Glycogen storage disease due to glycogen debranching enzyme deficiency

General Information (adopted from Orphanet):

Synonyms, Signs: GSDIII
GSD III
AGL DEFICIENCY
GLYCOGEN DEBRANCHER DEFICIENCY
FORBES DISEASE
GSD3
GSD IIIc, INCLUDED
cori disease
Glycogenosis due to glycogen debranching enzyme deficiency
amylo-1,6-glucosidase deficiency
GSD due to glycogen debranching enzyme deficiency
GSD IIId, INCLUDED
GLYCOGEN STORAGE DISEASE IIIc, INCLUDED
GSD type 3
limit dextrinosis
GSD IIIa, INCLUDED
GDE DEFICIENCY GLYCOGEN STORAGE DISEASE IIIa, INCLUDED
GDE deficiency
Forbe disease
Glycogenosis type 3
GLYCOGEN STORAGE DISEASE IIId, INCLUDED
Glycogen storage disease type 3
Cori-Forbes disease
GLYCOGEN STORAGE DISEASE IIIb, INCLUDED
GSD IIIb, INCLUDED
Number of Symptoms 37
OrphanetNr: 366
OMIM Id: 232400
ICD-10: E74.0
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: No data available.
Inheritance: Autosomal recessive
8755644 [IBIS]
Age of onset: Childhood
26067541 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Glycogen storage disease
 -Rare genetic disease
Glycogen storage disease with hypertrophic cardiomyopathy
 -Rare cardiac disease
 -Rare genetic disease
Muscular glycogenosis
 -Rare genetic disease
 -Rare neurologic disease

Comment:

GSD Type III (Cori Disease) comprises the following subgroups, that are distinguished by their residual enzyme activity: IIIa a liver and muscle form (0%), IIIb an isolated liver form (0% to 5%), IIIc an isolated muscle form (20% to 30%) and IIId ( (isolated transferase deficiency, 30% to 50%) (PMID:17027861). Selective loss of only one of the two GDE activities, glucosidase or transferase, results in GSD IIIc or GSD IIId, respectively (PMID:20648714).

Symptom Information: Sort by abundance 

1
(HPO:0000490) Deeply set eye 12002141 IBIS 131 / 7739
2
(HPO:0003128) Lactic acidosis 17027861 IBIS 116 / 7739
3
(HPO:0004322) Short stature Very frequent [Orphanet] 20648714 IBIS 1232 / 7739
4
(HPO:0001943) Hypoglycemia Very frequent [Orphanet] 17027861 IBIS 131 / 7739
5
(HPO:0001640) Cardiomegaly 17027861 IBIS 81 / 7739
6
(HPO:0001712) Left ventricular hypertrophy Occasional [IBIS] 32% (n=28) 26067541 IBIS 76 / 7739
7
(HPO:0001714) Ventricular hypertrophy 26067541 IBIS 20 / 7739
8
(HPO:0001638) Cardiomyopathy 26067541 IBIS 192 / 7739
9
(HPO:0011703) Sinus tachycardia Occasional [IBIS] 29% (n=28) 26067541 IBIS 5 / 7739
10
(HPO:0003236) Elevated serum creatine phosphokinase Frequent [IBIS] 75% (n=28) 26067541 IBIS 214 / 7739
11
(HPO:0003119) Abnormality of lipid metabolism Very frequent [Orphanet] 24997454 IBIS 60 / 7739
12
(HPO:0003077) Hyperlipidemia 24997454 IBIS 37 / 7739
13
(HPO:0002155) Hypertriglyceridemia 24997454 IBIS 67 / 7739
14
(HPO:0003693) Distal amyotrophy 26067541 IBIS 118 / 7739
15
(HPO:0003198) Myopathy Frequent [Orphanet] Frequent [IBIS] 61% (n=28) 26067541 IBIS 151 / 7739
16
(HPO:0001252) Muscular hypotonia 17027861 IBIS 990 / 7739
17
(HPO:0003546) Exercise intolerance 26067541 IBIS 62 / 7739
18
(HPO:0003750) Increased muscle fatiguability 26067541 IBIS 8 / 7739
19
(HPO:0001324) Muscle weakness 26067541 IBIS 859 / 7739
20
(HPO:0003477) Peripheral axonal neuropathy 26067541 IBIS 62 / 7739
21
(HPO:0001270) Motor delay 26067541 IBIS 322 / 7739
22
(HPO:0002910) Elevated hepatic transaminases 12002141 IBIS 158 / 7739
23
(HPO:0001395) Hepatic fibrosis 1293383 IBIS 67 / 7739
24
(HPO:0002240) Hepatomegaly 17027861 IBIS 467 / 7739
25
(HPO:0001433) Hepatosplenomegaly 17027861 IBIS 78 / 7739
26
(HPO:0006568) Increased hepatic glycogen content Very frequent [Orphanet] 20648714 IBIS 34 / 7739
27
(HPO:0000293) Full cheeks Very frequent [Orphanet] 12002141 IBIS 85 / 7739
28
(HPO:0011800) Midface retrusion 12002141 IBIS 221 / 7739
29
(HPO:0000219) Thin upper lip vermilion 12002141 IBIS 112 / 7739
30
(HPO:0000233) Thin vermilion border 12002141 IBIS 124 / 7739
31
(HPO:0000455) Broad nasal tip 12002141 IBIS 67 / 7739
32
(HPO:0005280) Depressed nasal bridge 12002141 IBIS 381 / 7739
33
(HPO:0001510) Growth delay 26067541 IBIS 295 / 7739
34
(HPO:0012758) Neurodevelopmental delay Very frequent [Orphanet] 26067541 IBIS 949 / 7739
35
(OMIM) Amylo-1,6-glucosidase deficiency 17027861 IBIS 1 / 7739
36
(OMIM) Bow-shaped lips 12002141 IBIS 1 / 7739
37
(OMIM) Broad upturned nasal tip 12002141 IBIS 1 / 7739

