Os transtornos da biogênese de peroxissomos, do espectro da síndrome de Zellweger (PBD-ZSS), são um grupo de doenças genéticas hereditárias (recessivas) que afetam a formação e o funcionamento dos peroxissomos, que são pequenas estruturas muito importantes dentro das células. Essas condições são caracterizadas por perda auditiva neurosensorial, degeneração pigmentar da retina (a parte do olho que capta a luz), problemas no funcionamento de vários órgãos do corpo e atraso no desenvolvimento motor e mental. Elas incluem as variantes: síndrome de Zellweger (ZS), adrenoleucodistrofia neonatal (NALD) e doença de Refsum infantil (IRD).
Introdução
O que você precisa saber de cara
Os transtornos da biogênese de peroxissomos, do espectro da síndrome de Zellweger (PBD-ZSS), são um grupo de doenças genéticas hereditárias (recessivas) que afetam a formação e o funcionamento dos peroxissomos, que são pequenas estruturas muito importantes dentro das células. Essas condições são caracterizadas por perda auditiva neurosensorial, degeneração pigmentar da retina (a parte do olho que capta a luz), problemas no funcionamento de vários órgãos do corpo e atraso no desenvolvimento motor e mental. Elas incluem as variantes: síndrome de Zellweger (ZS), adrenoleucodistrofia neonatal (NALD) e doença de Refsum infantil (IRD).
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1/20kRara
1/10kPouco freq.
1/5kIncomum
1/2k
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Sinais e sintomas
O que aparece no corpo e com que frequência cada sintoma acontece
Partes do corpo afetadas
+ 150 sintomas em outras categorias
Características mais comuns
Os sintomas variam de pessoa para pessoa. Abaixo estão as 362 características clínicas mais associadas, ordenadas por frequência.
Linha do tempo da pesquisa
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Genética e causas
O que está alterado no DNA e como passa nas famílias
Genes associados
14 genes identificados com associação a esta condição. Padrão de herança: Autosomal recessive.
Component of the PEX13-PEX14 docking complex, a translocon channel that specifically mediates the import of peroxisomal cargo proteins bound to PEX5 receptor (PubMed:24235149, PubMed:28765278, PubMed:9653144). The PEX13-PEX14 docking complex forms a large import pore which can be opened to a diameter of about 9 nm (By similarity). Mechanistically, PEX5 receptor along with cargo proteins associates with the PEX14 subunit of the PEX13-PEX14 docking complex in the cytosol, leading to the insertion
Peroxisome membrane
Peroxisome biogenesis disorder complementation group K
A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).
Peroxisomal docking factor that anchors PEX1 and PEX6 to peroxisome membranes (PubMed:12717447, PubMed:12851857, PubMed:16257970, PubMed:16763195, PubMed:16854980, PubMed:21362118). PEX26 is therefore required for the formation of the PEX1-PEX6 AAA ATPase complex, a complex that mediates the extraction of the PEX5 receptor from peroxisomal membrane (PubMed:12717447, PubMed:12851857, PubMed:16257970, PubMed:16763195, PubMed:16854980, PubMed:21362118)
Peroxisome membrane
Peroxisome biogenesis disorder complementation group 8
A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).
E3 ubiquitin-protein ligase component of a retrotranslocation channel required for peroxisome organization by mediating export of the PEX5 receptor from peroxisomes to the cytosol, thereby promoting PEX5 recycling (PubMed:24662292). The retrotranslocation channel is composed of PEX2, PEX10 and PEX12; each subunit contributing transmembrane segments that coassemble into an open channel that specifically allows the passage of PEX5 through the peroxisomal membrane (By similarity). PEX2 also regulat
Peroxisome membrane
Peroxisome biogenesis disorder complementation group 5
A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).
