Outcomes of mitochondrial long chain fatty acid oxidation and carnitine defects from a single center metabolic genetics clinic.

BACKGROUND: Mitochondrial long-chain fatty acid oxidation and carnitine metabolism defects are a group of inherited metabolic diseases. We performed a retrospective cohort study to report on the phenotypic and genotypic spectrum of mitochondrial long-chain fatty acid oxidation and carnitine metabolism defects as well as their treatment outcomes. METHODS: All patients with mitochondrial long-chain fatty acid oxidation and carnitine metabolism defects were included. We divided patients into two groups to compare outcomes of those treated symptomatically (SymX) and asymptomatically (AsymX). We reviewed patient charts for clinical features, biochemical investigations, molecular genetic investigations, cardiac assessments, neuroimaging, treatments, and outcomes. RESULTS: There were 38 patients including VLCAD (n = 5), LCHAD (n = 4), CACT (n = 3), MAD (n = 1), CPT-I (n = 13), CPT-II (n = 3) deficiencies and CTD (n = 9). Fourteen patients were diagnosed symptomatically (SymX), and 24 patients were diagnosed asymptomatically (AsymX). Twenty-eight variants in seven genes were identified in 36 patients (pathogenic/likely pathogenic n = 25; variant of unknown significance n = 3). Four of those variants were novel. All patients with LCHAD deficiency had the common variant (p.Glu474Gln) in HADHA and their phenotype was similar to the patients reported in the literature for this genotype. Only one patient with VLCAD deficiency had the common p.Val283Ala in ACADVL. The different genotypes in the SymX and AsymX groups for VLCAD deficiency presented with similar phenotypes. Eight patients were treated with carnitine supplementation [CTD (n = 6), CPT-II (n = 1), and MAD (n = 1) deficiencies]. Thirteen patients were treated with a long-chain fat restricted diet and MCT supplementation. A statistically significant association was found between rhabdomyolysis, and hypoglycemia in the SymX group compared to the AsymX group. A higher number of hospital admissions, longer duration of hospital admissions and higher CK levels were observed in the SymX group, even though the symptomatic group was only 37% of the study cohort. CONCLUSION: Seven different mitochondrial long-chain fatty acid oxidation and carnitine metabolism defects were present in our study cohort. In our clinic, the prevalence of mitochondrial long-chain fatty acid oxidation and carnitine defects was 4.75%.

Improved electroretinographic responses following dietary intervention in a patient with Refsum disease.

Refsum disease is a rare inherited metabolic disorder arising from a defect in peroxisomal metabolism. Patients lack the functional enzyme phytanoyl-CoA hydroxylase, resulting in perturbed alpha oxidation of fatty acids. Phytanic acid accumulates in nervous and adipose tissue and leads to several disease phenotypes including early-onset retinal degeneration, hearing loss, peripheral neuropathy, anosmia, and cerebellar ataxia, among others. Currently, restricting dietary phytanic acid is the only means of altering the chronic sequelae and the disease course. While dietary intervention has been demonstrated to improve peripheral neuropathy, ichthyosis, and ataxia, there have been no reports of improved retinal function in patients with Refsum disease. We describe the case of a 51-year-old patient with molecularly and biochemically confirmed Refsum disease who underwent electroretinography before and after beginning a phytanic acid-restricted diet. His post-intervention 30 Hz flicker electroretinogram demonstrated significantly improved waveform amplitudes and implicit times, suggesting improved retinal function. Thus, we propose that the possibility exists for some visual recovery in these patients and we highlight the utility of performing standardized electroretinography to assess treatment response in Refsum disease.

Prevalence of inadequate vitamin d status and associated factors in children with cystic fibrosis.

