Isovaleric acidemia (IVA), also known as the sweaty foot syndrome, is an autosomal recessive organic acid disorder due to a defect in the mitochondrial Flavin Adenine Dinucleotide (FAD)-dependent enzyme isovaleryl CoA dehydrogenase. Acute pancreatitis as a complication has been reported. We are presenting a rare case of recurrent acute pancreatitis complicating a 9-year-old girl with IVA. She presented with repeated attacks of vomiting, severe abdominal pain, and fever since the age of 18 months. These were diagnosed as attacks of pancreatitis with high serum amylase presenting clinically as diabetic ketoacidosis. Later, she developed chronic pancreatitis which is proved by lapratomy. In the last attack, she was comatosed with fulminant sepsis and sooner the patient died. Blood sample taken during this last attack confirmed the diagnosis of IVA. An inborn error of organic acid metabolism should be considered in children with pancreatitis of unknown origin.
Keywords: Child, diabetic ketoacidosis, isovaleric acidemia, pancreatitis
Isovaleric acidemia (IVA), also known as the sweaty foot syndrome, is an autosomal recessive organic acid disorder due to a defect in the mitochondrial FAD-dependent enzyme isovaleryl CoA dehydrogenase. It was the first condition to be recognized as an organic acidemia. Its incidence is approximately 1 in 230,000. It occurs in all racial and socioeconomic groups. It can present in the neonatal period with poor feeding, vomiting, convulsions, and decreased level of consciousness. The chronic intermittent form is the second type of presentation, so children get failure to thrive, developmental delay, or mental retardation. They get episodes of acute acidosis and metabolic decompensation due to intercurrent illnesses or other physiological stress. The diagnosis requires a high clinical suspicion. Effective therapy is available.
Treatment of acute attacks is aimed at hydration, reversal of catabolic state, correction of metabolic acidosis, and removal of the excess isovaleric acid. A leucine-free medical food is given. Avoidance of infection and long-term maintenance therapy with glycine and carnitine is established.
Acute pancreatitis as a complication has been reported. Acute pancreatitis is a life-threatening inflammatory condition with many known inciting factors, including inborn errors of metabolism, where IVA is one of them.,
An 8-year-old Saudi girl admitted to our pediatric ward in King Fahad Hospital-Albaha, because of fever, coffee ground vomiting, severe abdominal pain, and visual hallucination. She had four similar presentations, now and then, since the age of 18 months with the first hospital admission at the age of 3 years. She was investigated many times without a definite diagnosis. Her birth was normal with uneventful neonatal period. Her parents were first-degree cousins. There was a history of three neonatal deaths in this family with unknown cause. The family had eight living children, one of them suffering from migraine.
On examination, she was wasted, febrile, and acidotic. She was drowsy then became comatosed. She was not pale or jaundiced. There are no dysmorphic features and no skin changes. She had tachypnea with deep acidotic breathing; the abdomen was tender, mainly in the epigastrium, and distended with diminished bowel sounds. There is no oraganomegaly. Serum amylase was 912 U/L and sugar was 18.5 mmol/L. There was glucosuria. Ultrasound abdomen was performed which showed evidence of pancreatitis and pancreatic pseudocyst. Management for diabetic ketoacidosis (DKA) in the intensive care including ventilation was initiated. Intravenous ceftriaxone and hydrocortisone were given. Later on, while she was improving, it was decided to do laparotomy. The surgical report was as follows: Multiple calcification over the greater and lesser omentum. There is edematous pancreas with multiple calcifications on its surface.
She had improved and was discharged from the hospital to have regular administration of insulin therapy plus dietary management. One year later, she presented with acute pyelonephritis that was treated with antibiotics. Eight months later, at the age of 9 years, the child was admitted again with severe abdominal pain, coffee ground vomiting, fever, and drowsiness. She was febrile and acidosis. She was comatosed. Glasgow coma scale was three. She had a sweaty offensive odor. Serum amylase was 624 U/L, glucose 15.4, and sodium 161 mmol/L. The pH was 7.04 and pCO2 of 53. Electrocardiogram showed high and peaked T waves [Figure 1]. Hence, she was diagnosed as severe DKA, severe sepsis, and severe degree of metabolic acidosis. She was admitted to Pediatric Intensive Care Unit, ventilated and a central line was inserted. Management with intravenous fluids, correction of hyperglycemia and electrolytes disturbances, and administration of sodium bicarbonate and antibiotics had been started for the patient. She was followed with close monitoring.
