Could nodding syndrome in Northern Uganda be a form of autism spectrum disorder? an observational study design.

INTRODUCTION: Nodding syndrome (NS) is associated with high anion gap, biotinidase and acetyl carnitine deficiency, vitamin B6 and D deficiency and internal displacement. The objective of this study was to conduct a metabolic analysis on NS children and review literature on its similarities with ASD. METHODS: We conducted biochemical analysis on blood and urine of NS children at Hope for HumaNs (HfH) centre in 2014 and reviewed literature on its similarities with ASD. Ethical approval was obtained from an IRB. Data analysis was conducted using STATA version 12 and a p-value less than 0.05 was considered significant. RESULTS: We found biotinidase deficiency in NS with a mean 1.98 95% CI(1.61, 2.34; p < 0.001); Acetyl carnitine deficiency 16.92 95% CI(16.10,17.75; p<0.001); Low BMI-for-age 16.92 95% CI(16.10,17.75; p = 0.42); Age 14.08 95% CI(0.78,4.660; p = 0.007); IDP duration 4.82 95% CI(4.48, 5.21; p = 0.92); Age at NS onset 8.02 95% CI(7.03, 9.01; p = 0.001); NS associated with multiple nodding episodes (χ2)=22.15, p=0.005; NS siblings with NS (χ2) = 9.68, p = 0.004; NS were in IDPs (χ2) = 22.15, p = 0.005. CONCLUSION: These findings are indicative that NS is associated with biotinidase and acetyl carnitine deficiency, IDPs, and environmental exposures. There are no new cases of NS reported by Ugandan MOH and WHO since 2012 when the IDP camps were disbanded and communities resettled in their own communities and feed on their own grown foods. Perhaps NS may be akin to Autism Spectrum Disorder (ASD). This finding will help support all efforts towards the treatment and rehabilitation of NS children.

Acetyl-l-carnitine deficiency in patients with major depressive disorder.

The lack of biomarkers to identify target populations greatly limits the promise of precision medicine for major depressive disorder (MDD), a primary cause of ill health and disability. The endogenously produced molecule acetyl-l-carnitine (LAC) is critical for hippocampal function and several behavioral domains. In rodents with depressive-like traits, LAC levels are markedly decreased and signal abnormal hippocampal glutamatergic function and dendritic plasticity. LAC supplementation induces rapid and lasting antidepressant-like effects via epigenetic mechanisms of histone acetylation. This mechanistic model led us to evaluate LAC levels in humans. We found that LAC levels, and not those of free carnitine, were decreased in patients with MDD compared with age- and sex-matched healthy controls in two independent study centers. Secondary exploratory analyses showed that the degree of LAC deficiency reflected both the severity and age of onset of MDD. Moreover, these analyses showed that the decrease in LAC was larger in patients with a history of treatment-resistant depression (TRD), among whom childhood trauma and, specifically, a history of emotional neglect and being female, predicted the decreased LAC. These findings suggest that LAC may serve as a candidate biomarker to help diagnose a clinical endophenotype of MDD characterized by decreased LAC, greater severity, and earlier onset as well as a history of childhood trauma in patients with TRD. Together with studies in rodents, these translational findings support further exploration of LAC as a therapeutic target that may help to define individualized treatments in biologically based depression subtype consistent with the spirit of precision medicine.

Carnitine and/or Acetylcarnitine Deficiency as a Cause of Higher Levels of Ammonia.

Blood carnitine and/or acetylcarnitine deficiencies are postulated in the literature as possible causes of higher ammonia levels. The aim of this study was to investigate if the use of valproic acid, the age of the patients, or certain central nervous system pathologies can cause carnitine and/or acetylcarnitine deficiency leading to increased ammonia levels. Three groups of patients were studied: (A) epileptic under phenytoin monotherapy (n = 31); (B) with bipolar disorder under valproic acid treatment (n = 28); (C) elderly (n = 41). Plasma valproic acid and blood carnitine and acyl carnitine profiles were determined using a validated HPLC and LC-MS/MS method, respectively. Blood ammonia concentration was determined using an enzymatic automated assay. Higher ammonia levels were encountered in patients under valproic acid treatment and in the elderly. This may be due to the lower carnitine and/or acetylcarnitine found in these patients. Patients with controlled seizures had normal carnitine and acetylcarnitine levels. Further studies are necessary in order to conclude if the uncontrolled bipolar disorder could be the cause of higher carnitine and/or acetylcarnitine levels.

Carnitine palmitoyltransferase 2 deficiency: the time-course of blood and urinary acylcarnitine levels during initial L-carnitine supplementation.

