TRMU Deficiency

Disease Overview

Summary

TRMU deficiency is a rare genetic disorder that affects the mitochondria, the cell structures that make energy. Symptoms typically are observed in children between the ages of two to four months. It mainly affects the liver, causing acute liver dysfunction which can include the accumulation of enzymes called transaminases, liver function impairment and liver enlargement (hepatomegaly). Other findings may include buildup of lactic acid leading to lactic acidosis, low blood sugar (hypoglycemia), high levels of ammonia (hyperammonemia), poor weight gain and decreased muscle tone (hypotonia).

Children over the age of four months with TRMU deficiency may have a neurologic condition called Leigh-like syndrome. They can also have cardiomyopathy, which affects the heart muscle and its ability to pump blood.

Diagnosis can be suspected in children over the age of four months that present with enlargement of the liver, poor weight gain and buildup of lactic acid.

TRMU deficiency is caused by changes (variants) in the TRMU gene. Inheritance is autosomal recessive, meaning that two copies of a disease-causing TRMU gene variant, one from each parent, are required to cause this condition.

Introduction

The first group of patients with TRMU deficiency was described in 2009 by doctors in Israel. The first documented report of an infant with TRMU deficiency symptoms was in 2002. Limited research has been conducted on this rare condition.

Early diagnosis and recognition of signs of TRMU deficiency are important because many individuals are not diagnosed until they have liver failure. There is no cure, but early diagnosis can allow doctors to develop a treatment plan before acute and severe symptoms occur.

Next section >

< Previous section
Next section >

Synonyms

TRMU-related reversible infantile respiratory chain deficiency
TRMU-related mitochondrial hepatopathy
TRMU-related reversible infantile liver failure
acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins
acute infantile liver failure due to synthesis defect of mitochondrial DNA-encoded proteins
acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins
acute infantile liver failure
infantile liver failure caused by mutation in TRMU
LFIT
liver failure, infantile, transient
liver failure, transient infantile
transient infantile liver failure
TRMU infantile liver failure

< Previous section
Next section >

< Previous section
Next section >

Signs & Symptoms

Signs and symptoms of people affected by TRMU deficiency can vary in both frequency and severity and may include:

Liver disease: A common symptom of TRMU deficiency that can appear suddenly and usually start around two months of age if untreated but can improve with proper treatment. It may result in:

- High levels of liver enzymes
- An enlarged liver (hepatomegaly)
- Liver failure

- - The liver is vital for cleaning harmful substances from the blood, storing energy and creating important enzymes. When the liver doesn’t work properly, other health issues can develop.

Metabolic findings: (in more than 50% of patients) People with TRMU deficiency often have abnormal levels of certain molecules in their bodies. These include:

- Lactic acidosis: Too much lactic acid in the body, often occurring before liver issues
- Hyperalaninemia: Higher than normal levels of alanine in the blood
- Hypoglycemia: Low blood sugar levels
- Hyperammonemia: Excess ammonia in the body, usually with liver dysfunction

Muscle weakness (hypotonia): (in about one-third of patients)
Gastrointestinal problems: This can be an early sign, often appearing before liver disease symptoms, especially if a baby or child struggles to feed or absorb nutrients properly. TRMU deficiency can cause toxic molecules to build up, affecting the stomach and intestines and can lead to:

- Diarrhea
- Vomiting

Respiratory failure: Severe muscle weakness (hypotonia) can lead to respiratory failure, which means difficulty in breathing.
Leigh-like syndrome: Leigh-like syndrome has been reported in some people with TRMU deficiency, so TRMU gene testing is important; Leigh syndrome is characterized by:

- Acute liver failure
- Progressive muscle weakness (hypotonia)
- Brain dysfunction (encephalopathy)
- Delayed speech, movement and cognitive abilities (psychomotor delay)
- Seizures

Heart problems (dilated cardiomyopathy): Present in some affected babies
- Dilated cardiomyopathy (DCM) is when the heart’s main pumping chamber (left ventricle) becomes enlarged and weak, affecting the heart’s ability to pump blood
Kidney issues: (in some affected babies) Often improves over time and characterized by:
- Nephromegaly, which means large kidneys
- Proteinuria, which means high levels of protein in the urine
Developmental delay: Developmental delays vary among individuals with TRMU deficiency.
- These delays might be due to worsening liver disease, acute liver failure, or the underlying mitochondrial disorder.

< Previous section
Next section >

< Previous section
Next section >

Causes

TRMU deficiency is caused by changes (variants) in the TRMU gene. TRMU is a gene in the DNA in the cell nucleus involved in supporting DNA translation in the mitochondria. Mitochondria are organelles within cells that generate chemical energy needed to support and sustain cellular functions. DNA translation is an essential step in creating functional proteins from genetic material. Without this process, it is not possible for cells to maintain proper functioning which can lead to disease.

