam-

ple was paired-end sequenced (2 × 100) on 1 of12 high output

lanes of the Illumina HiSeq 1500. We generated 29,179,122

reads, 99% of the target was covered a minimum of 10 times,

and 96% a minimum of 20 times. The data were analyzed as

previously described (Ploski et al. 2014).

Based on NGS analysis, we found 50,602 variants which

passed the quality filter. After applying a population frequen-

cy filter (< 1% in EXAC, ESP6500, 1000 Genomes database,

as well as our own collection of 1343 Polish individuals

screened by whole exome sequencing or the Illumina

TruSight One™Sequencing Panel) and a filter removing syn-

onymous variants as well as variants located outside the cod-

ing sequence/splice sites, we obtained 99 sequence changes

for a final analysis. As we hypothesized a recessive inheri-

tance, we focused on biallelic (homozygous or compound

Fig. 1 Craniofacial dysmorphic features in the Zellweger syndrome (ZS)

patient: high forehead, broad nasal bridge, hypoplastic supraorbital ridges

476 J Appl Genetics (2017) 58:475–480

heterozygous) variants, and since the patient was male, hemi-

zygous variants on the X chromosome were also considered.

We found compound heterozygosity for CASC5

(rs200222327, rs201334214) and NBPF10 (chr1:145,299,871-

G>T, chr1:145,299,870-A>G), homozygosity for a hitherto

undescribed PEX6 variant (chr6:42,946,609-C>G,

NM_000287.3:p.Ala94Pro/c.280G>C), and hemizygosity for a

DM6A variant (rs141353229). No possible pathogenic variants

in the remaining 12 PEX genes were identified. Given the pa-

tient’s clinical picture, we prioritized the PEX6 p.Ala94Pro

Fig. 2 The patient’s central nervous system: magnetic resonance

imaging (MRI) and computed tomography (CT) examination. a–cMRI

examination at the age of 3 years. Coronal T2-weighted images (a,b).

Symmetrical white matter hyperintensity in the frontal and parietal lobes

(black arrow in a). High signal intensity involves pyramidal tracts (white

arrow in a) and superior cerebellar peduncles (white arrow in b). Axial

T2-weighted image (c) demonstrates high signal in the pyramidal tracts

(black arrow), medial lemniscus (white arrow), and middle cerebellar

peduncles (arrowhead). d–fCT examination at the age of 5 years

revealed severe brain atrophy. Symmetrical calcification of the

pyramidal tracts (white arrow in d). The small intraparenchymal cyst is

seen in the right frontal lobe (white matter in e). Symmetrical subcortical

and periventricular intensive calcification is seen (white arrows in f)

Tabl e 1 Results of very long

chain fatty acids (VLCFAs) and

phytanic acid in the presented

Zellweger syndrome (ZS) patient

Subject VLCFAs (μg/mL) Phytanic acid (μg/mL)

C24:0/C22:0 C26:0/C22:0 C26:0

Patient (age 3 years) 1.497 0.211 1.240 8.1

Patient (age 3 years 2 months) 1.492 0.204 1.516 26.8

Patient (age 4 years 3 months) 1.551 0.225 1.913 nd

Patient (age 4 years 8 months) 1.513 0.296 1.741 26.9

Patient (age 5 years 4 months) 1.614 0.190 1.914 18.2

ZS patients

2.130 ± 0.193 0.564 ± 0.137 5.40 ± 3.22 nd

Patient’s mother 0.787 0.007 0.15 nd

Control* 0.782 ± 0.060 0.008 ± 0.003 0.15 ± 0.05 < 2.3

nd No data

Source: Stradomska and Tylki-Szymańska (2009)

J Appl Genetics (2017) 58:475–480 477

(c.280G>C) variant (Fig. 3a) as the likely cause of the disease.

Sanger sequencing confirmed the proband’s homozygosity for

the PEX6 p.Ala94Pro mutation (Fig. 3b) and showed that his

mother was a heterozygous carrier (Fig. 3c). The father was not

available for analysis.

The PEX6 p.Ala94Pro mutation had not been previously

described and had 0 frequency in all the databases used in this

study (EXAC, ESP6500, 1000 Genomes database, as well as

in our own collection of 1343 Polish individuals screened by

whole exome sequencing or the Illumina TruSight One™

Sequencing Panel). In silico analysis of the PEX6

p.Ala94Pro pathogenicity yielded the following predictions:

Polyphen2HVAR - B (benign), Polyphen2HDIV - P (possibly

damaging), MutationAssessor - N (neutral), SIFT- T (tolerat-

ed), FATHMM - D (damaging), MutationTaster - N (polymor-

phism), MetaSVM - D (damaging), and MetaLR - D

(damaging).

Discussion

We report a case of mild ZS associated with homozygosity for

anovelPEX6 gene p.Ala94Pro missense mutation. The ZS

diagnosis was based on co-occurrence of adrenal insufficien-

cy, hypoacusis, and leukodystrophy, as well as increase of

VLCFAs and phytanic acid. The low severity of disease is

evidenced by the appearance of first symptoms at 2 years of

age and death at 6 years of age, which is relatively late for

typical ZS. The low disease severity was paralleled by labo-

ratory findings. The patient’s VLCFAs levels were distinctly

elevated and increased with disease progression, but were

generally below the values characteristic for patients with

classical severe disease. Conversely, the plasmalogen which

is usually decreased in ZS was within the normal range.

