Novel methionyl-tRNA synthetase gene variants/phenotypes in interstitial lung and liver disease: A case report and review of literature

Table 1 Changes in complete blood count, procalcitonin, serum biochemistry, and blood coagulation profiles

Age (mo) (1in-patient admission; 2discharge to out-patient follow-up)		5.1	5.61	6	6.2	6.5	6.8	7	7.22	9.5
Complete blood count (reference range)	White blood cell (4-10 × 109/L)	16.9	21.1	71.7	26.4	33.7	45.8	30.3	24.3	14.3
	Neutrophil (20%-50%)	58.1	39.8	58.0	63.1	62.0	63.0	62.7	64.4	38.9
	Lymphocyte (45%-75%)	36.2	53.1	31.1	28.7	28.9	15.0	29.5	27.8	51.4
	Abnormal lymphocytes (0%)	NA	0.0	0.0	NA	0.0	17.0	0.0	0.0	NA
	Platelet count (100-300 × 109/L)	764.0	513.0	993.0	464	387.0	494.0	279.0	397	386.0
	Hemoglobin (110-160 g/L)	78.0	85.2	78.2	60.1	64.0	65.2	90.0	88.0	122.0
	Red blood cell count (4.0-5.5 × 1012 /L)	3.5	3.1	2.8	2.0	2.0	2.2	2.9	2.9	4.3
	Reticulocyte (0.5%-1.5%)	NA	2.9	6.7	NA	6.3	7.8	3.3	6.8	1.0
	C-reactive protein (< 8 mg/L)	1.0	8.0	90.0	32.0	43.0	37.0	45.0	8.0	8.0
Procalcitonin (< 0.05 ng/mL)		NA	4.6	17.4	7.7	13.4	NA	NA	NA	NA
Serum biochemistry (reference range)	Albumin (35-55 g/L)	29.0	34.6	27.3	30.8	32.3	28.7	38.5	39.1	43.0
	Alanine aminotransferase (0-40 IU/L)	41.0	45.0	17.0	13.0	4.0	50.0	49.0	38.0	29.0
	Aspartate aminotransferase (0-40 IU/L)	100.0	104.0	46.0	37.0	66.0	98.0	70.0	62.0	41.0
	Total bilirubin (5.1-17.1 μmol/L)	68.0	120.4	133.0	132.9	126.8	110.6	90.1	42.9	8.1
	Direct bilirubin (0-6 μmol/L)	53.0	76.9	93.7	96.1	86.6	70.4	61.8	29.8	4.4
	γ-glutamyl transferase (7-50 IU/L)	73.0	61.0	76.0	58.0	54.0	57.0	107.0	230.0	122.0
	Total bile acid (0-10 μmol/L)	NA	182.8	123.3	152.4	137.2	157.4	311.7	282.3	34.6
	Alkaline phosphatase (42-383 IU/L)	307.0	137.0	149.0	119.0	122.0	148.0	178.0	214.0	378.0
	Blood glucose (3.9-5.8 mmol/L)	NA	1.2	1.6	8.4	1.1	NA	NA	3.6	NA
	Lactic acid (0-2 mmol/L)	NA	3.9	NA	3.6	3.6	NA	NA	NA	NA
	Ammonia (10-47 μmol/L)	NA	88.0	NA	NA	NA	NA	NA	55.0	NA
	Total cholesterol (3.1-5.2 mmol/L)	3.1	2.0	NA	2.3	2.5	NA	2.8	4.4	3.1
	LDL-cholesterol (1.30-3.90 mmol/L)	NA	NA	NA	1.0	NA	NA	NA	NA	NA
	HDL-cholesterol (0.91-2.05 mmol/L)	NA	NA	NA	0.3	NA	NA	NA	NA	NA
	Triglyceride (0.56-1.70 mmol/L)	NA	2.0	NA	2.7	2.1	NA	2.1	1.8	1.5
Blood coagulation profiles (reference range)	Activated partial thromboplastin time (28.0-44.5 s)	NA	48.1	NA	57.5	56.4	53.9	47.7	42.3	43.8
	D-dimer (0-0.3 mg/L)	NA	0.94	NA	2.06	1.15	0.97	0.7	0.51	NA
	Fibrinogen (2-4 g/L)	NA	1.45	NA	1.82	2.29	2.54	3.03	3.46	3.44
	Fibrinogen degradation products (0-5 μg/ML)	NA	1.31	NA	5.22	2.35	2.78	1.47	1.16	NA
	Thrombin time (14-21 s)	NA	20.4	NA	19.1	19.9	19.9	15.8	18.4	15.2
	International normalized ratio (0.8-1.2)	NA	NA	NA	1.29	1.26	1.35	1.3	1.03	0.99
	Prothrombin time (12.0-14.8 s)	NA	NA	NA	16	15.7	16.5	16.1	13.5	13.1
	Prothrombin time activity (80%-100%)	NA	NA	NA	67	69	63	66	95	103

NA: Not available.

