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.

• Pain

  […] mentioned in various sources for Mitochondrial trifunctional protein deficiency includes the 9 symptoms listed below: * Feeding difficulty * Lethargy * Lack of energy * Low blood sugar * Muscle weakness * Liver problems * Breakdown of muscle tissue * Muscle pain [checkorphan.org]

  A 21-year-old parous woman presented with nausea, genital bleeding and abdominal pain at 33 weeks of gestation. Laboratory data revealed hepatic failure and disseminated intravascular coagulopathy. [ncbi.nlm.nih.gov]

  Signs and symptoms of mitochondrial trifunctional protein deficiency that may begin after infancy include hypotonia, muscle pain, a breakdown of muscle tissue, and a loss of sensation in the extremities (peripheral neuropathy). [liquisearch.com]

  The person may experience hypotonia, muscle pain, muscle tissue breakdown, and suffer abnormalities in the nervous system affecting the arms and legs. Causes The disorder may manifest during infancy or late in life. [medigest.uk]

  The late-onset form is usually less severe; signs and symptoms can include hypotonia, muscle pain, a breakdown of muscle tissue, and abnormalities in the nervous system that affect arms and legs (peripheral neuropathy). [wikidoc.org]

• Feeding Difficulties

  Symptoms - Mitochondrial trifunctional protein deficiency The list of signs and symptoms mentioned in various sources for Mitochondrial trifunctional protein deficiency includes the 9 symptoms listed below: * Feeding difficulty * Lethargy * Lack of energy [checkorphan.org]

  Features that occur during infancy include feeding difficulties, lack of energy (lethargy), low blood sugar (hypoglycemia), weak muscle tone (hypotonia), and liver problems. [liquisearch.com]

  Symptoms and Signs Early signs of the disorder include feeding difficulties, lethargy, low blood sugar, weakness of muscles, and problems of the liver. [medigest.uk]

  Signs and symptoms of the early onset form can include feeding difficulties, lack of energy ( lethargy ), low blood sugar ( hypoglycemia ), muscle weakness ( hypotonia ), liver problems, and a high risk for complications such as life-threatening heart [wikidoc.org]

  Features that occur during infancy include feeding difficulties,lethargy, hypoglycemia, hypotonia, and liver problems. Infants with this disorder are also at high risk for serious heart problems, breathing difficulties, coma, and sudden death. [flybase.org]

• HELLP Syndrome

  Maternal HELLP syndrome occurred in two mothers independently of the fetal phenotype. Mutational analysis revealed 16 different mutations, the majority being missense mutations (n=12). [ncbi.nlm.nih.gov]

  Pre-eclampsia, eclampsia and HELLP syndrome accounted for 5 (11.6%). While 1 (2.3%) was diagnosed with hemolytic uremic syndrome and another one was diagnosed as ARF secondary to hypotension produced by hyperemesis gravidarum. [science.gov]

  In a small number of cases, HADHA mutations appear to increase a woman's risk of developing two serious liver disorders during pregnancy, known as acute fatty liver of pregnancy (AFLP) and HELLP syndrome. [ghr.nlm.nih.gov]

  Pediatr-Res. 2001 Jan; 49(1): 18-23 den-Boer,-M-E; Ijlst,-L; Wijburg,-F-A; Oostheim,-W; van-Werkhoven,-M-A; van-Pampus,-M-G; Heymans,-H-S; Wanders,-R-J Heterozygosity for the common LCHAD mutation (1528g>C) is not a major cause of HELLP syndrome and the [malattierare.regione.veneto.it]

• Fatigue

  He reported multiple episodes of exercise-induced severe muscle fatigue and brown urine in his childhood, which disappeared by age 20. [jstage.jst.go.jp]

  These patients have hypoketotic hypoglycemia, hepatomegaly, recurrent “infections”, and easy fatigue resulting in recurrent sore muscles. Some present with exercise-induced rhabdomyolysis. [genico.ch]

