. 2023 Sep 9;18:281. doi: 10.1186/s13023-023-02898-w

Table 3.

Gene mutations found in 61 Chinese patients with PA

Number	Exon/Intron	Nucleotide alteration	Protein alteration	Mutation type	Early/late onset	ACMG classification	CADD scores	MSC scores	References	Clinical features	Treatment	Outcome
PCCA
1	Exon10	NM_000282.4:c.802C > T	p.Arg268Cys	Missense	Late	Pathogenic	22.5	20	[110]	No specific clinical symptoms	NA	Following up eleven times within one year and three months after birth, liver and kidney function were normal
	Exon11	NM_000282.4:c.827delG	p.Gly276Valfs*46	Frameshift	Late	Likely Pathogenic	NA	NA	[110]	No specific clinical symptoms	NA
2	Intron8	NM_000282.4:c.638-1G > C	NA	Splice site mutation	Early	Likely Pathogenic	33	20	[61]	Mild anemia or mild jaundice, hyperammonemia, hyperlactatemia and hypoglycemia	Protein restriction with special protein powder and sufficient calories, L-carnitine and arginine supplementation, and regular follow-up checks	Normal development and no acute metabolic disorders were observed during the course of management
	NA	NA	NA	NA		NA	NA	NA
3	Exon9	NM_000282.4:c.688C > T	p.Arg230Cys	Missense		Pathogenic	28.3	20
	Intron13	NM_000282.4:c.1209 + 2 T > G	NA	Splice donor		Pathogenic	34	20
4	Intron2	NM_000282.4:c.183 + 1G > C	NA	Splice site mutation		Likely Pathogenic	33	20
	Exon21	NM_000282.4:c.1850 T > C	p.Leu617Pro	Missense		Likely Benign	24.5	20
5	Exon22	NM_000282.4:c.2002G > A	p.Gly668Arg	Missense		Pathogenic	32	20				Development delay in early infancy
	Exon22	NM_000282.4:c.2040G > A	p.Ala680Ala	Synonymous		Likely Pathogenic	24	20
6	Exon22	NM_000282.4:c.2002G > A	p.Gly668Arg	Missense		Pathogenic	32	20
	Exon2	NM_000282.4:c.131delinsATT	p.Cys44Tyrfs*3	Missense		Pathogenic	NA	NA
7	Intron3	NM_000282.4:c.231 + 1G > A	NA	Splice site mutation		Likely Pathogenic	34	20				NA
	Exon7	NM_000282.4:c.596 T > A	p.Val199Asp	Missense		Uncertain Significance	28.1	20				NA
8	Exon22	NM_000282.4:c.2002G > A	p.Gly668Arg	Missense	Early	Pathogenic	32	20	[59]	Respiratory failure, granulocytopenia, and cardiac damage with rapid progression	Anti-infection measures, atomization therapy, sputum suction, glucose infusion, protein restriction, and supplementation with calcium, arginine, l-carnitine, and l-creatinine phosphate. Efforts were also made to strengthen the respiratory tract and correct acidosis	Died at the age of eighth day after birth
	Exon22	NM_000282.4:c.2002G > A	p.Gly668Arg	Missense		Pathogenic	32	20				Died at the age of eighth day after birth
9	Exon22	NM_000282.4:c.2002G > A	p.Gly668Arg	Missense		Pathogenic	32	20		Disorders of consciousness, poor feeding, hyperammonemia, and metabolic acidosis	Anti-infection, fasting, restriction of protein intake, supplementation of hypertonic glucose, arginine iv to promote ammonia excretion	Died at the age of one month and seven days after birth
	Exon22	NM_000282.4:c.2002G > A	p.Gly668Arg	Missense		Pathogenic	32	20				Died at the age of one month and seven days after birth
10	Intron20	NM_000282.4:c.1845 + 1G > A	NA	Splice site mutation	Early	Pathogenic	34	20	[111]	NA	NA	Died during the neonatal period
	Exon6	NM_000282.4:c.446del	p.Asn149Thrfs*35	Frameshift	Early	Pathogenic	NA	NA		NA	NA	Died during the neonatal period
