Recognition and management of fatty acid oxidation defects: A series of 107 patients

Abstract

In a personal series of 107 patients, we describe clinical presentations, methods of recognition and therapeutic management of inherited fatty acid oxidation (FAO) defects. As a whole, FAO disorders appear very severe: among the 107 patients, only 57 are still living. Including 47 siblings who died early in infancy, in total 97 patients died, of whom 30% died within the first week of life and 69% before 1 year. Twenty-eight patients presented in the neonatal period with sudden death, heart beat disorders, or neurological distress with various metabolic disturbances. Hepatic presentations were observed in 73% of patients (steatosis, hypoketotic hypoglycaemia, hepatomegaly, Reye syndrome). True hepatic failure was rare (10%); cholestasis was observed in one patient with LCHAD deficiency. Cardiac presentations were observed in 51% of patients: 67% patients presented with cardiomyopathy, mostly hypertrophic, and 47% of patients had heart beat disorders with various conduction abnormalities and arrhythmias responsible for collapse, near-miss and sudden unexpected death. All enzymatic blocks affecting FAO except CPT I and MCAD were found associated with cardiac signs. Muscular signs were observed in 51% of patients (of whom 64% had myalgias or paroxysmal myoglobinuria, and 29% had progressive proximal myopathy). Chronic neurologic presentation was rare, except in LCHAD deficiency (retinitis pigmentosa and peripheral neuropathy). Renal presentation (tubulopathy) and transient renal failure were observed in 27% of patients. The diagnosis of FAO disorders is generally based on the plasma acylcarnitine profile determined by FAB-MS/MS from simple blood spots collected on a Guthrie card. Urinary organic acid profile and total and free plasma carnitine can also be very helpful, mostly in acute attacks. If there is no significant disturbance between attacks, the diagnosis is based upon a long-chain fatty acid loading test, fasting test, and in vitro studies of fatty acid oxidation on fresh lymphocytes or cultured fibroblasts. Treatment includes avoiding fasting or catabolism, suppressing lipolysis, and carnitine supplementation. The long-term dietary therapy aims to prevent periods of fasting and restrict long-chain fatty acid intake with supplementation of medium-chain triglycerides. Despite these therapeutic measures, the long-term prognosis remains uncertain.

Anaplerotic treatment of long-chain fat oxidation disorders with triheptanoin: Review of 15years Experience

“…This difference made comparison unequal. For example, mortality in the previously reported studies was 51.2% [2], and 65.1% [3,4] and was reduced to 11.5% in the TH trial. (Table 3)…”

“…Previous reports of mortality included many more patients with the neonatal-onset form of CPT II deficiency and CACT patients and did not describe the causes of death. [2–4] The TH trial included only 1 patient with neonatal CPT II and two patients with CACT deficiency. This difference made comparison unequal.…”

“…The adjusted mortality rates were only slightly reduced from 51.2% to 45% [2] and from 65.1 % to 60 % [3,4] compared to 8% for the 49 patients in the TH trial. The mortality rate with the TH trial was significantly reduced by either analysis.…”

MnSOD Overexpression Prevents Liver Mitochondrial DNA Depletion after an Alcohol Binge but Worsens This Effect after Prolonged Alcohol Consumption in Mice

“…Several inborn nuclear DNA (nDNA) defects impair the mitochondrial function (β-oxidation of fatty acids, respiration, tricarboxylic acid cycle, etc.) causing hepatic steatosis and energy deficiency during fasting episodes [2]. Inborn nDNA or mitochondrial DNA (mtDNA) mutations can decrease mitochondrial energy production and cause mitochondrial cytopathies [3], while acquired somatic mtDNA mutations and mtDNA damage play an important role in the ageing process [4] as well as in alcohol- and drug-induced liver toxicity [5,6,7,8,9,10,11,12].…”

Mitochondrial Trifunctional Protein Defects: Molecular Basis and Novel Therapeutic Approaches

“…Many LCHAD deficient patients develop retinal problems, peripheral neuropathy and recurrent episodes of aching muscle pain despite avoidance of hypoglycemic episodes. Patients who are diagnosed with the cardiac phenotype are permanently exposed to the risk of unexpected death, despite therapy [90].…”