Study Identifies 40 New Mutations That Cause Acute Intermittent Porphyria

Marisa Wexler MS avatar

by Marisa Wexler MS |

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HMBS mutations

Forty previously unreported mutations in the HMBS gene have been identified and found to be associated with the development of acute intermittent porphyria.

Researchers at the Icahn School of Medicine at Mount Sinai, New York, described the mutations in the study “Identification and characterization of 40 novel hydroxymethylbilane synthase mutations that cause acute intermittent porphyria,” which was published in the Journal of Inherited Metabolic Disease.

Acute intermittent porphyria (AIP) is the most common of the four types of acute porphyrias. It is caused by mutations in the gene that provides instruction to make the hydroxymethylbilane synthase, or HMBS, enzyme. These mutations often make the enzyme unable to carry out its normal function of helping to make heme, a molecule that helps red blood cells carry oxygen.

More than 90% of people with AIP are asymptomatic, meaning they never show signs of the disease. However, some patients may experience acute attacks that characterize the disease, which can result in abdominal pain, constipation, seizures, muscle weakness, high blood pressure, and elevated heart rate.

Genetic testing is crucial for diagnosis. Not only can this identify the problem in people with symptoms, it can allow asymptomatic individuals to be aware of the risks and the chance they will pass the mutated gene to their children.

“The diagnosis of AIP is usually significantly delayed due to the non-specific presenting symptoms of the disorder,” the researchers wrote in the study. Still, “once AIP is suspected establishing the diagnosis is fairly straightforward” by assessing the levels of abnormal porphyrin precursor, such as ALA and PBG, and porphyrin intermediates. “Alternatively, AIP may be diagnosed by demonstration of decreased HMBS enzymatic activity [in red-blood cells],” they added.

To date, more than 400 AIP-causing mutations have been identified. In this new study, researchers report on 40 more.

The mutations were found in 43 unrelated individuals who, after experiencing symptoms typical of AIP, had blood samples taken and had porphyria-related genes analyzed.

Most (28) of the mutations were predicted to severely impact the protein, changing its DNA sequence in such a way that the whole gene could not be properly read. These changes included premature stop signals (nonsense mutations), insertions and deletions that cause a frameshift of the sequence, and mutations that change how the gene is spliced (rearranged for making the protein).

Eleven mutations were missense, meaning they changed only one amino acid in the protein produced. There also was one deletion that did not cause a frameshift. The researchers used molecular tests to characterize these variants a little further, since the mechanism by which they prevent the protein from working was not fully clear.

HMBS proteins carrying each one of these mutations, with the exception of one mutation, were found to have significantly reduced activity — about less than 5% that of the non-mutated HMBS version. The exception, a mutation identified as p.A347P, had about half the activity of the non-mutated protein, but further tests revealed this mutation made the protein less stable.

Further characterization of these proteins revealed that the way they “broke” the protein depended on where the mutation appeared in the three-dimensional structure of the protein.

Specifically, mutations that changed the active pocket of HMBS — the portion responsible for doing the enzyme’s job — prevented it from working by directly changing it. In contrast, mutations on the outside of the protein appeared to reduce the activity of HMBS by making it less stable so that it  degraded rapidly.

“These studies facilitated the molecular diagnoses of AIP family members and further expanded the molecular heterogeneity of this acute hepatic porphyria,” researchers wrote.


Joyce Gould avatar

Joyce Gould

At long last. Robert J. Desnick must have slipped, "“Alternatively, AIP may be diagnosed by demonstration of decreased HMBS enzymatic activity [in red-blood cells],” they added." A porphyria expert term from the soutern hemisphere disputed that weak position yet APF, Desnick and several of his APF SAB colleagues have insisted--for decades--that urinary evidence (PBG) is required to diagnose AIP. With the APF/Alnylam partneship urinary "evidence" became the "gold standard." My daughter's life was ruined by Desnick/APF because she didn't (like multitudes of patients around the world) excrete U-PBG. Shame on him and his corrupt partners.

Barbara Bradbury avatar

Barbara Bradbury

Genes use to be absolute/immovable by APF spokespersons and its global medical followers. No reason nor logic could break through the absolute opinions. Maybe snd health this evidence will sway them. In the meantime the havoc, worsening and critical health and misery caused to so many living with porphyria (undiagnosed by urinary methods) have been horrendous.

