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Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Porphyrias are disorders caused by the deficiency of enzymes that participate in the synthesis of heme, which lead to the accumulation of intermediaries called porphyrins. Acute intermittent porphyria (AIP) is an autosomal dominant disorder with variable penetrance. Many patients remain asymptomatic throughout life. It is caused by a porphobilinogen deaminase deficiency; this enzyme catalyzes the conversion of porphobilinogen to hydroxymethylbilane. Without it, porphyrin precursors, porphobilinogen and delta-aminolevulinic acid, accumulate.
The Porphyrias
Published in Henry W. Lim, Nicholas A. Soter, Clinical Photomedicine, 2018
Porphobilinogen (PBG) deaminase catalyzes the condensation of four PBG molecules to form hydroxymethylbilane (Fig. 2). The deaminase furnishes a straight chain tetrapyrrole hydroxymethylbilane, but it is not an enzyme for ring-closure (9). Hydroxymethylbilane is converted by uroporphyrinogen (UROGEN) III cosynthase to UROGEN III; as an alternative it can undergo a spontaneous, nonenzymatic conversion to UROGEN I. The only difference between type I and type III isomers is that substituents on positions 17 and 18 of the “D” ring of the tetrapyrrole are switched (Fig. 1, Table 1).
Clinical value of identifying genes that inhibit hepatocellular carcinomas
Published in Expert Review of Molecular Diagnostics, 2022
Ugo Testa, Elvira Pelosi, Germana Castelli
The co-mutation of CTNNB1 with other genes may identify HCC subsets with peculiar properties. Thus, 9% of HCCs display concomitant CTNNB1 mutations and NRF2 activation, in part attributable to NFE2L2 or KEAP1 mutations [26]. In experimental models CTNNB1 and NFE2L2 mutations cooperate to promote hepatocarcinogenesis; these tumors are sensitive to mTOR inhibitors [26]. A recent study reported the occurrence of recurrent hydroxymethylbilane synthase (HMBS)-inactivating mutations in HCC; bi-allelic HMBS inactivation occurs both in patients with acute intermittent porphyria and sporadic HCC [27]. HMBS-mutated HCCs display concurrent activating CTNNB1 mutations and WNT/beta-catenin pathway activation, suggesting a cooperation between HMBS and CTNNB1 in promoting hepatocarcinogenesis [27].
Neurological and neuropsychiatric manifestations of porphyria
Published in International Journal of Neuroscience, 2019
Yiji Suh, Jason Gandhi, Omar Seyam, Wendy Jiang, Gunjan Joshi, Noel L. Smith, Sardar Ali Khan
AIP is inherited at birth, and is difficult to diagnose in prepubescent children. A mutation in the hydroxymethylbilane synthase gene will result in loss-of-function of prophobilinogen deaminase to function. It is not guaranteed one will develop porphyria if he or she possesses this mutation, as only 10% of people who possess the mutation show symptoms of porphyria [1]. Sweden has higher occurrences with 1 in 10,000 people possessing this disease [12]. It has been observed that 89% of people with AIP have mutations in the W198X, R173W, and R167W genes, with more clinical manifestations occurring in women [1, 13]. Heterozygous missense variants within the HMBS gene may also be attributed to causing encephalopathy in AIP [14]. A single base-pair insertion (887insA) in exon 14 or a missense mutation (Arg26His) in exon 2 within the porphobilinogen deaminase (PBG-D) gene can also cause acute intermittent porphyria [15, 16].
Safe usage of bicalutamide and goserelin in a male patient with acute intermittent porphyria and prostate cancer
Published in Scandinavian Journal of Urology, 2019
Frid Sofie Lichtwarck Bjugn, Elin Storjord, Roy Morten Kristensen, Ole-Lars Brekke
Acute intermittent porphyria (A.I.P.) is an autosomal dominant inherited metabolic disorder that is due to heterozygous mutations in the hydroxymethylbilane synthase enzyme of the haem biosynthesis [1]. Deficiency of the enzyme alone is not sufficient to cause attacks, since most patients with such mutations are asymptomatic [2]. Symptoms occur when exacerbating factors induce haem synthesis by increasing the activity of the rate limiting ALAS-1 enzyme, leading to accumulation of the porphyrin precursors porphobilinogen (P.B.G.) and aminolevulinic acid (A.L.A.) [1,2]. Medications are among the most important exacerbating factors and safe usage of drugs in A.I.P. patients may be a challenge [3]. The most common clinical presentation of A.I.P. is acute attacks with severe abdominal pain that may be accompanied by vomiting, fatigue, dark red urine, electrolyte disturbances and/or neuropsychiatric symptoms. Attacks are highly variable, both in severity and frequency. The secretion of A.L.A. and P.B.G. in urine is increased during attacks [4]. The northern parts of Sweden and Norway have the highest prevalence of A.I.P. in the world [2,5].