E3 ubiquitin-protein ligase component of a retrotranslocation channel required for peroxisome organization by mediating export of the PEX5 receptor from peroxisomes to the cytosol, thereby promoting PEX5 recycling (PubMed:24662292). The retrotranslocation channel is composed of PEX2, PEX10 and PEX12; each subunit contributing transmembrane segments that coassemble into an open channel that specifically allows the passage of PEX5 through the peroxisomal membrane (By similarity). PEX10 also regula
Peroxisome membrane
Peroxisome biogenesis disorder complementation group 7
A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).
Receptor that mediates peroxisomal import of proteins containing a C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) (PubMed:11101887, PubMed:11336669, PubMed:12456682, PubMed:16314507, PubMed:17157249, PubMed:17428317, PubMed:21976670, PubMed:26344566, PubMed:7706321, PubMed:7719337, PubMed:7790377). Binds to cargo proteins containing a PTS1 peroxisomal targeting signal in the cytosol, and translocates them into the peroxisome matrix by passing through the PEX13-PEX14 dock
Cytoplasm, cytosolPeroxisome matrix
Peroxisome biogenesis disorder 2A
A fatal peroxisome biogenesis disorder belonging to the Zellweger disease spectrum and characterized clinically by severe neurologic dysfunction with profound psychomotor retardation, severe hypotonia and neonatal seizures, craniofacial abnormalities, liver dysfunction, and biochemically by the absence of peroxisomes. Additional features include cardiovascular and skeletal defects, renal cysts, ocular abnormalities, and hearing impairment. Most severely affected individuals with the classic form of the disease (classic Zellweger syndrome) die within the first year of life.
Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling (PubMed:11439091, PubMed:16314507, PubMed:16854980, PubMed:21362118, PubMed:29884772). Specifically recognizes PEX5 monoubiquitinated at 'Cys-11', and pulls it out of the peroxisome lumen through the PEX2-PEX10-PEX12 retrotranslocation channel (PubMed:29884772). Extraction by the PEX1-PEX6 AAA A
Cytoplasm, cytosolPeroxisome membrane
Peroxisome biogenesis disorder complementation group 1
A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).
Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling (PubMed:16314507, PubMed:16854980, PubMed:21362118, PubMed:29884772). Specifically recognizes PEX5 monoubiquitinated at 'Cys-11', and pulls it out of the peroxisome lumen through the PEX2-PEX10-PEX12 retrotranslocation channel (PubMed:29884772). Extraction by the PEX1-PEX6 AAA ATPase complex is
Cytoplasm, cytosolPeroxisome membraneCell projection, cilium, photoreceptor outer segment
Peroxisome biogenesis disorder complementation group 4
A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).
Component of the PEX13-PEX14 docking complex, a translocon channel that specifically mediates the import of peroxisomal cargo proteins bound to PEX5 receptor (PubMed:28765278, PubMed:8858165, PubMed:9653144). The PEX13-PEX14 docking complex forms a large import pore which can be opened to a diameter of about 9 nm (By similarity). Mechanistically, PEX5 receptor along with cargo proteins associates with the PEX14 subunit of the PEX13-PEX14 docking complex in the cytosol, leading to the insertion o
Peroxisome membrane
Peroxisome biogenesis disorder complementation group 13
A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).
Involved in peroxisome biosynthesis and integrity. Assembles membrane vesicles before the matrix proteins are translocated. As a docking factor for PEX19, is necessary for the import of peroxisomal membrane proteins in the peroxisomes
Peroxisome membrane
Peroxisome biogenesis disorder complementation group 12
A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).
Component of a retrotranslocation channel required for peroxisome organization by mediating export of the PEX5 receptor from peroxisomes to the cytosol, thereby promoting PEX5 recycling (PubMed:24662292, PubMed:9354782, PubMed:9632816). The retrotranslocation channel is composed of PEX2, PEX10 and PEX12; each subunit contributing transmembrane segments that coassemble into an open channel that specifically allows the passage of PEX5 through the peroxisomal membrane (By similarity). PEX12 also re
Peroxisome membrane
Peroxisome biogenesis disorder complementation group 3
A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).
