Scientifica

Review Article

Human Metabolic Enzymes Deficiency: A Genetic Mutation Based Approach

Table 1

Metabolic enzymes deficiency disorders and genetic mutations.


Enzymes	Deficiency disorders	Mutations	Protein/amino acid/nucleotide	Mutation types	Gene location	Other complications	References

Glucose-6-phosphatase	Von Gierke’s disease	c.130C>T	p.P44S	Missense	Chromosome 17q21	Single episode of myositis	[9, 133]
		c.346A>G	p.M116V	Missense	17q21	T-cell lymphopenia, monocytosis, anemia, bilateral inguinal herniae, undescended testes, Dursun syndrome, and thymus hypoplasia	[9, 134]
		c.347 T>A	p.M116K	Missense	17q21	Learning difficulties and hypogonadotrophic hypogonadism, mild mitral and tricuspid insufficiency	[9, 133, 135]
		c.461 T>C	p.L154P	Missense	17q21	Hypercellular marrow, myeloid hyperplasia, no maturation arrest, frontal bossing, depressed nasal bridge, upturned nose, retrognathia, and learning difficulties	[136]
		c.554 T>C	p.L185P	Missense	17q21	Pulmonary valve stenosis	[137]
		c.623 T>G	p.L208R	Missense	17q21	Tricuspid insufficiency	[138]
		c.758G>A	p.R253H	Missense	17q21	Reduced mature neutrophils, discontinuous labia majora and minora, close set, down sloping eyes, low set ears, and bilateral cryptorchidism	[137–140]
		c.778G>C	p.G260R	Missense	17q21	Micropenis, mild developmental delay, hypoplastic nipples, malar flattening, reduced mature neutrophils, and cryptorchidism	[137, 139, 141]
		c.779G>A	p.G260D	Missense	17q21	Maturation arrest at myelocyte/promyelocyte stage, triangular face, frontal bossing, micrognathia, depressed nasal bridge, and cutis laxa	[139]
		c.144C>A	p.Y48X	Frame-shift and splice-site	17q21	Cryptorchidism, bilateral inguinal hernia, and cleft palate	[137]
		c.190_210del	p.T64_I70del	Frame-shift and splice-site	17q21	Granulomatous inflammatory bowel disease, splenomegaly, digital clubbing, and short stature	[138, 140]
		c.210delC	p.I70fsX46	Frame-shift and splice-site	17q21	Triangular face, depressed nasal bridge, growth retardation, enlarged anterior pituitary lobe, and maturation arrest at myelocyte/promyelocyte stage	[137, 142]
		c.218 + 1G >A	—	Frame-shift and splice-site	17q21	Reduced mature neutrophils and increased reticular staining, right inguinal hernia, bilateral cryptorchidism, and frontal bossing	[137]
		c.416G>T	—	Frame-shift and splice-site	17q21	Maturation arrest at myelocyte/promyelocyte stage, failure to thrive	[137]
		c.[766_777del]	p.[S255fs]	Frame-shift and splice-site	17q21	Broad face, prominent ears, small nose, big mouth, narrow forehead, short philtrum, and bilateral inner ear hearing loss	[137]
		c.131C>T; 758 G>A	p.P44L; R253H	Frame-shift and splice-site	17q21	Flat malar region, short philtrum, splenomegaly, and right ptosis	[139]
		c.210delC; 348G>A	p.I70fsX46; M116I	Frame-shift and splice-site	17q21	Triangular face, prominent upper lip, depressed tip of nose, and narrow thorax	[139, 142]
		c.677 + 1G>A; 829C>T	p.Gln277X	Frame-shift and splice-site	17q21	—	[9]
Fructose-1,6-bisphosphatase		581T>C,	F194S	—	9q22.2-q22.3	Hepatomegaly, acidosis, ketonuria, elevated uric acid level, and increased lactate and lipid level	[47]
		851C>G,	P284R	—	—	Vomiting, drowsiness, tachypnea, and hepatomegaly	[47]
		960/961insG	—	—	—	Glyceroluria	[45]
		A177D	530C-A	Missense	—	—	[45]
		E30X	88G-T	Nonsense	—	—	[45]
		V325A	974TC	Nonsense	—	—	[45]
Ribose-phosphate isomerase		c.540delG	—	Frame-shift	2p11.2	—	[113, 143]
		c.182C>T,	p.A61V	Missense	2p11.2	—	[113, 143]
Transaldolase		c.512_514delCCT	p.Ser171del	Homozygous	11p15.5-p15.4 1p34.1-p33 (pseudo-gene)	Aortic coarctation, tubulopathy, splenomegaly, and neonatal oedema	[118]
