3-methylcrotonyl-CoA carboxylase deficiency: Clinical, biochemical, enzymatic and molecular studies in 88 individuals

Grünert, Sarah C; Stucki, Martin; Morscher, Raphael J; Suormala, Terttu; Bürer, Celine; Burda, Patricie; Christensen, Ernst; Ficicioglu, Can; Herwig, Jürgen; Kölker, Stefan; Möslinger, Dorothea; Pasquini, Elisabetta; Santer, René; Schwab, K Otfried; Wilcken, Bridget; Fowler, Brian; Yue, Wyatt W; Baumgartner, Matthias R

doi:10.1186/1750-1172-7-31

Orphanet Journal of Rare Diseases

Table 1 Sociodemographic, biochemical, enzymatic, genetic and clinical information on 88 patients with MCC deficiency 53 Individuals identified by newborn screening without (n = 36) and with (n = 13) reported symptoms (n = 4 without clinical details)

From: 3-methylcrotonyl-CoA carboxylase deficiency: Clinical, biochemical, enzymatic and molecular studies in 88 individuals

Pt #	Sex	Ethnic origin	Current age (y)	Biochemical phenotype			Carboxylase activities in fibroblasts (pmol/ min/mg protein)¹		Genotype			Clinical phenotype^§
				DBS/ plasma	urine				affected gene	Nucleotide change (at RNA level)	Amino acid change (predicted from RNA)
				C5OH	3-HIVA	3MCG	MCC	PCC	affected gene	Allele 1 Allele 2	Amino acid change (predicted from RNA)
20	f	Caucasian	10	++	++	++	15.4	812	MCCC1	c.1155A>C	p.R385S	asymptomatic (fr)
										c.559T>C	p.S187P
21	f	Turkish	11	++	++	++	0	530	MCCC2	c.803G>C	p.R268T	asymptomatic (ltf, 0.3 y)
										(r.785_803del)	(p.G262_R268delfs*5)
										c.803G>C	p.R268T
										(r.785_803del)	(p.G262_R268delfs*5)
22	f	Turkish	12	++	++	++	5.7	587	MCCC2	c.464G>A	p.R155Q	asymptomatic (fr)
										c.464G>A	p.R155Q
23	f	Arab	12	++	++	++	0	594	MCCC2	c.469C>T	p.Q157*	asymptomatic (ltf, 1y)
										c.469C>T	p.Q157*
25	m	Caucasian	11	++	++	++	na	na	MCCC1	c.872C>T◊ -	p.A291V -	asymptomatic (ltf)
26	f	Caucasian	9	++	++	++	na	na	MCCC2	c.1690T>C◊ -	p.X564QLE -	asymptomatic (fr)
27	f	Caucasian	10	++	++	++	1.1	305	MCCC1	c.1155A>C◊ -	R385S -	asymptomatic, but facial dysmorphies with hypertelorism, mongoloid palpebral fissures, low set ears, mild macroglossia, normal karyotype 46XX (ltf, 0.3 y)
29	m	Turkish	10	++	++	++	1.5	723	MCCC2	c.295G>C	p.E99Q	asymptomatic (ltf, 6y)
										c.1574+1G>A	(p.F497Gfs*4)
34	m	Caucasian	9	++	++	++	16.2	542	MCCC2	c.845A>G	p.H282R	asymptomatic (fr)
										c.845A>G	p.H282R
39	f	Caucasian	9	++	++	++	0.7	696	MCCC2	c.517dupT	p.S173Ffs*25	asymptomatic (fr)
										c.1123G>T	p.V375F
40	m	Caucasian	9	++	++	++	5.1	620	MCCC2	c.214C>T	p.R72*	asymptomatic (fr)
										c.416_ 427del12ins16	p.T139_G143 >RWVPGEfs*35
41	m	Caucasian	8	++	++	++	0	595	MCCC1	c.694C>T◊ -	p.R232W -	asymptomatic, mild developmental delay within the first years of life, normal development at present (fr)
43a	f	Caucasian	8	++	++	++	8.1	704	MCCC1	c.640_641delGG	p.G214Nfs*5	asymptomatic (ltf)
										c.1930G>T	p.E644*
43b	f	Caucasian	7	++	++	++	na	na	MCCC1	c.640_641delGG	p.G214Nfs*5	asymptomatic (ltf)
										c.1930G>T	p.E644*
52a	m	Turkish	9	+	+	++	1.6	603	MCCC2	c.803G>C	p.R268T	asymptomatic (ltf)
