Glycogen Storage Patients: History
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Subjects: Pediatrics
Contributor:
Asuman Gedikbasi

Glycogen storage diseases (GSDs) are clinically and genetically heterogeneous disorders that disturb glycogen synthesis or utilization. Although it is one of the oldest inherited metabolic disorders, new genetic methods and long-time patient follow-ups provide us with unique insight into the genotype–phenotype correlations. The aim of this study was to share the phenotypic features and molecular diagnostic results that include new pathogenic variants in the GSD cases. Twenty-six GSD patients were evaluated retrospectively. Demographic data, initial laboratory and imaging features, and current findings of the patients were recorded. Molecular analysis results were classified as novel or previously defined variants. Novel variants were analyzed with pathogenicity prediction tools according to American College of Medical Genetics and Genomics (ACGM) criteria. Twelve novel and rare variants in six different genes were associated with the disease. Hearing impairment in two patients with GSD I, early peripheral neuropathy after liver transplantation in one patient with GSD IV, epilepsy and neuromotor retardation in three patients with GSD IXA were determined. A heterogeneous group of all diagnosed GSDs over a 5-year period was characterized in the institution, and identified novel variants and new clinical findings. It is still difficult to establish a genotype–phenotype correlation in GSDs.

  • glycogen storage disease
  • genotype–phenotype
  • novel variants

1. Introduction

Glycogen storage diseases [GSDs] are a large group of inherited metabolic diseases with abnormal storage or utilization of glycogen. They affect primarily the liver and muscle, followed by the nervous system, kidneys, intestine, and leukocytes [1]. The incidence of all forms of glycogen storage disease is 1/10,000 [2]. Depending on the type of enzyme deficiency in tissue, it is classified as muscle or liver glycogenosis. However, both muscle and liver can be affected in some types [3]. The diagnosis of GSDs is based on the enzyme assay and/or molecular analysis as a result of the biochemical analysis and biopsy examination of the patients with characteristic signs [4]. GSDs have broad genetic heterogeneity and phenotypical variations. Some GSDs lead to death within the first years of life, whereas some remain asymptomatic for life. Genotype–phenotype correlation has been reported for some mutations in GSD patients [5]. Patients with late-onset or atypical presentation can experience a delay in diagnosis and proper treatment. Some unexpected clinical findings may accompany classical features [6]. 