		c. 575G>A	p.Arg192His	Missense	11p15.5-p15.4 1p34.1-p33 (pseudo-gene)	Glomerular proteinuria, large venous duct, cardiomyopathy, and splenomegaly	[117]
		c.512_514delCCT	p.Ser171del	—	11p15.5-p15.4 1p34.1-p33 (pseudo-gene)	Nephrocalcinosis	[116]
		c.574C>T	p.Arg192Cys	—	11p15.5-p15.4 1p34.1-p33 (pseudo-gene)	Tubulopathy	[118]
		c.575G>A	p.Arg192His	Missense	11p15.5-p15.4 1p34.1-p33 (pseudo-gene)	Neonatal oedema, liver fibrosis, hepatosplenomegaly, and anaemia	[115]
Succinate dehydrogenase		IVS1+1G4T	c.72+1G4T	—	SDHB 1p35-p36.1	Paraganglioma, pheochromocytoma	[102]
		IVS4+1G4C	c.423+1G4C, c.423+1G4A	—	SDHB 1p35-p36.1	Progressive external ophthalmoplegia	[102, 144]
		c.45_46insCC	—	—	SDHB 1p35-p36.1	Paraganglioma, pheochromocytoma, and progressive external ophthalmoplegia	[102]
		c.43C4T	—	—	SDHC 1q21	Optic atrophy, ataxia, progressive myopathy, and developmental delay	[102]
		IVS5+1G4A	c.405+1G4A	—	SDHC 1q21	Progressive external ophthalmoplegia	[102, 145]
		c.57delG	—	—	SDHD 11q23	Optic atrophy, ataxia, progressive myopathy, developmental delay, and progressive external ophthalmoplegia	[102]
Glucose-6-phosphate dehydrogenase		202(GA)/ 376(AG)	—	—	Xq28	Hemolytic anemia	[109, 110]
		563CT	—	—	Xq28	Cyanosis, headache, fatigue, tachycardia, dyspnea, lethargy, lumbar/substernal pain, abdominal pain, splenomegaly, hemoglobinuria, and/or scleral icterus	[104, 109, 110]
		1003GA	—	—	Xq28	Splenomegaly, hemoglobinuria, and/or scleral icterus	[104, 109, 110]
		1376GC	—	—	Xq28	Cyanosis, headache, fatigue, tachycardia, lethargy, lumbar/substernal pain, and abdominal pain	[80, 104, 109, 110]
		68 ValMet	—	—	Xq28	Hemoglobinuria	[146]
		126 AsnAsp	—	—	Xq28	Lethargy, lumbar/substernal pain	[146]
Fumarase	Fumaric aciduria	c.1358T4C	p.L453P	—	1q42.1	Neurological impairment, microcephaly	[147]
		c.653T4C1	[p.L218P]	—	1q42.1	Encephalopathy, seizures, vomiting, and hypotonia	[96, 147]
		c.512G4A	p.S171N	—	1q42.1	Neurological impairment, encephalopathy, seizures, vomiting, and hypotonia	[96]
		A265T	—	Missense	1q42.1	Encephalopathy, seizures, vomiting, and hypotonia	[147]
		D383V	—	Missense	1q42.1	Microcephaly, seizures, developmental delay, or mental retardation	[147]
		F269C	—	Missense	1q42.1	Encephalopathy, mental retardation	[147]
		K187R	—	Missense	1q42.1	Microcephaly, seizures	[147]
		W458X	—	Nonsense	1q42.1	Seizures, vomiting, and hypotonia	[147]
Pyruvate dehydrogenase complex	Leigh disease	A1133G	—	Missense	Xp22 (E1α)	Hypotonia, developmental delay	[71, 148]
		C214T	—	Missense	Xp22 (E1α)	Corpus callosum abnormalities	[81]
		C615A	—	Missense	Xp22 (E1α)	Peripheral neuropathy	[81]
		R263G	—	Missense/nonsense	Xp22 (E1α)	Corpus callosum abnormalities, seizures, hypotonia, developmental delay, and peripheral neuropathy	[81, 149]
		R72	—	Missense/nonsense	Xp22 (E1α)	Callosal agenesis/dysgenesis, cerebral atrophy	[149]
		R378	—	Missense/nonsense	Xp22 (E1α)	Ataxia, relapsing dystonia	[149]
N-Acetylglutamate synthetase deficiency		TGGTAG	Trp324Ter	Null mutation	17q21.31	Hyperammonemia	[126]
		1025delG	—	Deletion	17q21.31	Vomiting, altered consciousness, seizures, and coma	[126]
		C200R	c.598T>C	Missense	17q21.31	Chronic headaches, nausea	[130, 150]
		S410P	c.1228T>C	Missense	17q21.31	Hyperammonemia, altered level of consciousness, seizures, coma, and chronic headaches	[130, 150]
		A518T	c.1552G>A	Missense	17q21.31	Vomiting, altered level of consciousness, seizures, coma, and neurological impairment	[120, 130, 150]
		L430P	c.1289T>C	—	17q21.31	Hyperammonemia, vomiting, coma, chronic headaches, and nausea	[130, 150]
		W484R	c.1450T>C	—	17q21.31	Hyperammonemia, neurological impairment	[123, 130, 150]