										(r.785_803del)	(p.G262_ R268delfs*5)
										c.803G>C	p.R268T
										(r.785_803del)	(p.G262_R268delfs*5)
55	m	Asian	7	++	++	na	18.3	634	MCCC2	c.351_353delTGG	p.G118del	asymptomatic (ltf, 0.6y)
										c.659G>A	p.G220E
56	m	Turkish	7	+	+	++	9.6	359	MCCC2	c.1567A>G	p.S523G	asymptomatic (fr)
										(exon 6 skipping)	(p.V171Dfs*20)
57	m	Asian	7	++	++	++	10.2	541	MCCC1	c.863A>G	p.E288G	asymptomatic (fr)
										c.863A>G	p.E288G
58	m	Turkish	7	++	++	++	5.2	1046	MCCC2	c.538C>T	p.R180*	asymptomatic (fr)
										c.538C>T	p.R180*
62	m	Turkish	7	++	++	++	9.5	856	MCCC1	c.873+4524_ 6787del2264	p.?	asymptomatic (fr)
										c.873+4524_ 6787del2264	p.?
64	f	Turkish	8	++	++	++	9.9	762	MCCC2	c.803G>C	p.R268T	asymptomatic (ltf, 5y)
										(r.785_803del)	(p.G262_R268delfs*5)
										c.803G>C	p.R268T
										(r.785_803del)	(p.G262_R268delfs*5)
67	f	Turkish	10	++	na	na	48.4	1065	MCCC2	c.464G>A	p.R155Q	asymptomatic (fr)
										c.1015G>A	p.V339M
70a	f	Caucasian	6	+	++	++	0	520	MCCC1	c.2079delA◊ -	p.V694* -	asymptomatic (fr)
72	m	Caucasian	7	++	++	++	11.5	451	MCCC2	c.455A>C	p.K152T	asymptomatic (ltf)
										c.903+6_ 903+9delTACG	p.?
78	f	Caucasian	6	++	++	++	4.8	416	MCCC2	c.671C>T	p.P224L	asymptomatic (fr)
										c.671C>T	p.P224L
82a	f	Caucasian	5	++	++	++	1.6	783	MCCC2	c.512-1G>A	p.?	asymptomatic (ltf, 1y)
										c.512-1G>A	p.?
82b	f	Caucasian	5	++	++	++	na	na	MCCC2	c.512-1G>A	p.?	asymptomatic (ltf, 1y)
										c.512-1G>A	p.?
91	m	Turkish	7	++	+	+	35.5	513	MCCC2	c.295G>C	p.E99Q	asymptomatic (fr)
										c.295G>C	p.E99Q
93b	m	Caucasian	8	++	na	+	na	na	na	na	na	asymptomatic (ltf)
107	m	Caucasian	2	++	++	++	4.0	613	MCCC2	c.1073-12C>G		asymptomatic (fr)
										(r.1073_1216del+ r.1073insr.1073-48_ r.1073-1)	(p.G358Vfs6+ p.G358Afs12)
										c.1073-12C>G
										(r.1073_1216del+ r.1073insr.1073-48_ r.1073-1)	(p.G358Vfs6+ p.G358Afs12)
112	m	Turkish	0.8	++	++	++	0	797	MCCC2	c.658_662delTCAGA c.658_662delTCAGA	p.S220Tfs15 p.S220Tfs15	asymptomatic, however hyperammonemia of 270 umol/l under leucine loading test (fr)
115	f	Caucasian	0.7	++	++	++	5.0	864	MCCC1	c.803C>A	p.A268D	asymptomatic (fr)
										c.1155A>C	p.R385S
125	f	Arab	3	+	n	na	102	726	MCCC2	c.1423G>A	p. G475R	asymptomatic (fr)
										c.1423G>A	p. G475R
126	m	Caucasian	3	+	+	na	60.6	791	MCCC2	c.1300G>C	p.V434L	asymptomatic (fr)
										c.1300G>C	p.V434L
137	m	Caucasian	5	++	++	++	na	na	MCCC2	c.518C>T	p.S173L	asymptomatic (fr)
										c.518C>T	p.S173L
138	m	Caucasian	1.5	++	++	++	na	na	MCCC1	c.1155A>C	p.R385S	asymptomatic (fr)
										c.2009_2043del35	p.A670Dfs*34
24	f	Turkish	10	++	++	++	1.8	390	MCCC2	c.295G>C c.295G>C	p.E99Q p.E99Q	attention deficit hyperactivity disorder (fr)
28	m	Caucasian	10	++	++	++	1.1	318	MCCC1	c.1155A>C (exon 15 skipping)	p.R385S (p.V562*)	attention deficit hyperactivity disorder (fr)
46	m	Caucasian/ African American	9	++	++	++	20.0	1054	MCCC1	c.2088dupA c.1526delG	p.V697Sfs19 p.C509Sfs14	3 metabolic decompensations with vomiting, hypoglycaemia and ketonuria (ltf, 7.5y)