BACKGROUND: This study aimed to determine the prevalence of inadequate serum 25-hydroxyvitamin D (25(OH)D) levels in a pediatric Canadian cystic fibrosis (CF) population and to assess the effectiveness of a vitamin D supplementation protocol on improving vitamin D status. A secondary objective was to analyze factors that may be associated with inadequate 25(OH)D levels. METHODS: Vitamin D supplementation, 25(OH)D levels, and factors hypothesized to be associated with 25(OH)D levels were collected through a retrospective chart review (2010 and 2011) of 96 patients (1-18 years) at one CF clinic in Canada. Adequacy of 25(OH)D was set at ≥75 nmol/L. Patients with inadequate 25(OH)D levels in 2010 were prescribed an additional 1000 IU/d for levels <60 nmol/L or 400 IU/d for levels 60-75 nmol/L. RESULTS: Inadequate 25(OH)D levels were observed in 26% of patients in 2010 and 23% in 2011. After supplementation was increased for those with inadequate 25(OH)D levels in 2010 (n = 20), a significant increase in 25(OH)D levels was observed in 2011 (P = .03). Adequate status was achieved in 50% of these patients (n = 10). Age was significantly negatively associated with 25(OH)D levels in both years (P = .002). Percentage of forced expiratory volume in 1 second was significantly positively associated with 25(OH)D levels in 2011 (P = .03). CONCLUSION: While vitamin D supplementation was effective at increasing serum 25(OH)D, this protocol did not achieve optimal serum 25(OH)D levels in 25% of the population. Increasing age had the strongest association with 25(OH)D. Current supplementation protocols may require reevaluation based on emerging evidence and revised Cystic Fibrosis Foundation guidelines.

Electrocortical activity in the near-term ovine fetus: automated analysis using amplitude frequency components.

We have designed an automated method for analyzing electrocortical (ECoG) activity in the near-term ovine fetus to process and quantitatively classify large amounts of data rapidly and objectively. Seven chronically catheterized fetal sheep were studied for 8h each at ~0.9 of gestation with continuous recording of ECoG activity using a computerized data acquisition system. Multiple ECoG amplitude and frequency parameters were scored from which we established animal specific parameter cut-off values as well as population based duration cut-off values to distinguish low-voltage/high frequency (LV/HF) and high-voltage/low frequency (HV/LF) state epochs, and indeterminate voltage/frequency (IV/F) and transition period activities. We have shown that the incidence of the predominant LV/HF and HV/LF activity states at 45% and 36% of the time, respectively, is comparable to that previously reported using semi-quantitative techniques with visual analysis. However, the duration of these state epochs is considerably shorter due to the detection of brief periods of IV/F activity which would be difficult to capture using visual analysis. Importantly, our findings in the healthy ovine fetus near-term using this automated ECoG scoring methodology now provide a framework from which to study maturational events in younger animals, and under adverse pregnancy conditions.

Maturational changes and effects of chronic hypoxemia on electrocortical activity in the ovine fetus.

We have studied the maturation of electrocortical (ECoG) activity in fetal sheep and the impact of chronic hypoxemia using a growth restriction model with placental embolizations. Twenty chronically catheterized fetal sheep (control, n=9; hypoxemic, n=11) were monitored at 116-119, 121-126 and 128-134 days gestational age (term=145 days), with ECoG activity scored using automated analysis of amplitude and frequency components to distinguish low-voltage/high frequency (LV/HF) and high-voltage/low frequency (HV/LF) state epochs, along with indeterminate voltage/frequency (IV/F) and transition period activities. We have shown that multiple aspects of ECoG state activity in the ovine fetus undergo maturational change as electrophysiologic measures of brain development. With chronic fetal hypoxemia, some maturational changes continue to occur, i.e. ECoG activity amplitude and 95% SEF, indicating the resiliency of these parameters to adverse conditioning. However, some maturational changes were altered, i.e. LV/HF and HV/LF incidence and duration, and likely regulated and adaptive with a decrease in the brain's nonessential energy needs, while some were altered, i.e. IV/F incidence and duration, and state transition times, and likely indicating a degree of aberrant development in associated control circuitries. This may then have consequences for disturbed sleep-wake patterns during later life and for adverse neurologic sequelae known to be increased in humans born with growth restriction.