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Mitochondrial Trifunctional Protein Deficiency

LCHADD

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.


Presentation

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 [1] [2]. 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 [3] [4]. Insufficiency of trifunctional protein causes severe impairment in the generation of energy, hence impacting multiple organs and resulting in early death if not treated [2]. This fatty oxidation disorder shares similar manifestations to isolated long-chain 3-hydroxy acyl-coenzyme A dehydrogenase (LCHAD) deficiency [5].

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 [1] [6]. Other features typically include cardiomyopathy, cardiac arrhythmias, hepatic steatosis, rhabdomyolysis, myopathy, peripheral neuropathy, and retinopathy [1] [6] [7]. Although uncommon, patients may also develop infant respiratory distress syndrome (IRDS) [8].

There is a milder form associated with later onset [9] [10]. These individuals show rhabdomyolysis and myalgia after exercise and have a better prognosis overall.

Complications

Studies have demonstrated that cases with this enzymatic deficiency suffer from chronic myopathy [11]. Additionally, this group of people is likely to have pigmentary retinopathy and progressive atrophy of eye structures.

Physical exam

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 [1] and jaundice.

Progressive Polyneuropathy
  • MTP deficiency is an autosomal recessive disorder that causes a clinical spectrum of diseases ranging from severe infantile cardiomyopathy to mild chronic progressive polyneuropathy.[ncbi.nlm.nih.gov]
Increased Energy
  • LCHADD and TFP deficiency cause cellular damage from accumulation of 3-OH-fatty acids, impaired energy production from longer chain fatty acids, and consequent hypoglycemic crises during prolonged fasting or increased energy demands, such as fever or[medicalhomeportal.org]
Respiratory Insufficiency
  • Neurologic episodes of painful paresthesias, weak- ness, paralysis, and respiratory insufficiency occur. There is a high risk for development of hepatic nodules and hepatocellular carcinoma. Most untreated patients die in infancy or early childhood.[genico.ch]
Muscle Hypotonia
  • The picture of methymalonic acidemia as recurrent vomiting, dehydration, respiratory distress, muscle hypotonia, and lethargy that can lead to coma and death is often seen in the first week of life. Metabolic acidosis is pronounced.[genico.ch]
Dark Urine
  • Patient 4, a 25-month-old baby, manifested recurrent episodes of lethargy, metabolic acidosis, elevated liver enzymes, and dark urine from the age of 10 months.[ncbi.nlm.nih.gov]
Absent Deep Tendon Reflex
  • Physical exam Significant neurologic deficits include hypotonia, significant weakness, and absent deep tendon reflexes.[symptoma.com]

Workup

The workup consists of patient and family history, precipitating factors such as fasting or illness, physical exam, and the appropriate tests.

Diagnostic tests

To confirm the diagnosis, a sample of cultured fibroblasts should demonstrate impaired activity in two or all three enzymes [1] [12].

Laboratory tests

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.

Imaging

Echocardiography assesses cardiac function and size while chest radiography displays cardiomegaly in patients with heart involvement.

Other

Electrocardiography (EKG) identifies any present arrhythmias and possibly structural abnormalities. Electroretinography detects retinal pathology [13]. Finally, nerve conduction studies can also be helpful.

Genetic analysis

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.

Screening

Note that mitochondrial trifunctional protein deficiency is among the ailments that are tested during routine newborn screening [2].

