2023.03.27 | Questions 41-42
Metabolic masquerading (2/3) - A teenager with recurrent abdominal pain
Hello,
This is the 2nd in a series of 3 posts titled “metabolic masquerading.” There are a number of metabolic disorders that may be misdiagnosed as “cerebral palsy,” “recurrent abdominal pain,” “clumsiness,” etc. Some of these disorders, such as the one described in this case, have treatment options that can improve symptoms, so they are important to recognize and diagnose.
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Have a great week!
-Daniel
Questions
Question 41
A 17-year-old girl presents to the emergency department with severe abdominal pain, vomiting, and constipation. Over the past year, she has experienced several similar episodes of abdominal pain and vomiting that coincide with her period. She recovers completely between episodes. Physical examination reveals diffuse abdominal tenderness without rebound or guarding. Laboratory studies reveal elevated urinary delta-aminolevulinic acid and porphobilinogen levels, normal urine succinylacetone, and normal lipase. What is the most likely diagnosis?
Question 42
Molecular sequencing is sent and shows a heterozygous stop-gain variant c.148C>T (p.Gln50Ter) in hydroxymethylbilane synthase (HMBS), confirming the diagnosis of acute intermittent porphyria (AIP). She should be counseled that AIP is inherited in which of the following manners?
Explanation
The patient's recurrent abdominal pain, vomiting, and constipation, in addition to the presence of elevated urinary delta-aminolevulinic acid and porphobilinogen levels, are highly suggestive of acute intermittent porphyria (AIP) (Question 41). AIP results from a deficiency of the enzyme porphobilinogen deaminase (aka hydroxymethylbilane synthase), leading to accumulation of heme precursors (i.e. porphobilinogen and delta-aminolevulinic acid) that are toxic to the nervous system and cause acute and recurrent attacks of abdominal pain, vomiting, and constipation. The abdominal pain is often described as colicky and is usually accompanied by nausea and vomiting. Acute attacks can be triggered by various factors, including hormonal changes during menstruation, infections, fasting, and alcohol. Patients typically recover completely between episodes. Onset is typically no earlier than the teenage years and may present in adulthood. Patients may also present with psychiatric symptoms such as depression, hallucinations, etc during the episodes. Rarely, patients may exhibit a motor neuropathy that presents with proximal muscle weakness and diaphragm involvement, leading to respiratory compromise.
💡 The features and symptoms of AIP can be remembered with the 5 P’s:
Painful abdomen
Port wine–colored urine
Polyneuropathy
Psychological disturbances
Precipitated by drugs (eg, cytochrome P-450 inducers), alcohol, starvation, menstruation
Inheritance of AIP
AIP is inherited in an autosomal dominant manner (Question 42), which is different from most other metabolic disorders (and therefore a good board question). AIP is caused by haploinsufficiency of porphobilinogen deaminase (PBD), aka hydroxymethylbilane synthase, which is encoded by the HMBS gene. Both heterozygous missense and non-sense variants in HMBS can result in disease.
AIP is characterized by incomplete penetrance and variable expressivity. The penetrance of AIP is estimated to be around 5-10%, which means that only a small percentage of individuals with a pathogenic variant will actually develop clinical symptoms. There is not a well-established genotype-phenotype correlation, and even family members with the same genetic variant may exhibit different degrees of severity of symptoms, triggers, and age of symptom onset.
What is heme?
PBD is the third enzyme in the eight-step heme biosynthesis pathway, which starts with succinyl-CoA and glycine and ends with heme. Heme then combines with multiple globin chains (the same globins involved in sickle cell and the thalassemias) to form the oxygen carrier molecule hemoglobin. Heme itself is made of 2 compounds, iron and protoporphyrin (see structure of heme below).
Porphyrias and their relation to heme biosynthesis
There are a total of eight types of porphyrias (one for each step of the heme synthesis pathway), which are disorders that result from enzymatic defects in the heme synthesis pathway. There are three porphyrias that are most commonly tested on exams. These can be subdivided by prevalence within different age groups (infants, teens, and adults). The most common porphyria in infants is congenital erythropoietic porphyria (CEP), caused by deficiency of uroporphyrinogen III synthase (UROS) (step 4; see diagram below). Patients present with cutaneous photosensitivity with blistering, dark discoloration of the urine, and hemolytic anemia. AIP is the most common porphyria to present in teenagers. Porphyria cutanea tarda (PCT) is the most common porphyria overall and typically presents in adults. Patient with PCT present with skin findings including skin blistering over sun-exposed areas, facial hypertrichosis, and hyperpigmentation. PCT is due to deficiency of uroporphyrinogen III decarboxylase (UROD) (step 5).
A simplified heme biosynthesis pathway is shown below (see Figure 1 at this link for a more detailed pathway). Note that the 3 disorders (AIP, CEP, and PCT) discussed above occur biochemically in sequence, with AIP affecting step 3, CEP affecting step 4, and PCT affecting step 5 in the heme synthesis pathway.
Treatment and management strategies
Management of porphyria is multifaceted and can be divided into acute and chronic management. Acute attacks should be treated with hemin and glucose infusion, which both inhibit DALA synthase and prevent accumulation of toxic intermediates. Chronic management depends on the severity of symptoms. In patients with mild or infrequent attacks, this may simply include avoidance of triggers and symptomatic treatment as needed. In patients with more frequent or severe attacks, this may include ovulation suppression (e.g. IUD) if attacks are triggered by menstruation, prophylactic hemin infusions, and givosiran (ALN-AS1), a small interfering RNA (siRNA) directed against delta-aminolevulinic acid synthase that reduces the frequency of attacks.
Incorrect answers (Question 41)
Alkaptonuria is an autosomal recessive disorder that results in the accumulation of homogentisic acid, which can cause ochronosis, arthritis, and renal stones. Patients with alkaptonuria may also have dark urine that turns black upon standing.
Hereditary pancreatitis is a rare autosomal dominant disorder that results from mutations in the trypsinogen gene. It is characterized by recurrent attacks of acute pancreatitis that can lead to chronic pancreatitis and pancreatic cancer. This patient’s lipase is normal, making pancreatitis less likely.
Tyrosinemia type I is an autosomal recessive disorder that results from a deficiency of the enzyme fumarylacetoacetate hydrolase. It is characterized by liver failure, renal tubular dysfunction, and peripheral neuropathy. Urine succinylacetone is characteristically elevated, and the fact that this patient’s succinylacetone levels are normal make it less likely that she has tyrosinemia type I.
Learning objective
AIP is caused by a deficiency of the enzyme porphobilinogen deaminase and leads to toxic accumulation of heme precursors that cause acute and recurrent attacks of abdominal pain, vomiting, and constipation. Symptoms can be remembered with the 5 P's: Painful abdomen, Port wine–colored urine, Polyneuropathy, Psychological disturbances, and Precipitated by drugs, alcohol, starvation, and menstruation. AIP is inherited in an autosomal dominant manner, and there is incomplete penetrance and variable expressivity. Treatment involves avoiding triggers, hemin and glucose for acute crises, and givosiran for preventing recurrent attacks.
2023 ABMGG General Exam Blueprint | V. Single Gene Inheritance → d. Single Gene Disorders → ix. Metabolic disease (page 3)
For more, please have a listen to this excellent podcast from JIMD that provides a comprehensive overview of the porphyrias that includes diagnosis and management!