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European Journal of Human Genetics :... Nov 2016Heimler syndrome (HS) consists of recessively inherited sensorineural hearing loss, amelogenesis imperfecta (AI) and nail abnormalities, with or without visual defects....
Heimler syndrome (HS) consists of recessively inherited sensorineural hearing loss, amelogenesis imperfecta (AI) and nail abnormalities, with or without visual defects. Recently HS was shown to result from hypomorphic mutations in PEX1 or PEX6, both previously implicated in Zellweger Syndrome Spectrum Disorders (ZSSD). ZSSD are a group of conditions consisting of craniofacial and neurological abnormalities, sensory defects and multi-organ dysfunction. The finding of HS-causing mutations in PEX1 and PEX6 shows that HS represents the mild end of the ZSSD spectrum, though these conditions were previously thought to be distinct nosological entities. Here, we present six further HS families, five with PEX6 variants and one with PEX1 variants, and show the patterns of Pex1, Pex14 and Pex6 immunoreactivity in the mouse retina. While Ratbi et al. found more HS-causing mutations in PEX1 than in PEX6, as is the case for ZSSD, in this cohort PEX6 variants predominate, suggesting both genes play a significant role in HS. The PEX6 variant c.1802G>A, p.(R601Q), reported previously in compound heterozygous state in one HS and three ZSSD cases, was found in compound heterozygous state in three HS families. Haplotype analysis suggests a common founder variant. All families segregated at least one missense variant, consistent with the hypothesis that HS results from genotypes including milder hypomorphic alleles. The clinical overlap of HS with the more common Usher syndrome and lack of peroxisomal abnormalities on plasma screening suggest that HS may be under-diagnosed. Recognition of AI is key to the accurate diagnosis of HS.
Topics: ATPases Associated with Diverse Cellular Activities; Adenosine Triphosphatases; Amelogenesis Imperfecta; Animals; Exome; Frameshift Mutation; Hearing Loss, Sensorineural; Heterozygote; Membrane Proteins; Mice; Mice, Inbred C57BL; Mutation, Missense; Nails, Malformed; Pedigree; Phenotype; Retina
PubMed: 27302843
DOI: 10.1038/ejhg.2016.62 -
Cardiovascular Therapeutics Apr 2017Acute coronary syndrome is a life-threatening condition of utmost clinical importance, which, despite recent progress in the field, is still associated with high... (Review)
Review
Acute coronary syndrome is a life-threatening condition of utmost clinical importance, which, despite recent progress in the field, is still associated with high morbidity and mortality. Acute coronary syndrome results from a rupture or erosion of vulnerable atherosclerotic plaque with secondary platelet activation and thrombus formation, which leads to partial or complete luminal obstruction of a coronary artery. During the last decade, scientific evidence demonstrated that when an acute coronary event occurs, several nonculprit plaques are in a "vulnerable" state. Among the promising approaches, several investigations provided evidence of photodynamic therapy (PDT)-induced stabilization and regression of atherosclerotic plaque. Significant development of PDT strategies improved its therapeutic outcome. This review addresses PDT's pertinence and major problems/challenges toward its translation to a clinical reality.
Topics: Acute Coronary Syndrome; Animals; Coronary Artery Disease; Coronary Vessels; Humans; Photochemotherapy; Photosensitizing Agents; Plaque, Atherosclerotic; Rupture, Spontaneous; Theranostic Nanomedicine; Translational Research, Biomedical; Treatment Outcome
PubMed: 27893195
DOI: 10.1111/1755-5922.12238 -
Metabolites May 2021Peroxisomes are central hubs for cell metabolism and their dysfunction is linked to devastating human disorders, such as peroxisomal biogenesis disorders and single...
Peroxisomes are central hubs for cell metabolism and their dysfunction is linked to devastating human disorders, such as peroxisomal biogenesis disorders and single peroxisomal enzyme/protein deficiencies. For decades, biochemical diagnostics have been carried out using classical markers such as very long-chain fatty acids (VLCFA), which can be inconspicuous in milder and atypical cases. Holistic metabolomics studies revealed several potentially new biomarkers for peroxisomal disorders for advanced laboratory diagnostics including atypical cases. However, establishing these new markers is a major challenge in routine diagnostic laboratories. We therefore investigated whether the commercially available AbsoluteIDQ p180 kit (Biocrates Lifesciences), which utilizes flow injection and liquid chromatography mass spectrometry, may be used to reproduce some key results from previous global metabolomics studies. We applied it to serum samples from patients with mutations in peroxisomal target genes , , and the gene. Here we found various changes in sphingomyelins and lysophosphatidylcholines. In conclusion, this kit can be used to carry out extended diagnostics for peroxisomal disorders in routine laboratories, even without access to a metabolomics unit.