Carnitine palmitoyltransferase 2 (CPT2) deficiency is one of the most common mitochondrial beta-oxidation defects. A female patient with an infantile form of CPT2 deficiency first presented as having a Reye-like syndrome with hypoglycemic convulsions. Oral L-carnitine supplementation was administered since serum free carnitine level was very low (less than 10 micromol/L), indicating secondary carnitine deficiency. Her serum and urinary acylcarnitine profiles were analyzed successively to evaluate time-course effects of L-carnitine supplementation. After the first two days of L-carnitine supplementation, the serum level of free carnitine was elevated; however, the serum levels of acylcarnitines and the urinary excretion of both free carnitine and acylcarnitines remained low. A peak of the serum free carnitine level was detected on day 5, followed by a peak of acetylcarnitine on day 7, and peaks of long-chain acylcarnitines, such as C16, C18, C18:1 and C18:2 carnitines, on day 9. Thereafter free carnitine became predominant again. These peaks of the serum levels corresponded to urinary excretion peaks of free carnitine, acetylcarnitine, and medium-chain dicarboxylic carnitines, respectively. It took several days for oral L-carnitine administration to increase the serum carnitine levels, probably because the intracellular stores were depleted. Thereafter, the administration increased the excretion of abnormal acylcarnitines, some of which had accumulated within the tissues. The excretion of medium-chain dicarboxylic carnitines dramatically decreased on day 13, suggesting improvement of tissue acylcarnitine accumulation. These time-course changes in blood and urinary acylcarnitine levels after L-carnitine supplementation support the effectiveness of L-carnitine supplementation to CPT2-deficient patients.

Protective effect of intravenous levocarnitine on subsequent-month hospitalization among prevalent hemodialysis patients, 1998 to 2003.

BACKGROUND: Levocarnitine deficiency in hemodialysis patients is common. Although the effect of intravenous levocarnitine therapy was studied in small trials, the effect on global outcomes in larger populations is unclear. STUDY DESIGN: Retrospective observational study. SETTING & PARTICIPANTS: Centers for Medicare & Medicaid Services data; prevalent hemodialysis patients, 1998 to 2003. PREDICTOR: Intravenous levocarnitine use, clinical characteristics, comorbid conditions. OUTCOMES & MEASUREMENTS: Effect of 1 g or greater per dialysis session of levocarnitine for 10 or more sessions during a month on subsequent hospitalization days. Repeated-measures and marginal structural models were fit, the latter to account for time-dependent confounding. RESULTS: Of the study population, 3% to 7% received levocarnitine for 1 month per year or more. Treated patients were older with more severe comorbidity and larger erythropoietin doses than untreated patients. In repeated-measures model analysis adjusted for demographic characteristics and disease severity, 1 g or greater per dialysis session of levocarnitine for 10 or more sessions during a month was associated with a 10.8% (95% confidence interval, 9.7 to 11.9; P < 0.01) subsequent-month decrease in hospitalization days. In marginal structural model analysis, levocarnitine therapy was associated with a 21.7% (95% confidence interval, 18.4 to 24.9; P < 0.01) decrease in hospitalization days. LIMITATIONS: Algorithm for identifying comorbid conditions from claims validated only for diabetes; biochemical marker levels unavailable in Medicare claims; levocarnitine therapy quantified only while patients were not hospitalized. CONCLUSION: Because hemodialysis patients are hospitalized about 15 days yearly, the association of monthly levocarnitine regimen with lower hospitalization rate is clinically significant. The causality of this association must be confirmed by randomized clinical trials.

Debate forum: levocarnitine therapy is rational and justified in selected dialysis patients.

Carnitine is a metabolic cofactor which is essential for normal fatty acid metabolism. Patients with chronic kidney disease on dialysis have been shown both to suffer from disordered fatty acid metabolism and to have a significant deficiency in plasma and tissue carnitine. Aberrant fatty acid metabolism has been associated with a number of cellular abnormalities such as increased mitochondrial permeability (a promoter of apoptosis), insulin resistance, and enhanced generation of free radicals. These cellular abnormalities have, in turn, been correlated with pathological clinical conditions common in dialysis patients including cardiomyopathy with attendant hypotension and resistance to the therapeutic effect of recombinant human erythropoietin (EPO). In 1999, the Food and Drug Administration approved levocarnitine injection for the prevention and treatment of carnitine deficiency in patients on dialysis based on documentation of free plasma carnitine levels in dialysis patients similar to other serious carnitine deficiency states for which treatment was required. Data analysis performed by expert panels convened by both the American Association of Kidney Patients and, subsequently, the National Kidney Foundation recommended a trial of levocarnitine therapy for specific subsets of dialysis patients including those with EPO resistance, dialysis-related hypotension, cardiomyopathy and muscle weakness. In 2003, the Centers for Medicare and Medicaid services convened a Medical Advisory Committee which established reimbursement on a national level for carnitine-deficient dialysis patients who had either dialysis-related hypotension or EPO resistance. Recently, a correlation between reductions in hospitalization rates of dialysis patients receiving levocarnitine therapy has been demonstrated in a large retrospective study. Despite data-based recommendations and national reimbursement, only a small minority of dialysis patients have been prescribed a therapeutic trial of levocarnitine. Whereas the reasons for the reluctance of nephrologists to prescribe this therapeutic trial are unclear, possible explanations include a lack of appreciation of the pivotal role played by carnitine in cellular metabolism and the strength of evidence for a substantial deficiency of carnitine in dialysis patients, an underestimation of the prognostic import of EPO resistance and dialysis-related hypotension, inadequate dissemination of the clinical trial data supporting the use of levocarnitine in dialysis patients, and the heterogeneous clinical response of dialysis patients to levocarnitine therapy. Difficulties in documenting both initial eligibility and evidence of improvement as a result of therapy may also be a contributing factor. This paper discusses the biological role of carnitine and its particular relevance to dialysis patients. Clinical trial data concerning an effect of therapy on EPO resistance and dialysis-related hypotension are summarized along with a discussion of the logic behind the use of levocarnitine in dialysis. Finally, the difficulties posed by a reimbursement policy based on clinical as opposed to laboratory endpoints and a heterogeneous response to therapy are addressed.

