Table 3.

Diagnostic evaluation of the patient with a methionyl-tRNA synthetase mutation

Etiological assessment	Investigations performed (normal unless otherwise indicated)
Infections	Serum procalcitonin levels (significantly elevated, Table 1);
	Serology for Hepatitis B, C, HIV, syphilis, EBV, CMV, HSV, toxoplasmin, and rubella virus;
	PCR for CMV; beta-d-glucan assay; galactomannan assay; T-Spot.TB test;
	Cerebrospinal fluid analysis for white blood cell count, protein, and glucose level;
	Complete blood count: anemia, elevated WBC and C-reactive protein (Table 1);
	Culture for blood, urine, sputum, alveolar lavage fluid, and cerebrospinal fluid;
	Sputum and alveolar lavage fluid for mycoplasma/chlamydia DNA detection;
	Sputum and alveolar lavage fluid for detection of respiratory syncytial virus, adenovirus, influenza virus, and para-influenza virus antigens;
	Alveolar lavage fluid smear for fungus detection
Radiology, endoscopy, and histopathology	Multiple chest X-rays and a contrast-enhanced computed tomography scan of the lung (alveolar effusions with severe interstitial lung disease) (Figure 1);
	Abdominal ultrasonography and CT scan (hepatomegaly, liver steatosis, kidney stones) (Figure 1);
	Bronchoscopy (chronic inflammatory changes in bronchiolar mucosa);
	X-ray imaging of the skull; CT scan of adrenal gland;
	X-ray imaging of long bones: (abnormally shallow hip socket that is suggestive of acetabular dysplasia or congenital hip dysplasia) (Figure 1);
	Liver biopsy (severe steatosis of hepatic cells with ballooning, lobular disarrays; mild changes, such as cholestasis, fibrosis, lymphocyte infiltration, Iron deposition, and bile duct proliferation);
	Bone marrow aspirate (extreme proliferation of bone marrow cells with few hemophagocytic cells); peripheral blood smear
Immunology	Immunoglobulin levels (after IVIG therapy at local hospital): elevated IgG (20.2 g/L, normal range 3.7-8.3 g/L), IgM (1.47 g/L, normal range 0.33-1.25 g/L), and IgA (0.63 g/L, normal range 0.14-0.5) levels; normal IgE, complement 4, and complement 3 levels;
	Neutrophil oxidative burst activity, and lymphocyte subpopulations;
	Autoimmune antibodies
Biochemical, metabolic and endocrine profiling	Glucose profiling (hypoglycemia); slightly elevated serum lactate (Table 1);
	Liver function test: cholestasis, hypoalbuminemia, abnormal blood coagulation profiles (Table 1);
	Creatine kinase, lactate dehydrogenase;
	Serum amino acids (proline 1803 μmol/L, normal range: 165-700 μmol/L; threonine 171 μmol/L, normal range: 17-90 μmol/L) and acyl-carnitine profile; urine organic acids (including succinylacetone); Urine acidoglycoprotein (51.98 mg/mmol creatinine, normal range: 59.70-78.52 mg/mmol creatinine).
	Low levels of total serum cholesterol, HDL and LDL cholesterol (Table 1).
	Serum cortisol level; thyroid function test (total triiodothyronine 52.6 ng/dL, normal range: 70-220 ng/dL)
	Ophthalmology, electrocardiology, and echocardiogram (patent foramen ovale, 2.6 mm)
Genetic disorders	White blood cell lysosomal enzyme screening for GM1 gangliosidosis, GM2 gangliosidosis, Sandhoff disease, Krabbe leukodystrophy, Gaucher disease, Fabry disease, Pompe disease, metachromatic leukodystrophy, Nieman-Pick disease, neuronal ceroid lipofuscinoses (1 and 2), mucopolysaccharidosis (type I-VII, IX), muculipidosis (type II and III).
	Liver panel including 41 genes known to cause liver diseases, and trio whole exome sequencing (Table 2).