53	f	Caucasian	7	+	++	++	28.4	773	MCCC1	c.1155A>C c.1315G>A	R385S p.V439M	at the age of 6 months minor psychomotor delay (ltf)
59	m	Faroe Islands	7	++	++	++	7.4	1051	MCCC1	c.1526delG c.1526delG	p.C509Sfs14 p.C509Sfs14	muscular hypotonia, muscle wakness, impaired physical performance (fr)
71	f	Turkish	died at 5 weeks	++	++	++	1.7	597	MCCC1	c.1136G>A c.1136G>A	p.G379D p.G379D	metabolic crisis, floppy infant, myoclonic jerks, respiratory insufficiency requiring mechanical ventilation, deceased at age 6 weeks
74	m	African American	6	++	+	+	23.0	749	MCCC1	c.1302T>G c.2123dupA	p.I434M p.H708Qfs*8	several metabolic decompensations, mild speech delay, immunodeficiency due to CD 16 deficiency (fr)
81	f	Caucasian	5	+	+	n	21.5	233	MCCC2	c.1015G>A◊ -	p.V339M -	Trisomy 21, psychomotor retardation, muscular hypotonia (fr)
90	m	Turkish	7	+	+	+	23.8	483	MCCC2	c.295G>C c.1015G>A	p.E99Q p.V339M	truncal and perioral hypotonia (fr)
105	m	Caucasian	3	++	++	++	0	412	MCCC1	c.1155A>C c.1820delG	p.R385S p.S607Ifs*5	unpleasant odour, failure to thrive, several acute metabolic decompensations with mild hyperammonemia during infections (fr)
108	m	Asian	2.5	++	++	++	0.8	456	MCCC2	c.518C>T c.518C>T	p.S173L p.S173L	recurrent infections, muscular hypertonia and hyperreflexia in infancy (fr)
127	m	Arab	2	+	na	na	92,9	755	MCCC2	c.1423G>C	p.G475R	muscle weakness (fr)
										c.1423G>C	p.G475R
136	f	Caucasian	8	++	++	++	na	na	MCCC2	c.1149+1G>T c.1149+1G>T	p.? p.?	3 metabolic decompensations with acidosis, hypoglycaemia, vomiting, encephalopathy and coma (fr)
31	f	Caucasian	10	na	na	na	12.4	518	MCCC1	c.1155A>C	p.R385S	?
										c.400G>A	p.E134K
103	m	Caucasian	3	++	++	++	0	545	MCCC2	(exon 7 to 14 skipping)	(p.I209Pfs*43)	?
										(exon 7 to 14 skipping)	(p.I209Pfs*43)
111	?	Caucasian	1	++	+	+	34.0	1083	MCCC2	c.1015G>A	p.V339M	?
										c.1309A>G
										(r.1309A>G+ r.1310_1373del64)	(p.I437V+ p.I437Tfs*15)
113	?	Caucasian	1	+	+	n	7.9	407	MCCC1	c.193A>T	p.M65L	?
										c.1193_1194delTG	p.V398Gfs*19

¹ control values measured in 53 cell lines, expressed as median value and (range): MCC activity, 305 pmol/min/mg protein (134-671); PCC activity, 583 (208-1165); ratio of PCC/MCC activity, 1.93 (1.19 – 2.58).
^§information in brackets: fr followed regularly, ltf lost to follow-up, age of last follow-up, if known. + slightly elevated; ++ massively elevated; C5OH 3-hydroxyisovalerylcarnitine; DBS dried blood spots; 3-HIVA 3-hydroxyisovaleric acid; 3-MCG 3-methylcrotonylglycine; f female; fr followed regularly; ltf lost to follow-up; m male; MCC methylcrotonyl-CoA carboxylase; n normal; na not available; NBS newborn screening; PCC propionyl-CoA carboxylase; Pt # Patient number; RNA nd RNA not detectable; SMS selective metabolic screening; y years; ◊ mutation heterozygous on genomic PCR, homozygous in RT-PCR; # diagnosed following the positive NBS result of their baby; ? not known.

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ISSN: 1750-1172

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