Required for peroxisome membrane biogenesis. May play a role in early stages of peroxisome assembly. Can recruit other peroxisomal proteins, such as PEX3 and PMP34, to de novo peroxisomes derived from the endoplasmic reticulum (ER). May function as receptor for PEX3
Peroxisome membrane
Peroxisome biogenesis disorder complementation group 9
A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).
Involved in peroxisomal proliferation (PubMed:9792670). May regulate peroxisome division by recruiting the dynamin-related GTPase DNM1L to the peroxisomal membrane (PubMed:12618434). Promotes membrane protrusion and elongation on the peroxisomal surface (PubMed:20826455)
Peroxisome membrane
Peroxisome biogenesis disorder 14B
An autosomal recessive peroxisome biogenesis disorder characterized clinically by mild intellectual disability, congenital cataracts, progressive hearing loss, and polyneuropathy. Additionally, recurrent migraine-like episodes following mental stress or physical exertion, not a common feature in peroxisome disorders, are observed.
Necessary for early peroxisomal biogenesis. Acts both as a cytosolic chaperone and as an import receptor for peroxisomal membrane proteins (PMPs). Binds and stabilizes newly synthesized PMPs in the cytoplasm by interacting with their hydrophobic membrane-spanning domains, and targets them to the peroxisome membrane by binding to the integral membrane protein PEX3. Excludes CDKN2A from the nucleus and prevents its interaction with MDM2, which results in active degradation of TP53
CytoplasmPeroxisome membrane
Peroxisome biogenesis disorder complementation group 14
A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).
Receptor required for the peroxisomal import of proteins containing a C-terminal PTS2-type peroxisomal targeting signal (PubMed:11931631, PubMed:22057399, PubMed:25538232, PubMed:9090381). Specifically binds to cargo proteins containing a PTS2 peroxisomal targeting signal in the cytosol (PubMed:11931631, PubMed:22057399, PubMed:25538232). Cargo protein-binding triggers interaction with PEX5 and formation of a ternary complex composed of PEX5 and PEX7 along with PTS2-containing cargo proteins, wh
Cytoplasm, cytosolPeroxisome matrix
Peroxisome biogenesis disorder complementation group 11
A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).
Variantes genéticas (ClinVar)
325 variantes patogênicas registradas no ClinVar.
Classificação de variantes (ClinVar)
Distribuição de 8,152 variantes classificadas pelo ClinVar.
Vias biológicas (Reactome)
6 vias biológicas associadas aos genes desta condição.
Diagnóstico
Os sinais que médicos procuram e os exames que confirmam
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🇧🇷 Atendimento SUS — Doença da biogênese dos peroxissomos
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Publicações mais relevantes
Identification of a new frameshift homozygous variant of PEX3 gene in a preterm infant with profound global developmental delay and bilateral ptosis: a case report and updated literature review.
Loss-of-function mutations in PEX3 have been associated with Zellweger syndrome (ZS), a severe form of peroxisome biogenesis disorder (PBD) characterized by significant global developmental delay, muscle weakness with bilateral ptosis, cholestasis, hypotonia, and seizures. ZS can be life-threatening if manifested in the neonatal period. This study presents a unique case of a male infant with severe ZS whose condition deteriorated despite intensive supportive treatment. Through whole-exome sequencing, an intronic variant NM_003630.2:c.288-10T > A, located 10 nucleotides before exon 4 of the PEX3 gene, was identified. Sanger sequencing revealed a homozygous variant in the infant and a heterozygous variant in both parents. Further analysis confirmed the abnormal transcript of the PEX3 gene caused by a frameshift variant resulting from the PEX3 gene c.288-10T > A mutation. This modification led to a splicing error that deleted exon 4, causing a direct splicing of exons 3 and 5. This alteration produced a truncated protein comprising 32 incorrect amino acids. We systematically summarized common phenotypes across 10 reported PEX3-related Zellweger spectrum disorder (ZSD) cases (including the current patient): profound global developmental delay (9/10), bilateral ptosis/ocular motility dysfunction (7/10), and hypotonia (7/10). These consistent phenotypes reflect genotype-phenotype correlation in PEX3-related ZSD, providing valuable clues for early clinical suspicion and diagnosis. We report the first Chinese case of severe ZSD caused by the PEX3 variant [c.288-10T > A: p.P97Ffs*33], broadening the spectrum of severe ZSDs associated with pathogenic PEX3 variants. Our summary of 10 PEX3-related ZSD cases identifies three core phenotypes—profound global developmental delay, bilateral ptosis, and hypotonia—that aid early clinical suspicion and targeted genetic testing. The online version contains supplementary material available at 10.1186/s12887-025-06472-0.
