Long-term prognosis of fatty-acid oxidation disorders in adults: Optimism despite the limited effective therapies available

Abstract

Introduction: Fatty-acid oxidation disorders (FAODs) are recessive genetic diseases.

Materials and methods: We report here clinical and paraclinical data from a retrospective study of 44 adults with muscular FAODs from six French reference centers for neuromuscular or metabolic diseases.

Results: The study cohort consisted of 44 adult patients: 14 with carnitine palmitoyl transferase 2 deficiency (32%), nine with multiple acyl-CoA deficiency (20%), 13 with very long-chain acyl-CoA dehydrogenase deficiency (30%), three with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (7%), and five with short-chain acyl-CoA dehydrogenase deficiency (11%). Disease onset occurred during childhood in the majority of patients (59%), with a mean age at onset of 15 years (range = 0.5-35) and a mean of 12.6 years (range = 0-58) from disease onset to diagnosis. The principal symptoms were acute muscle manifestations (rhabdomyolysis, exercise intolerance, myalgia), sometimes associated with permanent muscle weakness. Episodes of rhabdomyolysis were frequent (84%), with a mean creatinine kinase level of 68,958 U/L (range = 660-300,000). General metabolic complications were observed in 58% of patients, respiratory manifestations in 18% of cases, and cardiological manifestations in 9% of cases. Fasting acylcarnitine profile was used to orient genetic explorations in 65% of cases. After a mean follow-up of 10 years, 33% of patients were asymptomatic and 56% continued to display symptoms after exercise. The frequency of rhabdomyolysis decreased after diagnosis in 64% of cases.

Conclusion: A standardized register would complete this cohort description of muscular forms of FAODs with exhaustive data, making it possible to assess the efficacy of therapeutic protocols in real-life conditions and during the long-term follow-up of patients.

Keywords: acylcarnitine profile; beta-oxidation; exercise intolerance; fatty acids; genetic analyses; long-term improvement; muscle weakness; rhabdomyolysis.

FIGURE 1

Mitochondrial fatty‐acid oxidation. FABPpm, fatty‐acid binding protein; FADH2, reduced flavin‐adenine‐dinucleotide; CACT, carnitine acylcarnitine translocase; CPT, carnitine‐palmitoyl transferase; ETF, electron transfer flavoprotein; FAD, flavin–adenine–dinucleotide; LCAD, long‐chain acyl‐CoA dehydrogenase; LCEH, long‐chain enoyl‐CoA hydratase; LCFA, long‐chain fatty acid; LCHAD, long‐chain 3‐hydroxyacyl‐CoA dehydrogenase; LKCAT, long‐chain 3‐ketoacyl‐CoA thiolase; M/SCHAD, medium‐/short‐chain 3‐hydroxyacyl‐CoA dehydrogenase; MCAD, medium‐chain acyl‐CoA dehydrogenase; MCFA, medium‐chain fatty acid; MKCAT, medium‐chain 3‐ketoacyl‐CoA thiolase; NAD, nicotinamide‐adenine‐dinucleotide; NADH2, reduced nicotinamide‐adenine‐dinucleotide; OCTN2, organic cation transporter type 2; SCAD, short‐chain acyl‐CoA dehydrogenase; SCFA, short‐chain fatty acid; TFP, trifunctional protein; VLCAD, very long‐chain acyl‐CoA dehydrogenase.

FIGURE 2

Clinical presentation of the cohort. (a) Age at the onset of symptoms and time to diagnosis. (b) Type of revealing symptoms by age group. (c) Inaugural symptom revealing a fatty‐acid oxidation disorder. (d) All muscular and metabolic symptoms occurring during the course of the disease. CPTII, carnitine palmitoyl transferase 2; LCHAD, long‐chain 3‐hydroxy‐acyl‐CoA; MAD, multiple acyl‐CoA; NA, not available; SCAD, short‐chain acyl‐CoA dehydrogenase; VLCAD, very‐long‐chain acyl‐CoA dehydrogenase.

FIGURE 3

Biological tests. (a) Creatine phosphokinase (CK) level at rest and during rhabdomyolysis. (b) Results of urinary explorations. CPTII, carnitine palmitoyl transferase 2; LCHAD, long‐chain 3‐hydroxy‐acyl‐CoA; MAD, multiple acyl‐CoA; SCAD, short‐chain acyl‐CoA dehydrogenase; VLCAD, very‐long‐chain acyl‐CoA dehydrogenase.

FIGURE 4

Involvement of other organs. (a) Other symptoms. (b) Results of cardiac, respiratory, and abdominal explorations. CPTII, carnitine palmitoyl transferase 2; LCHAD, long‐chain 3‐hydroxy‐acyl‐CoA; MAD, multiple acyl‐CoA; SCAD, short‐chain acyl‐CoA dehydrogenase; VLCAD, very‐long‐chain acyl‐CoA dehydrogenase.

FIGURE 5

Long‐term follow‐up of the patients. (a) Duration of follow‐up. (b) Change in muscle symptoms. (c) Change in the frequency of rhabdomyolysis. (d) Changes in cardiac, respiratory, and metabolic symptoms. CPT II, carnitine palmitoyl transferase 2; LCHAD, long‐chain 3‐hydroxy‐acyl‐CoA; MAD, multiple acyl‐CoA; SCAD, short‐chain acyl‐CoA dehydrogenase; VLCAD, very‐long‐chain acyl‐CoA dehydrogenase.