11	Intron20	NM_000282.4:c.1845 + 1G > A	NA	Splice site mutation	NA	Pathogenic	34	20		Coma, convulsions, bronchopneumonia, anemia, thrombocytopenia	NA	Died after more than seven months old
	Exon6	NM_000282.4:c.446del	p.Asn149Thrfs*35	Frameshift	NA	Pathogenic	NA	NA			NA	Died after more than seven months old
12	Exon3	NM_000282.4:c.229C > T	p.Arg77Trp	Missense	NA	Pathogenic	25.1	20	[112]	NA	NA	NA
	Intron21	NM_000282.4:c.1899 + 1G > A	NA	Splice site mutation	NA	Likely Pathogenic	NA	NA	[112]	NA	NA	NA
13	Exon14	NM_000282.4:c.1262A > C	p.Gln421Pro	Missense	Newborn screening	Uncertain Significance	22.8	20	[64]	No typical PA symptoms, no hyperammonemia	Low-protein diet and l-carnitine supplementation	No significant development delay
	Exon3	NM_000282.4:c.229C > T	p.Arg77Trp	Missense	Newborn screening	Pathogenic	25.1	20	[64]	No typical PA symptoms, no hyperammonemia	Low-protein diet and l-carnitine supplementation	No significant development delay
14	Exon15	NM_000282.4:c.1288C > T	p.Arg430Ter	Nonsense	Newborn screening	Pathogenic	37	20	[113]	NA	NA	NA
	Exon3	NM_000282.4:c.229C > T	p.Arg77Trp	Missense	Newborn screening	Pathogenic	25.1	20		NA	NA	NA
15	Intron13	NM_000282.4:c.1210-7C > G	NA	Splice site mutation	Newborn screening	Uncertain Significance	25.3	20		NA	NA	NA
	Exon13	NM_000282.4:c.1185A > C	p.Ala395Ala	Samesense	Newborn screening	Likely Benign	9.037	20		NA	NA	NA
16	Exon22	NM_000282.4:c.2002G > A	p.Gly668Arg	Missense	Newborn screening	Pathogenic	32	20	[114]	NA	NA	NA
	Exon22	NM_000282.4:c.2002G > A	p.Gly668Arg	Missense	Newborn screening	Pathogenic	32	20	[114]	NA	NA	NA
17	Exon12	NM_000282.4:c.937C > T	p.Arg313Ter	Nonsense	Early	Pathogenic	38	20	[37]	Tachypnea, poor reaction, seizures, lethargy, irritability	Antibiotics treatment, supplementation of l-carnitine, folic acid, and biotin; protein restriction	Died at approximately two months of age
	Exon10-	NM_000282.4:c.773_819 + 47delinsAA	NA	Complex deletion–		Likely Pathogenic	NA	NA
	Intron10	NM_000282.4:c.773_819 + 47delinsAA	NA	Insertion (delins) mutation		Likely Pathogenic	NA	NA
18	Exon15	NM_000282.4:c.1288C > T	p.Arg430Ter	Nonsense	Early	Pathogenic	37	20	[7]	Generalized tonic–clonic seizures, metabolic acidosis and hyperammonemia	NA	Died at six and a half months old from sudden cardiac arrest
	Exon22	NM_000282.4:c.2002G > A	p.Gly668Arg	Missense	Early	Pathogenic	32	20			NA
19	Exon16	NM_000282.4:c.1426C > T	p.Arg476Ter	Nonsense	Early	Pathogenic	41	20		Recurrent vomiting, lethargy and dyspnea	Low-isoleucine, − methionine, − threonine, and-valine diet, supplementation of l-carnitine and biotin	Mild intellectual disability
	Exon16	NM_000282.4:c.1426C > T	p.Arg476Ter	Nonsense	Early	Pathogenic	41	20		Recurrent vomiting, lethargy and dyspnea		Mild intellectual disability
20	Exon19	NM_000282.4:c.1746G > C	P.Ser582Ser	Synonymous	Early	Uncertain Significance	9.081	20	[36]	Cough, tachypnea, dyspnea and metabolic acidosis	NA	Died due to respiratory failure
	Exon3-4	NM_000282.4:Exon3-4del	NA	NA	Early	NA	NA	NA		Cough, tachypnea, dyspnea and metabolic acidosis	NA	Died due to respiratory failure
21	Exon19	NM_000282.4:c.1746G > C	P.Ser582Ser	Synonymous	Early	Uncertain Significance	9.081	20		Cough, tachypnea, dyspnea and metabolic acidosis	NA	NA
