scholarly journals Acute Intermittent Porphyria in a Man with Dual Enzyme Deficiencies

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
G. N. Cerbino ◽  
L. Abou Assali ◽  
L. S. Varela ◽  
L. Tomassi ◽  
A. Batlle ◽  
...  
Keyword(s):  
Biosynthetic Pathway ◽  
Metabolic Disorders ◽  
De Novo ◽  
Porphyria Cutanea Tarda ◽  
Acute Intermittent Porphyria ◽  
Uroporphyrinogen Decarboxylase ◽  
History Of ◽  
Biochemical Testing ◽  
De Novo Variant ◽  
Deficient Activity

Porphyrias are a heterogeneous group of metabolic disorders that result from the altered activity of specific enzymes of the heme biosynthetic pathway and are characterized by accumulation of pathway intermediates. Porphyria cutanea tarda (PCT) is the most common porphyria and is due to deficient activity of uroporphyrinogen decarboxylase (UROD). Acute intermittent porphyria (AIP) is the most common of the acute hepatic porphyrias, caused by decreased activity of hydroxymethylbilane synthase (HMBS). An Argentinean man with a family history of PCT who carried the UROD variant c.10_11insA suffered severe abdominal pain. Biochemical testing was consistent with AIP, and molecular analysis of HMBS revealed a de novo variant: c.344 + 2_ + 5delTAAG. This is one of the few cases of porphyria identified with both UROD and HMBS mutations and the first confirmed case of porphyria with dual enzyme deficiencies in Argentina.

scholarly journals Nearly Half of TP53 Germline Variants Predicted To Be Pathogenic in Patients With Osteosarcoma Are De Novo: A Report From the Children’s Oncology Group

2020 ◽  
pp. 1187-1195
Author(s):  
Brandon J. Diessner ◽  
Nathan Pankratz ◽  
Anthony J. Hooten ◽  
Lisa Mirabello ◽  
Aaron L. Sarver ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Rare Variants ◽  
De Novo ◽  
Phase 1 ◽  
Control Measures ◽  
Fisher Exact Test ◽  
Exact Test ◽  
Whole Exome ◽  
History Of ◽  
De Novo Variant

PURPOSE To ascertain the prevalence of recurrent de novo variants among 240 pediatric patients with osteosarcoma (OS; age < 20 years) unselected for family history of cancer. METHODS The identification of de novo variants was implemented in 2 phases. In the first, we identified genes with a rare (minor allele frequency < 0.01) de novo variant in > 1 of the 95 case-parent trios examined by whole-exome sequencing (WES) who passed quality control measures. In phase 2, 145 additional patients with OS were evaluated by targeted sequencing to identify rare de novo variants in genes nominated from phase 1. Recurrent rare variants identified from phase 1 and 2 were verified as either de novo or inherited by Sanger sequencing of affected patients and their parents. Categorical and continuous data were analyzed using Fisher exact test and t tests, respectively. RESULTS Among 95 case-parent trios who underwent WES, we observed 61 de novo variants in 60 genes among 47 patients, with TP53 identified as the only gene with a pathogenic or likely pathogenic (P/LP) de novo variant in more than one case-parent trio. Among all 240 patients with OS, 13 (5.4%) harbored a P/LP TP53 germline variant, of which 6 (46.2%) were confirmed to be de novo. CONCLUSION Apart from TP53, we did not observe any other recurrent de novo P/LP variants in the case-parent trios, suggesting that new mutations in other genes are not a frequent cause of pediatric OS. That nearly half of P/LP TP53 variants in our sample were de novo suggests universal screening for germline TP53 P/LP variants among pediatric patients with OS should be considered.

Identification of Two Types of Porphyria Cutanea Tarda by Measurement of Erythrocyte Uroporphyrinogen Decarboxylase

1980 ◽  
Vol 58 (6) ◽  
pp. 477-484 ◽  
Author(s):  
G. H. Elder ◽  
Diane M. Sheppard ◽  
R. E. De Salamanca ◽  
A. Olmos
Keyword(s):  
Family History ◽  
Autosomal Dominant ◽  
Porphyria Cutanea Tarda ◽  
Dominant Gene ◽  
Decarboxylase Activity ◽  
Hepatic Enzyme ◽  
Uroporphyrinogen Decarboxylase ◽  
History Of ◽  
The Common ◽  
Dominant Characteristic

