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CASE REPORT
Year : 2021 | Volume
: 13
| Issue : 3 | Page : 148-152
Delayed presentation of late-onset glutamic aciduria type II: A disease of infancy presenting in an adult
Abdul Karim Arida1, Wala Kamel Hamed1, Omar Khaddam1, Hussain Alawadhi2, Jozef Hertecant3
1 Department of Internal Medicine, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
2 Department of Medicine, Sheikh Khalifa Medical City, Ajman, United Arab Emirates
3 Department of Pathology, Tawam Hospital, Al-Ain, United Arab Emirates
Correspondence Address:
Dr. Omar Khaddam
Department of Internal Medicine, Sheikh Shakhbout Medical City, Abu Dhabi
United Arab Emirates
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/ijmbs.ijmbs_125_20
Glutamic aciduria Type II is an uncommon inborn error of metabolism. It has a rare late-onset variant that can present in adulthood with recurrent lethargy, vomiting, metabolic acidosis, and myopathy. This is a case of a 27-year-old previously healthy gentleman who presented with complains of daily vomiting and generalized body aches that started 3 days after initiation of strenuous exercise and poor oral intake. Initially found to have high anion gap metabolic acidosis, elevated creatinine kinase levels and hypoglycaemia that improved with intravenous fluids. He later deteriorated and he was transferred to the intensive care unit for intubation and monitoring of his mental status. Labs were evident of hyperammonaemia not responding to lactulose. Further management with continuous venovenous hemodialysis (CVVHD) for ammonia clearance was required. This presentation raised the suspicion for metabolic disease and work up done was suggestive of Type II glutaric aciduria. After a long stay of 28 days in the hospital the patient recovered his mental status and was discharged home on carnitine and riboflavin. The diagnosis was confirmed with further genetic testing. He was later found to have concurrent celiac disease that was confirmed by duodenal biopsy.
Keywords: Glutamic aciduria Type II, inborn errors of metabolism, late-onset variant, metabolic acidosis
Though infrequent, inborn errors of metabolism are complex disorders increasingly being identified and diagnosed, mainly due to advances in the medical field in the current era. They are primarily disorders caused by gene mutations leading to defects in enzymes and proteins involved in cell metabolism. Until the previous decade, they have been considered pediatric diseases. However, it has been proven that they could present at any age.[1] This could be secondary to multiple factors, including recognizing milder forms of the disease diagnosed in adulthood, improved diagnosis of late-onset disorders, and improved survival rate of children with inborn errors of metabolism due to advances in therapeutic options.[2]
Inborn errors of metabolism can be essentially classified into one of five groups; (a) disorders of energy metabolism, (b) intoxication syndromes, (c) lipid storage disorders, (d) metal storage disease, and (e) neurotransmitter metabolism defects. Each of these groups consists of multiple conditions with various presentations; therefore, it is crucial to identify and recognize their clinical features to run a thorough diagnostic approach.[1]
The most common presentation of these disorders, especially in adulthood, is with neuropsychiatric symptoms. Even though diagnosing these conditions can pose a challenge, they can be effectively treated when identified timely.[1] It is imperative to identify and diagnose these disorders as they require specialized care, mainly since the adult inborn errors of the metabolism population is expanding without significant proportionate experience in managing these conditions in adults.[2]
This report presents a young 23-year-old gentleman presenting with nonspecific signs and symptoms over several years who was eventually diagnosed with glutamic aciduria Type II.
Case ReportCase presentation
A 27-year-old, previously healthy gentleman presented with a new-onset history of generalized body aches associated with nausea and persistent vomiting of more than ten times a day despite anti-emetics usage. His symptoms were precipitated with a strenuous exercise, which he started 3 days before the onset of his symptoms. Initially, he had no change in mental status, fever, or respiratory symptoms. This was the first time he experiences these symptoms. He denied alcohol intake, illicit drug use, and ingesting of any medications. Family history was significant for consanguinity; however, his seven other siblings are healthy. He had two sisters born with brain atrophy. There was no family history of any metabolic disorders. On examination, his vital signs were within the normal limit, and had a Glasgow coma scale (GSC) of 15/15. The rest of the examination was not significant. Initial investigations showed high anion gap metabolic acidosis and hypoglycemia, which normalized after receiving intravenous (IV) fluids. His urine toxicology screen was negative [Table 1] and [Table 2].
