Mary Schloetter ~ Dna Diagnosis

Type of Porphyria: 
Acute Intermittent Porphyria (AIP)

I first became sick in 1995 after taking sulfonamide antibiotics for an ear infection. Over the next 18 months, I had 12 porphyria attacks. The majority of these attacks were severe enough to land me in the hospital. While waiting to be admitted from ER into the hospital one night, a doctor walking down the hall picked up my urine cup, and joked to the nurses, “I thought I told you not to drink red wine from the urine cups.” I yelled out into the corridor, “That’s not wine. That’s my urine!” He came into my room, and began asking question while flipping through my chart. “Is you urine always port wine colored when you’re sick?” “They keep testing it for blood, right? And it’s always negative?” Yes, and yes. He then asked the question that changed my entire life - “Has any doctor ever tested you for porphyria?” When I answered, “No,” he gave me a Cliff’s Notes version of the disease, then said he probably would have never thought of it in the past, but he had just watched the movie The Madness of King George three nights prior. When my lab results came back, my local doctor forwarded them to South African porphyria specialist Dr. Neville Pimstone at UC Davis. Three weeks later, I saw Dr Pimstone and he diagnosed me with porphyria. He spent almost four hours with me explaining my disease, and talking about what steps we needed to take going forward, as well as what further labs needed to be done.


In doing those labs, some interesting results were found. “Significant labs are that her ALA and PBG levels in the urine are significantly raised, ten to twenty times normal and dropped significantly also when she was recovering from the acute attack of pain. What is confusing to me is that 25-uroporphyrin is 2416 mcg per day and her urine coproporphyrin is also elevated at a level of 717. Also confusing is the fact that her stool coproporphyrin level of 217 is about ten times higher than stool protoporphyrin level which is 20. This patient has a urine and stool porphyrin profile which is quite atypical for acute proliferative porphyria. Urine coproporphyrin level is elevated and significantly a stool coproporphyrin level is very much elevated in relation to protoporphyrin. There are two possibilities for patients with this is that she may have acute intermittent porphyria and a genetic trait for porphyria cutaneatarde. If she does have dual porphyria, the PCT is not manifest clinically. The other possibility is that she may have another form of genetic hepatic porphyria called hereditary coproporphyria.”


Since I offered such a mysterious case, Dr. Pimstone sent me to see porphyria expert Dr. Montgomery Bissell at UC San Francisco, and in 1999, they contacted Dr Robert Desnick, head of Pediatric Genetics at Mt. Sinai Hospital in New York, whose speciality was genetic porphyria. At this time, genetics was in its infant stages, and I did not have much hope that the mystery of my conflicting labs would be solved.


After DNA testing for the three acute porphyrias as well as PCT, it was found that I only had a mutation on the HMBS gene for AIP. At that time, I wasn’t given any paperwork specifying my genetic mutation; I was told in a face-to-face meeting with a genetic counselor that AIP was confirmed. My father tested negative, but since my mother was out of town, she was not tested at that time. For years we assumed the genetic defect came through my mother’s side of the family, and my mom followed porphyria medication precautions.


Fast forward to 2015 when I enrolled in the Longitudinal Study. This is a fantastic study to be involved in for people having a genetic disease. This study not only tested my parents, but my brother and sister too. If someone has positive biochemical proof of porphyria, which I have 22 years of, Mt. Sinai’s genetics lab will continue searching the porphyria genes on DNA until they find the mutated allele. Once they found my exact mutation, A122D, they then searched my parents’ and siblings’ DNA for that variant. Surprisingly, neither of my parents had that mutation! So, they retested my parents, sequencing my parents' entire gene, rather than looking for my specific familial mutation. Mt. Sinai discovered that neither of my parents had any mutations or SNPs on their HMBS (AIP) gene. This means that I have a spontaneous, de novo mutation. A de novo mutation is an alteration in a gene that is present for the first time in one family member as a result of a mutation in a germ cell (egg or sperm) of one of the parents or in the fertilized egg itself.


Most interesting, is that the mutation they found on my HMBS (AIP) gene - A122D - is a novel mutation. A novel mutation is a newly discovered, distinct genetic alteration. This means it has never before been discovered in any other human. Many worry that they could have a new mutation and that genetics labs like Mt. Sinai or Invitae will not find their mutation. This is not true. Like me, if you have positive biochemical proof (from urine, stool and/or blood tests), geneticists will keep searching until they find your mutation. It took Mt. Sinai about two months, but my brand new mutation was found.