The relatively low disease severity in our proband is also

apparent when serum VLCFAs accumulation is expressed as

Fig. 3 Sequencing results. aIGV

view of the PEX6 p.Ala94Pro

mutation in the proband. bSanger

sequencing chromatogram

showing homozygosity for PEX6

p.Ala94Pro in the proband. c

Sanger sequencing showing

heterozygosity for PEX6

p.Ala94Pro in the proband’s

mother

478 J Appl Genetics (2017) 58:475–480

the C26:0/C22:0 ratio, which, according to our previous ob-

servations (Stradomska and Tylki-Szymańska 2009), may be

an indicator of disease severity. In patients with severe pheno-

type and shorter survival (< 12 months and < 17 months), high

C26:0/C22:0 ratios were found (> 0.60 and > 0.30, respective-

ly) (Levesque et al. 2012; Raas-Rothschild et al. 2002),

whereas in patients with milder phenotype and longer survival

(> 8 years), the C26:0/C22:0 ratio was less than 0.10

(Berendse et al. 2016;Raas-Rothschildetal.2002;Tran

et al. 2014). Our patient’s values for the C26:0/C22:0 ratio

and survival were clearly between these ranges (0.22 and 6

years).

Despite the relatively low disease severity, our proband had

consistently elevated serum phytanic acid. However, phytanic

acid is derived from the diet and, thus, is not a fully reliable

biomarker for peroxisomal dysfunction, particularly in

infancy.

Although a ketogenic diet and liver dysfunction may affect

the VLCFAs levels (Stradomska et al. 2013), our case adds to

reports emphasizing the role of testing this metabolite for the

diagnosis of mild cases of ZSDs. Poll-The et al. (2004), in 31

patients with ZSDs and prolonged survival, reported elevated

serum VLCFAs in 31/31 cases and phytanic acid in 26/31

cases. Similar results were presented by Berendse et al.

(2016), 19/19 and 14/19 cases, respectively. Notably, reduc-

tion of the formation of plasmalogen was found only in about

half of the patients (Berendse et al. 2016;Poll-Theetal.2004).

Intriguingly, in the presented case, there was also concor-

dance between the relatively mild clinical phenotype and in

silico assessment of the PEX6 p.Ala94Pro mutation’sfunc-

tional impact. The majority of in silico analyses suggested that

this variant was not pathogenic (Polyphen2HVAR,

MutationAssessor, SIFT, MutationTaster) or only possibly

damaging (Polyphen2HDIV). Only three programs (FATH,

MetaSVM, and MetaLR) indicated pathogenicity.

Interestingly, two of these programs (MetaSVM and

MetaLR) are based on a joint assessment (meta-analysis) of

up to ten analyses based on different algorithms. Whereas

these results confirm the superiority of in silico analyses based

on multiple approaches, they also indicate that algorithmic

predictions of mutation pathogenicity are not fully accurate

and may be misleading. Our report suggests that, in a case

of very rare disorders, extremely low population frequency

of a mutation may actually give a stronger signal of potential

pathogenicity than in silico functional assessment (PEX6

p.Ala94Pro was absent from all the tested databases, including

the EXAC database, which has data from > 65,000 subjects).

In ZSDs patients with prolonged survival, diagnosis age, de-

fined as the age at which the disease was biochemically con-

firmed, has been high for a long time (Berendse et al. 2016). The

diagnostic process in these patients may become improved by

the implementation of newborn screening for X-

adrenoleukodystrophy based on C26:0-lysophosphatidylcholine

(C26:0-lysoPC) detection (Klouwer et al. 2015). Our case illus-

trates that NGS can also be useful in this respect.

In summary, we report a case of mild of ZS associated with

anovelPEX6 mutation. The clinical diagnosis was based on

adrenal insufficiency, hypoacusis, and leukodystrophy, as well

as elevated serum VLCFAs. There was a notable concordance

between in silico prediction of mutation pathogenicity and the

relatively mild clinical phenotype.

Author contributions MR and PG performed NGS analysis, TJS per-

formed fatty acid profiling, EJ performed radiological evaluation, EJ per-

formed clinical data collection, GK performed Sanger sequencing for

replication study, RP and AT-S conceived and supervised the study, RP,

AT-S, and MR drafted the manuscript. All authors read and approved the

final manuscript.FundingThe study was supported by the National

Science Centre (NCN) Poland, grant number 2013/11/B/NZ7/04944.

Compliance with ethical standards

Conflict of interest The authors declare that they have no conflict of

interest.

Ethical approval All procedures performed in studies involving hu-

man participants were in accordance with the ethical standards of the

Bioethical Committee at the Children’s Memorial Health Institute of

Warsaw and with the 1964 Helsinki declaration and its later amendments

or comparable ethical standards.

Informed consent Informed consent for the genetic analysis was ob-

tained from all individual participants included in the study. Written con-

sent was obtained for publication of the patient’s photography.

References

Barth PG, Gootjes J, Bode H, Vreken P, Majoie CB, Wanders RJ (2001)

Late onset white matter disease in peroxisome biogenesis disorder.

Neurology 57:1949–1955

Berendse K, Engelen M, Ferdinandusse S, Majoie CB, Waterham HR,

Vaz FM, Koelman JH, Barth PG, Wanders RJ, Poll-The BT (2016)

Zellweger spectrum disorders: clinical manifestations in patients

surviving into adulthood. J Inherit Metab Dis 39:93–106. https://

doi.org/10.1007/s10545-015-9880-2

Ebberink MS, Csanyi B, Chong WK, Denis S, Sharp P, Mooijer PA,

Dekker CJ, Spooner C, Ngu LH, De Sousa C, Wanders RJ, Fietz

MJ, Clayton PT, Waterham HR, Ferdinandusse S (2010)

Identification of an unusual variant peroxisome biogenesis disorder

caused by mutations in the PEX16 gene. J Med Genet 47:608–615.

https://doi.org/10.1136/jmg.2009.074302

Ebberink MS, Mooijer PA, Gootjes J, Koster J, Wanders RJ, Waterham

HR (2011) Genetic classification and mutational spectrum of more

than 600 patients with a Zellweger syndrome spectrum disorder.