A couple of days later, his mental status deteriorated during his admission, and he became agitated. He was refusing to eat or communicate with anyone, including his family members. Ultrasound of the abdomen showed normal-sized organs with fatty liver infiltration. Both computed tomography (CT) and magnetic resonance imaging of his brain were normal. Lumbar puncture was later done to rule out any possible infection element because of the sudden change in mental status and was also normal. An electroencephalogram did not show any seizure activity.
Initial management and response
On evaluation the next day, he was awake but not alert nor oriented. He had a blank stare without reaction to any visual stimuli. The pupils were equally dilated bilaterally with a sluggish reaction. Muscle tone and reflexes were normal. GCS was 9/15; he was promptly transferred to the intensive care unit for further neurological monitoring. Repeat laboratory investigations showed high anion gap metabolic acidosis alongside hypophosphatemia, hypoglycemia, and ketonemia. He also had a mild increase in his Aspartate transaminase (AST) and Alanine Aminotransferase (ALT). Because of the sudden drop in mental status, the ammonia level was requested and was surprisingly high at 257 micromol/L (normal: 11–32 micromol/L). The combination of metabolic acidosis and elevated ammonia raised the suspicion of metabolic disorders of the liver. Creatinine kinase was also elevated at 954 IU/L (normal 22–198 IU/L). He was stared on lactulose, and repeat ammonia levels were trending down very slowly even with rigorous hydration. He remained encephalopathic with tachypnea and tachycardia. He had a poor gag reflex and was at high risk of aspiration; therefore, he was intubated to protect his airway. Because of inadequate response to treatment, the decision to start on continuous venovenous haemodialysis (CVVHD) was taken, and his ammonia levels started trending down significantly.
Further specialized investigations
After a discussion with the geneticist in a neighboring institution, there were multiple possibilities: organic acidurias, urea cycle defects, or fatty acid oxidation disorders. The metabolic workup included urine organic acid, plasma amino acids, carnitine, acylcarnitine levels, and Guthrie test. The amino acid profile proved deficiency in some amino acids, which can be due to acute catabolism or low protein intake; however, urine amino acid was normal. Levels of urinary amino acids were within normal. Urine organic acid reported a high peak of glutaric acid and dicarboxylic acids and small peaks of 2-ketobutyric acid, acetoacetic acid, and 4-hydroxybutyric acid isobutyrylglycine, isovalerylglycine, ethylmalonic acid, and hexanoylglycine detected. This was highly suggestive of Type 2 glutaric aciduria.
The patient was started on Na benzoate, Na phenylbutyrate, carnitine, riboflavin, and IV dextrose 10% at a high rate. Close monitoring of mental status and repeat CT brain to ensure no worsening brain edema was performed. Initially, he was kept nil per oris (NPO) but slowly started a diet consisting of main carbohydrates with minimal fat and protein.
Cardiac echocardiography showed a globally hypokinetic left ventricle with a left ventricle ejection fraction of 35%. After an extended stay of 28 days in the hospital, the patient recovered well, and his mental status was recovered completely. On discharge, he was asymptomatic and advised to follow up regularly in the clinic. He was discharged on carnitine and riboflavin.
Outcome
He traveled to the United States for further management. He was seen by a metabolic specialist where genetic testing confirmed multiple acyl-CoA dehydrogenase deficiency or glutaric aciduria Type II, caused by a homozygous pathogenic variant in ETFDH gene c. 807A >C (p. Gln269His). He was also seen by a gastroenterologist and was found to have elevated anti-tissue transglutaminase IgA, which raised the possibility of celiac disease. Further evaluation endoscopy and colonoscopy, along with a liver biopsy. The duodenal biopsy was highly suggestive of celiac disease; however, the liver biopsy was unremarkable. Regular follow-up in the metabolic/genetic and gastroenterology clinic was uneventful, and the patient is now compliant with a gluten-free diet and on carnitine and riboflavin. Yearly cardiac echocardiography was also recommended.