Acetyl-carnitine deficiency in AIDS patients with neurotoxicity on treatment with antiretroviral nucleoside analogues.

OBJECTIVE: A severe dose limiting axonal peripheral neuropathy may develop in subjects on treatment with the nucleoside analogues didanosine (ddl), zalcitabine (ddC), and stavudine (d4T). The impairment of mitrochondrial DNA synthesis is crucial to the pathogenesis of this disorder although other mechanisms have not been ruled out. The depletion of acetyl-carnitine, which regulates the metabolism and function of peripheral nerves could contribute to the neurotoxicity of these compounds. DESIGN: Non-randomized, cross-sectional study of selected patients. METHODS: We measured the serum levels of acetyl- and total carnitine in 12 subjects with axonal peripheral neuropathy developed on treatment with different regimens of neurotoxic nucleoside analogues (ddl, ddC, d4T). Subjects who did not develop peripheral neuropathy while staying on treatment with ddl (n = 10) or zidovudine (n = 11) served as the control groups. HIV-negative subjects with axonal on demyelinating autoimmune neuropathies (n = 10) and healthy individuals (n = 13) were additional control groups. RESULTS: Subjects experiencing axonal peripheral neuropathy on treatment with ddl, ddC and d4T had significantly reduced levels of acetyl-carnitine in comparison to the control groups. No difference was observed in the levels of total carnitine between study subjects and the control groups. CONCLUSIONS: Our results demonstrate that subjects who developed peripheral neuropathy while staying on treatment with ddl, ddC and d4T had acetyl-carnitine deficiency. The normal levels of total carnitine in the study group appear to indicate the specificity of the defect and rule out coexisting relevant nutritional problems. The critical role of acetyl-carnitine for the metabolism and function of the peripheral nerves supports the view that the acetyl-carnitine deficiency found in these subjects may contribute to the neurotoxicity of ddl, ddC and d4T, even though the interference with mitochondrial DNA synthesis is regarded as the main cause of their toxicity.

Acetyl-L-carnitine deficiency as a cause of altered nerve myo-inositol content, Na,K-ATPase activity, and motor conduction velocity in the streptozotocin-diabetic rat.

Defective metabolism of long-chain fatty acids and/or their accumulation in nerve may impair nerve function in diabetes by altering plasma or mitochondrial membrane integrity and perturbing intracellular metabolism and energy production. Carnitine and its acetylated derivatives such as acetyl-L-carnitine (ALC) promote fatty acid beta-oxidation in liver and prevent motor nerve conduction velocity (MNCV) slowing in diabetic rats. Neither the presence nor the possible implications of putative ALC deficiency have been definitively established in diabetic nerve. This study explored sciatic nerve ALC levels and the dose-dependent effects of ALC replacement on sciatic nerve metabolites, Na,K-ATPase, and MNCV after 2 and 4 weeks of streptozotocin-induced diabetes (STZ-D) in the rat. ALC treatment that increased nerve ALC levels delayed (to 4 weeks) but did not prevent nerve myo-inositol (MI) depletion, but prevented MNCV slowing and decreased ouabain-sensitive (but not -insensitive) ATPase activity in a dose-dependent fashion. However, ouabain-sensitive ATPase activity was also corrected by subtherapeutic doses of ALC that did not increase nerve ALC or affect MNCV. These data implicate nerve ALC depletion in diabetes as a factor contributing to alterations in nerve intermediary and energy metabolism and impulse conduction in diabetes, but suggest that these alterations may be differentially affected by various degrees of ALC depletion.