	Exon3-4	NM_000282.4:Exon3-4del	NA	NA	Early	NA	NA	NA		Cough, tachypnea, dyspnea and metabolic acidosis	NA	NA
22	Exon22	NM_000282.4:c.2002G > A	p.Gly668Arg	Missense	Late	Pathogenic	32	20	[62]	Poor feeding, intermittent vomiting, dilated cardiomyopathy	Liver transplantation	Liver transplantation improved cardiac function but did not significantly impact growth, even with a normal diet, except when supplemented with l-carnitine
	Exon22	NM_000282.4:c.2002G > A	p.Gly668Arg	Missense	Late	Pathogenic	32	20	[62]	Poor feeding, intermittent vomiting, dilated cardiomyopathy	Liver transplantation
23	Exon21	NM_000282.4:c.1850 T > C	p.Leu617Pro	Missense	Newborn screening	Likely Benign	24.5	20	[108]	NA	NA	NA
	Exon4	NM_000282.4:c.297 T > A	p.Ser99Arg	Missense	Newborn screening	Uncertain Significance	20.4	20	[108]	NA	NA	NA
24	Intron15	NM_000282.4:c.1353 + 5_1353 + 9del	NA	Splice site mutation	Late	Uncertain Significance	NA	NA	[52]	NA	Low protein diet, special milk powder, oral l-carnitine and arginine	Physical and intellectual development is normal and noacute metabolic disorders
	NA	NA	NA	NA	Late	NA	NA	NA	[52]	NA
25	Exon3	NM_000282.4:c.229C > T	p.Arg77Trp	Missense	Newborn screening	Pathogenic	25.1	20	[109]	NA	NA	NA
	Exon22	NM_000282.4:c.2002G > A	p.Gly668Arg	Missense	Newborn screening	Pathogenic	32	20	[109]	NA	NA	NA
PCCB
1	Exon13	NM_000532.5:c.1301C > T	p.Ala434Val	Missense	Early	Pathogenic	32	20	[65]	Poor feeding, hyperglycinemia, hyperammonemia, metabolic acidosis, early recurrent infections, and development delay	Sodium bicarbonate IV to correct acidosis, l-carnitine supplementation, BCAA restriction and protein intake reduction	Obvious development delay and intellectual disability
	Exon13	NM_000532.5:c.1301C > T	p.Ala434Val	Missense	Early	Pathogenic	32	20				Obvious development delay and intellectual disability
2	Exon1	NM_000532.5:c.167_179del13insC	p.Asp56_Lys60delinsAla	Deletion and insertion mutation	Late	NA	NA	NA		Hyperglycininemia	l-carnitine supplementation, BCAA restriction and protein intake reduction	Mental and language development is slightly delayed
	Exon1	NM_000532.5:c.167_179del13insC	p.Asp56_Lys60delinsAla	Deletion and insertion mutation	Late	NA	NA	NA		Hyperglycininemia		Mental and language development is slightly delayed
3	Exon1	NM_000532.5:c.132_134delGACinsAT	p.Thr45SerfsTer20	Deletion and insertion mutation	Early	Likely Pathogenic	NA	NA	[115]	Repeated seizures, hyperammonemia, ketoacidosis, hyperglycaemia, anemia	Protein restriction along with phenobarbital, l-carnitine, and arginine supplementation. Treatments to correct acidosis and electrolyte disorders	Symptoms were improved
	NA	NA	NA	NA	Early	NA	NA	NA	[115]			Symptoms were improved
4	Exon14	NM_000532.5:c.1403C > T	p.Ala468Val	Missense	Early	Likely Pathogenic	27.1	20	[61]	Mild anemia or mild jaundice, metabolic acidosis, hyperammonemia, hyperlactatemia and hypoglycemia	Similar to PCCA cases No. 2- 7	Physical and intellectual development is normal
	Exon8	NM_000532.5:c.838dup	p.Leu280fs	Frameshift	Early	Pathogenic	NA	NA				Physical and intellectual development is normal