Detection of a Novel Homozygous PEX5 Stop-Loss Variant Associated with Zellweger Syndrome in a Highly Endogamic Family.
Zellweger syndrome (ZS) is a heterogeneous group of clinical conditions that commonly manifest with neurodevelopmental delay, multiple neurological abnormalities, visual and auditory impairments, and adrenocortical dysfunction. ZS is an autosomal recessive peroxisomal disorder resulting from mutations in one of over 13 identified genes. We report the case of a male child with episodic seizures starting at 18 days of life, followed by neurodevelopmental delay and neuroimaging findings of asymmetric polymicrogyria and cortical abnormalities. His healthy parents were consanguineous, and notably, a brother, who passed away at the age of 5 years-old, had epilepsy and adrenoleukodystrophy. Exome sequencing allowed the identification of a novel stop-loss homozygous variant in the PEX5 gene in the index case. The phenotype associated to this gene, Zellweger syndrome, as well as the inheritance mechanism, is consistent with that observed in both the patient and his brother. PEX7-related rhizomelic chondrodysplasia punctata (PEX7-RCDP), a peroxisome biogenesis disorder (PBD), has a classic (severe) form and a nonclassic (mild) form. Classic (severe) PEX7-RCDP is characterized by proximal shortening of the humerus (rhizomelia) and to a lesser degree the femur, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata, or CDP), coronal clefts of the vertebral bodies, and cataracts that are usually present at birth or appear in the first few months of life. Birth weight, length, and head circumference are often at the lower range of normal; postnatal growth deficiency is profound. Intellectual disability is severe, and most children develop seizures. Most affected children do not survive the first decade of life; a proportion die in the neonatal period. Nonclassic (mild) PEX7-RCDP is characterized by congenital or childhood cataracts, CDP or, infrequently, chondrodysplasia manifesting only as mild epiphyseal changes, joint contractures, neurobehavioral abnormalities, and milder intellectual disability and growth restriction than classic PEX7-RCDP. The diagnosis of PEX7-RCDP is established in a proband with suggestive clinical, radiographic, and laboratory findings and biallelic pathogenic variants in PEX7 identified on molecular genetic testing. Treatment of manifestations: In those with classic (severe) PEX7-RCDP, management is supportive and limited by the severe health issues present at birth and poor outcome. Dietary restriction of phytanic acid to avoid the consequences of phytanic acid accumulation over time may benefit individuals with mild PEX7-RCDP. Physical therapy to improve contractures; orthopedic procedures may improve function in some individuals; consider need for positioning and mobility devices; spinal decompression with or without fusion depending on region of compression and myelopathic signs; cataract extraction may restore and/or preserve vision; community vision services through early intervention or school district; poor feeding and recurrent aspiration may necessitate placement of a gastrostomy tube; developmental and educational support; standard treatment of seizures by an experienced neurologist; good pulmonary clearance and attention to respiratory function; influenza vaccine, RSV monoclonal antibody, and other interventions to prevent lung disease; management of congenital heart disease per cardiologist; dermatologist management of skin manifestations; management of kidney and urinary tract anomalies per nephrologist and/or urologist; social work and care coordination as needed. Surveillance: Annual measurement of phytanic acid levels in children with non-classic (mild) PEX7-RCDP; musculoskeletal assessment, assessment for kyphosis and scoliosis, and neurologic exam with assessment for seizures at each visit; vision assessment every three months until cataracts are detected and then as recommended by ophthalmologist; assessment of growth, nutritional status, safety of oral intake, development, behavior, and respiratory function at each visit; cardiac exam, echocardiogram, and EKG with frequency per treating cardiologist; urine and imaging studies to assess for kidney stones as needed; assessment for skin issues and family needs at each visit. PEX7-RCDP is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PEX7 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the PEX7 pathogenic variants have been identified in an affected family member, molecular genetic carrier testing of at-risk relatives and prenatal/preimplantation genetic testing are possible.