Hum Mutat 32:59–69. https://doi.org/10.1002/humu.21388

Grou CP, Carvalho AF, Pinto MP, Alencastre IS, Rodrigues TA, Freitas

MO, Francisco T, Sá-Miranda C, Azevedo JE (2009) The peroxi-

somal protein import machinery—a case report of transient

ubiquitination with a new flavor. Cell Mol Life Sci 66:254–262.

https://doi.org/10.1007/s00018-008-8415-5

Klouwer FC, Berendse K, Ferdinandusse S, Wanders RJ, Engelen M,

Poll-The BT (2015) Zellweger spectrum disorders: clinical

J Appl Genetics (2017) 58:475–480 479

overview and management approach. Orphanet J Rare Dis 10:151.

https://doi.org/10.1186/s13023-015-0368-9

Krause C, Rosewich H, Thanos M, Gärtner J (2006) Identification of

novel mutations in PEX2, PEX6, PEX10, PEX12, and PEX13 in

Zellweger spectrum patients. Hum Mutat 27:1157. https://doi.org/

10.1002/humu.9462

Krause C, Rosewich H, Woehler A, Gärtner J (2013) Functional analysis

of PEX13 mutation in a Zellweger syndrome spectrum patient re-

veals novel homooligomerization of PEX13 and its role in human

peroxisome biogenesis. Hum Mol Genet 22:3844–3857. https://doi.

org/10.1093/hmg/ddt238

Levesque S, Morin C, Guay SP, Villeneuve J, Marquis P, Yik WY,

Jiralerspong S, Bouchard L, Steinberg S, Hacia JG, Dewar K,

Braverman NE (2012) A founder mutation in the PEX6 gene is

responsible for increased incidence of Zellweger syndrome in a

French Canadian population. BMC Med Genet 13:72. https://doi.

org/10.1186/1471-2350-13-72

Mignarri A, Vinciguerra C, Giorgio A, Ferdinandusse S, Waterham H,

Wanders R, Bertini E, DottiMT, Federico A (2012) Zellweger spec-

trum disorder with mild phenotype caused by PEX2 gene mutations.

JIMD Rep 6:43–46. https://doi.org/10.1007/8904_2011_102

Ploski R, Pollak A, Müller S, Franaszczyk M, Michalak E, Kosinska J,

Stawinski P, Spiewak M, Seggewiss H, Bilinska ZT (2014) Does

p.Q247X in TRIM63 cause human hypertrophic cardiomyopathy?

Circ Res 114:e2–e5. https://doi.org/10.1161/CIRCRESAHA.114.

302662

Poll-The BT, Gootjes J, Duran M, de Klerk JB, Maillette de Buy

Wenniger‐Prick LJ, Admiraal RJ, Waterham HR, Wanders RJ,

Barth PG (2004) Peroxisome biogenesis disorders with prolonged

survival: phenotypic expression in a cohort of 31 patients. Am J

Med Genet A 126A:333–338. https://doi.org/10.1002/ajmg.a.20664

Raas-Rothschild A, Wanders RJ, Mooijer PA, Gootjes J, Waterham HR,

Gutman A, Suzuki Y, Shimozawa N, Kondo N, Eshel G, Espeel M,

Roels F, Korman SH (2002) A PEX6-defective peroxisomal biogen-

esis disorder with severe phenotype in an infant, versus mild phe-

notype resembling Usher syndrome in the affected parents. Am J

Hum Genet 70:1062–1068. https://doi.org/10.1086/339766

Régal L, Ebberink MS, Goemans N, Wanders RJ, De Meirleir L, Jaeken

J, Schrooten M, Van Coster R, Waterham HR (2010) Mutations in

PEX10 are a cause of autosomal recessive ataxia. Ann Neurol 68:

259–263. https://doi.org/10.1002/ana.22035

Sevin C, FerdinandusseS, Waterham HR, Wanders RJ, Aubourg P (2011)

Autosomal recessive cerebellar ataxia caused by mutations in the

PEX2 gene. Orphanet J Rare Dis 6:8. https://doi.org/10.1186/

1750-1172-6-8

Stradomska TJ, Tylki-Szymańska A (1996) Examination of very long

chain fatty acids in diagnosis of X-linked adrenoleukodystrophy.

Pediatr Pol 71:197–201

Stradomska TJ, Tylki-Szymańska A (2009) Serum very-long-chain fatty

acids levels determined by gas chromatography in the diagnosis of

peroxisomal disorders in Poland. Folia Neuropathol 47:306–313

Stradomska TJ, Bachański M, Pawłowska J, Syczewska M, Stolarczyk

A, Tylki-Szymańska A (2013) The impact of a ketogenic diet and

liver dysfunction on serum very long-chain fatty acids levels. Lipids

48:405–409. https://doi.org/10.1007/s11745-013-3761-y

Takemoto Y, Suzuki Y, Horibe R, Shimozawa N, Wanders RJ, Kondo N

(2003) Gas chromatography/mass spectrometry analysis of very

long chain fatty acids, docosahexaenoic acid, phytanic acid and

plasmalogen for the screening of peroxisomal disorders. Brain Dev

25:481–487

Tran C, Hewson S, Steinberg SJ, Mercimek-Mahmutoglu S (2014) Late-

onset Zellweger spectrum disorder caused by PEX6 mutations mim-

icking X-linked adrenoleukodystrophy. Pediatr Neurol 51:262–265.

