Acute Intermittent Porphyria

Case Report

The patient was an 8-year-old white boy with a history of global developmental delay and intractable seizures. He presented with a 1-month history of increasing lethargy, behavioral regression, persistent seizures, poor oral intake, and dark-colored urine. He was on four different antiepileptic medications, including carbamazepine, topiramate, valproic acid, and lorazepam. 4 months before the current admission, his seizures increased and he was started on clobazam, which resulted in some improvement. A month before admission, he was treated with amoxicillin for an otitis media. His parents reported that he appeared to have generalized myalgia, manifested by his curling up frequently in the fetal position.

The patient was born at full term via spontaneous vaginal delivery with a birth weight of 3.2 kg and no obvious perinatal complications. He had neonatal seizures and was initially diagnosed with infantile spasms. He was treated with adrenocorticotropic hormone, and subsequently phenytoin and carbamazepine. However, his seizures remained refractory to medical treatment, and he continued to have frequent episodes of status epilepticus for which he was admitted multiple times. His diagnostic workup included a brain magnetic resonance image, which showed right hemimegalencephaly (Figure 1). At 4 months of age, he underwent right hemispherotomy, which initially resulted in complete resolution of his clinical seizures, with subclinical seizures still noted on electroencephalography (EEG). Optimal control was eventually obtained with valproic acid, carbamazepine, and topiramate. The patient exhibited global developmental delays.

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Figure 1.

Brain magnetic resonance image of patient at 3 years of age showing right hemimegalencephaly status post right hemispherotomy (186 × 239 mm; 300 × 300 DPI).

A year prior to the current admission, the patient presented with decreased oral intake, and because of a positive rapid strep test, he was started on amoxicillin. He subsequently developed dark-colored urine and was found to be hypertensive. His serum complement 3 level was 75.2 mg/dL (normal range: 83-185 mg/dL). A diagnosis of acute poststreptococcal glomerulonephritis was highly suspected. His hypertension was treated with amlodipine until his blood pressure normalized after approximately 7 weeks.

There was no family history of hypertension, recurrent abdominal pains, seizure disorder, psychiatric illnesses, or renal conditions. His dietary and drug history were negative for food products or medications that are known to cause a reddish discoloration of urine.

Examination revealed a small boy with height and weight less than the third percentile, lying in a fetal position, and in apparent distress. He was microcephalic with no dysmorphic features. He was tachycardic with regular heart sounds and no murmurs appreciated. His neurologic examination was significant for depressed mental status with excessive sleepiness and lethargy. Muscle bulk and tone were decreased throughout, with multiple contractures in his extremities. His reflexes were increased.

His initial diagnostic workup showed normal serum complement levels, normal serum electrolytes, and mild anemia. Repeat urine analyses were obtained and were consistently positive for blood with no red blood cells or casts. Serum creatinine kinase and urine myoglobin were normal. A head computed tomographic scan showed no acute process or interval changes while an EEG showed voltage differences between the left and right hemisphere consistent with his hemispherotomy, multifocal interictal epileptiform abnormalities, and occasional brief subclinical seizures. A lumbar puncture revealed a slight increase in protein level with no evidence of cytoalbuminemic dissociation.

The dark-colored urine and the patient’s symptoms raised the possibility of acute intermittent porphyria. A random urine sample revealed elevated porphobilinogen at 263.2 μM (normal <1.3). A 24-hour urine revealed elevated aminolevulinic acid at 135 μmol/24 h (normal 0-57), uroporphyrin 881 μg/24 h (normal 3-25), heptacarboxylporphyrin 43 μg/24 h (normal 0-7), hexacarboxylporphyrin 26 μg/24 h (normal 0-6), pentacarboxyporphyrin 156 μg/24 h (normal 0-7), coproporphyrin 982 μg/24 h (normal 25-150), and porphobilinogen 176.9 mg/24 h (normal 0.0-0.5). Fecal porphyrins showed marked elevation of uroporphyrin I/III, heptacarboxyl III, hexacarboxyl III, isohexacarboxyl, pentacarboxyl I/III, isopentacarboxyl, and coproporphyrin I/III. The porphobilinogen deaminase activity in erythrocytes was 22.7 nmol/L/sec (normal ≥7).