5	Intron1	NM_000532.5:c.184-2A > G	NA	Splice site mutation	Early	Pathogenic	33	20		Repeated vomiting, lethargy, dyspnea, hypotonia, metabolic acidosis, hyperammonemia, liver dysfunction		Death from an acute metabolic disorder occurred at the age of seven months
	Exon7	NM_000532.5:c.733G > A	p.Gly245Ser	Missense	Early	Likely Pathogenic	28.9	20
6	Exon3	NM_000532.5:c.331C > T	p.Arg111Ter	Nonsense	Early	Pathogenic	36	20	[116]	Lethargy, poor feeding	l-carnitine, special milk powder	Died at three months old after birth
	Exon12	NM_000532.5:c.1228C > T	p.Arg410Trp	Missense	Early	Pathogenic	37	20		Lethargy, poor feeding	l-carnitine, special milk powder	Died at three months old after birth
7	Exon1	NM_000532.5:c.146delG	p.Gly49Glufs*16	Frameshift	Late	Likely Pathogenic	NA	NA		Vomiting, lethargy, poor spirit	l-carnitine, special milk powder	Poor compliance and intermittent treatment, significant development delay
	Exon12	NM_000532.5:c.1253C > T	p.Ala418Val	Missense	Late	Likely Pathogenic	27.4	20		Vomiting, lethargy, poor spirit	l-carnitine, special milk powder
8	Exon10	NM_000532.5:c.1087 T > C	p.Ser363Pro	Missense	Late	Likely Pathogenic	30	20	[47]	NA	NA	NA
	Exon10	NM_000532.5:c.1087 T > C	p.Ser363Pro	Missense	Late	Likely Pathogenic	30	20	[47]	NA	NA	NA
9	Intron1	NM_000532.5:c.184-2A > G	NA	Splice site mutation	Early	Pathogenic	33	20	[117]	Abdominal distension, vomiting, poor feeding, dyspnea, and hyperammonemia	NA	NA
	Exon7	NM_000532.5:c.733G > A	p.Gly245Ser	Missense	Early	Likely Pathogenic	28.9	20	[117]		NA	NA
10	NA	NA	NA	NA	Late	NA	NA	NA	[64]	Recurrent vomiting, disorders of consciousness, hyperventilation, and metabolic acidosis	NA	Died at the age of two years and eight months after birth
	NA	NA	NA	NA	Late	NA	NA	NA			NA	Died at the age of two years and eight months after birth
11	Exon13	NM_000532.5:c.1316A > G	p.Tyr439Cys	Missense	Prenatal diagnosis	Pathogenic	31	20		NA	NA	Miscarriage occurred at twenty-one weeks of gestation
	Intron1	NM_000532.5:c.-4156_183 + 3713del	NA	NA	Prenatal diagnosis	NA	NA	NA		NA	NA	Miscarriage occurred at twenty-one weeks of gestation
12	Exon13	NM_000532.5:c.1301C > T	p.Ala434Val	Missense	Early	Pathogenic	32	20		Jaundice, poor feeding, hypotonia, metabolic acidosis, hyperglycaemia, and hyperammonemia	NA	NA
	Exon5	NM_000532.5:c.580 T > C	p.Ser194Pro	Missense	Early	Likely Pathogenic	28.8	20			NA	NA
13	Exon13	NM_000532.5:c.1301C > T	p.Ala434Val	Missense	Early	Pathogenic	32	20		Poor feeding, severe jaundice, metabolic acidosis, and hyperammonemia	NA	Died at the age of one year and eight months after birth
	Exon13	NM_000532.5:c.1301C > T	p.Ala434Val	Missense	Early	Pathogenic	32	20			NA	Died at the age of one year and eight months after birth
14	NA	NA	NA	NA	Early	NA	NA	NA		Poor feeding, vomiting, hyperammonemia, metabolic acidosis, and recurrent infections	NA	Died at the age of one year and six months of a severe infection
	NA	NA	NA	NA	Early	NA	NA	NA			NA
15	Intron1	NM_000532.5:c.-4156_183 + 3713del	NA	NA	Prenatal diagnosis	NA	NA	NA		Poor feeding, vomiting, and hyperammonemia	l-carnitine, special milk powder, phenylbutyric acids	Moderate developmental delay
	Exon13	NM_000532.5:c.1301C > T	p.Ala434Val	Missense	Prenatal diagnosis	Pathogenic	32	20		Poor feeding, vomiting, and hyperammonemia	l-carnitine, special milk powder, phenylbutyric acids	Moderate developmental delay
