Inheritance in Erythropoietic Protoporphyria: A Common Wild-Type Ferrochelatase Allelic Variant With Low Expression Accounts for Clinical Manifestation

Blood ◽  
1999 ◽  
Vol 93 (6) ◽  
pp. 2105-2110 ◽  
Author(s):  
Laurent Gouya ◽  
Herve Puy ◽  
Jerôme Lamoril ◽  
Vasco Da Silva ◽  
Bernard Grandchamp ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Absolute Risk ◽  
Clinical Manifestations ◽  
Allelic Variant ◽  
Control Group ◽  
Wild Type ◽  
Clinical Expression ◽  
Erythropoietic Protoporphyria ◽  
Autosomal Dominant Disorder ◽  
Low Expression

Erythropoietic protoporphyria (EPP) is a rare autosomal dominant disorder of heme biosynthesis characterized by partial decrease in ferrochelatase (FECH; EC 4.99.1.1) activity with protoporphyrin overproduction and consequent painful skin photosensitivity and rarely liver disease. EPP is normally inherited in an autosomal dominant pattern with low clinical penetrance; the many different mutations that have been identified are restricted to one FECH allele, with the other one being free of any mutations. However, clinical manifestations of dominant EPP cannot be simply a matter ofFECH haploinsufficiency, because patients have enzyme levels that are lower than the expected 50%. From RNA analysis in one family with dominant EPP, we recently suggested that clinical expression required coinheritance of a normal FECH allele with low expression and a mutant FECH allele. We now show that (1) coinheritance of a FECH gene defect and a wild-type low-expressed allele is generally involved in the clinical expression of EPP; (2) the low-expressed allelic variant was strongly associated with a partial 5′ haplotype [−251G IVS1−23T IVS2μsatA9] that may be ancestral and was present in an estimated 10% of a control group of Caucasian origin; and (3) haplotyping allows the absolute risk of developing the disease to be predicted for those inheriting FECH EPP mutations. EPP may thus be considered as an inherited disorder that does not strictly follow recessive or dominant rules. It may represent a model for phenotype modulation by mild variation in expression of the wild-type allele in autosomal dominant diseases.

scholarly journals Imaging to intervention: a review of what the Interventionalist needs to Know about Hereditary Hemorrhagic Telangiectasia

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Stephanie Sobrepera ◽  
Eric Monroe ◽  
Joseph J. Gemmete ◽  
Danial Hallam ◽  
Jason W. Pinchot ◽  
...  
Keyword(s):  
Hereditary Hemorrhagic Telangiectasia ◽  
Multidisciplinary Approach ◽  
Autosomal Dominant ◽  
Clinical Manifestations ◽  
Massive Hemorrhage ◽  
Endovascular Management ◽  
Autosomal Dominant Disorder ◽  
Screening Guidelines ◽  
Organ Systems ◽  
Arteries And Veins

AbstractHereditary hemorrhagic telangiectasia (HHT) is a disorder that affects 1 in 5000–10,000 people worldwide and can result in devastating complications such as cerebral abscess, stroke, massive hemorrhage, and even death. HHT is an autosomal dominant disorder that leads to the formation of abnormal communication between the arteries and veins with a resultant spectrum of vascular anomalies. The disorder affects many organ systems and thus requires a dedicated multidisciplinary approach. Interventional radiologists are vital members of this team providing expertise not only in disease management, but in complex embolotherapy, helping to maintain the health of these patients. This article reviews clinical manifestations, screening guidelines, diagnostic criteria, and endovascular management of HHT.

A new ferrochelatase mutation combined with low expression alleles in a Japanese patient with erythropoietic protoporphyria

2002 ◽  
Vol 102 (5) ◽  
pp. 501-506 ◽  
Author(s):  
Yumiko YASUI ◽  
Shikibu MURANAKA ◽  
Tsuyoshi TAHARA ◽  
Ryo SHIMIZU ◽  
Sonoko WATANABE ◽  
...  
Keyword(s):  
Base Pair ◽  
Japanese Patient ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Amino Acid Position ◽  
Molecular Defect ◽  
Wild Type ◽  
Erythropoietic Protoporphyria ◽  
Base Pair Deletion ◽  
Low Expression

