Also known as TRNT1 deficiency, it is an inherited condition caused due to mutations (alterations) in the TRNT1 gene. Although it affects different parts of the body, TRNT1 deficiency is known for its characteristic visual and immunological complications known as retinitis pigmentosa (RP) and erythrocytic microcytosis (EM).
RP is a condition that affects the retina (a light-sensitive layer at the back of the eye) of the eye; it gradually destroys the photoreceptor (specialized cells that function in the initial step of the vision) cells present in the retina, which will lead to progressive vision loss.
The EM seen in REPM is rather complicated in nature; REPM causes a condition called sideroblastic anemia, which is a type of anemia that results from abnormal utilization of iron during the formation of red blood cells. As a result, the red blood cells formed are reduced in number and in size. The state of unusually small red blood cells is known as erythrocytic microcytosis.
Other associated features of REPM include immunodeficiency, periodic fevers, developmental delay, hearing loss, etc. It can be diagnosed with the help of clinical manifestations, laboratory investigations, and genetic testing. Treatment primarily involves managing the complications, which improve over time.
What Causes REPM?
REPM is caused due to mutations in the TRNT1 gene, which are inherited in an autosomal recessive pattern. The TRNT1 gene is responsible for providing instructions for a protein called TRNT1 protein. This protein modifies transfer ribonucleic acid (tRNA) in a way that it only binds to its respective amino acid and assembles it in its specific location so that the protein synthesis happens in an organized and predetermined manner.
However, in TRNT1 deficiency, the TRNT1 protein is not synthesized properly, which leads to improper binding of the tRNA to the amino acids resulting in the dysfunction of the protein synthesis. Researchers have observed that TRNT1 deficiency exclusively affects the protein synthesis in mitochondria, which is an energy-producing center of the cell.
In TRNT1 deficiency, the mitochondria will not be able to produce enough energy to meet the demands of the various systems in the body, especially the brain, blood cells, eyes, etc., leading to their dysfunction and their associated complications.
What Are the Complications of REPM?
REPM causes a spectrum of symptoms ranging from a childhood-onset complex disease with manifestations in most organs to an adult-onset isolated RP presentation. The possible clinical complications of REPM are:
1. Sideroblastic Anemia- It is the kind of anemia that results from an abnormal build-up of iron during the formation of red blood cells. It can be either microcytic (as seen or REPM) or macrocytic (seen in bone marrow disorders).
It is known to be sideroblastic because when the red blood cells in this type of anemia are stained with certain types of dyes in the lab, a characteristic blue ring appears inside these cells. The blue rings represent the mitochondria's unutilized iron, which in the absence of REPM, would have been used for the formation of normal-sized red blood cells.
2. Immunodeficiency- REPM, along with red blood cells, also affects the formation of B and T lymphocytes which are essential to protect the body from infections. As a result of these malformations, the individual will be subjected to repeated infections which can be life-threatening.
3. Recurrent Fever Syndrome- This is a peculiar feature of REPM; the fevers seen in this condition are not due to an infection and occur in episodes lasting for five to seven days every 2 to 4 weeks.
The fever is accompanied by vomiting, nausea, and diarrhea and can lead to frequent hospitalization.
4. Developmental Delay- REPM individuals during infancy will suffer from neurological complications that will lead to delay in speech, motor delay (like walking, sitting, standing, etc.), hypotonia (low muscle tone), and an overall failure to thrive.
All of the features mentioned above are collectively known as sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) syndrome. This was considered to be a childhood-limited manifestation of TRNT1 deficiency, but in recent times researchers have observed that some adults were also affected by these manifestations, which made them conclude that SIFD, along with RP and EM, combines to form TRNT1 deficiency.
Multisystem Mitochondrial Disease:
Retinitis Pigmentosa- A condition where the retina's photoreceptor cells gradually degenerate, leading to progressive vision loss.
Hepatosplenomegaly- It is a condition where the liver and spleen are enlarged beyond the normal size.
Exocrine Pancreatic insufficiency- It is a condition that occurs due to insufficient production of digestive enzymes by the pancreas.
Renal Tubulopathy- It is a kidney complication that occurs due to impaired function of the tubules in the nephron (functional unit of the kidney).
All the conditions mentioned in the multisystem mitochondrial diseases comprise the REPM part of the TRNT1 deficiency. Besides SIFD and REPM, TRNT1 deficiency can also present with clinical features like sensorineural deafness (a type of hearing loss), cerebellar atrophy (deterioration and death of the cerebellar neurons), brittle hair, partial villous atrophy (disappearance of the intestinal villi which are necessary for absorption), and nephrocalcinosis (generalized calcium deposits in the kidney).
How Is TRNT1 deficiency Diagnosed?
TRNT1 can be diagnosed with the help of the patient's family’s medical history, clinical manifestations, laboratory investigations, and genetic testing. TRNT1 deficiency is inherited in an autosomal recessive manner, meaning the individual must have two copies (one from each parent) of the defective gene for the condition to manifest. The patient's family history will reveal individuals that might have been affected previously, aiding in the diagnosis.
The clinical features, on the other hand, are severe in infancy; the commonly seen features are- immunodeficiency, fluctuating hemoglobin percentage, fever, etc. The symptoms tend to improve with age, and adults are typically affected by RP and EM.
Laboratory investigations include complete blood count, urinalysis, immunological analysis, genetic testing, etc.
How Is TRNT1 Deficiency Treated?
There is no complete cure for genetic conditions; however, most of the conditions, including TRNT1 deficiency, can be managed to a certain extent with the help of medications and adjunct therapy.
This can include corticosteroids and immunoglobulin therapy for febrile episodes, Pyridoxine or blood transfusion for sideroblastic anemia, UV sunglasses, or an artificial retina for RP. In the end extreme cases, bone marrow transplant should be considered, which will halt the episodic febrile and metabolic decompression, thereby improving quality of life.
TRNT1 deficiency is an inherited condition that is extremely rare in nature. Clinical manifestations include two ends of the spectrum- SIFD and REPM, and the patient’s family history plays an important role in the diagnosis of the condition. Treatment involves conventional medical management and genetic counseling, which plays an important role in understanding the condition of the patient and their family members.