Reversible weakness and encephalopathy while on long-term valproate treatment due to carnitine deficiency

Al-Sharefi, Ahmed; Bilous, Rudy

doi:10.1136/bcr-2015-210727

Cited by 7 publications

(6 citation statements)

References 16 publications

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“…L-carnitine is a well-established treatment for LSM’s, including primary carnitine deficiency [ 11 ]. These patients can show a rapid reversal of clinical symptoms within one month [ 22 – 24 ] and, consistent with our murine data, L-carnitine needs to be maintained to provide ongoing symptomatic relief [ 9 , 25 ]. While it can be challenging to extrapolate clinical timelines from animal data, the effects in our model were seen rapidly–as early as 4 weeks in the mice.…”

Section: Discussionsupporting

confidence: 56%

Evaluating modified diets and dietary supplement therapies for reducing muscle lipid accumulation and improving muscle function in neurofibromatosis type 1 (NF1)

et al. 2020

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Neurofibromatosis type 1 (NF1) is a genetic disorder that affects a range of tissue systems, however the associated muscle weakness and fatigability can have a profound impact on quality of life. Prior studies using the limb-specific Nf1 knockout mouse (Nf1 Prx1-/-) revealed an accumulation of intramyocellular lipid (IMCL) that could be rescued by a diet supplemented with L-carnitine and enriched for medium-chain fatty acids (MCFAs). In this study we used the Nf1 Prx1-/mouse to model a range of dietary interventions designed to reduce IMCL accumulation, and analyze using other modalities including in situ muscle physiology and lipid mass spectrometry. Histological IMCL accumulation was significantly reduced by a range of treatments including L-carnitine and high MCFAs alone. A low-fat diet did not affect IMCL, but did provide improvements to muscle strength. Supplementation yielded rapid improvements in IMCL within 4 weeks, but were lost once treatment was discontinued. In situ muscle measurements were highly variable in Nf1 Prx1-/mice, attributable to the severe phenotype present in this model, with fusion of the hips and an overall small hind limb muscle size. Lipidome analysis enabled segregation of the normal and modified chow diets, and fatty acid data suggested increased muscle lipolysis with the intervention. Acylcarnitines were also affected, suggestive of a mitochondrial fatty acid oxidation disorder. These data support the theory that NF1 is a lipid storage disease that can be treated by dietary intervention, and encourages future human trials.

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Section: Discussionsupporting

confidence: 56%

Evaluating modified diets and dietary supplement therapies for reducing muscle lipid accumulation and improving muscle function in neurofibromatosis type 1 (NF1)

et al. 2020

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“…Likewise, metabolites accumulated after long term utilization of pharmacological therapies, such as valproate [79] and the antibiotic cefditoren pivoxil [80], can be conjugated to carnitine and result in carnitine depletion. Secondary carnitine deficiency may also arise from other deleterious conditions such as hemodialysis or renal tubular dysfunction, which result in excessive loss of carnitine in urine.…”

Section: Neuroprotection Afforded By L-carnitine Supplementation In Pmentioning

confidence: 99%

“…Secondary carnitine deficiency may also occur in malnutrition or prematurity, due to reduced intake or uptake of carnitine from the diet, or reduced reuptake in kidney [41, 81, 82]. Treatment with L-carnitine ameliorated symptoms of encephalopathy subsequent to long term use of valproate [79], and the antibiotic cefditoren pivoxil [80]. Case reports indicate that improvement with L-carnitine treatment was also seen in hyperammonemic encephalopathy caused by carnitine deficiency that manifested several years after gastrointestinal bypass surgery [83] and in encephalopathy secondary to gluten enteropathy [84].…”

Section: Neuroprotection Afforded By L-carnitine Supplementation In Pmentioning

confidence: 99%

l-Carnitine and Acetyl-l-carnitine Roles and Neuroprotection in Developing Brain

2017

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L-Carnitine functions to transport long chain fatty acyl CoAs into the mitochondria for degradation by β-oxidation. Treatment with L-carnitine can ameliorate metabolic imbalance in many inborn errors of metabolism. In recent years there has been considerable interest in the therapeutic potential of L-carnitine and its acetylated derivative acetyl-L-carnitine (ALCAR) for neuroprotection in a number of disorders including hypoxia-ischemia, traumatic brain injury, Alzheimer’s disease and in conditions leading to central or peripheral nervous system injury. There is compelling evidence from preclinical studies that L-carnitine and ALCAR can improve energy status, decrease oxidative stress and prevent subsequent cell death in models of adult, neonatal and pediatric brain injury. ALCAR can provide an acetyl moiety that can be oxidized for energy, used as a precursor for acetylcholine, or incorporated into glutamate, glutamine and GABA, or into lipids for myelination and cell growth. Administration of ALCAR after brain injury in rat pups improved long-term functional outcomes, including memory. Additional studies are needed to better explore the potential of L-carnitine and ALCAR for protection of developing brain as there is an urgent need for therapies that can improve outcome after neonatal and pediatric brain injury.

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“…Several risk factors have been associated with hyperammonemic encephalopathy: concurrent therapy with antipsychotic drugs,12 concurrent therapy with liver enzyme-inducing antiepileptics,12 concurrent therapy with topiramate,13 14 poor nutritional status15 or a deficiency of carnitine16 and urea cycle disorders 17. The data on the risk associated with VPA dosage appear inconsistent, with some showing risk with overdose or higher doses,12 18 while others showing that the length of VPA treatment, VPA dosage or serum VPA level do not appear to correlate with onset or severity of hyperammonemic encephalopathy 17.…”

Section: Discussionmentioning

confidence: 99%

Hyperammonemic encephalopathy induced by valproic acid

Zhu,

Singh,

Chang

et al. 2024

BMJ Case Rep

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Valproate (VPA) is broad-spectrum antiepileptic drug. Several adverse reactions including hepatotoxicity, fetal risk and pancreatitis are well known and labelled as boxed warnings in the USA. One adverse reaction that is less well known but clinically significant for its severe morbidity is hyperammonemic encephalopathy. We present a case of woman with hyperammonemic encephalopathy following the initiation of VPA therapy; she had a favourable outcome with discontinuation of the drug and prompt treatment with lactulose and L-carnitine.

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Reversible weakness and encephalopathy while on long-term valproate treatment due to carnitine deficiency

Cited by 7 publications

References 16 publications

Evaluating modified diets and dietary supplement therapies for reducing muscle lipid accumulation and improving muscle function in neurofibromatosis type 1 (NF1)

Evaluating modified diets and dietary supplement therapies for reducing muscle lipid accumulation and improving muscle function in neurofibromatosis type 1 (NF1)

l-Carnitine and Acetyl-l-carnitine Roles and Neuroprotection in Developing Brain

Hyperammonemic encephalopathy induced by valproic acid

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