16	Exon13	NM_000532.5:c.1301C > T	p.Ala434Val	Missense	Newborn screening	Pathogenic	32	20		Classic PA phenotype and moderate developmental delay	Low-protein diet supplemented with l-carnitine, metronidazole, and growth hormone, liver transplantation	No classical PA phenotypic symptoms was observed during the twelve-month follow-up after liver transplantation
	Exon15	NM_000532.5:c.1534C > T	p.Arg512Cys	Missense	Newborn screening	Pathogenic	28.6	20		Classic PA phenotype and moderate developmental delay
17	Exon13	NM_000532.5:c.1301C > T	p.Ala434Val	Missense	Early	Pathogenic	32	20		Hypoactivity, poor feeding and tachypnea hypotonia, hepatomegaly, disorders of consciousness, and hyperammonemia	NA	Died at six days old after birth
	Exon8	NM_000532.5:c.838dup	p.Leu280fs	Frameshift	Early	Pathogenic	NA	NA			NA	Died at six days old after birth
18	Intron1	NM_000532.5:c.-4156_183 + 3713del	NA	NA	Newborn screening	NA	NA	NA		Hyperammonemia and hypoglycemia	Low-protein diet supplemented with l-carnitine	Mild development delay
	Exon13	NM_000532.5:c.1301C > T	p.Ala434Val	Missense	Newborn screening	Pathogenic	32	20		Hyperammonemia and hypoglycemia	Low-protein diet supplemented with l-carnitine	Mild development delay
19	Exon8	NM_000532.5:c.838dup	p.Leu280fs	Frameshift	Newborn screening	Pathogenic	NA	NA	[67]	NA	NA	NA
	Exon13	NM_000532.5:c.1316A > G	p.Tyr439Cys	Missense		Pathogenic	31	20
20	Exon8	NM_000532.5:c.838dup	p.Leu280fs	Frameshift		Pathogenic	NA	NA
	Exon13	NM_000532.5:c.1316A > G	p.Tyr439Cys	Missense		Pathogenic	31	20
21	Exon3	NM_000532.5:c.370C > T	p.Gln124Ter	Nonsense		Likely Pathogenic	48	20
	Exon12	NM_000532.5:c.1283C > T	p.Thr428Ile	Missense		Pathogenic	27.9	20
22	Exon3	NM_000532.5:c.331C > T	p.Arg111Ter	Nonsense		Pathogenic	36	20
	Exon10	NM_000532.5:c.1087 T > C	p.Ser363Pro	Missense		Likely Pathogenic	30	20
23	Exon12	NM_000532.5:c.1220del	p.Gly407Alafs*36	Frameshift		Pathogenic	NA	NA
	Exon10	NM_000532.5:c.1015A > T	p.Asn339Asp	Missense		Likely Pathogenic	29.3	20
24	Exon13	NM_000532.5:c.1316A > G	p.Tyr439Cys	Missense	Newborn screening	Pathogenic	31	20
	NA	NA	NA	NA	Newborn screening	NA	NA	NA
25	Exon8	NM_000532.5:c.838dup	p.Leu280fs	Frameshift	Early	Pathogenic	NA	NA	[16]	Hypotonia, disorders of consciousness, pancytopenia metabolic acidosis and hyperammonemia	Protein restriction and supplementation of l-carnitine, mannitol, and calories. Correct acidosis and electrolyte disorders	Died from pneumonia approximately thirty days after birth
	Exon8	NM_000532.5:c.838dup	p.Leu280fs	Frameshift	Early	Pathogenic	NA	NA	[16]			Died from pneumonia approximately thirty days after birth
26	Exon6	NM_000532.5:c.634G > T	p.Asp212Tyr	Missense	Early	Likely Pathogenic	29.6	20	[118]	Poor feeding, hypotonia, pancytopenia, hyperlactatemia	l-carnitine, vitamin B12, special milk powder, a restricted protein diet	Development delay, intellectual disability
	Exon8	NM_000532.5:c.838dup	p.Leu280fs	Frameshift	Early	Pathogenic	NA	NA	[118]	Poor feeding, hypotonia, pancytopenia, hyperlactatemia		Development delay, intellectual disability
