Recurrent Metabolic Encephalopathy in an Adult With Angelman Syndrome, Lennox-Gastaut Syndrome, and VLCAD Deficiency: When Remedy For One Malady is the Catalyst For Another

Document Type

Conference Proceeding

Publication Date

10-2024

Publication Title

Chest

Abstract

INTRODUCTION: Angelman syndrome stems from a genetic anomaly affecting the UBE3A gene on maternal chromosome 15. It manifests with global developmental delay, speech impairments, ataxia, hypotonia, skeletal abnormalities, temperature sensitivity and seizures. Constipation, and cyclic vomiting are also common due to hypotonia. Seizures pose a significant challenge in management, occurring in both epileptic and non-epileptic forms, the latter often presenting as altered mental status.(1) Lennox-Gastaut syndrome comprises cognitive impairment, intractable seizures, and a slow spike-and-wave pattern on EEG. (2) Chromosome 15 duplication has been linked to late-onset Lennox-Gastaut syndrome with hypotonia(3), hinting at a potential overlap with Angelman syndrome. Very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency is a metabolic anomaly leading to the decreased breakdown of long-chain fatty acids into acetyl CoA. Due to the body's inability to produce ketones during hypoglycemia, metabolism shifts toward protein breakdown, resulting in hyperammonemia. Diagnosis is based on specific patterns of acylcarnitine elevation.(4) CASE PRESENTATION: The 38-year-old male, with Angelman syndrome related seizures treated with valproate, levetiracetam, levocarnitine, presented due to increased seizure frequency and myoclonic jerks. EEG showed spike and wave pattern, consistent with Lennox-Gastaut syndrome. Clobazam and lacosamide reduced seizures initially, but lethargy developed post-discharge. ED admission followed in 4 weeks with altered mental status, hypothermia, hypoxemia, and hypotension. Initial workup showed hypercarbia, metabolic alkalosis, and mild hyperammonemia. Mental status improved post-clobazam reduction, IV fluids, and oxygen. Four weeks later, he was readmitted for altered mental status; EEG showed absence and atonic seizures. IV antiepileptics improved status, but complications arose: fever, leukocytosis, acute hypoxemic respiratory failure. Chest xray showed left lower lobe consolidation. MICU transfer, intubation, tube feeds, and IV antibiotics followed. Workup revealed severe hyperammonemia, elevated creatine kinase, negative urine ketones. Further workup revealed elevated acylcarnitine (C.14:1) levels consistent with VLCAD deficiency. Bronchoscopy removed mucous plug with subsequent improvement. Levocarnitine was increased due to concerns for valproate toxicity however both serum valproate and carnitine were within normal limits. Subsequent decline in serum ammonia and creatine kinase, alongside increased glucose, correlated with mental status improvement. Five months later, he was readmitted for increased lethargy and valproate-induced hyperammonemia was detected. His condition improved over 48 hours after increasing levocarnitine dose. A year later, altered mental status recurred; severe hyperammonemia persisted despite increased levocarnitine dose. Serum carnitine was elevated. IV dextrose infusion reduced serum ammonia from 150 to 44 within 48 hours, restoring mental status. DISCUSSION: Our patient initially presented with intractable seizures but experienced multiple subsequent hospitalizations due to metabolic encephalopathy and respiratory failure. The first exacerbation was attributed to clobazam, with a component of hyperammonemia. The second hospitalization revealed hyperammonemia despite normal valproate levels; further workup revealed VLCAD deficiency. Decreased oral intake exacerbated encephalopathy in the setting of low blood sugars due to increased ammonia production. The third episode resulted from valproate-induced hyperammonemia managed with increased levocarnitine. The fourth exacerbation again stemmed from hyperammonemia worsened by decreased oral intake. Hyperammonemia improved promptly with glucose infusion. CONCLUSIONS: Establishing the cause of metabolic encephalopathy in patients with complex syndromic pathology is essential to improve prognosis alongside empiric management.

Volume

166

Issue

4 Suppl

First Page

A2800

Comments

Chest 2024 Annual Meeting, October 6-9, 2024, Boston, MA

Last Page

A2801

DOI

10.1016/j.chest.2024.06.1696

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