1. Erythrocyte uroporphyrinogen decarboxylase activity has been measured in 27 patients with porphyria cutanea tarda, of whom 11 had a family history of overt porphyria cutanea tarda. 2. Eight patients from six families had erythrocyte uroporphyrinogen decarboxylase activities that were decreased to about half of control values. This decrease was shown by family studies to be inherited as an autosomal dominant characteristic. Two of these patients had no family history of overt porphyria cutanea tarda. 3. Nineteen patients had uroporphyrinogen decarboxylase activities close to or within the range found in 18 control subjects. Of these, five patients had a family history of porphyria cutanea tarda. 4. Inheritance of an autosomal dominant gene which decreases uroporphyrinogen decarboxylase activity in erythrocytes and liver is an uncommon cause of porphyria cutanea tarda and may not explain all cases of familial porphyria cutanea tarda. The hepatic enzyme defect in the common type of porphyria cutanea tarda, in which erythrocyte uroporphyrinogen decarboxylase activity is normal, may be caused either by inheritance of a gene whose effect is restricted to the liver or by chemicals that selectively inhibit the hepatic enzyme.

scholarly journals Acute Intermittent Porphyria: A Report of 3 Cases with Neuropathy

2019 ◽  
Vol 11 (1) ◽  
pp. 32-36
Author(s):  
Mohammed Alqwaifly ◽  
Vera Bril ◽  
Dubravka Dodig
Keyword(s):  
Biosynthetic Pathway ◽  
Metabolic Disorders ◽  
Case Series ◽  
Acute Intermittent Porphyria ◽  
Genetic Mutation ◽  
Nerve Conduction Studies ◽  
Porphobilinogen Deaminase ◽  
Motor Neuropathy ◽  
Clinical Presentations ◽  
Associated Symptoms

The porphyrias are metabolic disorders due to a defect in the heme biosynthetic pathway. Patients have diverse clinical presentations with neuropathy being frequent in acute intermittent porphyria (AIP). Associated symptoms are abdominal pain and seizures. Three patients presenting with neuropathy were later diagnosed with AIP on the basis of clinical features, erythrocyte porphobilinogen deaminase activity, neuropathic patterns, and nerve conduction studies. Testing for the HMBS genetic mutation confirmed the diagnosis of AIP in 1 patient. The findings from this case series confirm that porphyric neuropathy in AIP is a predominantly motor neuropathy with differing neuropathic presentations ranging from focal motor neuropathy to quadriplegia and respiratory failure.

Porphyria and dementia: a case report

2003 ◽  
Vol 20 (3) ◽  
pp. 96-99
Author(s):  
Dympna Gibbons ◽  
Anne Cullen ◽  
Malcom Garland
Keyword(s):  
Case Report ◽  
General Population ◽  
Cognitive Decline ◽  
Metabolic Disorders ◽  
Psychiatric Symptoms ◽  
Psychiatric Patients ◽  
Acute Intermittent Porphyria ◽  
Cognitive State ◽  
Advanced Stage ◽  
History Of

AbstractThe porphyrias are a group of rare hereditary metabolic disorders where there is an excess formation and excretion of porphyrins or their precursors. Type IIA, acute intermittent porphyria (AIP), has an estimated prevalence of one to eight per 100,000 in the general population but is thought to have a higher prevalence in psychiatric patients. AIP can present with a variety of psychiatric symptoms, often misdiagnosed. Associated neuropathological changes including focal cerebral ischaemic lesions have been found. However, to our knowledge, no case of dementia and AIP has been described. We present the case of a 56 year old man with a five-year history of progressive cognitive decline, diagnosed with AIP at an advanced stage of dementia. Whether AIP contributed to the dementia or is a coincidental finding is unknown. However treatment of AIP in this case resulted in some improvement in the patient's cognitive state.

Erythrocyte uroporphyrinogen decarboxylase activity and therapeutic phlebotomy in porphyria cutanea tarda

2000 ◽  
Vol 04 (08) ◽  
pp. 736-738
Author(s):  
FERENC KÓSZÓ ◽  
MÁRTA MORVAY ◽  
ATTILA DOBOZY ◽  
KRISZTINA BODA
Keyword(s):  
Porphyria Cutanea Tarda ◽  
Decarboxylase Activity ◽  
Type I ◽  
Type Ii ◽  
Uroporphyrinogen Decarboxylase ◽  
The Family ◽  
Different Types ◽  
History Of ◽  
A Minor ◽  
Genetically Determined

On the basis of the uroporphyrinogen decarboxylase ( UD ) activity in the erythrocytes, and the family history of the disease, different types of porphyria cutanea tarda ( PCT ) can be distinguished. In some cases, however, the distinction may involve some uncertainty (overlapping of subgroups). The question arises of whether the current erythrocyte UD activities in the different types of PCT are determined merely genetically. The erythrocyte UD activities in 72 unrelated patients with different forms of PCT (62 with type I PCT and 10 with type II PCT ), in different stages of the disease, were measured in order to test whether the activity exhibits any change during the long period of recovery. In both types the activities were faintly but significantly increased, from 94.9% (in PCT I) or 54.3% (in PCT II) up to 98.4% or 56.1% respectively. In both types the lower activity in the untreated condition can be attributed to a combination of several factors, including oxidative damage to UD , which results in a minor additional inhibition of the genetically determined enzyme activities.

