Aminoacyl-tRNA synthetase deficiencies
Aminoacyl-tRNA synthetase (aARS) deficiencies are a group of inheritable disorders of metabolism, caused by mutations in genes encoding one of the many aARS enzymes. These enzymes play a crucial role in protein translation, by coupling an amino acid to a transfer RNA (tRNA), which carries the amino acid to the ribosome for incorporation into a protein.
aARSs couple amino acids to either cytosolic tRNAs (aARS1) or mitochondrial tRNAs (aARS2), or both (KARS1, GARS1, QARS1). The first letter refers to the amino acid it couples. Specific ARSs exist for every amino acid, except EPRS1 (glutamyl-prolyl-RS).
Autosomal dominant variants in cytosolic aARS1 genes cause Charcot-Marie-Tooth neuropathies and white matter disease. Autosomal recessive variants in cytosolic aARS1 genes cause a severe multi-organ phenotype (described below). We focus specifically on autosomal recessive aARS1 deficiencies. Patients with leukodystrophies are seen at the leukodystrophy expertise center (Amsterdam UMC).
Autosomal recessive aARS1 mutations lead to decreased enzyme activity. In general, patients have more than 10% residual enzyme activity, and patients with activity of up to 50% have been described (SARS1). Residual enzymatic activity below 10% is likely incompatible with life. Recently, it was found that certain mutations may cause a severe further decrease of enzyme activity, even to 0% at 38.5 °C in one patients (FARSB).
Use of whole-exome sequencing has led to an increasing number of diagnoses with aARS1 deficiencies. The first report appeared in 2012. Since then, more than 200 patients with various aARS1 deficiencies have been described. Not all aARS1 genes are associated with disease, yet.
Currently, autosomal recessive mutations in the following aARS1 genes are associated with disease. Number of patients reflect published reports and other patients known to us (current through 18 May 2021):
- AARS1 (16 patients, OMIM:601065, ORPHA:442835)
- CARS1 (4 patients, OMIM:123859)
- DARS1 (10 patients, OMIM:603084)
- FARSA (4 patients, OMIM:602918)
- FARSB (16 patients, OMIM:609690, ORPHA:178506)
- GARS1 (3 patients, OMIM:600287)
- HARS1 (5 patients, OMIM:142810, ORPHA:231183)
- IARS1 (7 patients, OMIM:600709, ORPHA:541423)
- KARS1 (23 patients, OMIM:601421, ORPHA:90636)
- LARS1 (19 patients, OMIM:151350, ORPHA:370088)
- MARS1 (36 patients, OMIM:156560, ORPHA:440427 & ORPHA:401835)
- NARS1 (27 patients, OMIM:108410)
- RARS1 (20 patients, OMIM:107820)
- SARS1 (8 patients, OMIM:607529, ORPHA:88616)
- TARS1 (2 patients, OMIM:187790)
- VARS1 (3 patients, OMIM:192150)
- YARS1 (10 patients, OMIM:603623)
- QARS1 (20 patients, OMIM:603727, ORPHA:404437 & ORPHA:423306)
On regular basis, new reports are published, and additional aARS1 genes are associated with disease. We expect the actual number of patients to be much higher. The incidence is unknown, but we estimate an incidence of 1:50.000.
ARS1 deficiencies have only been recognized recently. Therefore, little is known about the natural course of disease. For various aARS1 deficiencies, life expectancy is reduced (sometimes to months to years). However, there are also reports of patients who are now teenagers or even adults. Most retain severe growth retardation, intellectual disability, restrictive pulmonary disease and liver dysfunction. Long-term effects of dietary interventions are to be seen.
The most prominent symptom is a symmetrical dysmaturity of head circumference, height and weight (except HARS1). Postpartum, patients have feeding difficulties and may become dependent on tube feeding. Different organ systems may be affected:
- central nervous system: most patients have a global developmental delay with intellectual disability. Where imaging is available, many children have cortical atrophy and white matter abnormalities (e.g., in AARS1, DARS1, HARS1, IARS1, NARS1, RARS1 and VARS1).
- liver: many patients have liver dysfunction, with elevated transaminases (e.g., prominent in LARS1), sometimes with progression to severe liver failure and ascites (e.g., AARS1, IARS1, FARSA/FARSB, SARS1).
- lungs: some patients have a severe interstitial lung disease (extensively described for MARS1, but also for IARS1 and AARS1), which is progressive and requires oxygen therapy. Lung cysts may form in some cases.
- hypoalbuminemia: many patients have hypoalbuminemia in the first year of life, which may require infusions. This symptom often disappears with age.
- blood: in the first year of life, patients may have an anemia (e.g., in IARS1, LARS1, KARS1), which may require frequent transfusions.
- kidneys: patients may have a temporary tubulopathy.
- heart: heartproblems are mostly seen in patients with combined cytosolic-mitochondrial aARS1 deficiencies. These patients may have cardiomyopathiy. Also, pulmonaly valve stenosis and atrial septal defects have been reported.
- muscles: hypotonia and muscle weakness are seen in many aARS1 deficiencies, but are more frequent for combined cytosolic-mitochondrial aARS1 deficiencies. Furthermore, lactic acidosis has been described.
Overall, symptoms are most severe during periods of high translational demand, e.g., the first year of life and during infectious episodes. During infections, liver dysfunction, epilepsy and decrease in conciousness have been described.
Diagnosis is based on DNA-analysis of aARS1 genes. To confirm the pathology, aARS enzyme activity should be measured in patients fibroblasts (aARS1) or lymphoblasts (aARS2).