Mitochondria and Peroxisome Crosstalk in Peroxisome Biogenesis Disorder 8A Caused by a Rare Variant in PEX16 Gene.
Peroxisome biogenesis disorder 8A is a rare autosomal recessive disorder caused by mutations in the PEX16 gene. We report the clinical, biochemical, and molecular features of a patient harboring the homozygous NM_004813.4: c.526C>T, p.(Arg176*) mutation in PEX16 associated with mitochondrial dysfunction. This newborn presented with microcephaly, encephalopathy, hypotonia, failure to thrive, hepatomegaly, and abnormal retinal pigmentation. He had elevated plasma very long-chain fatty acids. Skeletal muscle biopsy revealed significant mitochondrial depletion with deficiencies of the respiratory chain Complexes I-IV, with significant reductions in cytochrome c oxidase and citrate synthase activity. The peroxisome biogenesis disorder 8A was confirmed by whole genome sequencing. This is the first case delineating the association of mitochondrial dysfunction with peroxisome biogenesis disorder 8A caused by the above mutation. Further studies are needed to elucidate the underlying pathophysiological mechanisms of mitochondria and peroxisome crosstalk.
Using multiple modalities to confirm diagnosis in patients with suspected peroxisome biogenesis disorders.
Zellweger spectrum disorder (ZSD) results from biallelic variants in any one of 13 PEX genes involved in peroxisome biogenesis and function. The majority of ZSD cases result from pathogenic variants in PEX1. Here, we present 3 patients with suspected PEX1-related ZSD and non-diagnostic whole exome sequencing and describe the use of multiple modalities to ascertain their diagnosis. We confirmed peroxisomal dysfunction in the patients by demonstrating abnormal peroxisome metabolite levels in blood and peroxisome import dysfunction in patient fibroblasts. RNA studies including RNA-seq and RT-PCR, followed by Sanger sequencing showed leaky splice variants including an intron 13 variant causing exon 14 skipping (Patient 1), an intron 22 variant causing intron 22 retention (Patient 2), and a synonymous splice-site variant causing exon 16 skipping (Patient 3). All three patients had very low amounts of canonical PEX1 transcripts on RNA-seq, as well as residual but reduced PEX1 protein levels on immunoblotting, which likely explains their non-severe ZSD phenotype. This study suggests that a multi-modality approach combining biochemical testing, functional assays in fibroblasts and molecular investigations including sequencing of non-coding regions and RNA analysis may aid in diagnosis of patients with suspected PBD-ZSD and inconclusive WES.
Identification of a novel heterozygous variant in the PEX26 gene in an infant: a case report.