https://doi.org/10.1016/j.pediatrneurol.2014.03.020

Waterham HR, Ebberink MS (2012) Genetics and molecular basis of

human peroxisome biogenesis disorders. Biochim Biophys Acta

1822:1430–1441. https://doi.org/10.1016/j.bbadis.2012.04.006

Zeharia A, Ebberink MS, Wanders RJ, Waterham HR, Gutman A,

Nissenkorn A, Korman SH (2007) A novel PEX12 mutation iden-

tified as the cause of a peroxisomal biogenesis disorder with mild

clinical phenotype, mild biochemical abnormalities in fibroblasts

and a mosaic catalase immunofluorescence pattern, even at 40 de-

grees C. J Hum Genet 52:599–606. https://doi.org/10.1007/s10038-

007-0157-y

Zhang Z, Suzuki Y, Shimozawa N, Fukuda S, Imamura A, Tsukamoto T,

Osumi T, Fujiki Y, Orii T, Wanders RJ, Barth PG, Moser HW, Paton

BC, Besley GT, Kondo N (1999) Genomic structure and identifica-

tion of 11 novel mutations of the PEX6 (peroxisome assembly

factor-2) gene in patients with peroxisome biogenesis disorders.

Hum Mutat 13:487–496. https://doi.org/10.1002/(SICI)1098-

1004(1999)13:6<487::AID-HUMU9>3.0.CO;2-T

480 J Appl Genetics (2017) 58:475–480

Serum very long-chain fatty acids (VLCFA) levels as predictive biomarkers of diseases severity and probability of survival in peroxisomal disorders

Article

Full-text available

Sep 2020
PLOS ONE

Peroxisomal disorders (PD) are a heterogeneous group of rare diseases caused by a defect in peroxisome biogenesis or a disruption of a peroxisomal function at a single enzyme or at transporter level. The main biochemical markers for PD are very long-chain fatty acids (VLCFA). The aim of the study was to investigate the correlation of basic diagnostic parameter, i.e. VLCFA, with disease severity, determined through the survival time. We performed a retrospective study in patients with PD (n = 31; aged 1 week—21 years). Evaluation of VLCFA results from patients were as follows: 15 patients with classical Zellweger syndrome (ZS), 3 patients with mild outcome of ZS, 9 individuals with D-Bifunctional Protein Deficiency (DBP), and no specified results in the case of 4 patients. Patients with classical ZS had higher VLCFA levels, compared to individuals with mild form of ZS and also to patients with DBP; for C26:0/C22:0: 0.65±0.18; 0.11±0.09; 0.30±0.13 (P < 0.001) and for C26:0: 5.20±1.78; 0.76±0.46; 2.61±0.97[mg/mL] (P < 0.001) respectively. The only variable parameter, i.e. the one that determines the survival time of patients, was C26:0 (Chi² = 19,311, P < 0.0001). Correlation coefficient between survival time and C26:0 level was statistically significant (r = -0.762), and the results showed that high levels of C26:0 were associated with short survival time. Conclusion VLCFA levels correlate with the severity of the clinical course of ZS, DBP and mild ZSD. The best predictive value for estimating the projected disease severity and survival time is a concentration of C26:0.

Severe Zellweger spectrum disorder due to a novel missense variant in the PEX13 gene: A case report and the literature review

Article

Full-text available

Nov 2023

Background Peroxisome biogenesis disorders (PBDs) are caused by variants in PEX genes that impair peroxisome function. Zellweger spectrum disorders (ZSDs) are the most severe and common subtype of PBDs, affecting multiple organ systems due to peroxisomal involvement in various metabolic functions. PEX13 gene variants are rare causes of ZSDs, with only 21 cases reported worldwide and none in China. Methods We describe an infant with biochemically and molecularly confirmed ZSDs due to variants in the PEX13 gene, identified by whole exome sequencing and validated by Sanger sequencing. The patient's treatment and prognosis were followed up. We also reviewed the literature on previously reported cases with PEX13 variants. Results The patient had severe hypotonia, seizures, hepatic dysfunction, failure to thrive, and dysmorphic features. Serum analysis revealed elevated levels of very long‐chain fatty acids (VLCFA), phytanic acid, and pipecolic acid. We detected a novel homozygous missense variant c.493G>C (p. Ala165Pro) in the PEX13 gene (NM_002618.3), which caused severe clinical manifestations and was inherited from the consanguineous parents. The patient died at the age of 14 months. Conclusion We report the first case of ZSDs due to the PEX13 variant in China. Our findings broaden the mutational spectrum of the PEX13 gene and indicate that missense variants can lead to severe ZSDs phenotypes, which has implications for genotype–phenotype correlations and genetic counseling.

Monomethyl branched-chain fatty acids: Health effects and biological mechanisms

Article

Apr 2023
PROG LIPID RES

Branched-chain fatty acids (BCFA) are a group of lipids that are widely present in various organisms; they take part in numerous biochemical processes and affect multiple signaling pathways. However, BCFA are not well explored in terms of their effects on human health. Recently, they have been gaining interest, especially in relation to various human diseases. This review describes the occurrence of BCFA, their dietary sources, their potential health effects, and the current state of knowledge concerning their mechanism(s) of action. Many studies have been conducted so far in cellular and animal models, which reveal potent anti-cancer, lipid lowering, anti-inflammatory and neuroprotective actions. Research in humans is scarce. Therefore, further studies on animals and humans should be performed to confirm and expand these findings, and improve our understanding of the potential relevance of BCFA to human health and disease.