PubMed: 34072483
DOI: 10.3390/metabo11060347 -
The International Journal of... Jun 2023
Topics: Humans; Takotsubo Cardiomyopathy; Predictive Value of Tests; Heart; Electrocardiography; Acute Coronary Syndrome
PubMed: 36913156
DOI: 10.1007/s10554-023-02813-1 -
Molecular Genetics and Metabolism... Sep 2022Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder caused by variants in the gene and can lead to Addison disease, childhood cerebral ALD, or...
BACKGROUND
Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder caused by variants in the gene and can lead to Addison disease, childhood cerebral ALD, or adrenomyeloneuropathy. Presymptomatic hematopoietic stem cell transplantation is the only curative treatment for the disease and requires early detection through newborn screening (NBS) and close follow-up.
METHODS
An NBS program for ALD was performed by a two-tiered dried blood spot (DBS) lysophosphatidylcholine C26:0 (C26:0-LPC) concentration analysis. sequencing was eventually added as a third-tier test, and whole exome sequencing was used to confirm the diagnosis of all peroxisomal diseases. Affected newborns were followed-up for adrenal insufficiency and cerebral white matter abnormalities.
RESULTS
We identified 12 males and 10 females with variants, and 3 patients with Zellweger syndrome from 320,528 newborns. Eight (36.4%) variants identified in the current study were null variants, but there were no hotspots or founder effect. During a median follow-up period of 2.28 years, two (16.7%) male patients with variants developed Addison's disease. Extended family screening revealed one 28-year-old asymptomatic hemizygous father of a null variant (c.678delC). Among the three with Zellweger syndrome, one died at the age of 3 months, one showed developmental delay at the age of 1 year, and one was lost to follow-up.
CONCLUSION
Screening for ALD has been added to the NBS program in Taiwan with a high degree of success. The screening algorithm revealed a high proportion of null variants in cases found by NBS in Taiwan, a subset of patients who may have earlier disease onset. We also demonstrate the feasibility of combining the diagnosis of ALD and other peroxisomal disorders into one screening algorithm.
PubMed: 36046390
DOI: 10.1016/j.ymgmr.2022.100902 -
Sudanese Journal of Paediatrics 2011Zellweger syndrome, a paradigm of human peroxisomal disorders is characterized by dysmorphic features, hypotonia, severe neuro-developmental delay, hepatomegaly, renal...
Zellweger syndrome, a paradigm of human peroxisomal disorders is characterized by dysmorphic features, hypotonia, severe neuro-developmental delay, hepatomegaly, renal cysts, sensorineural deafness and retinal dysfunction. This is a case report of a baby boy born with facial dysmorphism, profound hypotonia, seizures, and hepatomegaly. The diagnosis was not evident initially but only later when he presented with obstructive jaundiced and renal cysts. He died at the age of seven months. Biochemical studies revealed elevation of very long chain fatty acids and phytanic acid consistent with a peroxisomal disorder. The recognition of this syndrome is important since it is a fatal hereditary disease. Zellweger syndrome should be included in the differential diagnosis of infantile hypotonia and dysmorphism.
PubMed: 27493320
DOI: No ID Found -
Molecular Genetics and Metabolism Oct 1999Genetically determined human peroxisomal disorders are subdivided into two major categories: disorders of peroxisome biogenesis (PBD), in which the organelle is not... (Review)
Review
Genetically determined human peroxisomal disorders are subdivided into two major categories: disorders of peroxisome biogenesis (PBD), in which the organelle is not formed normally, and those that involve a single peroxisomal enzyme. Twelve PBD have been identified, and the molecular defects have been defined in 10. All involve defects in the import of proteins into the organelle. Factors required for this import are now referred to as peroxins (PEX) and form the basis of a new and preferred classification system. The PBD are associated with four clinical phenotypes, named before their association with the organelle was recognized: Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata (RCDP). The first three are associated with 9 of the 10 PEX defects that have been defined so far, and represent a clinical continuum with variant severity, with ZS the most severe, NALD intermediate, and IRD the least severe. RCDP is associated with PEX7. Genotype-phenotype correlations are complicated by the fact that the clinical manifestations of the ZS-NALD-IRD continuum can be mimicked by disorders that affect single enzymes of peroxisomal fatty acid oxidation, and PEX7 by disorders of plasmalogen synthesis enzymes. Furthermore, clinical manifestations of each of the PEX disorders may vary. Phenotypic expression varies with the nature of the mutation, the milder phenotypes being associated with mutations that do not abolish function completely, or with mosaicism. Definition of the molecular defects is of great value for genetic counseling and may be of aid in establishing prognosis.
