Clinical, Biochemical and Molecular Characterization of a Cohort of Glycogen Storage Disease Type I Patients in a High Complexity Hospital in Argentina

Bindi, Verónica; Eiroa, Hernán D.; Crespo, Carolina; Martinez, María; Bay, Luisa

doi:10.1590/2326-4594-JIEMS-2020-0028

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Journal of Inborn Errors of Metabolism and Screening

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Original Article • J. inborn errors metab. screen. 9 • 2021 • https://doi.org/10.1590/2326-4594-JIEMS-2020-0028 copy

Clinical, Biochemical and Molecular Characterization of a Cohort of Glycogen Storage Disease Type I Patients in a High Complexity Hospital in Argentina

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Glycogen storage disease type I is an autosomal recessive disorder of carbohydrate metabolism that manifests mainly by hepatomegaly and hypoglycemia with short fasts. Despite strict therapy, patients present long-term renal and liver complications. Data of 36 patients,29 GSD Ia and 7 Ib from a high complexity Hospital in Argentina was collected retrospectively. Collected data included diagnosis, anthropometric, biochemical parameters, therapy and follow-up. Treatment increased Height SDS (p=0.012). Patients with good adherence to therapy presented better growth parameters (p=0.049). Instead, admissions were detrimental (p =0.031) and were more common in Ib patients (p=0.002). The early appearance of complications (liver adenomas and nephropathy) was related to sustained triglyceride values > 500mg / dl (p=0.009 and 0.046 respectively). With intensive dietary treatment, clinical and biochemical status improves but cannot be completely corrected in most patients. Growth improves with treatment and this is optimized with adequate adherence. We must take into account that with ageing, more complications will develop.

Keywords:
Glycogen storage disease I; growth; metabolic control; Complications; liver adenoma; Hypertriglyceridemia; Lactic acidemia; nephropathy

Patient	Gender	GSD Type	Age at symptoms (months)	Age at diagnosis (months)	Hypoglycemia	Hepatomegaly	Other features	DNA analysis
1	M	a	0.07	5	+	+	Lactic acidosis, Neonatal seizures, hypotonia, microcephaly	G6PC: c.161A>C (;)563-3C>G p.(Gln54Pro)(;)(?)
2	M	a	0.07	5	+	+	Microcephaly, lactic acidosis, neonatal seizures
3	F	a	12	16	+	+	growth retardation
4	M	a	4	5	+	+	—	G6PC: c. [247C>T];[=] p.[(Arg83Cys)];[=]
5	M	a	12	24	+	+	—
6	M	a	4	7	+	+	lactic acidosis, growth, retardation
7	M	a	6	7	+	+	growth retardation	G6PC: c. [247C>T];[=] p.[(Arg83Cys)];[=]
8	F	a	0.67	8	+	+	lactic acidosis, neonatal seizures	G6PC: c.[247C>T];[ 247C>T] p.[(Arg83Cys)];[ (Arg83Cys)
9	F	a	4	6	+	+	growth retardation
10¹	F	a	12	132	—	+	lactic acidosis, bleeding (epistaxis)
11	M	a	12	12	—	+	lactic acidosis , growth retardation, bleeding	G6PC: c.100delT (;)820G>A p.(Leu33fs)(;)(Ala274Thr)
12	M	a	0.8	4	+	+	lactic acidosis, growth retardation, neonatal seizures
13	F	a	7	13	+	+	lactic acidosis	G6PC: c.161A>C (;)1039C>T p.( Gln54Pro)(;)(Gln347Ter)
14	F	a	7	12	+	+	lactic acidosis
15	F	a	8	11	+	—
16	M	a	0.63	1	+	+	growth retardation, neonatal seizures
17	F	a	8	24	+	—	lactic acidosis	G6PC: c. [382T>G];[=] p.[(Tyr128Asp)];[=]
18²	F	a	8	11	+		lactic acidosis
19³	F	a	5	5	+	+		G6PC: c.[247C>T];[ 247C>T] p.[(Arg83Cys)];[ (Arg83Cys)
20	F	a	0.47	5	+	+	neonatal seizures	G6PC: c.[247C>T];[ 247C>T] p.[(Arg83Cys)];[ (Arg83Cys)]
21	M	a	5	13	+	+	Microcephaly, hypotonia
22	M	a	2	3	+	+	growth retardation	G6PC: c. [247C>T];[=] p.[(Arg83Cys)];[=]
23	M	a	0.63	1	+	+	lactic acidosis, neonatal seizures	G6PC: c.[247C>T];[ 247C>T] p.[(Arg83Cys)];[ (Arg83Cys)]
24	F	a	0.10	2	+	+	growth retardation lactic acidosis, neonatal seizures
25	F	a	5	32	+	+	growth retardation	G6PC: c.247C>T (;)1039C>T p.( Arg83Cys)(;)(Gln347Ter)
26⁴	M	a	30	72	—	+	chronic diarrhea, growth retardation	G6PC: c.247C>T (;)473G>A p.( Arg83Cys)(;)(Gly158Glu)
27	M	a	30	72	—	+	chronic diarrhea, growth retardation	G6PC: c.247C>T (;)473G>A p.( Arg83Cys)(;)(Gly158Glu)
28	M	a	6	20	+	+	growth retardation	G6PC: c.508C>T (;)626A>G p.( Arg170Ter)(;)(Tyr209Cys)
29	F	a	6	9	+	+	—	Negative (G6PC)
30	F	b	2	3	+	—	lactic acidosis	SLC37A4: c.[1042_1043del];[1042_1043del] p.[(Leu348fs)]; [(Leu348fs)]
31	F	b	7	27	+	+	growth retardation
32	F	b	4	7	+	+	growth retardation, lactic acidosis	SLC37A4:c.149G>A (;)202G>A p.(Gly50Glu)(;)(Gly68Arg
33	M	b	5	9	+	+	lactic acidosis	SLC37A4: c.[1042_1043del];[1042_1043del] p.[(Leu348fs)]; [(Leu348fs)]
34	F	b	1.67	2	+	—	lactic acidosis, growth retardation, hypotonia
35	M	b	4	12	+	—	growth retardation, microcephaly	SLC37A4:c.898C>T(;)1015G>T p.(Arg300Cys)(;)(Gly339Cys)
36	M	b	4	6	+	—	lactic acidosis, growth retardation	SLC37A4: c.[703_705delGTG];[703_705delGTG] p.[(Val236del)];[(Val236del)]