Dysfunctional peroxisomal lipid metabolisms and their ocular manifestations

Article

Full-text available

Sep 2022

Retina is rich in lipids and dyslipidemia causes retinal dysfunction and eye diseases. In retina, lipids are not only important membrane component in cells and organelles but also fuel substrates for energy production. However, our current knowledge of lipid processing in the retina are very limited. Peroxisomes play a critical role in lipid homeostasis and genetic disorders with peroxisomal dysfunction have different types of ocular complications. In this review, we focus on the role of peroxisomes in lipid metabolism, including degradation and detoxification of very-long-chain fatty acids, branched-chain fatty acids, dicarboxylic acids, reactive oxygen/nitrogen species, glyoxylate, and amino acids, as well as biosynthesis of docosahexaenoic acid, plasmalogen and bile acids. We also discuss the potential contributions of peroxisomal pathways to eye health and summarize the reported cases of ocular symptoms in patients with peroxisomal disorders, corresponding to each disrupted peroxisomal pathway. We also review the cross-talk between peroxisomes and other organelles such as lysosomes, endoplasmic reticulum and mitochondria.

Non-syndromic inherited retinal diseases in Poland: Genes, mutations, and phenotypes

Article

Full-text available

Jul 2021
MOL VIS

Purpose: Inherited retinal diseases (IRDs), encompassing many clinical entities affecting the retina, are classified as rare disorders. Their extreme heterogeneity made molecular screening in the era before next-generation sequencing (NGS) expensive and time-consuming. Since then, many NGS studies of IRD molecular background have been conducted in Western populations; however, knowledge of the IRD mutational spectrum in Poland is still limited. Until now, there has been almost no comprehensive analysis of this particular population regarding the molecular basis and inheritance of IRDs. Therefore, the purpose of this study was to gain knowledge about the type and prevalence of causative variants in the Polish population. Methods: We recruited 190 Polish families with non-syndromic IRDs, including Stargardt disease (STGD), retinitis pigmentosa (RP), cone- and cone-rod dystrophy (CD/CRD), achromatopsia, and congenital stationary night blindness. A pool of molecular inversion probes was used, which targeted 108 genes associated with non-syndromic IRDs known in 2013. We applied filtering for known variants occurring with an allele frequency >0.5% in public and in-house databases, with the exception of variants in ABCA4, when the frequency filter was set to 3.0%. Hypomorphic p.(Asn1868Ile) was added manually. In the case of novel missense or splicing variants, we used in silico prediction software to assess mutation causality. Results: We detected causative mutations in 115 of the 190 families with non-syndromic IRD (60.2%). Fifty-nine individuals with STGD, RP, and CD/CRD carried causal variants in ABCA4. Novel single nucleotide variants were found in ABCA4, CEP290, EYS, MAK, and CNGA3. The complex allele c.[1622T>C;3113C>T], p.[Leu541Pro;Ala1038Val] was found in 33 individuals with ABCA4-associated disorders, which makes it the most prevalent allele in the Polish population (17% of all solved cases). Diagnosis was reevaluated in 16 cases. Conclusions: Previously, there were no comprehensive reports of IRDs in the Polish population. This study is the first to indicate that the most common IRDs in Poland are ABCA4-associated diseases, regardless of the phenotype. In Polish patients with RP, the second most prevalent causal gene was RHO and the third RPGR, while there were not as many mutations in EYS as in Western populations. The number of initial erroneous diagnoses may be the result of limited access to diagnostics with advanced tools, such as electroretinography; however, it is necessary to raise awareness among Polish ophthalmologists of rare IRDs. Additionally, it must be emphasized that in some cases genetic analysis of the patient is necessary to achieve an accurate diagnosis.

Mild form of Zellweger Spectrum Disorders (ZSD) due to variants in PEX1: Detailed clinical investigation in a 9-years-old female

Article

Full-text available

Sep 2020

Peroxisomal biogenesis disorders (PBD) are rare autosomal recessive disorders with various degrees of severity caused by hypomorphic mutations in 13 different peroxin (PEX) genes. In this study, we report the clinical and molecular characterization of a 9-years-old female presenting an apparently isolated pre-lingual sensorineural hearing loss (SNHL) and early onset Retinitis Pigmentosa (RP) that may clinically overlap with Usher syndrome. Genetic testing by clinical exome sequencing identified two variants in PEX1: the missense variant c.274G > C; p.(Val92Leu) that was already reported in a PBD patient, and the variant c.2140_2145dup; p.(Ser714_Gln715dup) which is a novel, non-frameshift variant, absent in control databases. On the basis of the molecular analysis, a thorough clinical examination revealed nail and dental abnormalities, a mild cognitive impairment, learning disabilities and poor feeding, apart from the retinal and audiological features initially identified. The clinical and molecular findings led us to the diagnosis of a mild form of PBD. This study further emphasizes that mild forms of PBD can be a differential diagnosis of Usher syndrome and suggests that patients with mild cognitive impairment associated to visual and hearing loss should perform a comprehensive mutation screening that includes PEX genes.

Characterization of Severity in Zellweger Spectrum Disorder by Clinical Findings: A Scoping Review, Meta-Analysis and Medical Chart Review

Article

Full-text available

Jun 2022

Zellweger spectrum disorder (ZSD) is a rare, debilitating genetic disorder of peroxisome biogenesis that affects multiple organ systems and presents with broad clinical heterogeneity. Although severe, intermediate, and mild forms of ZSD have been described, these designations are often arbitrary, presenting difficulty in understanding individual prognosis and treatment effectiveness. The purpose of this study is to conduct a scoping review and meta-analysis of existing literature and a medical chart review to determine if characterization of clinical findings can predict severity in ZSD. Our PubMed search for articles describing severity, clinical findings, and survival in ZSD resulted in 107 studies (representing 307 patients) that were included in the review and meta-analysis. We also collected and analyzed these same parameters from medical records of 136 ZSD individuals from our natural history study. Common clinical findings that were significantly different across severity categories included seizures, hypotonia, reduced mobility, feeding difficulties, renal cysts, adrenal insufficiency, hearing and vision loss, and a shortened lifespan. Our primary data analysis also revealed significant differences across severity categories in failure to thrive, gastroesophageal reflux, bone fractures, global developmental delay, verbal communication difficulties, and cardiac abnormalities. Univariable multinomial logistic modeling analysis of clinical findings and very long chain fatty acid (VLCFA) hexacosanoic acid (C26:0) levels showed that the number of clinical findings present among seizures, abnormal EEG, renal cysts, and cardiac abnormalities, as well as plasma C26:0 fatty acid levels could differentiate severity categories. We report the largest characterization of clinical findings in relation to overall disease severity in ZSD. This information will be useful in determining appropriate outcomes for specific subjects in clinical trials for ZSD.