After the diagnosis was established, the antiepileptic medications were tapered with withdrawal of valproic acid and clobazam. He was also weaned off carbamazepine and topiramate and started on levetiracetam. An increase in clinical seizure frequency was noted at this time, and evaluation revealed severe hyponatremia with a serum sodium of 115 mmol/L. Serum and urine osmolalities were consistent with syndrome of inappropriate antidiuretic hormone secretion. The patient was transferred to the intensive care unit where he received hypertonic saline and was fluid restricted. In addition, he was started on intravenous hemin, which was administered for 5 days with dramatic improvement in his mental status and the frequency of his clinical seizures. This improvement persisted 3 months later when he came for an outpatient follow-up visit. The patient’s oral intake improved and he gained 5 kg within 3 months.

Sequencing of the HMBS gene, which encodes porphobilinogen deaminase, was positive for a missense mutation, R321H, confirming the diagnosis of acute intermittent porphyria. A targeted mutation testing was offered to the parents but was declined.

Discussion

Attacks of acute intermittent porphyria usually occur in the third and fourth decades of life and are more common in females. ⁴ The recognition of early clinical findings is important to establish prompt treatment but can be challenging because of the highly variable clinical presentation and the nonspecific symptoms.

The most common presenting finding among patients with acute intermittent porphyria is severe abdominal pain. Other gastrointestinal symptoms include nausea, vomiting, diarrhea, or constipation. Neurologic symptoms may also develop, including flaccid paralysis, seizures, and neuropsychiatric symptoms. Status epilepticus has been reported as a presenting feature of acute intermittent porphyria. ^5,6 Peripheral neuropathy is the most common neurologic feature of an acute attack and can present as generalized paresthesia and muscle weakness. The most devastating complication of muscle weakness is respiratory failure secondary to diaphragmatic paresis. With progressive muscle weakness, the severity of the abdominal pain may decrease confounding diagnosis. ^{7 –9} A remarkable feature of peripheral neuropathy is preservation of the ankle jerk reported in 50% of patients in a case series in contrast to global areflexia. ⁷ With prolonged attacks, cranial nerve involvement may be seen, which can lead to cardiopulmonary compromise. ¹⁰ Autonomic manifestations include tachycardia, hypertension, tremors, and diaphoresis. Urinary symptoms such as retention or incontinence and constipation are also neuropathic manifestations of acute intermittent porphyria. Mental status changes and seizures could also be presenting features, ¹¹ and cases of reversible posterior leukoencephalopathy have been reported. ¹² Our patient presented with nonspecific symptoms of increasing lethargy and behavioral regression. He already had baseline seizures associated with his underlying neurologic abnormality, which further confounded the diagnosis. Moreover, his inability to communicate, presented challenges in obtaining an accurate history, especially since symptoms could only be gleaned from his mother’s perception of his baseline behavior.

Dark- or red-colored urine as seen in our patient can be an early presenting symptom in acute intermittent porphyria. The differential diagnosis for dark- or red-colored urine is broad and includes mainly renal and urologic conditions. In our patient, the presence of hypertension with dark-colored urine was a confounding factor and, along with low complement 3 levels, suggested the diagnosis of acute poststreptococcal glomerulonephritis. The initial low complement 3 level may have been spurious, since it was found to be normal during the second attack. In retrospect, the hypertension in our patient was most probably a manifestation of autonomic neuropathy.

Hyponatremia, as seen in this case, can occur with an acute exacerbation of acute intermittent porphyria in approximately 20% of symptomatic patients. ¹³ In most cases, it is due to inappropriate anti-diuretic hormone secretion from hypothalamic involvement. It can also result from increased gastrointestinal or renal sodium losses. Other electrolyte imbalances like hypomagnesemia and hypercalcemia have also been reported with porphyria.