scholarly journals A computational workflow for the expansion of heterologous biosynthetic pathways to natural product derivatives

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jasmin Hafner ◽  
James Payne ◽  
Homa MohammadiPeyhani ◽  
Vassily Hatzimanikatis ◽  
Christina Smolke
Keyword(s):  
Biosynthetic Pathway ◽  
De Novo ◽  
Pharmaceutical Compounds ◽  
De Novo Biosynthesis ◽  
Benzylisoquinoline Alkaloid ◽  
Medicinal Use ◽  
Starting Point ◽  
History Of ◽  
Computational Workflow ◽  
Pharmaceutical Molecules

AbstractPlant natural products (PNPs) and their derivatives are important but underexplored sources of pharmaceutical molecules. To access this untapped potential, the reconstitution of heterologous PNP biosynthesis pathways in engineered microbes provides a valuable starting point to explore and produce novel PNP derivatives. Here, we introduce a computational workflow to systematically screen the biochemical vicinity of a biosynthetic pathway for pharmaceutical compounds that could be produced by derivatizing pathway intermediates. We apply our workflow to the biosynthetic pathway of noscapine, a benzylisoquinoline alkaloid (BIA) with a long history of medicinal use. Our workflow identifies pathways and enzyme candidates for the production of (S)-tetrahydropalmatine, a known analgesic and anxiolytic, and three additional derivatives. We then construct pathways for these compounds in yeast, resulting in platforms for de novo biosynthesis of BIA derivatives and demonstrating the value of cheminformatic tools to predict reactions, pathways, and enzymes in synthetic biology and metabolic engineering.

The Porphyrias

2016 ◽  
Author(s):  
Karl E Anderson ◽  
Attallah Kappas
Keyword(s):  
Biosynthetic Pathway ◽  
Aminolevulinic Acid ◽  
Clinical Symptoms ◽  
Porphyria Cutanea Tarda ◽  
Acute Intermittent Porphyria ◽  
Genetic Traits ◽  
Molecular Defects ◽  
Clinical Presentations ◽  
Congenital Erythropoietic Porphyria ◽  
Hereditary Coproporphyria

The porphyrias are uncommon disorders caused by deficiencies in the activities of enzymes of the heme biosynthetic pathway. The enzymatic defects that cause porphyrias are inherited, with the exception of porphyria cutanea tarda, which is primarily acquired. In all porphyrias, there is significant interplay between genetic traits and acquired or environmental factors in the expression of clinical symptoms. This review discusses the classification, pathophysiology, and clinical presentations of the porphyrias. These include those associated with neurovisceral attacks (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and δ-aminolevulinic acid dehydratase [alad] deficiency porphyria) and the porphyrias associated with cutaneous photosensitivity (porphyria cutanea tarda, hepatoerythropoietic porphyria, erythropoietic protoporphyria, and congenital erythropoietic porphyria). Specific emphasis on the epidemiology, molecular defects and pathophysiology, clinical features, diagnosis, and treatment are discussed for each of these disorders. A table lists the safe and unsafe drugs for patients with porphyrias. Figures illustrate the genetic pathways of the disorders and the activities of enzymes of the heme biosynthetic pathway. This review contains 2 highly rendered figures, 1 table, and 96 references.

Gut Microbiota Patterns in Obese and Type 2 Diabetes (T2D) Patients from Romanian Black Sea Coast Region

2018 ◽  
Vol 69 (8) ◽  
pp. 2260-2267 ◽  
Author(s):  
Andra Iulia Suceveanu ◽  
Anca Pantea Stoian ◽  
Irinel Parepa ◽  
Claudia Voinea ◽  
Razvan Hainarosie ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Organic Acid ◽  
Black Sea ◽  
Metabolic Disorders ◽  
Obese Patients ◽  
Bacterial Counts ◽  
Black Sea Coast ◽  
History Of ◽  
Coast Region ◽  
Sea Coast