Hypoketotic Hypoglycemia
  • Laboratory tests Pertinent studies assessing acute hypoketotic hypoglycemia include blood glucose and urinary ketones.[symptoma.com]
  • Nine (43%) patients presented with rapidly progressive clinical deterioration; six (67%) of them had hypoketotic hypoglycemia.[ncbi.nlm.nih.gov]
  • Patients with long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency manifest hypoketotic hypoglycemia, hepatomegaly, hypotonia, lactic acidemia, acute renal failure, cardiomyopathy, and sudden death.[ncbi.nlm.nih.gov]
  • Three clinical phenotypes are apparent: a severe neonatal presentation with cardiomyopathy, Reye-like symptoms, and early death (n 4); a hepatic form with recurrent hypoketotic hypoglycemia (n 2); and a milder later-onset neuromyopathic phenotype with[ncbi.nlm.nih.gov]
  • Its deficiency impairs the energy generating function of this pathway and causes hypoketotic hypoglycemia once hepatic glycogen stores are depleted. A Reye-like syndrome, cardiomyopathy, and sudden death may follow.[ncbi.nlm.nih.gov]
Hypoketotic Hypoglycemia
  • Laboratory tests Pertinent studies assessing acute hypoketotic hypoglycemia include blood glucose and urinary ketones.[symptoma.com]
  • Nine (43%) patients presented with rapidly progressive clinical deterioration; six (67%) of them had hypoketotic hypoglycemia.[ncbi.nlm.nih.gov]
  • Patients with long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency manifest hypoketotic hypoglycemia, hepatomegaly, hypotonia, lactic acidemia, acute renal failure, cardiomyopathy, and sudden death.[ncbi.nlm.nih.gov]
  • Three clinical phenotypes are apparent: a severe neonatal presentation with cardiomyopathy, Reye-like symptoms, and early death (n 4); a hepatic form with recurrent hypoketotic hypoglycemia (n 2); and a milder later-onset neuromyopathic phenotype with[ncbi.nlm.nih.gov]
  • Its deficiency impairs the energy generating function of this pathway and causes hypoketotic hypoglycemia once hepatic glycogen stores are depleted. A Reye-like syndrome, cardiomyopathy, and sudden death may follow.[ncbi.nlm.nih.gov]
Liver Biopsy
  • The activity of CPS can be measured in a liver biopsy. Mutation analysis of the CPS gene may be useful for prenatal diagnosis in future pregnancies.[genico.ch]

Treatment

  • In spite of early diagnosis and treatment, only a few patients with this condition have survived.[ncbi.nlm.nih.gov]
  • Management and treatment Treatment involves adherence to a low fat diet with restriction of long chain fatty acid intake and substitution with medium chain fatty acids.[orpha.net]
  • The Intellectual Disability, Treatment & Management contains management information.[medicalhomeportal.org]
  • Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Springer. ISBN 9783642403378. External links [ edit ] Media related to Mitochondrial trifunctional protein deficiency at Wikimedia Commons[en.wikipedia.org]

Prognosis

  • Prognosis Prognosis for the severe neonatal form of TFPD is very poor. The later onset mild form has a far more favorable prognosis. The documents contained in this web site are presented for information purposes only.[orpha.net]
  • Prognosis Prognosis for the severe neonatal form of TFPD is very poor. The later onset mild form has a far more favorable prognosis. Last updated: 2/1/2014[rarediseases.info.nih.gov]
  • These individuals show rhabdomyolysis and myalgia after exercise and have a better prognosis overall. Complications Studies have demonstrated that cases with this enzymatic deficiency suffer from chronic myopathy.[symptoma.com]
  • Prognosis - Mitochondrial trifunctional protein deficiency Not supplied. Treatment - Mitochondrial trifunctional protein deficiency Not supplied. Resources - Mitochondrial trifunctional protein deficiency Not supplied.[checkorphan.org]

Etiology

  • The differential diagnosis is extensive and includes various etiologies, such as infection, inflammation, trauma, endocrinopathies, and congenital muscular and metabolic disorders.[ncbi.nlm.nih.gov]
  • Etiology The TFP, composed of 4 alpha and 4 beta subunits, catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids which are the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase (LCEH), and long-chain thiolase[orpha.net]
  • Rounding out the coverage of this exciting field are critical and comprenhesive discussions on the use of molecular, genetic and cellular techniques used to identify the etiology and pathophysiology of specific cardiac diseases. * Discusses diagnostic[books.google.com]
  • Export Citation: APA/MLA Format Download EndNote Download BibTex MeSH Terms Descriptor/Qualifier: Female Humans Hypocalcemia / blood, etiology*, therapy Hypoparathyroidism / blood, complications* Infant Multienzyme Complexes / deficiency* Phosphates [biomedsearch.com]

Epidemiology

  • Summary Epidemiology TFPD has been reported in less than 100 cases in the literature. Clinical description The neonatal onset, severe form manifests as hepatic steatosis, cardiomyopathy, skeletal myopathy and neuropathy and is usually fatal.[orpha.net]
  • Epidemiology TFPD has been reported in less than 100 cases in the literature. Clinical description The neonatal onset, severe form manifests as hepatic steatosis, cardiomyopathy, skeletal myopathy and neuropathy and is usually fatal.[rarediseases.info.nih.gov]
  • Chronic hemolytic anemia and delayed CNS myelination have also been reported. [9] Epidemiology Frequency United States The incidence of isolated LCHAD activity deficiency and trifunctional protein deficiency is unknown in the United States.[emedicine.medscape.com]
Sex distribution
Age distribution

