Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency

Abstract

General mitochondrial trifunctional protein (TFP) deficiency leads to a wide clinical spectrum of disease ranging from severe neonatal/infantile cardiomyopathy and early death to mild chronic progressive sensorimotor poly-neuropathy with episodic rhabdomyolysis. Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency resulting from the common Glu510Gln mutation usually gives rise to a moderately severe phenotype with multiorgan involvement with high morbidity and mortality. However, isolated LCHAD deficiency can also be consistent with long-term survival in patients identified and treated from an early age. We present biochemical, clinical and mutation data in 9 patients spanning the full spectrum of disease. Fibroblast acylcarnitine profiling shows good correlation with clinical phenotype using the ratio C18(OH)/(C14(OH)+C12(OH)). This ratio shows a gradation of values, from high in four patients with severe neonatal disease (2.5+/-0.8), to low in two neuromyopathic patients (0.35, 0.2). Fibroblast fatty acid oxidation flux assays also show correlation with the patient phenotype, when expressed either as percentage residual activity with palmitate or as a ratio of percentage activity of myristate/oleate (M/O ratio). Fibroblasts from four patients with severe neonatal disease gave an M/O ratio of 4.0+/-0.6 compared to 1.97 and 1.62 in two neuromyopathic patients. Specific enzyme assay of LCHAD and long-chain 3-ketothiolase activity in patient cells shows lack of correlation with phenotype. These results show that measurements in intact cells, which allow all determinative and modifying cellular factors to be present, better reflect patient phenotype. Mutation analysis reveals a number of alpha- and beta-subunit mutations. Peripheral sensorimotor polyneuropathy, often as the initial major presenting feature but usually later accompanied by episodic rhabdomyolysis, is a manifestation of mild TFP protein deficiency. The mild clinical presentation and relative difficulty in diagnosis suggest that this form of TFP is probably underdiagnosed.

Prevalence of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency in Estonia

“…The 20 exons that make up the HADHA gene and nearby intronic elements were sequenced as described by Olpin et al (2005).…”

Necrotizing Enterocolitis and Respiratory Distress Syndrome as First Clinical Presentation of Mitochondrial Trifunctional Protein Deficiency

“…Severe IRDS has been recognized as a rare early symptom in MTP deficiency (Olpin et al 2005). Cardiomyopathy, which was present in both patients, is a frequently reported complication in MTP deficiency (den Boer et al 2003;Olpin et al 2005;Purevsuren et al 2009;Spiekerkoetter et al 2003).…”

“…It has also been shown that FAO enzymes are expressed abundantly in human placentas (Shekhawat et al 2003). Furthermore, patients with longchain defects in FAO may already display cardiomyopathy before and immediately after birth (den Boer et al 2003;Olpin et al 2005;Purevsuren et al 2009;Spiekerkoetter et al 2004), demonstrating a role for long-chain FAO during intrauterine life. Finally, the (pre)eclampsia, the premature delivery and the foetal distress seen in both hereby described patients, is also in line with this hypothesis (Oey et al 2005).…”

“…Patients with MTP deficiency, including isolated LCHAD deficiency, most often present with acute metabolic decompensation consisting of hypoketotic hypoglycemia and rhabdomyolysis, generally followed by cardiomyopathy and later peripheral neuropathy. Hypotonia, areflexia and hepatic encephalopathy have also been described (Choi et al 2007;den Boer et al 2003;Olpin et al 2005;Purevsuren et al 2009;Saudubray et al 1999;Spiekerkoetter et al 2003;Ushikubo et al 1996). In contrast, isolated LCKAT deficiency appears extremely rare and only one patient, who presented with lethal cardiorespiratory failure, has been reported (Das et al 2006).…”

“…While no patients with isolated LCEH deficiency have been reported, MTP deficiency has been reported in relatively large series of patients (Choi et al 2007;den Boer et al 2003;Olpin et al 2005;Purevsuren et al 2009;Saudubray et al 1999;Spiekerkoetter et al 2003;Ushikubo et al 1996). Patients with MTP deficiency, including isolated LCHAD deficiency, most often present with acute metabolic decompensation consisting of hypoketotic hypoglycemia and rhabdomyolysis, generally followed by cardiomyopathy and later peripheral neuropathy.…”