DiscussionGlutaric aciduria Type II, known as multiple acyl CoA dehydrogenase deficiency, is a relatively recently described autosomal recessive disorder of fatty acid and amino acid metabolism.[3] Mutations in the a-or b-subunits of the electron transfer flavoprotein or electron transfer protein dehydrogenase lead to defective or deficient enzymes, leading to impaired electron transfer from flavoprotein dehydrogenases to the respiratory chain. This, in turn, leads to the accumulation of abnormal amino acid and fatty acid metabolites in addition to high amounts of glutaric acid.[4],[5] Glutamic aciduria Type II is characterized pathologically by fatty acid degeneration of liver parenchymal cells, renal tubular epithelium, and myocardial tissue.[4]
Glutaric aciduria Type II primarily has three clinical phenotypes. A fatal neonatal-onset form is characterized by severe nonketotic hypoglycemia, metabolic acidosis, and congenital anomalies. Also, a neonatal-onset form without congenital anomalies exists, and a third late-onset form is scarce.
The age and presentation of the late-onset form are very highly variable and range from subtle lethargy to very debilitating episodes of frequent vomiting.[5],[6],[7],[8] However, the predominating symptoms in the late-onset form are hypoglycemia and metabolic acidosis, as was our patient.[9] Other presenting features in the late-onset form include muscle weakness and myalgia, liver dysfunction, and proximal muscle weakness with respiratory involvement that may eventually cause hypoventilation and respiratory failure.[10] The phenotypic variability of glutamic aciduria Type II may be explained by the enzymatic defect.[8]
It is crucial to have a high index of suspicion and a structured diagnostic approach, because disorders of riboflavin transport, including Brown Vialetto-Van Laere syndrome and Fazio-Londe disease, can present with similar clinical and biochemical features to glutamic aciduria Type II.[11]
The diagnostic approach to most inborn metabolism errors usually starts with a search for abnormal metabolites in blood or urine, especially acylcarnitines, and diagnosis is then confirmed using enzyme assays or mutation analysis. Acylcarinitine analysis is usually done using mass spectrometry and gas chromatography, which show corresponding abnormalities of oxidation of fatty acids, lysine, and branched-chain amino acids. It is important to note that urine organic acid analysis may be normal during asymptomatic periods. During acute episodes of the disease or catabolic stress, analysis can demonstrate dicarboxylic acid compounds, including suberic acid, sebacic acid, and adipic acid.[12],[13]
The findings of routine laboratory tests are highly variable in these patients. They include high anion gap metabolic acidosis, hypoglycemia, elevations in serum transaminases, hyperbilirubinemia, prolonged coagulation times, and elevations in lactate dehydrogenase and lactic acid.[14] Ammonia levels are often elevated during metabolic crises. Besides, most reported cases had evidence of cardiomegaly and poor ventricular function on chest X-ray and echocardiography. Other commonly reported features include lung consolidations, pneumothorax, and lobulation in the liver and kidneys.[15]
The primary treatment modality for glutamic aciduria Type II is, in addition to the consumption of a diet low in fat and protein, supplementation with carnitine, riboflavin, and coenzyme Q10. Out of those, reports have shown that the most effective treatment leading to improvement in clinical and biochemical aspects is riboflavin.[16],[17] Of note, it has been demonstrated that IV carnitine is 150% more effective than its oral variant and that its use during metabolic crises facilitated urinary excretion of acylcarnitines 21 times more than when used between crisis.[18] Therapy has been proven to be much more successful in patients with the late-onset disease than those who present as neonates.[19]
In summary, glutamic aciduria Type II is a rare but potentially fatal disorder that usually presents in neonates with or without congenital abnormalities. It has an uncommon late-onset type, which presents with intermittent lethargy, vomiting, acidosis, and myopathy. Once suspected, this disease can be easily diagnosed, and treatment with dietary modification and supplementation of carnitine and riboflavin is usually adequate, especially for the late-onset type. Our patient was suffering from frequent lethargy episodes and vomiting for years before diagnosis; however, glutamic aciduria was not suspected until he presented with severe metabolic acidosis with no apparent cause.
Declaration of patient consent
The authors certify that they have obtained the appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published, and due efforts will be made to conceal the identity, but anonymity cannot be guaranteed.
Authors' contributions
All authors have contributed equally to the manuscript.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Compliance with ethical principles
No prior ethical approval is required for single case reports. However, the patient provided consent for publication, as stated above.
References
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