Diagnostic challenges and disease management in patients with a mild Zellweger spectrum disorder phenotype

Article

Sep 2021
MOL GENET METAB

Peroxisome Biogenesis Disorders-Zellweger spectrum disorder (PBD-ZSD) is a rare, autosomal recessive peroxisome biogenesis disorder that presents with variable symptoms. In patients with PBD-ZSD, pathogenic variants in the PEX family of genes disrupt normal peroxisomal function, impairing α- and β-oxidation of very-long-chain fatty acids and synthesis of bile acids, resulting in increased levels of toxic bile acid intermediates and multisystem organ damage. The spectrum of severity in PBD-ZSD is variable, with some patients dying in the first year of life, while others live into adulthood. Symptoms of mild PBD-ZSD include various combinations of developmental delay, craniofacial dysmorphic features, visual impairment, sensorineural hearing loss, liver disease, and adrenal insufficiency. Disease progression in mild PBD-ZSD is generally slow, and may include extended periods of stability in some cases. The presence and extent to which symptoms occur in mild PBD-ZSD represent a diagnostic challenge that can cause delays in diagnosis with potential significant implications related to disease monitoring and treatment. There is some support for the pharmacologic therapies of Lorenzo's oil, docosohexanoic acid, and batyl alcohol in altering symptoms; however, systematic long-term studies are lacking. Cholic acid (CA) therapy has demonstrated treatment efficacy in patients with PBD-ZSD, including decreased toxic bile acid intermediates, transaminase levels, and liver inflammation, with improvement in growth parameters. However, these responses are most apparent in patients diagnosed and treated at a young age. Advanced liver disease may limit the efficacy of CA, underscoring the need to diagnose and treat these patients before significant liver damage and other related complications occur. Here we discuss the signs and symptoms of PBD-ZSD in patients with mild disease, standard diagnostic tools, factors affecting disease management, and available pharmacological interventions.

Saudi Patient with peroxisome biogenesis disorder with novel variant: a case report

Article

Dec 2021

Background: Peroxisomes are cells' organelles that responsible for the metabolism of branched-chain and very-long-chain fatty acids (VLCFA), polyamines, and amino acids. Peroxisomal biogenesis factor 6 (PEX6) is one of the factors required for the import of the proteins into peroxisomes. Mutation in any one of PEX genes will result in Zellweger syndrome (ZS), one of the peroxisome biogenesis disorder. Case Presentation: A 11-year-old girl referred was with central hypotonia and global developmental delay and feeding problems. She has an open and flat fontanel. Liver function tests and thyroid-stimulating hormone were elevated. Plasma VLCFA C26, VLCFA C24/C22, and VLCFA C26/C22 were elevated. Cerebrospinal fluid flow artifact and posterior displacement of the basilar artery findings raised the possibility of increased intracranial pressure. X-ray showed mild irregularity in the end plates of the lumbar vertebrae, bilateral coxa valga, irregularity in the articular surfaces of the ossified epiphysis of the upper and lower limbs, and generalized osteopenia. The audiological assessment profound hearing loss in both ears. Inborn error of metabolism, next-generation sequencing gene panel analysis, and whole exome sequencing showed that no pathogenic or likely pathogenic variants explaining the phenotypes. The single nucleotide polymorphisms testing showed a deletion in PEX6 gene (homozygous variant of uncertain significance). Conclusion: We report a case of ZS associated with a new PEX6 mutation that has not been previously reported in the literature. [JBCGenetics 2021; 4(2.000): 115-117]

Structural mapping of missense mutations in the Pex1/Pex6 complex

Article

Jan 2021

Peroxisome biogenesis disorders (PBDs) are nontreatable hereditary diseases with a broad range of severity. Approximately 65% of patients are affected by mutations in the peroxins Pex1 and Pex6. The proteins form the heteromeric Pex1/Pex6 complex, which is important for protein import into peroxisomes. To date, no structural data are available for this AAA+ ATPase complex. However, a wealth of information can be transferred from low-resolution structures of the yeast scPex1/scPex6 complex and homologous, well-characterized AAA+ ATPases. We review the abundant records of missense mutations described in PBD patients with the aim to classify and rationalize them by mapping them onto a homology model of the human Pex1/Pex6 complex. Several mutations concern functionally conserved residues that are implied in ATP hydrolysis and substrate processing. Contrary to fold destabilizing mutations, patients suffering from function-impairing mutations may not benefit from stabilizing agents, which have been reported as potential therapeutics for PBD patients.

Zellweger spectrum disorders: Clinical overview and management approach

Article

Full-text available

Dec 2015
ORPHANET J RARE DIS

Zellweger spectrum disorders (ZSDs) represent the major subgroup within the peroxisomal biogenesis disorders caused by defects in PEX genes. The Zellweger spectrum is a clinical and biochemical continuum which can roughly be divided into three clinical phenotypes. Patients can present in the neonatal period with severe symptoms or later in life during adolescence or adulthood with only minor features. A defect of functional peroxisomes results in several metabolic abnormalities, which in most cases can be detected in blood and urine. There is currently no curative therapy, but supportive care is available. This review focuses on the management of patients with a ZSD and provides recommendations for supportive therapeutic options for all those involved in the care for ZSD patients.