Associated genes:

AGL;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference
AGL rs113994126 pathogenic RCV000001153.3
AGL rs113994126 pathogenic RCV000020373.2
AGL rs113994128 pathogenic RCV000020372.1
AGL rs113994128 pathogenic RCV000001165.3
AGL rs113994129 pathogenic RCV000020375.2
AGL rs113994129 pathogenic RCV000001154.3
AGL rs113994130 pathogenic RCV000020376.2
AGL rs113994131 pathogenic RCV000020377.2
AGL rs113994132 pathogenic RCV000020378.2
AGL rs113994132 pathogenic RCV000001162.3
AGL rs118203964 pathogenic RCV000001161.3
AGL rs193186112 pathogenic RCV000177086.1
AGL rs199922945 likely pathogenic RCV000169137.1
AGL rs199922945 pathogenic RCV000001159.3
AGL rs267606639 pathogenic RCV000001166.3
AGL rs267606640 pathogenic RCV000001167.3
AGL rs369973784 pathogenic RCV000001158.3
AGL rs369973784 pathogenic RCV000001157.3
AGL rs370792293 likely pathogenic RCV000169374.1
AGL rs387906244 likely pathogenic RCV000169573.1
AGL rs387906244 pathogenic RCV000001152.3
AGL rs387906245 pathogenic RCV000177731.2
AGL rs387906245 pathogenic RCV000001156.3
AGL rs387906246 pathogenic RCV000001163.4
AGL rs771961377 likely pathogenic RCV000169437.1
AGL rs776977863 likely pathogenic RCV000169313.1
AGL rs781580050 likely pathogenic RCV000169056.1
AGL rs786204481 likely pathogenic RCV000169136.1
AGL rs786204489 likely pathogenic RCV000169156.1
AGL rs786204490 likely pathogenic RCV000169157.1
AGL rs786204595 likely pathogenic RCV000169345.1
AGL rs786204616 likely pathogenic RCV000169381.1
AGL rs786204655 likely pathogenic RCV000169447.1
AGL rs786204678 likely pathogenic RCV000169486.1
AGL rs794727051 pathogenic RCV000174259.1
AGL rs794727255 pathogenic RCV000001155.3
AGL rs794727255 pathogenic RCV000175637.2
AGL rs794727706 pathogenic RCV000178792.1
AGL rs794729209 pathogenic RCV000184029.1

Additional Information:

Description: (OMIM) Glycogen storage disease III is an autosomal recessive metabolic disorder caused by deficiency of the glycogen debrancher enzyme and associated with an accumulation of abnormal glycogen with short outer chains. Most patients are enzyme-deficient in both liver and ...
Diagnosis OMIM Shen et al. (1997) used 3 polymorphic markers within the AGL gene for linkage analysis of GSD III and showed the potential use of these markers for carrier detection and prenatal diagnosis.
Clinical Description OMIM Brunberg et al. (1971) reported an adult with GSD III who had diffuse muscle weakness and wasting. DiMauro et al. (1979) reported 5 adult patients with adult-onset, slowly progressive muscle weakness associated with debrancher enzyme deficiency. Two patients ...
Molecular genetics OMIM In 3 unrelated patients with GSD IIIb, Shen et al. (1996) identified homozygous or compound heterozygous mutations in the AGL gene (see, e.g., 610860.0002-610860.0004). One of the mutations (17delAG; 610860.0004) was found in 8 of 10 additional GSD ...
Population genetics OMIM In Israel, 73% of glycogen storage disease was of type III. All cases were non-Ashkenazim, being mainly of North African extraction, in which group the incidence was 1 in 5,420 (Levin et al., 1967).

The overall ...

Diagnosis GeneReviews Glycogen storage disease type III (GSD III) is characterized by variable liver, cardiac muscle, and skeletal muscle involvement....
Clinical Description GeneReviews Both GSD IIIa and GSD IIIb typically present in childhood with hepatomegaly and ketotic hypoglycemia with markedly elevated liver transaminases and hypertriglyceridemia. The spectrum of presentation may include severe hypoglycemia as seen in GSD I or asymptomatic hepatomegaly. ...
Genotype-Phenotype Correlations GeneReviews There is a clear genotype-phenotype correlation with at least two mutations in exon 3 (c.17_18delAG and c.16C>T) associated with GSD IIIb. It is unclear, however, what mechanism enables individuals with mutations in exon 3 to retain debranching enzyme activity in muscle tissue. A possible explanation was proposed by Goldstein et al [2010] in which the exon 3 mutation is bypassed using a downstream start codon, thus creating a fully functioning isoform without the exon 3 mutations. ...
Differential Diagnosis GeneReviews Findings in GSD III that may help distinguish it from other forms of GSD include the following:...
Management GeneReviews To establish the extent of disease and needs of an individual diagnosed with glycogen storage disease type III (GSD III), the following are recommended:...
Molecular genetics GeneReviews Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....