The protein PEX26 is involved in the biogenesis and maintenance of peroxisomes, which are organelles within cells. Dysfunction of PEX26 results in peroxisome biogenesis disorders (PBDs) complementation group 8 (CG8), leading to Zellweger spectrum disorders (ZSDs). These disorders present as a syndrome with multiple congenital anomalies, varying in clinical severity. We present the case of a 7-month-old boy who exhibited hepatic impairment with hepatomegaly, sensorineural hearing loss, developmental delay, abnormal ossification, and mild craniofacial dysmorphology. Tandem mass spectrometry analysis of plasma isolated from whole blood revealed a significant increase in the levels of very long chain fatty acids (VLCFAs) C26:0, C26:0/C22:0, and C24:0/C22:0, consistent with peroxisomal fatty acid oxidation disorder. Exome sequencing identified two variants in the PEX26 gene (c.347T>C and c.616C>T), with the latter being a suspected pathogenic variation. The variant can lead to a defect in the PEX26 gene, resulting in impaired peroxisome biogenesis, β-oxidation of VLCFAs, and disruption of other biochemical pathways. Ultimately, this cascade of events manifests as ZSDs. Currently, symptomatic supportive treatment is the main approach for managing this condition and regular follow-up is being conducted for the patient. The present study introduces a novel heterozygous variant comprising two previously unidentified variants in the PEX26 gene, thereby expanding the range of known genetic alterations and highlighting the effectiveness of highly efficient exome sequencing in patients with undetermined multiple system dysfunctions.
Publicações recentes
A novel case of Heimler syndrome in a young child with compound heterozygous PEX26 mutations: clinical and genetic insights with literature review.
Identification of a new frameshift homozygous variant of PEX3 gene in a preterm infant with profound global developmental delay and bilateral ptosis: a case report and updated literature review.
Detection of a Novel Homozygous PEX5 Stop-Loss Variant Associated with Zellweger Syndrome in a Highly Endogamic Family.
PEX7-Related Rhizomelic Chondrodysplasia Punctata.
Mitochondria and Peroxisome Crosstalk in Peroxisome Biogenesis Disorder 8A Caused by a Rare Variant in PEX16 Gene.
📚 EuropePMC27 artigos no totalmostrando 61
Identification of a new frameshift homozygous variant of PEX3 gene in a preterm infant with profound global developmental delay and bilateral ptosis: a case report and updated literature review.
BMC pediatricsDetection of a Novel Homozygous PEX5 Stop-Loss Variant Associated with Zellweger Syndrome in a Highly Endogamic Family.
The application of clinical geneticsMitochondria and Peroxisome Crosstalk in Peroxisome Biogenesis Disorder 8A Caused by a Rare Variant in PEX16 Gene.
Clinical geneticsUsing multiple modalities to confirm diagnosis in patients with suspected peroxisome biogenesis disorders.
Molecular genetics and metabolismVariable Clinical Spectrum of Inborn Errors of Bile Acid Synthesis: A Report of 10 Cases.
Experimental and clinical transplantation : official journal of the Middle East Society for Organ TransplantationExtended Phenotype of PEX11B Pathogenic Variants: Ataxia, Tremor, and Dystonia Due to a Novel C.2T > G Variant.
Movement disorders clinical practicePigmentary retinal dystrophy associated with peroxisome biogenesis disorder-Zellweger syndrome spectrum.
Oxford medical case reportsTwo siblings with PEX11B-related peroxisome biogenesis disorder.
European journal of medical geneticsZellweger Syndrome: A Case Report.
JNMA; journal of the Nepal Medical AssociationIdentification of a novel heterozygous variant in the PEX26 gene in an infant: a case report.
Translational pediatricsDried blood spot-based newborn screening for bile acid synthesis disorders, Zellweger spectrum disorder, and Niemann-Pick type C1 by detection of bile acid metabolites.
Molecular genetics and metabolismPEX6 Mutation in a Child with Infantile Refsum Disease-A Case Report and Literature Review.
Children (Basel, Switzerland)PEX13 prevents pexophagy by regulating ubiquitinated PEX5 and peroxisomal ROS.
AutophagyThe Cys-N-degron pathway modulates pexophagy through the N-terminal oxidation and arginylation of ACAD10.
AutophagyStructural Characterization and Quantitation of Ether-Linked Glycerophospholipids in Peroxisome Biogenesis Disorder Tissue by Ultraviolet Photodissociation Mass Spectrometry.
