2,4-Dienoyl-Coa Reductase Deficiency

A number sign (#) is used with this entry because of evidence that 2,4-dienoyl-CoA reductase deficiency (DECRD) is caused by homozygous mutation in the NADK2 gene (615787) on chromosome 5p13. One such patient has been reported.

Description

DECR deficiency is a rare autosomal recessive inborn error of metabolism resulting in mitochondrial dysfunction. Affected individuals have a severe encephalopathy with neurologic and metabolic dysfunction beginning in early infancy. Laboratory studies show decreased activity of the mitochondrial NADP(H)-dependent enzymes DECR1 (222745) and AASS (605113), resulting in increased C10:2-carnitine levels and hyperlysinemia (summary by Houten et al., 2014).

Clinical Features

In a black female infant presenting in the neonatal period with persistent hypotonia, Roe et al. (1990) found deficiency of 2,4-dienoyl-coenzyme A reductase. Biochemical studies had shown hyperlysinemia, hypocarnitinemia, a normal organic acid profile, and an unusual acylcarnitine species in both urine and blood. The latter metabolite was identified by mass spectrometry as 2-trans,4-cis-decadienoylcarnitine, derived from incomplete oxidation of linoleic acid. In spite of dietary therapy, the patient died of respiratory acidosis at 4 months of age. Samples of liver and muscle taken at autopsy showed that the level of 2,4-dienoyl-coenzyme A reductase activity was 40% of the control value in liver and only 17% of that found in normal muscle. Roe et al. (1990) stated that this was the first report of a patient with an enzyme defect related only to unsaturated fatty acid oxidation.

Houten et al. (2014) reported a male infant, born of unrelated Hispanic parents, who presented at 8 weeks of age with failure to thrive, microcephaly, central hypotonia, and mild dysmorphic features. Metabolic studies showed increased plasma C10:2-carnitine, low free carnitine, and increased lysine in plasma, cerebrospinal fluid (CSF), and urine. Blood and CSF lactate were also increased. Urinary organic acids showed several abnormalities consistent with mitochondrial dysfunction. Over the next few years, he showed little developmental progress and had multiple neurologic problems, including nystagmus, hypertonia, clonus, choreoathetosis, dystonia, spastic quadriplegia, cortical blindness, epilepsy, and episodic central apnea, all consistent with severe encephalopathy. Additional features included pancreatitis and renal tubular acidosis. Brain imaging showed progressive leukodystrophy, generalized cerebral atrophy, enlarged ventricles, and T2-weighted abnormalities in the basal ganglia. He died at age 5 years of aspiration pneumonia. Residual DECR activity was 10% in the lysate of patient fibroblasts, but no mutations were identified in the DECR1 gene.

Molecular Genetics

In a Hispanic boy with 2,4-dienoyl-CoA reductase deficiency, Houten et al. (2014) identified a homozygous nonsense mutation in the NADK2 gene (R340X; 615787.0001). The mutation was found by exome sequencing and segregated with the disorder in the family. Mitochondria isolated from patient fibroblasts showed decreased levels of NADP(H). Although NADPH did not restore DECR activity in patient cells, transfection of wildtype NADK2 was able to rescue the DECR deficiency. A mitochondrial stress test indicated overall decreased oxygen consumption and increased extracellular acidification in patient cells compared to controls. Houten et al. (2014) suggested that the severe phenotype likely resulted from impairment of multiple mitochondrial NADP-dependent processes.