Molecular Testing Used for 1st Time to Confirm AIP Case in Thailand

Estimates point to 350 undiagnosed porphyria patients in country

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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For the first time in Thailand, home to an estimated 350 undiagnosed acute intermittent porphyria (AIP) patients, molecular testing was used to confirm an AIP attack in a 14-year-old girl, researchers report.

The teen had experienced bouts of abdominal pain and neuropsychiatric symptoms that are a hallmark of acute porphyria.

With the molecular testing, “she finally received a definitive diagnosis … after having numerous investigations for her condition,” the team wrote in the case report.

According to the researchers, while estimates point to the existence of well over 300 patients with AIP in Thailand, the disease has only been diagnosed in less than five. Thus, “it remains difficult to infer whether the prevalence of AIP in Thai people is lower than that in Europeans or if the diagnosis of AIP has not been made.”

The case report study, “Acute Intermittent Porphyria: Complete Phenotype in a Patient with p.Arg173Trp Variant in Thailand,” was published in the American Journal of Case Reports.

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AIP is characterized by low levels of the enzyme hydroxymethylbilane synthase, due to mutations in the HMBS gene. This enzyme is involved in the production of heme, a molecule that plays a key role in oxygen transport in living cells.

Symptoms of AIP typically include recurrent acute abdominal pain, which is often accompanied by gastrointestinal complications such as nausea, vomiting, and constipation.

Patients also may show increased blood pressure (hypertension) and a fast heart beat (tachycardia). In some cases, patients can develop neurological symptoms like seizures, confusion, insomnia, anxiety, and depression.

These symptoms, however, are common to other diseases, posing a challenge to its diagnosis. In fact, “currently, few patients worldwide have been reported with AIP,” the researchers wrote.

In Thailand, while some studies have reported AIP cases, “none have been confirmed by molecular genetics diagnosis,” they wrote.

Now, a team of medical students and clinicians at the Thammasat University, in Pathumthani, reported the case of girl with AIP whose disease was confirmed by molecular testing.

The girl, born in Thailand and now a teenager, had an uneventful medical history with the exception of a history of febrile seizure when she was a 2 years old. There was no family history of illness.

In the 10 days prior to her hospital admission, she developed severe intermittent abdominal pain, accompanied by repeated episodes of nausea and vomiting that occurred four to six times daily. She went to a local hospital first and received treatment for gastritis and indigestion. However, despite the treatment, her symptoms worsened.

Then, at the general hospital, she was diagnosed with gastritis with moderate dehydration, for which she was medicated. Again, her condition continued to progress, and she developed loose stools twice a day. The girl received treatment with the antibiotic ceftriaxone for what was considered an inflammation of the small intestine (enteritis).

After one day, however, she had two brief generalized tonic-clonic seizures — those caused by abnormal electrical activity in the entire brain — which caused her to momentarily lose consciousness. For the next three days, her blood pressure was abnormally high.

At this point, the girl was referred to the university hospital. During the 10 days of treatment, she had lost a total of 5 kg (about 11 pounds). At her  physical examination, the child was feverish, and showed high blood pressure and an increased heart and breathing rate.

A neurological examination was normal, as were assessments of other key organs, including the heart, and lungs.

She was initially screened for a wide range of diseases, with extensive lab work. A brain MRI revealed changes consistent with posterior reversible encephalopathy syndrome (PRES),  a condition that can occur along with AIP. PRES is a neurotoxic state that usually occurs due to acute high blood pressure and swelling in certain parts of the brain.

She received treatment for PRES, along with medications for enteritis and indigestion. Her blood pressure dropped to normal levels for her age. However, abdominal pain persisted and was now accompanied by constipation. She was given polyethylene glycol (sold as GaviLAX, among other brand names), which is commonly used to treat constipation.

Within five days after her admission, her blood pressure normalized and she had no fever or signs of infection.

However, she began feeling confusion, which was accompanied by muscle weakness. Further lab work revealed signs of syndrome of inappropriate antidiuretic hormone secretion (SIADH), a condition that arises when the body produces excessive amounts of antidiuretic hormones — those that help the kidneys regulate the amount of water lost in the urine.

At this point, her continued unexplained abdominal pain, along with SIADH and PRES, led physicians to suspect AIP.

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Doctors ordered a urine screening test, which came back positive for high levels of porphobilinogen and aminolevulinic acid, two heme precursors whose levels tend to be higher than normal in porphyria patients.

She was prescribed a combination of glucose and dextrose, two types of sugar, directly into the bloodstream. Sugar, in the form of dextrin, also was added to her drinking water and she was instructed to follow a high-carbohydrate diet. Additionally, she was medicated for her abdominal pain, nausea, and vomiting.

After beginning AIP treatment, her blood pressure and heart rate normalized. She had no more abdominal pain, but muscle weakness persisted. She became depressed in mood by day 12.

She was discharged after 14 days. Her muscle weakness and depression lasted for another three weeks, but she was back to normal by week eight after her AIP attack.

According to physicians, the “trigger may have been the fasting 12 h per day that she had done 1 week prior to the onset of her symptoms.”

She underwent molecular testing that revealed the presence of a known disease-causing mutation in the HMBS gene. Researchers extended the analysis to her family, and found the same mutation was present in her father, paternal grandmother, and sister, However, none of them showed signs of the disease.

She later experienced one to two acute attacks per year, but was given prompt treatment. However, her kidney function has declined and she has been diagnosed with chronic kidney disease.

“Because AIP is considered a rare disease due to its low incidence and varying symptoms and manifestations that make diagnosis challenging, this case report is aimed to improve the awareness of medical practitioners,” the authors wrote.

“Earlier diagnosis of AIP leads to prompt and specific treatment that can shorten the duration of attacks, prevent complications, lower the cost of treatment, and reduce the mortality rate,” they wrote.