Pathophysiology

  • Rounding out the coverage of this exciting field are critical and comprenhesive discussions on the use of molecular, genetic and cellular techniques used to identify the etiology and pathophysiology of specific cardiac diseases. * Discusses diagnostic[books.google.com]
  • Pathophysiology The molecular defect occurs in the mitochondrial trifunctional protein (MTP).[emedicine.medscape.com]
  • Spiekerkötter et al. ( 9 ) investigated the pathophysiologic mechanisms in MTP deficiency.[clinchem.aaccjnls.org]

Prevention

  • Definition Mitochondrial trifunctional protein deficiency is a disorder that prevents certain fats in the body to convert to energy, specifically during periods of no food.[medigest.uk]
  • Mitochondrial trifunctional protein deficiency is a rare inherited condition that prevents the body from converting certain fats to energy, particularly during periods without food.[wikidoc.org]
  • Causes - Mitochondrial trifunctional protein deficiency Other Possible Causes of these Symptoms * Feeding difficulty * Lack of energy * Lethargy * Liver problems * Low blood sugar * Muscle pain * Muscle weakness * Peripheral neuropathy Prevention - Mitochondrial[checkorphan.org]
  • [From OMIM:609015, 2016.06.16] Mitochondrial trifunctional protein deficiency is a rare condition that prevents the body from converting certain fats to energy, particularly when fasting.[flybase.org]
  • [updated Jul. 2017 by FlyBase; FBrf0222196 ] Disease Summary Information Parent Disease Summary: mitochondrial trifunctional protein deficiency Symptoms and phenotype Mitochondrial trifunctional protein deficiency is a rare condition that prevents the[flybase.org]

References

Article

  1. Matern D, Strauss AW, Hillman SL, et al. Diagnosis of mitochondrial trifunctional protein deficiency in a blood spot from the newborn screening card by tandem mass spectrometry and DNA analysis. Pediatr Res. 1999;46(1):45-49.
  2. De Biase I, Viau KS, Liu A, et al. Diagnosis, Treatment, and Clinical Outcome of Patients with Mitochondrial Trifunctional Protein/Long-Chain 3-Hydroxy Acyl-CoA Dehydrogenase Deficiency. JIMD Rep. 2017;31:63-71.
  3. Diekman EF, Boelen CCA, Prinsen BHCMT, et al. Necrotizing Enterocolitis and Respiratory Distress Syndrome as First Clinical Presentation of Mitochondrial Trifunctional Protein Deficiency. JIMD Rep. 2013;7:1-6.
  4. Ushikubo S, Aoyama T, Kamijo T, et al. Molecular characterization of mitochondrial trifunctional protein deficiency: formation of the enzyme complex is important for stabilization of both alpha- and beta-subunits. Am J Hum Genet. 1996;58(5):979-988.
  5. Grünewald S, Bakkeren J, Wanders RA, Wendel U. Neonatal lethal mitochondrial trifunctional protein deficiency mimicking a respiratory chain defect. J Inherit Metab Dis. 1997;20(6):835-836.
  6. Den Boer ME, Wanders RJ, IJlst L, et al. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients. Pediatrics. 2002;109(1):99–104.
  7. Den Boer MEJ, Dionisi-Vici C, Chakrapani A, et al. Mitochondrial trifunctional protein deficiency: a severe fatty acid oxidation disorder with cardiac and neurologic involvement. J Pediatr. 2003;142(6):684–689.
  8. Olpin SE, Clark S, Andresen BS, et al. Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency. J Inherit Metab Dis. 2005;28(4):533–544.
  9. Miyajima H, Orii KE, Shindo Y, et al. Mitochondrial trifunctional protein deficiency associated with recurrent myoglobinuria in adolescence. Neurology. 1997;49(3):833–837.
  10. Schaefer J, Jackson S, Dick DJ, Turnbull DM. Trifunctional enzyme deficiency: adult presentation of a usually fatal β-oxidation defect. Ann Neurol. 1996;40(4):597–602.
  11. Schiff M, Mohsen AW, Karunanidhi A, et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013;109(1):21-27.
  12. Roe CR, Coates PM. Mitochondrial fatty acid oxidation disorders. In: Scriver CR, Beaudet AL, Sly WS, et al, eds. The metabolic and molecular bases of inherited disease. New York, NY: McGraw-Hill;1995:1501–1533.
  13. Spiekerkoetter U, Lindner M, Santer R, et al. Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from a workshop. J Inherit Metab Dis. 2009;32(4):488–497.

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Last updated: 2019-07-11 19:55