Topics: Genotype; Humans; Mutation; Peroxisomal Disorders; Peroxisomes; Phenotype; Proteins
PubMed: 10527683
DOI: 10.1006/mgme.1999.2926 -
Cleveland Clinic Journal of Medicine Mar 2004Many health claims for fish oil (which contains omega-3 fatty acids) in conditions from Alzheimer disease to Zellweger syndrome are based on indirect evidence. But the... (Review)
Review
Many health claims for fish oil (which contains omega-3 fatty acids) in conditions from Alzheimer disease to Zellweger syndrome are based on indirect evidence. But the evidence is direct for a benefit in coronary heart disease prevention, and the American Heart Association recently issued guidelines for the intake of omega-3 oils. This article answers a series of questions that health care professionals often ask regarding fish oil, such as what are proper dosages, and are there risks of ingesting pollutants by eating more fish or using supplements?
Topics: Coronary Disease; Dietary Supplements; Fatty Acids, Omega-3; Fish Oils; Health; Humans; Seafood
PubMed: 15055244
DOI: 10.3949/ccjm.71.3.208 -
American Journal of Human Genetics Oct 2015Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or... (Comparative Study)
Comparative Study
Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS-affected family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define HS as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6.
Topics: ATPases Associated with Diverse Cellular Activities; Adenosine Triphosphatases; Adolescent; Adult; Amelogenesis Imperfecta; Case-Control Studies; Cells, Cultured; Child; Child, Preschool; Female; Fibroblasts; Follow-Up Studies; Hearing Loss, Sensorineural; Humans; Infant; Infant, Newborn; Male; Membrane Proteins; Mutation; Nails, Malformed; Pedigree; Peroxisomes; Phenotype; Prognosis; Survival Rate; Young Adult
PubMed: 26387595
DOI: 10.1016/j.ajhg.2015.08.011 -
Proceedings of the National Academy of... Nov 1991By both histological and biochemical criteria, peroxisomes in patients with Zellweger syndrome appear to be absent or severely deficient. By using 15-30% (wt/vol)... (Comparative Study)
Comparative Study
By both histological and biochemical criteria, peroxisomes in patients with Zellweger syndrome appear to be absent or severely deficient. By using 15-30% (wt/vol) Nycodenz/sucrose gradients to study the subcellular localization of extraperoxisomal catalase activity, a commonly used marker for mature peroxisomes, we detected a single peak of activity in Zellweger syndrome fibroblasts at an equilibrium density of 1.13 g/cm3, lower than the expected 1.17 g/cm3 of mature peroxisomes. Upon recentrifugation in either the original gradient or one with a higher salt concentration, essentially all catalase activity was recovered in fractions of the original densities. The activity of the catalase peak was further analyzed by a digitonin titration and filtration assay in combination with Triton X-100 treatment. The catalase activity passed through 0.1-microns and 0.22-microns but was retained on 0.025-microns membrane filters (mean pore size). After treatment with Triton X-100 nearly all catalase activity passed through the filters. The results from fractionations data, digitonin latency measurement, and the detergent effect on the filtration behavior suggest that catalase is not free in the cytosol of Zellweger syndrome fibroblasts as commonly thought but in particles (W-particles). Similar low-density catalase-containing particles, distinct from peroxisomes, are also found in normal fibroblasts. We found that L-alpha-hydroxyacid oxidase, another peroxisomal matrix enzyme, is also present in W-particles derived from normal and Zellweger syndrome fibroblasts. We speculate that the low-density catalase-containing W-particle may represent an immature or incomplete form of peroxisome distinct from previously described "peroxisomal ghosts" in Zellweger syndrome fibroblasts.
Topics: Biomarkers; Catalase; Cell Fractionation; Cell Line; Centrifugation, Density Gradient; Digitonin; Fibroblasts; Humans; Microbodies; Organelles; Zellweger Syndrome
PubMed: 1946426
DOI: 10.1073/pnas.88.22.10084