Patients with primary carnitine deficiency treated with L-carnitine are alive and doing well-A 10-year follow-up in the Faroe Islands.

Primary carnitine deficiency (PCD) can be lethal. Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for ß-oxidation. The reported prevalence of PCD in the Faroe Islands of 1:300 is the highest in the world. The Faroese PCD patient cohort has been closely monitored and we now report results from a 10-year follow-up study of 139 PCD patients. Four patients have died of natural causes since diagnosis. There were no signs of cardiac complications related to PCD. 70.5% reported an effect of L-carnitine treatment. 33.7% reported current symptoms with fatigue and low stamina being the most common. 65.1% had experienced side effects during L-carnitine treatment. Most common side effects were fish odor, abdominal pain, and diarrhea. The overall mean L-carnitine dosage was 66.3 mg/kg/day. Free p-carnitine was similar between male and female patients on L-carnitine-18.6 and 18.8 µmol/L, respectively. L-carnitine supplementation seems to be a safe and effective treatment when suffering from PCD. PCD patients in the Faroe Islands are alive and doing well more than 10 years after diagnosis.

Cardiac function and incidence of unexplained myocardial scarring in patients with primary carnitine deficiency - a cardiac magnetic resonance study.

Primary carnitine deficiency (PCD) not treated with L-Carnitine can lead to sudden cardiac death. To our knowledge, it is unknown if asymptomatic patients treated with L-Carnitine suffer from myocardial scarring and thus be at greater risk of potentially serious arrhythmia. Cardiac evaluation of function and myocardial scarring is non-invasively best supported by cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE). The study included 36 PCD patients, 17 carriers and 17 healthy subjects. A CMR cine stack in the short-axis plane were acquired to evaluate left ventricle (LV) systolic and diastolic function and a similar LGE stack to evaluate myocardial scarring and replacement fibrosis. LV volumes and ejection fraction were not different between PCD patients, carriers and healthy subjects. However, LV mass was higher in PCD patients with the severe homozygous mutation, c.95 A > G (p = 0.037; n = 17). Among homozygous PCD patients there were two cases of unexplained myocardial scarring and this is in contrast to no myocardial scarring in any of the other study participants (p = 0.10). LV mass was increased in PCD patients. L-carnitine supplementation is essential in order to prevent potentially lethal cardiac arrhythmia and serious adverse cardiac remodeling.

Is L-Carnitine Supplementation Beneficial in 3-Methylcrotonyl-CoA Carboxylase Deficiency?

BACKGROUND: 3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCd) is an autosomal recessive disorder in the catabolism of leucine. In the present study, we investigated the current and prior medical condition of patients with 3-MCCd in the Faroe Islands and their carnitine levels in blood, urine and muscle tissue with and without L-carnitine supplementation to evaluate the current treatment strategy of not recommending L-carnitine supplementation to Faroese 3-MCCd patients. METHODS: Blood and urine samples and muscle biopsies were collected from patients at inclusion and at 3 months. Eight patients received L-carnitine supplementation when recruited; five did not. Included patients who received supplementation were asked to stop L-carnitine, the others were asked to initiate L-carnitine supplementation during the study. Symptoms were determined by review of hospital medical records and questionnaires answered at baseline and after the intervention. RESULTS: The prevalence of 3-MCCd in the Faroe Islands was 1:2,400, the highest reported worldwide. All patients were homozygous for the MCCC1 mutation c.1526delG. When not administered L-carnitine, the 3-MCCd patients (n = 13) had low plasma and muscle free carnitine levels, 6.9 (SD 1.4) µmol/L and 785 (SD 301) nmol/g wet weight, respectively. L-Carnitine supplementation increased muscle and plasma carnitine levels to a low-normal range, 25.5 (SD 10.9) µmol/L and 1,827 (SD 523) nmol/g wet weight, p < 0.01, respectively. Seven of the thirteen 3-MCCd subjects suffered from self-reported fatigue with some alleviation after L-carnitine supplementation. CONCLUSION: 3-MCCd is common in the Faroe Islands. Some symptomatic 3-MCCd patients may benefit biochemically and clinically from L-carnitine supplementation, a more general recommendation cannot be given.

Primary Carnitine deficiency in the Faroe Islands: health and cardiac status in 76 adult patients diagnosed by screening.

BACKGROUND: Carnitine deficiency can cause cardiomyopathy and cardiac arrhythmia. The prevalence in the Faroe Islands is the highest reported in the world (1:300). A nationwide screening program identified 76 Faroese adult patients (15-80 years) with Primary Carnitine Deficiency (PCD). We describe prior and current health status and symptoms in these patients, especially focusing on cardiac characteristics. METHODS: Upon identification, patients were immediately admitted for physical examination, ECG, blood tests and initiation of L-carnitine supplementation. Medical records were reviewed and patients were interviewed. Echocardiography and blood tests were performed in 35 patients before and after L-carnitine supplementation. RESULTS: All patients were either asymptomatic or had minor symptoms when diagnosed. Echocardiography including LVEF, global longitudinal strain and dimensions were normal apart from left ventricular hypertrophy with normal systolic function in one young male. Symptoms, e.g. fatigue, were reported in 43 % with a reduction to 12 % (p < 0.01) following initiation of L-carnitine supplementation. Eighty two % reported participation in sports of which 52 % were on a competitive level. ECGs showed limited changes and blood tests were normal. Mean plasma free carnitine increased from 6.1 µmol/L to 15.1 µmol/L (p < 0.01) within 50 days of L-carnitine supplementation. CONCLUSION: PCD in adults can cause serious symptoms, but adult Faroese patients identified through a screening program were predominantly asymptomatic with a normal cardiac structure and function.

The in vivo toxicity of hydroxyurea depends on its direct target catalase.

Hydroxyurea (HU) is a well tolerated ribonucleotide reductase inhibitor effective in HIV, sickle cell disease, and blood cancer therapy. Despite a positive initial response, however, most treated cancers eventually progress due to development of HU resistance. Although RNR properties influence HU resistance in cell lines, the mechanisms underlying cancer HU resistance in vivo remain unclear. To address this issue, we screened for HU resistance in the plant Arabidopsis thaliana and identified seventeen unique catalase mutants, thereby establishing that HU toxicity depends on catalase in vivo. We further demonstrated that catalase is a direct HU target by showing that HU acts as a competitive inhibitor of catalase-mediated hydrogen peroxide decomposition. Considering also that catalase can accelerate HU decomposition in vitro and that co-treatment with another catalase inhibitor alleviates HU effects in vivo, our findings suggests that HU could act as a catalase-activated pro-drug. Clinically, we found high catalase activity in circulating cells from untreated chronic myeloid leukemia, offering a possible explanation for the efficacy of HU against this malignancy.