Amanda Ballan avatar

Amanda Ballan

My daughter and son have HCP and had decades of suffering due to the APF and their affiliates in our country who refused to conceded that even though they had a DNA diagnosis, classic porphyria symptoms, including trigger from sun exposure, Copro ratio reversed, etc, that they were not suffering attacks because they were symptomatic as children. Children, apparently, do not have porphyria attacks. Once the children's hospital intervened and testing was done, my son was deemed to be in an attack at 7 years of age, due to unsafe epilepsy medicines, as he also had high urinary PBG. My daughter, however, could not get treatment for chronic porphyria attacks due to a lack of elevated U/PBG! Thankfully, once in a wheelchair and having had to drop out of school, my daughter found doctors in other states who questioned the validity of the sole reliance on U/PBG and organised haem infusions for her. The biochemist who was affiliated with the APF ruined decades of her life with his ignorant stance, fed solely due to his association with the APF. The fact that they are now coming out with statements regarding testing for low genetic activity and ALA makes me wonder if they are loosening testing regimes to garner more patients for their new iRNA drug, as they stand to benefit considerably from sales of the drug through a higher patient population.

Deborah Kinateder avatar

Deborah Kinateder

And how many of us have had to suffer and nearly die because of the ridiculous stance that one MUST pee out astronomically high amounts of PBG! Not to mention the difficulty of actually catching it at the right time or having the test properly done when you live extremely rural. Why are clinical symptoms, textbook attacks with absolutely no other explanation ignored? I have an HMBS mutation that was at first kept a secret from me. Upon further pressing for my variant report, a little paragraph was snuck in a revised report that said my HMBS mutation "might be a disease causing alteration". I've never peed out magical amounts of PBG but my ALA has been 4-5 times my baseline during mild to moderate attacks. My coproporphyrins I and III have been very high as well as hexa and heptacab porphyrins. I've had exactly 48 classic, textbook attacks beginning with migraine, abdominal seizures that drop me to the ground, vomiting, with tachycardia, low O2 sats, massive neurological fallout for days to weeks, urinary retention, and finally excruciating bone pain and lower extremity paresis and I would argue gastroparesis for a time after the attack. I was hospitalized 9 times in 3 years for two weeks with attacks that nearly killed me. Somehow magically dextrose infusions end my bone pain and lower extremity paresis, and oxygen with hyoscyamine many times halt my abdominal seizures and I escape the neurological fallout. But prior to getting a common sense GP to order those things for me, I suffered beyond belief, was bedridden for up to five weeks at a time, unable to eat, and getting down to 104 pounds afraid for my life with excruciatingly painful ribs, spleen and adrenal gland,blamed on a "floating rib" which magically disappeared when I finally recovered. I was given a lidocaine patch which made me worse! It's a trigger! I also have a homozygous variant on CPOX and my labs support HCP more than AIP. The "experts" would say that I don't have porphyria. My question to them is what pratel has caused these 48 and counting attacks that have ruined my life, left me with neurological damage and why do oxygen and dextrose infusions help me so much? And if these 40 new variants have been identified, what's to say there aren't more? With respect to both HMBS and CPOX? I was stopped from going to France to get the CPOX enzyme text that's not available here in the US. So I push forward, with what I can, trying to save my own life and mitigate my attacks and symptoms without the help of any "experts". I just lost my GP to retirement. God only knows if I'll find a willing participant to take his place. It was nothing short of a miracle to get him to help me and save my life, which he did. This U-BP horsecrap is just that, horsecrap! People are suffering and dying who legitimately have AIP, HCP and probably other types and combinations. Academia and those who hinder diagnoses in the name of drug trials, patents and money should hang their heads in shame. They know who they are, as do we, the misfit porph community.

Sharon avatar


Our children suffered immense pain because of this twisted set of lies.🔥😖

Joyce Gould avatar

Joyce Gould

“'Alternatively, AIP may be diagnosed by demonstration of decreased HMBS enzymatic activity [in red-blood cells],' they added." Interesting that this information "slipped out." Mount Sinai's chief geneticist has denied that very statement for decades, insisting that decreased erythrocyte HMBS (aka PBGD) enzymatic activity is used only to CONFIRM the urinary PBG diagnosis. Fortunately, there ARE porphyria experts in the world who disagree with US porphyria "experts" position that urinary biochemical evidence (U-BP) is required to diagnose acute porphyria (not just AIP). The Dutch are moving in the right direction but aren't entirely there yet; some southern hemisphere porphyria experts are. One disputed the Mount Sinai chief geneticist's position on my daughter's AIP dx--which,5-1/2 years after granting it(2009),he revoked it,causing her successful treatment plan to be terminated and ruining her health. A southern hemisphere porphyria team's expert opinion stated, "In the presence of typical symptoms, a low enzymatic activity is diagnostic, even with absent U-BP." Acute Porphyria patients the world over know that they do not excrete U-BP with every attack--and so do porphyria experts.

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