We investigated the molecular defect of the ferrochelatase gene in a Japanese patient with erythropoietic protoporphyria (EPP), and identified a novel 16 base pair (574-589) deletion within exon 5. This deletion resulted in a frame-shift mutation and created a premature stop codon at amino acid position 198. The same molecular defect was also identified in his mother and a brother who had symptomatic EPP, but not in his father who was asymptomatic. The subjects with EPP were homozygous for the low expression haplotype, while his father was heterozygous for this haplotype. These results indicate that the combination of a 16 base pair deletion and low expression of the wild-type allelic variant is responsible for EPP in this pedigree.

scholarly journals Diagnosis of hereditary hemorrhagic telangiectasia in a pediatric patient admitted with diabetes: the utility of genetic testing

2021 ◽  
Vol 2 (3) ◽  
pp. 01-02
Author(s):  
Alvaro E. Galvis ◽  
Beatrice Batoczki ◽  
Iris S. Pecson ◽  
Evan Vidal ◽  
Craig T. Nakamura
Keyword(s):  
Genetic Testing ◽  
Pediatric Patient ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Autosomal Dominant ◽  
Wide Spectrum ◽  
Clinical Manifestations ◽  
Autosomal Dominant Disorder ◽  
Case Presentation ◽  
History Of ◽  
Vascular Dysplasia

Background: Hereditary hemorrhagic telangiectasia (HHT) formerly known as Osler-Weber-Rendu syndrome is a rare autosomal dominant disorder characterized by vascular dysplasia and a wide spectrum of clinical manifestations. Case presentation: We report the case of an undiagnosed pediatric patient who presented hypoxemia on clinical exam as the only suggestive feature for the presence of HHT. Conclusions: Although HHT diagnosis is based on the finding of characteristic clinical features genetic testing should also be implemented when a family history of the disease is present to help confirm or refute the diagnosis.

scholarly journals Production and characterization of erythropoietic protoporphyric heterodimeric ferrochelatases

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 1098-1104 ◽  
Author(s):  
Wided Najahi-Missaoui ◽  
Harry A. Dailey
Keyword(s):  
A Priori ◽  
Residual Activity ◽  
Wild Type ◽  
Potential Significance ◽  
Erythropoietic Protoporphyria ◽  
Dimer Interface ◽  
Type Mutant ◽  
Low Expression

AbstractMutations resulting in diminished activity of the dimeric enzyme ferrochelatase are a prerequisite for the inherited disorder erythropoietic protoporphyria (EPP). Patients with clinical EPP have only 10% to 30% of normal levels of ferrochelatase activity, and although many patients with EPP have one mutant allele and one “low-expression” normal allele, the possibility remains that, for some, low ferrochelatase activity may result from an EPP mutation that has an impact on both subunits of the wild-type/mutant heterodimer. Here we present data for 12 ferrochelatase wild-type/EPP mutant heterodimers showing that some mutations result in heterodimers with the residual activity anticipated from individual constituents, whereas others result in heterodimers with significantly lower activity than would be predicted. Although the data do not allow an a priori prediction of heterodimeric residual activity based solely on the in vitro activity of EPP homodimers or the position of the mutated residue within ferrochelatase, mutations that affect the dimer interface or [2Fe-2S] cluster have a significantly greater impact on residual activity than would be predicted. These data suggest that some EPP mutations may result in clinically overt EPP in the absence of a low-expression, wild-type allele; this is of potential significance for genetic counseling of patients with EPP.

scholarly journals Sepsis from Neurofibromatosis

2006 ◽  
Vol 33 (3) ◽  
pp. 328-328
Author(s):  
Navdeep Tangri ◽  
Shireen Sirhan ◽  
Gordon Crelinsten
Keyword(s):  
Autosomal Dominant ◽  
Clinical Manifestations ◽  
Neurofibromatosis Type ◽  
Large Mass ◽  
Type I ◽  
Neurofibromatosis Type I ◽  
Autosomal Dominant Disorder ◽  
Chest Wound ◽  
History Of ◽  
The Right

Neurofibromatosis Type I or von Recklinghausen’s neurofibromatosis is an autosomal dominant disorder with a high index of spontaneous mutations and extremely varied and unpredictable clinical manifestations. We present a case of sepsis secondary to an infected hematoma, enclosed within a massive neurofibroma.A 42-year-old man presented to the emergency department with a one week history of fever and chills. He reported an increase in pain and size of a growth near his chest. The patient was noted to be febrile on arrival. On physical examination, a very large neurofibroma was seen extending from the right upper chest. Wound and blood cultures were obtained. Computed Tomography (CT) of the thorax revealed a hematoma contained within the large mass.