Analytical chemistryA Pex7 Deficient Mouse Series Correlates Biochemical and Neurobehavioral Markers to Genotype Severity-Implications for the Disease Spectrum of Rhizomelic Chondrodysplasia Punctata Type 1.
Frontiers in cell and developmental biologyCharacterization of Severity in Zellweger Spectrum Disorder by Clinical Findings: A Scoping Review, Meta-Analysis and Medical Chart Review.
CellsClinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series.
NeurogeneticsPeripheral Vestibular Dysfunction Is a Common Occurrence in Children With Non-syndromic and Syndromic Genetic Hearing Loss.
Frontiers in neurologyAAV-mediated PEX1 gene augmentation improves visual function in the PEX1-Gly844Asp mouse model for mild Zellweger spectrum disorder.
Molecular therapy. Methods & clinical developmentDiagnostic challenges and disease management in patients with a mild Zellweger spectrum disorder phenotype.
Molecular genetics and metabolismCholbam® and Zellweger spectrum disorders: treatment implementation and management.
Orphanet journal of rare diseasesStop Codon Context-Specific Induction of Translational Readthrough.
BiomoleculesLC-MS Based Platform Simplifies Access to Metabolomics for Peroxisomal Disorders.
MetabolitesAutophagy Inhibitors Do Not Restore Peroxisomal Functions in Cells With the Most Common Peroxisome Biogenesis Defect.
Frontiers in cell and developmental biologyTwins with PEX7 related intellectual disability and cataract: Highlighting phenotypes of peroxisome biogenesis disorder 9B.
American journal of medical genetics. Part AA Novel Mutation in PEX11β Gene.
Iranian journal of child neurologyZellweger Syndrome Disorders: From Severe Neonatal Disease to Atypical Adult Presentation.
Advances in experimental medicine and biologyHigh Dose Versus Low Dose Syngeneic Hepatocyte Transplantation in Pex1-G844D NMRI Mouse Model is Safe but Does Not Achieve Long Term Engraftment.
CellsZellweger spectrum disorder: A cross-sectional study of symptom prevalence using input from family caregivers.
Molecular genetics and metabolism reportsGenome sequencing identifies a rare case of moderate Zellweger spectrum disorder caused by a PEX3 defect: Case report and literature review.
Molecular genetics and metabolism reportsLongitudinal study of Pex1-G844D NMRI mouse model: A robust pre-clinical model for mild Zellweger spectrum disorder.
Biochimica et biophysica acta. Molecular basis of diseaseRecent insights into peroxisome biogenesis and associated diseases.
Journal of cell scienceA peroxisome deficiency-induced reductive cytosol state up-regulates the brain-derived neurotrophic factor pathway.
The Journal of biological chemistryAccurate and live peroxisome biogenesis evaluation achieved by lentiviral expression of a green fluorescent protein fused to a peroxisome targeting signal 1.
Histochemistry and cell biologyEvaluation of X-Linked Adrenoleukodystrophy Newborn Screening in North Carolina.
JAMA network openVariant analysis of PEX11B gene from a family with peroxisome biogenesis disorder 14B by whole exome sequencing.
Molecular genetics & genomic medicineTwo novel mutations of PEX6 in one Chinese Zellweger spectrum disorder and their clinical characteristics.
Annals of translational medicineLiver disease predominates in a mouse model for mild human Zellweger spectrum disorder.
Biochimica et biophysica acta. Molecular basis of diseaseEmotional experience in parents of children with Zellweger spectrum disorders: A qualitative study.
Molecular genetics and metabolism reportsAtaxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders.
Clinical neurology and neurosurgeryZellweger spectrum disorder patient-derived fibroblasts with the PEX1-Gly843Asp allele recover peroxisome functions in response to flavonoids.
Journal of cellular biochemistryAtypical PEX16 peroxisome biogenesis disorder with mild biochemical disruptions and long survival.
Brain & developmentRenal oxalate stones in children with Zellweger spectrum disorders.