• Short Stature

  Late diagnosis is associated with markedly advanced skeletal maturation and accelerated linear growth initially, but early natural puberty and ultimately short stature. [genico.ch]

• Overeating

  We would like to take this opportunity to thank you for your support over the years. The Wikispaces team [bio122honorsoption.wikispaces.com]

  A pigmentary retinopathy may also develop over time. Very occasionally, adults presenting for the first time with a previously unrecognized disease are described. [orpha.net]

  Rosenberg has published over 270 original scientific papers, chapters, reviews and editorials. [books.google.com]

• Failure to Thrive

  The remaining 12 patients presented with a much more insidious disease with nonspecific chronic symptoms, including hypotonia (100%), cardiomyopathy (73%), failure to thrive, or peripheral neuropathy. [ncbi.nlm.nih.gov]

  Eleven patients (22%) presented with chronic problems, consisting of failure to thrive, feeding difficulties, cholestatic liver disease, and/or hypotonia. [pediatrics.aappublications.org]

  The variable presentation includes infantile hypoketotic hypoglycemia, vomiting, lethargy, hypotonia, and failure to thrive. [genedx.com]

  Failure to thrive, vomiting, and hypoglycemia may be seen. [genico.ch]

  Patients showed hypoketotic hypoglycemia in 78%, chronic liver disease, failure to thrive, feeding difficulties/hypotonia in 22%. [ojrd.biomedcentral.com]

• Abdominal Pain

  A 21-year-old parous woman presented with nausea, genital bleeding and abdominal pain at 33 weeks of gestation. Laboratory data revealed hepatic failure and disseminated intravascular coagulopathy. [ncbi.nlm.nih.gov]

  AFLP begins with abdominal pain and can rapidly progress to liver failure. HELLP stands for hemolysis (the breakdown of red blood cells), elevated liver enzyme levels, and low platelets (cell fragments involved with blood clotting). [ghr.nlm.nih.gov]

  There is a small risk of: excess vomiting abdominal pain high blood pressure jaundice severe bleeding abnormal fat storage in the liver All women with a family history of TFP deficiency should share this information with their obstetricians and other [newbornscreening.info]

• Nausea

  A 21-year-old parous woman presented with nausea, genital bleeding and abdominal pain at 33 weeks of gestation. Laboratory data revealed hepatic failure and disseminated intravascular coagulopathy. [ncbi.nlm.nih.gov]

  Some of the first symptoms of a metabolic crisis are: extreme sleepiness behavior changes irritable mood muscle weakness poor appetite Some of these other symptoms may also follow: fever nausea diarrhea vomiting hypoglycemia increased levels of acidic [newbornscreening.info]

• Visual Impairment

  Aside from visual impairment, patients with gyrate atrophy are for the most part asymptomatic. [genico.ch]

• Muscle Hypotonia

  Patients have hypotonia, progressive muscle weakness, developmental delay and, possibly seizures. Failure to thrive, vomiting, and hypoglycemia may be seen. [genico.ch]

• Muscle Cramp

  Additional presentations are cardiomyopathy and cardiac conduction defects, severe liver disease, recurrent muscle cramps, seizures, coma or sudden death (SIDS). Peripheral neuromyopathy, and pigmentary retinopathy may develop at a later age. [genedx.com]

• Seizure

  There are over 200 inherited disorders that are associated with seizures and prompt identification and intervention is crucial for a positive outcome. [books.google.com]

  Here, we report the case of a Korean male newborn who presented with severe lactic acidosis, seizures, and heart failure. [ncbi.nlm.nih.gov]

  Additional presentations are cardiomyopathy and cardiac conduction defects, severe liver disease, recurrent muscle cramps, seizures, coma or sudden death (SIDS). Peripheral neuromyopathy, and pigmentary retinopathy may develop at a later age. [genedx.com]