27	Exon3	NM_000532.5:c.359_360delAT	p.Tyr120Cysfs*40	Frameshift	Early	Likely Pathogenic	NA	NA	[7]	Recurrent infections, diarrhea, metabolic acidosis, and generalized tonic–clonic seizures	Low isoleucine, methionine, threonine and proline diet with the supplementation of l-carnitine and biotin	Moderate intellectual disability and development delay
	Intron13	NM_000532.5:c.1398 + 1G > A	NA	Splice site mutation	Early	Likely Pathogenic	35	20	[7]			Moderate intellectual disability and development delay
28	Exon13	NM_000532.5:C.1381G > C	p.Ala461Pro	Missense	Early	Likely Pathogenic	30	20	[66]	Vomiting	Special milk powder and oral administration of l-carnitine from 100 to 200 mg/kg every day	NA
	Exon13	NM_000532.5:c.1301C > T	p.Ala434Val	Missense	Early	Pathogenic	32	20		Vomiting		NA
29	Exon13	NM_000532.5:C.1381G > C	p.Ala461Pro	Missense	Early	Likely Pathogenic	30	20		Poor feeding	NA	Died due to severe multiple organ failure
	Exon13	NM_000532.5:c.1301C > T	p.Ala434Val	Missense	Early	Pathogenic	32	20		Poor feeding	NA	Died due to severe multiple organ failure
30	Exon15	NM_000532.5:c.1535G > A	p.Arg512His	Missense	Early	Pathogenic	31	20		Poor feeding, lethargy, coma, hypotonia, metabolic acidosis and hyperammonemia	NA	Died from a severe multiple organ failure after the discharge requested by the parents at twenty-four days old
	Exon15	NM_000532.5:c.1535G > A	p.Arg512His	Missense	Early	Pathogenic	31	20			NA
31	Exon11	NM_000532.5:c.1131dup	p.Val378Cysfs*5	Frameshift	Early	Likely Pathogenic	NA	NA	[119]	Lethargy, irregular breathing, with groaning and snoring, hypotonia, non-rosy skin, hypoglycemia, and metabolic acidosis	NA	Died due to respiratory failure
	Exon1	NM_000532.5:c.-10_183 + 10del203	NA	Deletion mutation	Early	NA	NA	NA			NA
32	Exon11	NM_000532.5:c.1131dup	p.Val378Cysfs*5	Frameshift	Early	Likely Pathogenic	NA	NA			NA
	Exon1	NM_000532.5:c.-10_183 + 10del203	NA	Deletion mutation	Early	NA	NA	NA			NA
33	Exon8	NM_000532.5:c.838dup	p.Leu280ProfsTer11	Frameshift	Early	Pathogenic	NA	NA		Poor feeding, hypotonia, sepsisticemia, and multiple organ failure	NA	Died at seven days old after birth
	Exon11	NM_000532.5:C.1098G > C	P.Leu366Phe	Missense	Early	Likely Pathogenic	25.8	20			NA	Died at seven days old after birth
34	Intron14	NM_000532.5:c.1498 + 1G > A	NA	Splice site mutation	Early	Likely Pathogenic	34	20		NA	NA	Died shortly after birth due to metabolic abnormalities
	Intron14	NM_000532.5:c.1498 + 1G > A	NA	Splice site mutation	Early	Likely Pathogenic	34	20		NA	NA	Died shortly after birth due to metabolic abnormalities
35	Exon2	NM_000532.5:c.224A > C	p.Asp75Ala	Missense	Newborn screening	Likely Pathogenic	29.9	20	[114]	NA	NA	NA
	Exon13	NM_000532.5:c.1339C > T	p.Leu447Phe	Missense	Newborn screening	Uncertain Significance	25.5	20	[114]	NA	NA	NA
36	Exon13	NM_000532.5:c.1301C > T	p.Ala434Val	Missense	Early	Pathogenic	32	20	[107]	Jaundice, hyperammonemia, and metabolic acidosis	Special milk powder and supplementation of l-carnitine	Regular follow-up revealed mild development delay and intellectual disability
	Exon10	NM_000532.5:c.1087 T > C	p.Ser363Pro	Missense	Early	Likely Pathogenic	30	20	[107]	Jaundice, hyperammonemia, and metabolic acidosis	Special milk powder and supplementation of l-carnitine

NA, not available; MSC, Mutation Significance Cutoff