She was deteriorating and in spite of resuscitative measures including cardiopulmonary resuscitation, she died 11 h later. On this last admission, as part of workup, a blood sample was taken for metabolic screening. This was analyzed by tandem mass spectrometry (MS/MS). The result revealed and confirmed the diagnosis of IVA.
IVA is an autosomal recessive condition which presents either in an acute form in the neonatal period or as a chronic intermittent form later with variable manifestations. It can be diagnosed presymptomatically with newborn screening by MS/MS.
It is clear from our case report that our patient was born with IVA which was undiagnosed. It was of late presentation type because her first symptoms were at the age of 18 months. There was a history of three neonatal deaths and first-degree consanguinity in the family support and in favor of this diagnosis. Unfortunately, suspicion and confirmation of diagnosis was established only at the time of death. The cause of death in our patient was due to severe and fulminant sepsis and severe DKA.
Gas chromatography-MS remains the assay of choice for the evaluation of known organic acidemias, as well as the discovery of new ones. In 2007, Lin et al. in Taiwan investigated six patients with IVA from five families and then followed them up. All of their urines contained raised amounts of 3-hydroxy isovaleric acid and isovaleryl glycine. These are urine metabolites that can help in diagnosis.
Our patient was presenting as the chronic intermittent form of IVA with metabolic decompensation, sepsis, recurrent acute abdomen, and DKA. During the course of the disease and finally immediately before death, she suffered from attacks of acute pancreatitis. It is known that acute pancreatitis is a rare but a serious complication in children suffering from IVA. It is true that pancreatitis has been described in a number of inborn errors of metabolism including organic acidemias. Still recurrent attacks of pancreatitis as a complication of IVA are rare. Reviewing the history, it is clear that our patient was presenting with repeated attacks of acute pancreatitis including the last one at the time of death. From the lapratomy findings, it is clear that the girl developed chronic pancreatitis that was superimposed with these recurrent acute attacks.
Coskun et al. in 1997 in Ankara presented a 2-year-old girl with coma. Her urine analysis showed glutaric aciduria Type II. Pancreatitis was diagnosed at autopsy. Hence, pancreatitis should be searched for in organic aciduria patients and measurement of plasma amylase, and lipase levels should be added to the battery of laboratory investigations in such cases. Conversely, an inborn error of organic acid metabolism should be considered in children with pancreatitis of unknown origin.
In a study by Sánchez-Ramírez et al. in Mexico in 2007 assessing the etiological factors of acute and recurrent pancreatitis in children, they stated that the most common causes were biliary stones, drug ingestion, and hypercalcemia with an evidence of family history of pancreatitis. Hence, inborn error of metabolism as an etiological factor is considered as a rare cause which can easily be missed like in our case. In the same study, it was found that the most frequent symptom in acute and recurrent pancreatitis was abdominal pain followed by vomiting and ileus. This is comparable to our patient symptomatology who was admitted many times with similar complains.
Marquard et al. from Germany reported about a patient with methyl malonic acidemia who developed chronic pancreatitis after several episodes of acute attacks. They concluded that any form of pancreatitis should be ruled out in the assessment of acutely ill patients with branched-chain organic acidurias.
In 2004, Liang et al. in Taiwan reported a similar case of a 22-year-old female who had suffered from several episodes of acute pancreatitis since the age of 11. At the age of 21, with clinical manifestation and investigations, the diagnosis of glutaric aciduria Type II was confirmed. It was the first reported case of recurrent pancreatitis in this disease. In Turkey-Ankara, Tokatli et al. in 1998 reported six patients with IVA. As in our case, all except one had positive family history of sibling deaths, and all parents were related. Also, like in our patient, four of them presented in a chronic intermittent form. One patient died during the metabolic crisis. They concluded that the presented cases illustrate that IVA can be managed successfully once the diagnosis is made.
Beside recurrent pancreatitis, our patient developed diabetes as another complication. Full blown picture of DKA during the last admission contributed to our patient death. Patil et al. in India reported a 3½-year-old girl with recurrent vomiting that needed hospital admissions. A sibling died with similar complains at the age of 19 days. With investigation, IVA was confirmed, and she improved when started on carnitine and multivitamins.
We state that our patient presented with the chronic intermittent form of IVA. Family history of neonatal deaths and consanguinity were supportive of the final diagnosis. Acute recurrent pancreatitis and DKA were the complications our girl presented with. DKA with septicemia was the cause of death. Screening for inborn errors of metabolism should be a rule if we get neonatal deaths in the family. Pancreatitis should be suspected and looked for in children with organic acidurias, and conversely an inborn error of organic acid metabolism should be considered in children with pancreatitis of unknown origin.
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