Zellweger spectrum disorders: clinical manifestations in patients surviving into adulthood

Article

Full-text available

Aug 2015

We describe the natural history of patients with a Zellweger spectrum disorder (ZSD) surviving into adulthood. Retrospective cohort study in patients with a genetically confirmed ZSD. All patients (n = 19; aged 16-35 years) had a follow-up period of 1-24.4 years (mean 16 years). Seven patients had a progressive disease course, while 12 remained clinically stable during follow-up. Disease progression usually manifests in adolescence as a gait disorder, caused by central and/or peripheral nervous system involvement. Nine were capable of living a partly independent life with supported employment. Systematic MRI review revealed T2 hyperintense white matter abnormalities in the hilus of the dentate nucleus and/or peridentate region in nine out of 16 patients. Biochemical analyses in blood showed abnormal peroxisomal biomarkers in all patients in infancy and childhood, whereas in adolescence/adulthood we observed normalization of some metabolites. The patients described here represent a distinct subgroup within the ZSDs who survive into adulthood. Most remain stable over many years. Disease progression may occur and is mainly due to cerebral and cerebellar white matter abnormalities, and peripheral neuropathy.

Functional analysis of PEX13 mutation in a Zellweger syndrome spectrum patient reveals novel homooligomerization of PEX13 and its role in human peroxisome biogenesis

Article

Full-text available

May 2013
HUM MOL GENET

In humans the concerted action of at least 13 different peroxisomal PEX proteins is needed for proper peroxisome biogenesis. Mutations in any of these PEX genes can lead to lethal neurometabolic disorders of the Zellweger syndrome spectrum (ZSS). Previously, we identified the W313G mutation located within the SH3 domain of the peroxisomal protein, PEX13. As this tryptophan residue is highly conserved in almost all known SH3 proteins, we investigated the pathogenic mechanism of the W313G mutation and its role in PEX13 interactions and functions in peroxisome biogenesis. Here, we report for the first time that human PEX13 interacts with itself in peroxisomes in living cells. We demonstrate that the import of PTS1 (peroxisomal targeting signal 1) proteins is specifically disrupted when homooligomerization of PEX13 is interrupted. Live cell FRET microscopy in living cells as well as co-immunoprecipitation experiments reveal that the highly conserved W313 residue is important for self-association of PEX13 but is not required for interaction with PEX14, a well established interaction partner at the peroxisomal membrane. Experiments with truncated constructs indicate that although the W313G mutation resides in the C-terminal SH3 domain, the N-terminal half is necessary for peroxisomal localization, which in turn appears to be crucial for homooligomerization. Furthermore, rescue of homooligomerization in the W313G mutant cells through complementation with truncation constructs restores import of peroxisomal matrix proteins. Taken together, the thorough analyses of a ZSS patient mutation unraveled the general cell biological function of PEX13 and its mechanism in the import of peroxisomal matrix PTS1 proteins.

Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations

Article

Full-text available

Jan 2012

The Zellweger spectrum disorders (ZSDs) are known to be severe disorders with onset in the newborn period or later in childhood, frequently resulting in death during childhood or adolescence. Here, we report a case of ZSD due to mutations in the PEX2 gene, with very mild phenotype. A 51-year-old Italian man was referred to us because of a clinical picture characterized by ataxia, areflexia, nystagmus, and strabismus, with childhood onset and slowly progressive course. The patient showed no cognitive impairment. Neurological examination revealed gait ataxia, dysarthria, dysmetria, areflexia, and bilateral pes cavus. Nerve conduction studies indicated a severe axonal sensorimotor polyneuropathy. Brain MRI showed marked cerebellar atrophy and absence of white matter involvement. MR spectroscopy uncovered a decreased N-acetyl aspartate peak. Biochemical analyses suggested a mild peroxisomal defect. Sequence analysis of the PEX2 gene identified two heterozygous mutations. The clinical phenotype of our patient differs from previously reported ZSD patients with PEX2 gene mutations and suggests that genetic screening of PEX2 is warranted in children and adults with otherwise unexplained autosomal recessive ataxia. MRI findings diverged from the "classic" spectrum observed in ZSDs. The moderate impairment in peroxisome biogenesis seems to affect predominantly neuronal cells in cerebellum, leading to cerebellar atrophy.

A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population

Article

Full-text available

Aug 2012
BMC MED GENET

Background Zellweger syndrome (ZS) is a peroxisome biogenesis disorder due to mutations in any one of 13 PEX genes. Increased incidence of ZS has been suspected in French-Canadians of the Saguenay-Lac-St-Jean region (SLSJ) of Quebec, but this remains unsolved. Methods We identified 5 ZS patients from SLSJ diagnosed by peroxisome dysfunction between 1990–2010 and sequenced all coding exons of known PEX genes in one patient using Next Generation Sequencing (NGS) for diagnostic confirmation. Results A homozygous mutation (c.802_815del, p.[Val207_Gln294del, Val76_Gln294del]) in PEX6 was identified and then shown in 4 other patients. Parental heterozygosity was confirmed in all. Incidence of ZS was estimated to 1 in 12,191 live births, with a carrier frequency of 1 in 55. In addition, we present data suggesting that this mutation abolishes a SF2/ASF splice enhancer binding site, resulting in the use of two alternative cryptic donor splice sites and predicted to encode an internally deleted in-frame protein. Conclusion We report increased incidence of ZS in French-Canadians of SLSJ caused by a PEX6 founder mutation. To our knowledge, this is the highest reported incidence of ZS worldwide. These findings have implications for carrier screening and support the utility of NGS for molecular confirmation of peroxisomal disorders.