Patient	GSD type	Last height (SDS)	Last BMI (SDS)	Liver adenomas (LA)	Age of detection LA (years)/evolution	Nephropathy (N)	Age of detection N (years)/type	Liver transplant/age (years)	Age at death (years)/Cause of death	Follow up (years)
1	a	-0.32	1.7	no		no				9
2	a	0.65	1.8	no		no				14
3	a	-1.94	2.3	yes	11.6/suspected HCC	yes	16/MA	13.6		17
4	a	-0.78	0.3	no		no				9
5	a	0.1	N/A	no		no			20/metabolic derangement	12
6	a	-3	N/A	no		no				7
7	a	-0.92	1.7	no		no				16
8	a	-1.5	N/A	no		no				19
9	a	-1.5	N/A	no		no				0.9
10	a	0.71	0.8	no		no				5
11	a	-1,38	0.1	no		no				5
12	a	-2.1	-2.1	no		no			0.92/metabolic derangement	1
13	a	-0.58	>3	no		no				0.9
14	a	-1.27	1.3	no		yes	10.3/MA			11
15	a	-1	0.8	no		no				7
16	a	-1.5	2.3	no		yes	7.6/MA			10
17	a	-0.5	N/A	no		no				8
18	a	0.27	N/A	no		no			4/respiratory insufficiency	0.8
19	a	0.5	2.1	yes	9/disappeared after 4 years	no				18
20	a	0.4	2.3	no		no				18
21	a	-1.48	2.1	no		no				14
22	a	-1.1	1.7	no		no				15
23	a	-0.8	1.6	no		no				3
24	a	-3	>3	no		no				1.5
25	a	-2	1.7	no		yes	4/MA			2
26	a	-1.77	-1	no		N/A				4
27	a	-1.64	-1.1	no		N/A				4
28	b	-1.45	1	no		N/A				1
29	b	-0.92	0.4	no		no				19
30	b	-1.38	1.2	no		no				14
31	b	-2	N/A	Yes	10/disappeared after 2 years	yes	14.8/proteinuria			12
32	b	-1.4	1	no		no		7.6, intractable hypoglycemias		18
33	b	-0.44	1.8	yes	2.7/suspected HCC	yes,	11.1/MA progressed proteinuria	9.6		12
34	b	-2.66	0.9	yes	5.8/suspected HCC	yes	5.1/proteinuria	10.6, HCC		18
35	b	-2.91	1.8	no		yes	5.8/MA			6
36	b	-3.1	-0.8	no		no				1.5

Gene	Variant		Location	Number of alleles*	Reported or Novel	ACMG classification
Gene	c.DNA	Protein	Location	Number of alleles*	Reported or Novel	ACMG classification
G6PC	c.161A>C	p.Gln54Pro	Exon 1	2	Reported	Likely pathogenic
	c.247C>T	p. Arg83Cys	Exon 2	11	Reported	Pathogenic
	c.382T>G	p.Tyr128Asp	Exon 3	1	Novel	Likely pathogenic
	c.473G>A	p.Gly158Glu	Exon 4	1	Novel	Uncertain significance
	c.508C>T	p.Arg170Ter	Exon 4	1	Reported	Pathogenic
	c.563-3C>G	-	Intron 4	1	Reported	Uncertain significance
	c.626A>G	p.Tyr209Cys	Exon 5	1	Reported	Likely pathogenic
	c.820G>A	p.Ala274Thr	Exon 5	1	Novel	Likely pathogenic
	c.1004delT	p.Leu335fs	Exon 5	1	Reported	Pathogenic
	c.1039C>T	p.Gln347Ter	Exon 5	2	Reported	Pathogenic
SLC37A4	c.149G>A	p.Gly50Glu	Exon 2	1	Reported	Uncertain significance
	c.202G>A	p.Gly68Arg	Exon 4	1	Reported	Uncertain significance
	c.703_705del	p. Val236del	Exon 7	2	Reported	Uncertain significance
	c.898C>T	p.Arg300Cys	Exon 7	1	Novel	Likely pathogenic
	c.1015G>T	p.Gly339Cys	Exon 10	1	Reported	Pathogenic
	c.1042_1043del	p.Leu348fs	Exon 10	4	Reported	Pathogenic

Latin American Society Inborn Errors and Neonatal Screening (SLEIMPN); Instituto Genética para Todos (IGPT) Rua Ramiro Barcelos, 2350, CEP: 90035-903, Porto Alegre, RS - Brasil, Tel.: 55-51-3359-6338, Fax: 55-51-3359-8010 - Porto Alegre - RS - Brazil
E-mail: rgiugliani@hcpa.edu.br

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[1] Corresponding Author:
Veronica Bindi, Email:verogbindi@gmail.com