Nivolumab with radiation therapy in a glioblastoma patient with Lynch syndrome

2021 ◽  
Vol 14 (4) ◽  
pp. e241026
Author(s):  
Wendy Joyce Sherman ◽  
Todd W Vitaz
Keyword(s):  
Radiation Therapy ◽  
Lynch Syndrome ◽  
Autosomal Dominant ◽  
Cytotoxic Chemotherapy ◽  
Mismatch Repair Genes ◽  
Wild Type ◽  
Autosomal Dominant Disorder ◽  
Off Label ◽  
Glioblastoma Patient ◽  
Repair Genes

Lynch syndrome is an autosomal dominant disorder leading to cancer predisposition caused by mutations in mismatch repair genes. There is minimal published experience treating glioblastoma in patients with Lynch syndrome. We report a patient with Lynch syndrome who was initially diagnosed with a left occipital isocitrate dehydrogenase (IDH) wild-type glioblastoma. After resection, she was treated with chemoradiation, followed by tumour treating fields. Three years after diagnosis, recurrence was resected. After refusing cytotoxic chemotherapy, decision was made to treat with off-label nivolumab concurrently with radiation. She has been maintained on nivolumab without recurrence of her glioblastoma now over 5 years out from her initial diagnosis. This case provides the first report of glioblastoma in a patient with Lynch syndrome responding to nivolumab and concurrent radiation. In patients with Lynch syndrome and glioblastoma, immunotherapy in the form of nivolumab may be an alternative option to standard cytotoxic chemotherapy.

scholarly journals Clinical and genetic charsteristics of the Bosch–Boonstra–Schaaf syndrome due to novel mutations in the NR2F1 gene

2020 ◽  
Vol 10 (4) ◽  
pp. 38-42
Author(s):  
E. L. Dadali ◽  
A. O. Borovikov ◽  
O. A. Shchagina ◽  
O. L. Mironovich
Keyword(s):  
Optic Atrophy ◽  
Attention Deficit Disorder ◽  
Autosomal Dominant ◽  
Clinical Manifestations ◽  
Autism Spectrum ◽  
Missense Mutations ◽  
Novel Mutations ◽  
Autosomal Dominant Disorder ◽  
Genetic Characteristics ◽  
Common Features

Bosch–Boonstra–Schaaf optic atrophy is autosomal dominant disorder caused by mutations in the NR2F1 gene. Its common features include optic atrophy and / or hypoplasia, developmental delay, intellectual disability, attention deficit disorder, autism spectrum disorder, seizures, hearing defects, spasticity, hypotonia, and thinning of the corpus callosum. We report of the clinical and genetic characteristics of two patients with Bosch-Boonstra-Schaaf syndrome with newly detected of the missense mutations с.329T>C (p.Phe110Ser) and с.413G>A (p.Cys138Tyr) in the gene NR2F1. The existence of a polymorphism of the clinical manifestations of the syndrome has been shown, and the necessity of using exome sequencing in the diagnosis of neuro-ophthalmic diseases has been substantiated.