Late-Onset Zellweger Spectrum Disorder Caused by PEX6 Mutations Mimicking X-Linked Adrenoleukodystrophy

Article

Aug 2014
PEDIATR NEUROL

Background Zellweger Spectrum Disorders (ZSD) are autosomal recessively inherited multisystem disorders caused by one of the 13 different PEX gene defects resulting in defective peroxisomal assembly and multiple peroxisomal enzyme deficiencies. We report a new patient with late onset ZSD mimicking X-linked adrenoleukodystrophy (X-ALD). Case report and results: This 8.5-year-old boy with normal development until 6.5 years of age presented with bilateral sensorial-neural-hearing loss during school hearing test. He then developed acute onset diplopia, clumsiness and cognitive dysfunction at age 7 years. Brain MRI showed symmetrical leukodystrophy, although without gadolinium enhancement. Elevated plasma very long chain fatty acids were suggestive of X-ALD, but his ABCD1 gene had normal coding sequence and dosage. We performed additional studies in cultured skin fibroblasts that were consistent with ZSD. Molecular testing identified disease causing compound heterozygous mutations in the PEX6 gene supporting the ZSD diagnosis in this patient. Conclusions We report a new patient with late onset ZSD caused by PEX6 mutations who presented with acute neurodegenerative disease course mimicking X-ALD. This provides an additional reason that molecular confirmation is important for the genetic counseling and management of patients with a clinical and biochemical diagnosis of X-ALD.

Does p.Q247X in TRIM63 cause human hypertrophic cardiomyopathy?

Article

Jan 2014
CIRC RES

Variants in TRIM63, including a nonsense mutation (p.Q247X), have been suggested recently to cause hypertrophic cardiomyopathy. To verify pathogenicity of TRIM63 p.Q247X detected by whole-exome sequencing in a symptomless professional sports player seeking medical advice because of a prolonged QT interval found during a routine check-up. Clinical studies were performed in the proband and his mother, who also carried TRIM63 p.Q247X. No evidence of hypertrophic cardiomyopathy was found in either person. The p.Q247X variant in TRIM63 is not likely to be a highly penetrant variant causing hypertrophic cardiomyopathy.

The Impact of a Ketogenic Diet and Liver Dysfunction on Serum Very Long-Chain Fatty Acids Levels

Article

Jan 2013
LIPIDS

Peroxisomes play an essential role in mammalian cellular metabolism, particularly in oxidation fatty acid pathways. Serum very long-chain fatty acids (VLCFA), the main biochemical diagnostic parameters for peroxisomal disorders, were examined in 25 neurological patients with epilepsy on a ketogenic diet and 27 patients with liver dysfunction. The data show that patients on a ketogenic diet have increased levels of C22:0 and C24:0, but not C26:0, and normal C24:0/C22:0 and C26:0/C22:0. Patients with liver insufficiency showed a slightly elevated level of C26:0, a normal level of C24:0 and a decreased level of C22:0; thus in 21/27 the ratio of C24:0/C22:0 was increased and 15/27 the ratio of C26:0/C22:0 was increased.

Genetics and molecular basis of human peroxisome biogenesis disorders

Article

Sep 2012
Biochim Biophys Acta

Human peroxisome biogenesis disorders (PBDs) are a heterogeneous group of autosomal recessive disorders comprised of two clinically distinct subtypes: the Zellweger syndrome spectrum (ZSS) disorders and rhizomelic chondrodysplasia punctata (RCDP) type 1. PBDs are caused by defects in any of at least 14 different PEX genes, which encode proteins involved in peroxisome assembly and proliferation. Thirteen of these genes are associated with ZSS disorders. The genetic heterogeneity among PBDs and the inability to predict from the biochemical and clinical phenotype of a patient with ZSS which of the currently known 13 PEX genes is defective, has fostered the development of different strategies to identify the causative gene defects. These include PEX cDNA transfection complementation assays followed by sequencing of the thus identified PEX genes, and a PEX gene screen in which the most frequently mutated exons of the different PEX genes are analyzed. The benefits of DNA testing for PBDs include carrier testing of relatives, early prenatal testing or preimplantation genetic diagnosis in families with a recurrence risk for ZSS disorders, and insight in genotype-phenotype correlations, which may eventually assist to improve patient management. In this review we describe the current status of genetic analysis and the molecular basis of PBDs. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease.

Mutations in PEX10 Are a Cause of Autosomal Recessive Ataxia

Article

Aug 2010
ANN NEUROL

Peroxisomal biogenesis disorders typically cause severe multisystem disease and early death. We describe a child and an adult of normal intelligence with progressive ataxia, axonal motor neuropathy, and decreased vibration sense. Both patients had marked cerebellar atrophy. Peroxisomal studies revealed a peroxisomal biogenesis disorder. Two mutations in PEX10 were found in the child, c.992G>A (novel) and c.764_765insA, and in the adult, c.2T>C (novel) and c.790C>T. Transfection with wild-type PEX10 corrected the fibroblast phenotype. Bile acid supplements and dietary restriction of phytanic acid were started. Peroxisomal biogenesis disorders should be considered in the differential diagnosis of autosomal recessive ataxia. ANN NEUROL 2010;68:259–263

Mild Zellweger syndrome due to a novel PEX6 mutation: correlation between clinical phenotype and in silico prediction of variant pathogenicity

Abstract

Recommended publications

Zellweger syndrome - A lethal peroxisome biogenesis disorder

Mild Zellweger syndrome due to functionally confirmed novel PEX1 variants

Late-Onset Zellweger Spectrum Disorder Caused by PEX6 Mutations Mimicking X-Linked Adrenoleukodystro...

A founder mutation in PEX12 among Egyptian patients in peroxisomal biogenesis disorder

Two novel mutations of PEX6 in one Chinese Zellweger spectrum disorder and their clinical characteri...