A new study presented the case of a patient with trifunctional protein (TFP) deficiency, 1 of the 6 types of long chain fatty acid oxidation disorders (LCFAOD), in the European Journal of Medical Genetics.

The authors of the study conducted a literature review of previously published cases and gathered that the presentation of the disease is phenotypically and molecularly highly heterogeneous. It’s also associated with high mortality rates.

“Although there is no strict clinical/biochemical phenotype-genotype correlation, [the] difference in ethnic and subunit mutations still have certain characteristics,” they wrote.

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Read more about LCFAOD etiology

The case presented is that of a Chinese baby who was diagnosed with hypoparathyroidism, neutropenia, and nephrotic syndrome. Whole exome sequencing analysis revealed that she was a compound heterozygote for 2 new variants in the HADHB gene, 1 of 2 genes in which a mutation leads to TFP deficiency. One of these variants was a nonsense substitution that she inherited from her father and the second was a splicing defect mutation that she inherited from her mother.

The researchers reported that the patient’s long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity was 27%, her 2-enoyl coenzyme A (CoA) hydratase (LCEH) was 25%, and her long-chain 3-ketoacyl CoA thiolase (LCKT) activity was 42%. “All clues pointed towards [mitochondrial trifunctional protein deficiency],” they wrote.

The literature review included 156 published cases and revealed that the disease has diverse clinical, biochemical, and molecular features. In most of these cases, the symptoms of the disease appeared in early childhood and affected the neuromuscular system.

In severe cases, the disease affected multiple organs and was characterized by respiratory failure. In milder cases, the main features were neuropathy and rhabdomyolysis. Biochemically, the most common finding was increased long-chain 3-OH-acylcarnitines (C16–OH, C18:1-OH). 

The researchers also found that mutations in the HADHB gene were more common in patients of Asian descent with complete TFP deficiency but there were no common variants in this gene. On the other hand, the common variant in the HADHA gene was 1528G > C. Finally, the disease phenotype seemed to be more related to the type of mutation than to residual enzyme activity.


Li Y, He C, Li S, Wang J, Jiang L, Guo Y. Hypoparathyroidism, neutropenia and nephrotic syndrome in a patient with mitochondrial trifunctional protein deficiency: A case report and review of the literature. Eur J Med Genet. 2021;17;64(12):104344. doi:10.1016/j.ejmg.2021.104344