Comparative analysis of polymorphic variants of IL-17A and MMP-1 genes with the risk of developing chronic periodontitis in petrochemical workers

2020 ◽  
Vol 60 (10) ◽  
pp. 687-693
Author(s):  
Iskander I. Zaidullin ◽  
Denis O. Karimov ◽  
Lilija K. Karimova ◽  
Milyausha F. Kabirova ◽  
Rasima R. Galimova ◽  
...  
Keyword(s):  
Ethylene Oxide ◽  
Chronic Periodontitis ◽  
Periodontal Diseases ◽  
Clinical Manifestations ◽  
Control Group ◽  
Periodontal Tissues ◽  
Dental Examination ◽  
Number Of Patients ◽  
Increased Risk ◽  
Harmful Substances

The susceptibility to the development and progression of inflammatory periodontal diseases, which depends on genetic and external factors (smoking, stress, oral hygiene), varies widely. In the development of these diseases, an important role is played not only by the presence of periodontal pathogenic microorganisms, but also by the presence of congenital or acquired immunodeficiency, immunoregulatory defects. The immune system plays a key role in the physiological and pathological processes of periodontal tissues. In this regard, IL17, produced by CD4+ Th cells, which has both Pro-inflammatory and protective activity, is of particular interest in the pathogenesis of periodontitis. The aim of study was to identify the relationship between polymorphic loci of the IL-17A (rs2275913) and MMP-1 (rs1799750) genes and clinical manifestations of chronic periodontitis in petrochemical workers. Dental examination was performed in 92 ethylene oxide production workers with chronic periodontitis and 74 patients with chronic periodontitis who did not come into contact with chemical factors (control group). Genotyping of polymorphisms rs2275913 of the IL17A gene and rs1799750 of the MMP1 gene was performed by allele-specific real-time polymerase chain reaction (PCR). Hygienic assessment of the degree of air pollution of the working area with harmful substances was carried out by gas chromatography according to the guidelines for the determination of harmful substances in the air № 5098-89, № 3119-84. When comparing the results of studies of both groups, there were no statistically significant differences in the frequency distributions of allelic variants and genotypes of the IL-17A and MMP-1 genes. The AA/AG genotypes of the IL-17A gene were associated with an increased risk of severe disease compared to the GG genotype in workers in the main group (OR=6.1; 95% CI 1.33-28.5; p=0.021) and in the control group (OR=7.26; 95% CI 1.34-39.25; p=0.016). Carriers of the A allele in the control group increased the risk of severe chronic periodontitis by 2.4 times compared to carriers of the G allele (OR=2.41; 95% CI 1.19-4.87; p=0.014). During the dental examination of employees of the ethylene oxide plant, the clinical course of periodontal diseases was more severe in comparison with the control group, and the number of patients with severe periodontitis was twice as high. It was found that the AA/AG genotypes of the IL-17A gene and the carrier of the A allele are associated with increased susceptibility to the development of severe chronic periodontitis. The association between the MMP-1 gene polymorphism and the risk of severe forms of chronic periodontitis has not been established. A risk factor for the development of inflammatory periodontal diseases in employees of the petrochemical complex is a complex of harmful production factors.

Efficacy and safety of denosumab treatment in a prepubertal patient with cherubism

2020 ◽  
Vol 33 (7) ◽  
pp. 963-966
Author(s):  
Haruka Kawamura ◽  
Satoshi Watanabe ◽  
Takashi I ◽  
Izumi Asahina ◽  
Hiroyuki Moriuchi ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Therapeutic Potential ◽  
Giant Cells ◽  
Efficacy And Safety ◽  
Autosomal Dominant Disorder ◽  
Osteolytic Lesions ◽  
Case Presentation ◽  
Childhood Growth ◽  
Receptor Activator ◽  
Denosumab Treatment

AbstractBackgroundDenosumab is an inhibitor of receptor activator of nuclear factor kappa-B ligand, which strongly suppresses osteoclasts. Cherubism is a rare autosomal dominant disorder characterized by symmetrical swelling of the jaws, in which the bone is replaced by a fibrous granuloma containing osteoclast-like giant cells.Case presentationWe report the efficacy and safety of denosumab treatment in a prepubertal boy with progressive cherubism. The treatment consisting of eight subcutaneous denosumab injections (120 mg/dose) in 6 months not only suppressed the expansion of the osteolytic lesions but also dramatically ossified them. However, a transiently decreased growth rate and rebounded asymptomatic hypercalcemia were associated with the treatment.ConclusionsThe present case demonstrated the therapeutic potential of denosumab for treatment of cherubism, although adverse effects, especially those on childhood growth, remain obscure. Further studies are needed to establish a safe and effective protocol for denosumab treatment of children.

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