Table 2 Genetic testing results

Genetic Tests	Gene	Transcript ID	Associated conditions (Inheritance patterns) in OMIM	Variant	Amino-acid change	Hom/Het	Parental origin	Prediction of pathogenicity
								Mutation taster	SIFT	Provean	Polyphen2
Liver Panel1	ATP8B1	NM _005603	Cholestasis, benign recurrent, intrahepatic (AR); cholestasis, intrahepatic, of pregnancy, 1 (AD); cholestasis, progressive familial intrahepatic 1 (AR)	c.234C> G	p.His78Gln	Het	NA	Polymorphism	Tolerated	Neutral	Benign
				c.1729A>G	p.Ile577Val	Het	NA	Polymorphism	Tolerated	Neutral	Possibly damaging
				c.2021T>C	p. Met674Thr	Het	NA	Polymorphism	Tolerated	Neutral	Benign
				c.3477C>T	Synonymous	Het	NA	Polymorphism	Tolerated	Neutral	NA
				c.3744C>A	Synonymous	Het	NA	Polymorphism	Tolerated	Neutral	NA
Whole exome sequencing	MARS	NM_004990	Charcot-Marie-Tooth disease, axonal, type 2U (AD); Interstitial lung and liver disease (AR)	c.2158C>T	p.Gln720Stop	Het	Maternal	Disease causing	NA	NA	NA
				c.893_894insTCG	p.Arg299dup	Het	Paternal	Disease causing	NA	Deleterious	NA
	ATP8B1	NM_005603	Cholestasis, benign recurrent, intrahepatic (AR); cholestasis, intrahepatic, of pregnancy, 1 (AD); cholestasis, progressive familial intrahepatic 1 (AR)	c.2021T>C	p. Met674Thr	Het	Paternal	polymorphism	Tolerated	Neutral	Benign
	CPT1A	NM_001876	CPT deficiency, hepatic, type IA (AR)	c.1163+5G>A	-	Het	Maternal	Disease causing	NA	NA	NA
	LRPPRC	NM_133259	Leigh syndrome, French-Canadian type (AR)	c.2965C>T	p.Arg989Cys	Het	Maternal	Disease causing	Damaging	Deleterious	Probably damaging
	FLG	NM_002106	Ichthyosis vulgaris (AD); (Dermatitis, atopic, susceptibility to, 2)	c.5841G>A	p.Trp1947Stop	Het	Maternal	Disease causing	NA	NA	NA
	G6PD	NM_00104251	Hemolytic anemia, G6PD deficient (favism) (XLD); (Resistance to malaria due to G6PD deficiency)	c.241C>T	p.Arg81Cys	Het	Maternal	Disease causing	Damaging	Deleterious	Benign
	POMGNT1	NM_017739	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 3 (AR); Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 3 (AR); Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 3 (AR); Retinitis pigmentosa 76 (AR)	c.794G>A	p.Arg265His	Het	Maternal	Disease causing	Damaging	Deleterious	Probably damaging
	SERPINC1	NM_000488	Thrombophilia due to antithrombin III deficiency (AD/AR)	c.719A>G	p.Asn240Ser	Het	Maternal	Polymorphism	Tolerated	Neutral	Benign
	TG	NM_003235	Thyroid dyshormonogenesis 3 (AR); (autoimmune thyroid disease, susceptibility to, 3)	c.5791A>G	p.Ile1931Val	Het	Paternal	Polymorphism	Tolerated	Neutral	Benign
	USH2A	NM_206933	Retinitis pigmentosa 39; Usher syndrome type 2A (AR)	c.8559-2A>G	-	Het	Paternal	Disease causing	NA	NA	NA

¹Genes included in liver panel: ATP8B1, ABCB11, ABCB4, TJP2, BAAT, CLDN1, HSD3B7, AKR1D1, CYP7B1, AMACR, CYP27A1, DHCR7, JAG1, NOTCH2, SLC25A13, DGUOK, MPV17, FAH, ABCC2, UGT1A1, NPC1, NPC2, GALT, GALE, ALDOA, ALDOB, KRT18, KRT8, CIRH1A, CFTR, GFDM1, EARS2, HSD17B4, LIPA, PEX1, PEX5, POU1F1, HESX1, SERPINA1, VIPAS39, and VPS33B. NA: Not available.

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).