Genetic information is contained in two types of DNA: nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). nDNA is contained in the nucleus of a cell and is inherited from both the egg and sperm, whereas mtDNA is contained in the mitochondria of cells and is inherited only from the egg. TRMU deficiency is caused by having two disease-causing variants in the TRMU gene which is in nDNA. These variants result in reduced or absent production of the molecule necessary for carrying out DNA translation in the mitochondria. As a result, the process for making protein in the mtDNA does not occur normally.

TRMU deficiency is inherited in a recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

< Previous section
Next section >

< Previous section
Next section >

Affected populations

TRMU deficiency develops in infancy, typically within the first few months of life, or early childhood. Approximately 60 individuals have been diagnosed with TRMU deficiency, and it may be more common in people with Yemenite Jewish ancestry. Due to limited reported cases in the medical literature, specific information about clinical age of onset, prevalence, or possible differences in males versus females is not fully known. TMRU deficiency likely underdiagnosed.

< Previous section
Next section >

< Previous section
Next section >

Disorders with Similar Symptoms

The following conditions have some similar symtoms with TMRU deficiency. Comparisons may be useful for differential diagnosis.

Leigh syndrome is a rare genetic neurometabolic disorder characterized by the deterioration of the central nervous system (i.e., brain, spinal cord and optic nerve). Individuals with Leigh syndrome typically show symptoms between the ages of three months and two years, but some people do not show symptoms until later in childhood. Symptoms involve progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability and/or seizures. As Leigh syndrome progresses, symptoms may also include generalized weakness, hypotonia and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. Leigh syndrome has over 100 genetic causes, all of which affect chemical energy production of the mitochondria. Leigh syndrome follows many inheritance patterns depending on the genetic change involved, but most commonly is inherited in an autosomal recessive pattern. X-linked recessive and maternal inheritance due to a mtDNA gene variant have also been reported.

Mitochondrial hepatopathy is a broad diagnosis category that includes many related mitochondrial diseases. These conditions tend to have a spectrum of diverse symptoms, but all result from mitochondrial respiratory chain dysfunction. All these conditions typically present early in childhood but can present later in life and are due to genetic changes in mtDNA . The instructions to make (encode) the proteins that are needed to make the mtDNA are in genes found in the nucleus of cells. When gene variants impair the function of any one of these genes, mtDNA synthesis is impaired. Symptoms include signs of liver disease such as jaundice, vomiting, weakness, sleepiness, elevated liver blood enzymes and an increased amount of lactic acids in the blood. Additional signs include low muscle tone, delayed motor skill development and convulsions or seizures.

Organic acidemias (OAs) are a group of inherited disorders of protein metabolism. Most organic acidemias are caused by deficiencies of enzymes involved in breaking down parts of protein called amino acids. This inability to break down amino acids leads to toxic accumulation of organic acids. Symptoms of OAs are typically seen at birth but can present at any age. Because of the early onset of symptoms, these conditions are usually screened for at birth and detected through newborn screening programs. However, not all OAs are detected by newborn screening, and these programs vary by state and country.

Fatty acid oxidation disorders (FAODs) are another group of inborn errors of metabolism in which there is a disruption of the pathway essential for breaking down fats (Merritt et.al., 2018). Fat is key in energy production which occurs in the mitochondria. In FAODs, this inability to break down fat leads to deficient energy production and the accumulation of toxic metabolites. As with OAs, symptoms of FAODs are typically seen at birth but can present at any age. They are also screened for on newborn screenings but not all FAODs are detected by newborn screening and, depending on the state or country or birth, screening may not be comprehensive of all FAODs.

OAs and FAODs can present in infancy with poor feeding, vomiting, low muscle tone and increased lethargy. Initial presentation in older infants and children includes similar symptoms that were listed previously in addition to seizures and loss of previously acquired motor and cognitive skills. FAODs can also include some cardiovascular symptoms such as cardiomyopathy or ventricular dysrhythmias.

< Previous section
Next section >

< Previous section
Next section >

Diagnosis

TRMU deficiency may be suspected based on symptoms of developmental regression, low blood sugar levels and buildup of lactic acid and/or ammonia. The diagnosis is confirmed with genetic testing. Possible types of genetic testing are a mitochondrial disorders genetic testing panel, a cholestasis panel, or an acute infantile liver failure multigene panel that includes the TRMU gene.

Prior to the availability of molecular genetic testing, liver and muscle biopsies were used to diagnose TRMU deficiency.