Acute intermittent porphyria can be precipitated by conditions that increase hepatic heme synthesis such as medications, stress, starvation, severe illness, infection, and surgery. Porphyrinogenic medications and alcohol trigger acute attacks through the induction of the rate-limiting hepatic enzyme aminolevulinic acid synthase. The list of these medications is long and includes danazol, estrogens, progesterone, griseofulvin, rifampin, sulfonamides, pyrazinamide, metoclopramide, and antiepileptics such as barbiturates, valproic acid, phenytoin, and benzodiazepines. The half-normal hepatic porphobilinogen deaminase activity in this patient was sufficient to “handle” the baseline flux through the heme biosynthetic pathway. However, the capacity of this system became compromised when the induction of the hepatic aminolevulinic acid synthase activity exceeded a certain limit. The precipitant of acute intermittent porphyria in our patient does not appear to be his antiepileptic regimen solely. In fact, his treatment had mostly remained unchanged for several years, with the exception of starting clobazam 4 months before his second presentation. One possibility is that the intake of multiple porphyrinogenic drugs along with decreased oral intake ¹⁴ acted synergistically to compromise the capacity of the already-reduced porphobilinogen deaminase activity. The use of amoxicillin appeared to have preceded both episodes; however, amoxicillin has not been reported to be porphyrinogenic.

A high index of suspicion is required to obtain the relevant diagnostic investigations for porphyria as its variable clinical presentation might be confusing. Diagnosis is made by finding increased urinary porphobilinogen and aminolevulinic acid excretion, as in our case. Urinary porphobilinogen testing is very sensitive. ^15,16 Measuring levels of metabolites of the heme pathway are important to determine the type of porphyria. Fecal excretion of porphyrins is also increased.

The mainstay of therapy in porphyria is identification and discontinuation, when possible, of the precipitating factors. Supportive measures include providing adequate hydration and administration of hemin during an acute exacerbation. ¹⁵ Hemin reduces the synthesis of aminolevulinic acid by decreasing aminolevulinic acid synthase activity and subsequently results in dramatic clinical resolution. ³ Since syndrome of inappropriate antidiuretic hormone secretion can occur as a complication of acute intermittent porphyria, careful monitoring of electrolytes is important with institution of fluid restriction and administration of hypertonic fluids in severe cases

Management of seizures in patients with acute intermittent porphyria remains a challenge for clinicians since many antiepileptic drugs are porphyrinogenic. Phenytoin, carbamazepine, phenobarbital, sodium valproate, lamotrigine, topiramate, and tiagabine have all been shown to worsen porphyria. ¹⁷ Clonazepam has been successful at low doses in multiple case reports, but it has also been shown to exacerbate porphyria at higher doses. ^11,18 Oxcarbazepine has been shown to be effective in a case report of resistant complex partial seizures, but should be used with caution given its potential for hyponatremia. ^17,19 Recently, case reports have demonstrated the efficacy and safety of the newer antiepileptic drugs gabapentin and levetiracetam. ^5,20,21 These drugs have no hepatic metabolism and have not been shown to exacerbate porphyria. Information on antiepileptic use in the setting of porphyria has been limited and has come largely in the form of in vitro studies, animal models, and multiple case reports, as randomized controlled trials comparing safety and efficacy are neither ethical nor feasible.

Molecular testing is available to detect the responsible porphobilinogen deaminase mutation. DNA analysis can detect more than 97% of known disease-causing mutations. This is recommended after the diagnosis of acute intermittent porphyria has been established to aid in genetic counseling so that asymptomatic family members who are carriers can be identified. It allows for early diagnosis and appropriate management in order to avoid or minimize disease complications. Our patient had the R321H missense mutation, which has been previously reported in 2 additional patients. ^22,23

In conclusion, acute intermittent porphyria is extremely rare among prepubertal children. We report this case to emphasize the variable clinical presentations of acute intermittent porphyria including concomitant underlying neurologic disorders and renal-associated symptoms that can confound the diagnosis. The diagnosis should therefore be entertained in patients with underlying neurologic defects who present with nonspecific neurovisceral symptoms or with unexplained neurologic deterioration. Diagnosis and institution of management in a timely manner is essential to prevent later-onset and irreversible neurologic sequelae.