Saudi journal of anaesthesiaLiving-donor liver transplantation for mild Zellweger spectrum disorder: Up to 17 years follow-up.
Pediatric transplantationA metabolomic map of Zellweger spectrum disorders reveals novel disease biomarkers.
Genetics in medicine : official journal of the American College of Medical GeneticsAllelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder.
American journal of human geneticsNeonatal Rhizomelic Chondrodysplasia Punctata Type 1: Weaving Evidence Into Clinical Practice.
The Journal of perinatal & neonatal nursingMild Zellweger syndrome due to a novel PEX6 mutation: correlation between clinical phenotype and in silico prediction of variant pathogenicity.
Journal of applied geneticsDevelopment and validation of a severity scoring system for Zellweger spectrum disorders.
Clinical geneticsIdentification of a novel mutation in PEX10 in a patient with attenuated Zellweger spectrum disorder: a case report.
Journal of medical case reportsThe peroxisomal AAA ATPase complex prevents pexophagy and development of peroxisome biogenesis disorders.
AutophagyBiochemical and clinical profiles of 52 Tunisian patients affected by Zellweger syndrome.
Pediatrics and neonatologyAtaxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype.
Journal of the neurological sciencesPexophagy is responsible for 65% of cases of peroxisome biogenesis disorders.
AutophagyNovel PEX11B Mutations Extend the Peroxisome Biogenesis Disorder 14B Phenotypic Spectrum and Underscore Congenital Cataract as an Early Feature.
Investigative ophthalmology & visual sciencePeroxisomal protein PEX13 functions in selective autophagy.
EMBO reportsMitochondrial changes and oxidative stress in a mouse model of Zellweger syndrome neuropathogenesis.
NeuroscienceSevere early onset retinitis pigmentosa in a Moroccan patient with Heimler syndrome due to novel homozygous mutation of PEX1 gene.
European journal of medical geneticsEffect of l-Arginine in One Patient with Peroxisome Biogenesis Disorder due to PEX12 Deficiency.
NeuropediatricsNDRC: A Disease-Causing Genes Prioritized Method Based on Network Diffusion and Rank Concordance.
IEEE transactions on nanobioscienceAssociações
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Referências e fontes
Bases de dados externas citadas neste artigo
Publicações científicas
Artigos indexados no PubMed ligados a esta doença no grafo RarasNet — título, periódico e PMID direto da fonte, sem intermediação de IA.
- Identification of a new frameshift homozygous variant of PEX3 gene in a preterm infant with profound global developmental delay and bilateral ptosis: a case report and updated literature review.
- Detection of a Novel Homozygous PEX5 Stop-Loss Variant Associated with Zellweger Syndrome in a Highly Endogamic Family.
- Mitochondria and Peroxisome Crosstalk in Peroxisome Biogenesis Disorder 8A Caused by a Rare Variant in PEX16 Gene.
- Using multiple modalities to confirm diagnosis in patients with suspected peroxisome biogenesis disorders.
- Identification of a novel heterozygous variant in the PEX26 gene in an infant: a case report.
- A novel case of Heimler syndrome in a young child with compound heterozygous PEX26 mutations: clinical and genetic insights with literature review.
- PEX7-Related Rhizomelic Chondrodysplasia Punctata.
Bases de dados e fontes oficiais
Identificadores e referências canônicas usadas para montar este verbete.
- ORPHA:79189(Orphanet)
- MONDO:0019234(MONDO)
- GARD:11890(GARD (NIH))
- Variantes catalogadas(ClinVar)
- Busca completa no PubMed(PubMed)
- Q61913385(Wikidata)
Dados compilados pelo RarasNet a partir de fontes abertas (Orphanet, OMIM, MONDO, PubMed/EuropePMC, ClinicalTrials.gov, DATASUS, PCDT/MS). Este conteúdo é informativo e não substitui avaliação médica.
Conteúdo mantido por Agente Raras · Médicos e pesquisadores podem colaborar
