Genetic, biochemical, and clinical spectrum of patients with mitochondrial trifunctional protein deficiency identified after the introduction of newborn screening in the Netherlands

Abstract

Long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency (LCHADD) is included in many newborn screening (NBS) programs. Acylcarnitine‐based NBS for LCHADD not only identifies LCHADD, but also the other deficiencies of the mitochondrial trifunctional protein (MTP), a multi‐enzyme complex involved in long‐chain fatty acid β‐oxidation. Besides LCHAD, MTP harbors two additional enzyme activities: long‐chain enoyl‐CoA hydratase (LCEH) and long‐chain ketoacyl‐CoA thiolase (LCKAT). Deficiency of one or more MTP activities causes generalized MTP deficiency (MTPD), LCHADD, LCEH deficiency (not yet reported), or LCKAT deficiency (LCKATD). To gain insight in the outcomes of MTP‐deficient patients diagnosed after the introduction of NBS for LCHADD in the Netherlands, a retrospective evaluation of genetic, biochemical, and clinical characteristics of MTP‐deficient patients, identified since 2007, was carried out. Thirteen patients were identified: seven with LCHADD, five with MTPD, and one with LCKATD. All LCHADD patients (one missed by NBS, clinical diagnosis) and one MTPD patient (clinical diagnosis) were alive. Four MTPD patients and one LCKATD patient developed cardiomyopathy and died within 1 month and 13 months of life, respectively. Surviving patients did not develop symptomatic hypoglycemia, but experienced reversible cardiomyopathy and rhabdomyolysis. Five LCHADD patients developed subclinical neuropathy and/or retinopathy. In conclusion, patient outcomes were highly variable, stressing the need for accurate classification of and discrimination between the MTP deficiencies to improve insight in the yield of NBS for LCHADD. NBS allowed the prevention of symptomatic hypoglycemia, but current treatment options failed to treat cardiomyopathy and prevent long‐term complications. Moreover, milder patients, who might benefit from NBS, were missed due to normal acylcarnitine profiles.

Thermo‐sensitive mitochondrial trifunctional protein deficiency presenting with episodic myopathy

“…This resulted in the final diagnosis of LCKATD. LCKATD has only been reported in four patients: three with cardiomyopathy and all with fatal outcome before 13 months of life 11,17,25 . Here, we describe the first adult LCKATD patient with a relatively mild muscular phenotype, showing that LCKATD has a wider clinical spectrum than described thus far, similar to other lcFAOD.…”

“…LCHAD and LCKAT activities were measured in fibroblast homogenates using 3‐keto‐palmitoyl‐CoA as substrate, as described previously 11 . Short‐chain acyl‐CoA dehydrogenase (SCHAD) activity was measured essentially as described by Wanders et al 12 …”

“…LCHAD and LCKAT activities were measured in fibroblast homogenates using 3-keto-palmitoyl-CoA as substrate, as described previously. 11 Short-chain acyl-CoA dehydrogenase (SCHAD) activity was measured essentially as described by Wanders et al 12 LcFAO-flux analysis was performed in fibroblasts by measuring the production of radiolabeled H 2 O from [9,10-3 H(N)]-oleic acid. [13][14][15] The lcFAO-flux was expressed as a percentage of the mean activity simultaneously measured in three healthy control fibroblast lines cultured at the same temperature.…”

Recurrent metabolic alkalosis following ketone body treatment of adult mitochondrial trifunctional protein deficiency: A case report

“…This case presentation is based on a retrospective data analysis of a single patient with MTPD. Enzymatic studies (LCHAD and LCTH activity measurements in lymphocytes and fibroblasts, and long chain‐FAO flux analysis in fibroblasts) were performed as previously described 19 . Genetic analysis was done by performing Sanger sequencing of all exons and flanking intronic sequences of the HADHA and HADHB genes.…”

“…Blood pH, bicarbonate-, and pCO 2 levels following daily administration of A., sodium βHB as a hospital pharmacy preparation (day 2-17) and B., sodium and potassium βHB (day[17][18][19][20] …”