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Introduction

The mitochondrial trifunctional protein (MTP) is located on the inner mitochondrial membrane and catalyzes three of the four chain-shortening reactions in the mitochondrial β-oxidation of long-chain fatty acids. The three enzymes involved in these reactions are 2-enoyl coenzyme A (CoA) hydratase, long-chain 3-ketoacyl CoA thiolase, and long-chain 3-hydroxy acyl-coenzyme A dehydrogenase (LCHAD), which catalyzes the conversion of long-chain 3-hydroxyacyl-CoA esters into 3-ketoacyl-CoA esters.

Incidence

Unknown, but estimates put it in the range of 1 in 50,000 to 100,000 live births.

Inheritance

The defect follows autosomal recessive inheritance and is caused by mutations in the alpha subunit of the MTP, also known as Hydroxyacyl-CoA Dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA Hydratase (trifunctional protein), Alpha subunit (HADHA) gene, which has been mapped to chromosome 2p23.3.

Diagnosis

LCHAD deficiency can be demonstrated by an increase in urinary concentrations of 3-hydroxy-dicarboxylic acids and/or plasma concentration of 3-hydroxyacyl-carnitines. Definitive confirmation requires either mutational analysis or LCHAD activity measurement in lymphocytes, fibroblasts, muscle, or liver biopsies.

Clinical aspects

Fetal LCHADD predisposes the mother to pregnancy-related complications, such as acute fatty liver of pregnancy, preeclampsia, and HELLP-Syndrome. The majority of these patients (78%) present in the first month of life (15% in the neonatal period) with acute hepatic dysfunction and hypoketotic hypoglycemia (79%), coma (56%) and seizures (38%), apnea (23%), cardiorespiratory arrest (21%), and sudden death (9%). A minority (22%) presents with a more chronic course with feeding difficulties and failure to thrive, severe cholestatic liver disease, cardiomyopathy, and/or hypotonia. Hypoglycemic episodes are usually not reported in this group. Hepatomegaly with hepatic dysfunction and cholestasis, cardiomyopathy and failure to thrive affect both groups; however, hepatomegaly and cardiomyopathy are more frequent in the acute onset group. In hindsight, careful history taking in the acute onset group revealed that some of the unfortunately unspecific symptoms that are present in children with the more chronic course of the disease could have been detected before the acute episode unfolded. Mortality in patients presenting with an acute episode was 38%, which was almost identical to the one in the chronic symptom group. Nearly a third of patients died even before the diagnosis of LCHADD was made. The high mortality in LCHADD probably arises from a combination of toxic long-chain acyl-CoA esters accumulation in the myocardium causing cardiomyopathy with arrhythmias and blockage of long-chain fatty acid oxidation with the inability to synthesize ketone bodies and/or adenosine triphosphate (ATP). However, once the diagnosis has been established and proper measures are taken (avoiding fasting and following a diet high in carbohydrate content and low in long-chain fatty acids and enriched with medium-chain triglycerides), survival increases, particularly with early diagnosis, aggressive treatment (hospitalization with any illness), and follow-up regimens (regular echocardiography and ECG, consults by cardiology, neurology, ophthalmology, metabolics, and the dietitian), but long-term prognosis still remains guarded. The recommended ...

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