Gut microbiota plays a major role in the process of food absorption and low grade inflammation, two key steps in obesity and diabetes mellitus occurrence. Gut microbiota metabolites, such as short chain fatty acids (SCFA), have an important impact over the metabolic pathways like insulin signalling, incretin production and inflammation. [1-3] We aimed to study the microbiota patterns in obese and T2D patients from Black Sea Coast region, considering the ethnic mixture, environmental and geographical particularities, involving diet or various habits in this area. 100 patients and 100 controls matched by age, gender and ethnicity were studied regarding feaces predominance of Lactobacillus and Bifidobacterium species. We compared the results of microbiota patterns from patients to those obtained in a similar control group of healthy subjects. The standard pour plate 0.05% L-cystine enriched method was used to obtain the bacterial cultures and anaerobic conditions. Morphological and biochemical tests were used to identify the Lactobacillus and Bifidobacterium spp. Fecal organic acid concentrations were explored in frozen samples. The association between bacterial counts/organic acid concentrations and independent variables, including age, diet, ethnicity and other risk factors were calculated using multivariable linear regression analysis. Pearson�s correlation coefficients were calculated to detect associations between fecal bacteria counts/organic acid concentrations and laboratory variables (serum biomarkers, body mass index, age, and severity of obesity/T2D according to international scales). Junk and sweet diets, lack of physical activity and familial aggregation of hypercholesterolemia and diabetes were significantly more often present in our T2D/obese patients than in controls. The bacterial counts of the L. acidophilus, L plantarum and L. reuteri subgroups of Lactobacillus sp were significantly lower among patients with T2D and obesity than in controls. The counting of Bifidobacterium spp revealed a higher presence of B. bifidum in controls than in obese or T2D patients. Diet type (junk food and sweets), BMI (]25) and personal history of metabolic disorders were associated with decreased counts of L acidophilus and increased counts of L. fermentum and B. adolescentis in T2D patients. Ethnicity, metabolic disorders history and junk and sweet diet were associated with low counts of L. acidophilus and L. reuteri and low counts of B. longum. Junk and sweet diet was associated with low counts of B. bifidum. Romanian ethnicity and metabolic disorders were associated with low counts of B. choerinum at obese patients, independent of age or previous antidiabetic treatments. The concentrations of acetic and butyric acids were significantly lower in all patients groups, while the concentrations of valeric acid were significantly higher in patients with untreated T2D and obese patients compared to the controls. Low counts of L. acidophilus and L. reuteri were positively correlated with the increased levels of HbA1c, LDL cholesterol, TG and inflammatory markers such as CRP, ESR and IL-6, no matter of diet, age, ethnicity or metabolic disorders history. Also, low counts of B. bifidum and B. infantis were positively correlated with high levels of CRP, IL-6 and TG. In obese patients, statistic analysis results showed that low counts of L. acidophilus, L. plantarum, L. johnsonii and L. reuteri were positively associated with increased levels of CPR, IL-6 and TG, while low counts of B. bifidum, B infantis and B. breve were positively correlated with higher counts of CPR, LDL cholesterol and TG. Low counts of B. bifidum and B choerinum were positively correlated with low counts of HDL cholesterol in Romanian ethnicity patients and in those with previous metabolic disorders. Low bacterial counts of some particular strains of Lactobacillus spp and Bifidobacterium spp were positively correlated with diet type, BMI, Romanian ethnicity and personal history of metabolic disorders obese and T2D patients from Romanian Black Sea Coast Region.

De Novo variant in GNB2 associated with neurodevelopmental disease

2021 ◽  
Vol 132 ◽  
pp. S282
Author(s):  
Florencia del Viso ◽  
Lisa Lansdon ◽  
Emily Fleming ◽  
Bonnie Sullivan ◽  
Carol Saunders
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disease ◽  
De Novo Variant

scholarly journals R1352Q CACNA1A Variant in a Patient with Sporadic Hemiplegic Migraine, Ataxia, Seizures and Cerebral Oedema: A Case Report

2021 ◽  
pp. 123-130
Author(s):  
Anker Stubberud ◽  
Emer O’Connor ◽  
Erling Tronvik ◽  
Henry Houlden ◽  
Manjit Matharu
Keyword(s):  
Mental Retardation ◽  
Case Report ◽  
Genetic Testing ◽  
Head Trauma ◽  
Cerebral Oedema ◽  
De Novo ◽  
Minor Head Trauma ◽  
Hemiplegic Migraine ◽  
Wide Range ◽  
History Of

Mutations in the <i>CACNA1A</i> gene show a wide range of neurological phenotypes including hemiplegic migraine, ataxia, mental retardation and epilepsy. In some cases, hemiplegic migraine attacks can be triggered by minor head trauma and culminate in encephalopathy and cerebral oedema. A 37-year-old male without a family history of complex migraine experienced hemiplegic migraine attacks from childhood. The attacks were usually triggered by minor head trauma, and on several occasions complicated with encephalopathy and cerebral oedema. Genetic testing of the proband and unaffected parents revealed a de novo heterozygous nucleotide missense mutation in exon 25 of the <i>CACNA1A</i> gene (c.4055G&#x3e;A, p.R1352Q). The R1352Q <i>CACNA1A</i> variant shares the phenotype with other described <i>CACNA1A</i> mutations and highlights the interesting association of trauma as a precipitant for hemiplegic migraine. Subjects with early-onset sporadic hemiplegic migraine triggered by minor head injury or associated with seizures, ataxia or episodes of encephalopathy should be screened for mutations. These patients should also be advised to avoid activities that may result in head trauma, and anticonvulsants should be considered as prophylactic migraine therapy.

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