Mitochondrial trifunctional protein deficiency is an autosomal recessive disorder in the fatty acid oxidation pathway, which causes severe organ dysfunction. The onset is induced by fasting or illness and manifests as hypoketotic hypoglycemia. The diagnosis is achieved by personal and family history, physical exam, and appropriate studies.
Mitochondrial trifunctional protein deficiency (MTPD) is a genetic disorder in which there is a deficiency in the key enzyme (trifunctional protein) involved in the catalysis of several steps in long-chain fatty acid oxidation  . This disease is inherited in an autosomal recessive pattern, which results from mutations in the hydroxy acyl-coenzyme A dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) or hydroxy acyl-coenzyme A dehydrogenase trifunctional multienzyme complex subunit beta (HADHB) genes  . Insufficiency of trifunctional protein causes severe impairment in the generation of energy, hence impacting multiple organs and resulting in early death if not treated . This fatty oxidation disorder shares similar manifestations to isolated long-chain 3-hydroxy acyl-coenzyme A dehydrogenase (LCHAD) deficiency .
Patients with MTPD may present in the neonatal period, infancy, or later. Hypoketotic hypoglycemia, the initial manifestation in very young individuals, follows stressful events such as fasting or even illness like viral infection  . Other features typically include cardiomyopathy, cardiac arrhythmias, hepatic steatosis, rhabdomyolysis, myopathy, peripheral neuropathy, and retinopathy   . Although uncommon, patients may also develop infant respiratory distress syndrome (IRDS) .
Studies have demonstrated that cases with this enzymatic deficiency suffer from chronic myopathy . Additionally, this group of people is likely to have pigmentary retinopathy and progressive atrophy of eye structures.
Significant neurologic deficits include hypotonia, significant weakness, and absent deep tendon reflexes. Moreover, auscultation yields abnormal heart rhythm while an ophthalmology exam reveals a pale fundus and numerous other abnormalities, especially with time. Finally, the overall examination is also notable for hepatomegaly  and jaundice.
The workup consists of patient and family history, precipitating factors such as fasting or illness, physical exam, and the appropriate tests.
To confirm the diagnosis, a sample of cultured fibroblasts should demonstrate impaired activity in two or all three enzymes  .
Pertinent studies assessing acute hypoketotic hypoglycemia include blood glucose and urinary ketones. Additional exams to understand the full clinical picture should include measurements of liver function tests (LFTs), lactic acid, creatine phosphokinase, uric acid, and ammonia. These are usually elevated during acute events.
In order to support the diagnosis, a plasma profile of organic acids is obtained, of which the results typically reveal elevated levels of long-chain hydroxy acylcarnitine compounds. Urine analysis may show hydroxy dicarboxylic aciduria. Note that such changes may not be noticed in the asymptomatic periods.
Echocardiography assesses cardiac function and size while chest radiography displays cardiomegaly in patients with heart involvement.
Electrocardiography (EKG) identifies any present arrhythmias and possibly structural abnormalities. Electroretinography detects retinal pathology . Finally, nerve conduction studies can also be helpful.
Testing for defects in the HADHA or HADHB genes is an option for families with specific and known mutations.
Chorionic villus sampling (CVS) can be performed to test for enzymatic activity in cases with personal or family history of this disease.
Note that mitochondrial trifunctional protein deficiency is among the ailments that are tested during routine newborn screening .