Differential HMG‐CoA lyase expression in human tissues provides clues about 3‐hydroxy‐3‐methylglutaric aciduria

Abstract

3-Hydroxy-3-methylglutaric aciduria is a rare human autosomal recessive disorder caused by deficiency of 3-hydroxy-3-methylglutaryl CoA lyase (HL). This mitochondrial enzyme catalyzes the common final step of leucine degradation and ketogenesis. Acute symptoms include vomiting, seizures and lethargy, accompanied by metabolic acidosis and hypoketotic hypoglycaemia. Such organs as the liver, brain, pancreas, and heart can also be involved. However, the pathophysiology of this disease is only partially understood. We measured mRNA levels, protein expression and enzyme activity of human HMG-CoA lyase from liver, kidney, pancreas, testis, heart, skeletal muscle, and brain. Surprisingly, the pancreas is, after the liver, the tissue with most HL activity. However, in heart and adult brain, HL activity was not detected in the mitochondrial fraction. These findings contribute to our understanding of the enzyme function and the consequences of its deficiency and suggest the need for assessment of pancreatic damage in these patients.

3-Hydroxy-3-methylglutaric aciduria with bilateral basal ganglia lesion: A case report

“…All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation of The First Hospital of Jilin University (Changchun, China) and with the Helsinki Declaration of 1975, as revised in 2000 (7). Informed consent was obtained from the parents of the patient.…”

“…In the absence of HL, leucine cleavage is incomplete, resulting in accumulation of metabolic acids and compromised ketone body synthesis (6). Elevated levels of metabolic acids often cause liver damage and/or hepatomegaly in 3-HMG patients (7). Normally, during periods of fasting or infection, generation of ketone bodies in mitochondria provide an alternative energy source for the brain, heart and kidney (6).…”

HMG–CoA Lyase Deficiency

“…However, its distribution and activity in human tissues have been limited to enzyme assay in fibroblast (Wanders et al, 1988b) lymphoblast (Wysocki et al, 1976b) liver biopsy (Robinson et al,1980) amniocytes and chorionic villi (Wanders et al, 1988b) or pancreatic islets (MacDonald et al, 2007). Recently, it has been reported the first study of mRNA levels, protein expression and enzyme activity of human HMG-CoA lyase in kidney, pancreas, testis, heart, skeletal muscle and brain (Puisac et al, 2010). The highest HL activity was found in liver and pancreas was the second with more activity (Figure 4c).…”

“…It has been reported that organs such as the brain, the liver and occasionally the pancreas and the heart are affected (Gibson et al, 1994;Leung et al, 2009;Muroi et al, 2000a;Urganci et al, 2001;Wilson et al, 1984;Zafeiriou et al, 2007;Zoghbi et al, 1986). Recently, a study of mRNA levels, protein expression and enzyme activity of human HMG-CoA lyase in kidney, pancreas, testis, heart, skeletal muscle and brain has contributed to better understanding of the enzyme function and of the involvement of these organs in 3-hydroxy-3-methylglutaric aciduria (Puisac et al, 2010). The liver is the organ most frequently affected in this deficiency, although involvement is usually mild, with elevated transaminases and hepatomegaly (Urganci et al, 2001;Wysocki & Hahnel, 1986).…”

“…The finding of higher enzymatic activity in pancreas (Puisac et al, 2010) indicates that it may be more susceptible to toxic accumulation of metabolites. Among the brain abnormalities in these patients, cerebral white matter involment is the most common reported finding (Lisson et al, 1981;Yalcinkaya et al, 1999;Zafeiriou et al, 2007) and also one case of prominent corticospinal tract and pontine involvement has also been reported (Yylmaz et al, 2006).…”