• Irritability

  The symptoms may include irritability, sleeping longer, tiredness, vomiting, weak muscle tone (hypotonia), poor appetite, fever, diarrhea, low blood sugar (hypoglycemia), no reflexes or pain responses, developmental delays, and behavior changes. [diseaseinfosearch.org]

  Signs of early TFP include: Poor appetite Sleeping longer or more often Tiredness Weak muscle tone (called hypotonia) Fever Vomiting Diarrhea Low blood sugar (called hypoglycemia) Irritability Behavior changes No reflexes or pain responses Developmental [babysfirsttest.org]

  Some of the first symptoms of a metabolic crisis are: extreme sleepiness behavior changes irritable mood muscle weakness poor appetite Some of these other symptoms may also follow: fever nausea diarrhea vomiting hypoglycemia increased levels of acidic [newbornscreening.info]

  As an alternate presentation, an affected infant may be delayed in achieving early motor milestones and appear irritable, jittery, hypotonic, and have impaired voluntary movements. [genico.ch]

• Excitement

  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]

  She's very excited," Mrs Davies said. "She loves doing craft and meeting new people and she says to her little brother that she's a big girl now." [illawarramercury.com.au]

• Confusion

  […] possibility of early diagnosis of rare genetic diseases before they cause serious damage to the child There are rare genetic diseases, mainly metabolic, not easily diagnosable, that occur in the first days of life with generic symptoms which are often confused [bigroup.bioscienceclinic.com]

  Differential Diagnosis The infant form may be confused with other rare forms of cardiomyopathy, including glycogen storage disease type 2 (Pompe disease), VLCAD and multiple acyl-CoA dehydrogenase deficiency, and other carnitine disorders, such as carnitine-acylarnitine [medicalhomeportal.org]

• Dizziness

  Hypoglycemia causes: weakness shakiness dizziness clammy, cold skin if untreated, coma, and sometimes death In children with TFP deficiency, either hypoglycemia or a metabolic crisis can happen: after going too long without food after long periods of [newbornscreening.info]

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]

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]

In spite of early diagnosis and treatment, only a few patients with this condition have survived. [ncbi.nlm.nih.gov]

The Intellectual Disability, Treatment & Management contains management information. [medicalhomeportal.org]

"Management of fatty acid oxidation disorders: a survey of current treatment strategies". J Am Diet Assoc. 102 (12): 1800–1803. doi : 10.1016/S0002-8223(02)90386-X. [en.wikipedia.org]

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]

Prognosis - Mitochondrial trifunctional protein deficiency Not supplied. Treatment - Mitochondrial trifunctional protein deficiency Not supplied. Resources - Mitochondrial trifunctional protein deficiency Not supplied. [checkorphan.org]

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]

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]

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]

^ "Long-Chain Acyl CoA Dehydrogenase Deficiency: Background, Pathophysiology, Epidemiology". eMedicine. 24 March 2016. [en.wikipedia.org]

Relevant External Links for HADHB Genetic Association Database (GAD) HADHB Human Genome Epidemiology (HuGE) Navigator HADHB Atlas of Genetics and Cytogenetics in Oncology and Haematology: HADHB No data available for Genatlas for HADHB Gene Fluorescence [genecards.org]

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]

^ "Long-Chain Acyl CoA Dehydrogenase Deficiency: Background, Pathophysiology, Epidemiology". eMedicine. 24 March 2016. [en.wikipedia.org]

Pathophysiology The molecular defect occurs in the mitochondrial trifunctional protein (MTP). [emedicine.medscape.com]

Recommendations for diabetes screening and preventive measures specific to Asian American populations are warranted 611 2 7 |a Comparative Study |2 gnd 611 2 7 |a Journal Article |2 gnd 653 2 |a Adult |6 D000328 653 2 |a Age of Onset |6 D017668 653 2 [pubpharm.de]

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]

[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]

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]

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.