Clinical Testing and Work Up

Abdominal ultrasound can be used to detect abnormalities in the liver such as enlargement of the liver and the accumulation of triglycerides within the liver as well as persistent hepatic nodules. Brain MRI findings such as lesions of the thalami, abnormalities of the putamen, basal nuclei, pontine tracts, upper cerebellar peduncles, subthalamic nuclei, and brain stem can be suggestive of TRMU deficiency, although brain imaging may be normal in some children.

MR spectroscopy can indicate a lactate peak at age two to four months.

< Previous section
Next section >

< Previous section
Next section >

Standard Therapies

There is no cure for TRMU deficiency. Treatment is focused on managing specific symptoms in an individual patient. Each person’s treatment plan is different because symptoms can vary between individuals. A team of healthcare providers will generally manage the care for a person with TRMU deficiency. Members of this team may include a pediatrician, hepatologist (a liver specialist), gastroenterologist (a stomach, intestine, colon, pancreas, liver and rectum specialist), neurologist (a brain, nerves and nervous system specialist), physical therapist, occupational therapist, cardiologist, speech language pathologist, medical geneticist and genetic counselor.

A detailed treatment and surveillance (check-up) plan should be created for each individual with TRMU deficiency by the team of specialist physicians. Some common treatments include L-cysteine and N-acetylcysteine therapy and liver transplant.

Symptoms like liver dysfunction, metabolic findings and weakness can be improved by giving TRMU deficient patients L-cysteine and N-acetylcysteine. L-cysteine is an amino acid that the body needs to function. In people with TRMU deficiency, L-cysteine may be used by the body to help the TRMU enzyme work more effectively. L-cysteine is often given to patients in the form of N-acetylcysteine.

Liver transplantation is a treatment option for TRMU deficiency patients with liver dysfunction. Liver transplant removes parts of a person’s non-functioning liver and replaces it with a part of a healthy liver from a donor. Sometimes the entire liver is replaced and other times it is just a portion of the liver. A study following 63 patients with TRMU deficiency showed that out of the 43 individuals with acute liver failure, 11 of them received a liver transplant. Of the 11 individuals with TRMU deficiency who received a liver transplant, 4 of them survived but had neurodevelopmental delay.

Genetic counseling is recommended for individuals with TRMU deficiency and their families.

< Previous section
Next section >

< Previous section
Next section >

Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact: http://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

< Previous section
Next section >

< Previous section
Next section >

References

JOURNAL ARTICLES
Vogel GF, Mozer-Glassberg Y, Landau YE, et al. Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants [published correction appears in Genet Med. 2023 Jun;25(6):100828. doi: 10.1016/j.gim.2023.100828]. Genet Med. 2023;25(6):100314. doi:10.1016/j.gim.2022.09.015

Guilder LL and Kronick JB. Organic Acidemias. Pediatrics In Review. 2022; 43(3): 123–134. https://doi.org/10.1542/pir.2020-000562

Murali CN, Soler-Alfonso C, Loomes KM, et al. TRMU deficiency: A broad clinical spectrum responsive to cysteine supplementation. Mol Genet Metab. 2021;132(2):146-153. doi:10.1016/j.ymgme.2021.01.005

Sala-Coromina J, Miguel LD, de Las Heras J, et al. Leigh syndrome associated with TRMU gene mutations. Mol Genet Metab Rep. 2020;26:100690. Published 2020 Dec 15. doi:10.1016/j.ymgmr.2020.100690

Merritt JL 2nd, Norris M, Kanungo S. Fatty acid oxidation disorders. Ann Transl Med. 2018;6(24):473. doi:10.21037/atm.2018.10.57

Lev D, Gilad E, Leshinsky-Silver E, et al. Reversible fulminant lactic acidosis and liver failure in an infant with hepatic cytochrome-c oxidase deficiency. J Inherit Metab Dis. 2002;25(5):371-377. doi:10.1023/a:1020195616081

INTERNET
Reinhart M, Muraresku C, Ganetzky R. TRMU Deficiency. 2023 May 11. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK591557/ Accessed July 23, 2024.

Bodamer OA, Organic acidemias: An overview and specific defects. UpToDate. last updated: Jun 26, 2024. https://www.uptodate.com/contents/organic-acidemias-an-overview-and-specific-defects#H4 Accessed July 23, 2024.

Mitochondrial Hepatopathies. The Childhood Liver Disease Research Network. (n.d.). https://childrennetwork.org/Clinical-Studies/Mitochondrial-Hepatopathies Accessed July 23, 2024.

< Previous section
Next section >

Programs & Resources

RareCare^® Assistance Programs

Floxuridine Medication Assistance

Accepting Applications

Phone: 203-516-0962 Email: [email protected] Fax: 203-207-9896

Related Rare Diseases: Cholangiocarcinoma, Polycystic Liver Disease, Carcinoma de células de Merkel, ...

Resource(s): Floxuridine-Medication Assistance -12-2023

Apply Online

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/