2. Demographic and Findings

Twenty-six patients diagnosed with GSD from 24 unrelated families were investigated. The initial laboratory findings are shown in Table 1. As a result of molecular analysis, 12 novel pathogenic variations were detected; GYS2 c.607A>G (p.Thr203Ala) and c.1307A>C (p.Gln436Pro), G6PC c.562+1G>A (p.), GBE1 c.1054G>C (p.Asp352His), PYGL c.1355G>T (p.Gly452Val), c.2380-1G>C p.(?), c.921_924del (p.His308Leufs*8), PHKA2 c.1978C>T (p.Leu660Phe), c.3028-2A>G (p.), c.3201G>T (p.Trp1067Cys), PHKB exon 18–21 deletion (p.), PHKA1 c.1963C>T (p.Arg655Cys) (Table 2).
Table 1. Initial laboratory and imaging features of patients.
ID Type Glycose
mg/dL		 AST
U/L		 ALT
IU/L		 CPK
U/L		 LDL
mg/dL		 HDL
mg/dL		 Cholesterol
mg/dL		 Triglyceride
mg/dL		 AFP
ng/mL		 Lactate
mg/dL		 Ketone Ultrasound and/or ECHO
P1 GSD0 37 26 16 55 95 61 168 68 1 30 + normal
P2 GSD0 35 30 18 68 79 68 172 56 1 26 ++ normal
P3 GSD0 49 16 30 67 58 65 136 64 1 11 + normal
P4 GSDIa 12 134 73 57 126 27 323 2007 2 65 + grade 1 steatosis
P5 GSDIa 14 65 71 49 136 41 213 546 2 40 ++ hepatomegaly
P6 GSDIa 9 282 133 67 149 23 341 1158 1 53 +++ heterogeneity in liver and kidney
P7 GSDIa 16 257 305 97 171 13 304 1200 2 97 + heterogeneity in liver and kidney
P8 GSDIa 73 197 187 67 184 44 284 944 1.5 35 neg hepatomegaly, heterogenity
P9 GSDIb 20 62 45 76 94 19 167 267 1.2 26 neg grade 1 steatosis
P10 GSD III 34 226 327 1760 138 12 225 370 1 43 neg grade 2 steatosis hepatomegaly
P11 GSDIII 71 705 867 867 186 30 217 479 4.4 42 neg grade 1 steatosis, hepatomegaly
P12 GSDIII 23 160 123 424 145 8 234 471 41 25 + grade 1 heterogeneity, hepatomegaly
P13 GSDIV 74 317 137 54 96 28 139 75 13 12 neg nodular heterogeneous liver
P14 GSDIV 65 158 14 57 104 46 172 106 18 13 neg nodular heterogeneous in liver
P15 GSDV 86 50 29 556 78 45 139 69 0.8 15 neg normal
P16 GSDV 100 33 18 318 95 38 178 69 − − neg normal
P17 GSDVI 74 545 444 87 104 22 178 241 2 25 + hepatomegaly
P18 GSDVI 48 193 78 69 72 29 124 115 1.9 26 ++ hepatomegaly
P19 GSDVI 39 60 64 98 94 36 158 138 2.7 31 + hepatomegaly
P20 GSDVI 59 74 78 89 112 39 125 67 1.7 12 + grade 1 steatosis, hepatomegaly
P21 GSDIXa 45 225 189 356 153 17 224 276 1 12 + hepatomegaly, grade 1 steatosis
P22 GSDIXa 56 199 111 525 107 33 159 98 2 38 ++ hepatomegaly
P23 GSDIXa 65 86 98 215 164 45 198 218 1.2 15 neg hepatomagaly, heterogenity, hypertophic CMP
P24 GSDIXa 75 68 64 218 120 72 208 71 − 26 neg hepatomagaly
P25 GSDIXb 78 74 50 562 89 61 169 76 5 11 ++ grade 1 heterogeneity
P26 GSDIXd 67 80 84 292 76 48 138 67 1 9 +++ hepatomegaly
Abbreviations: AST: Aspartate transaminase, ALT: Alanine transaminase, CPK: Creatine phosphokinase, LDL: Low-density lipoprotein-cholesterol, HDL: High-density lipoprotein-cholesterol, AFP: Alpha-fetoprotein, ECHO: echocardiography. “+” (plus) means presence of the finding, “−” (minus) means absence of the finding.
Table 2. Molecular and enzymatic assays of patients.
ID Type Gene Inheritence Allele 1 Allele 2
P1 GSD0 GYS2 AR c.607A>G p.Thr203Ala c.1145G>A p.(Gly382Glu)
P2 GSD0 GYS2 AR c.607A>G p.Thr203Ala c.1145G>A p.(Gly382Glu)
P3 GSD0 GYS2 AR c.1307A>C p.Gln436Pro c.1307A>C p.Gln436Pro
P4 GSDIa G6PC AR c.247C>T p.R83C c.247C>T p.R83C
P5 GSDIa G6PC AR c.247C>T p.R83C c.247C>T p.R83C
P6 GSDIa G6PC AR c.562+1G>A c.562+1G>A
P7 GSDIa G6PC AR c.247C>T p.Arg83Cys c.247C>T p.Arg83Cys
P8 GSD1a G6PC AR c.247C>T p.Arg83cys c.247C>T p.Arg83cys
P9 GSDIb SLC37A4 AR c.1043_1044delCT p.Pro348ArgfsTer5 c.1043_1044delCT p.Pro348ArgfsTer5
P10 GSD III AGL AR c.1019delA p.Gln340fs c.1019delA p.Gln340fs
P11 GSDIII AGL AR c.1020del p.Glu340Aspfs*9 c.1020del p.Glu340Aspfs*9
P12 GSDIII AGL AR c.4126C>T p.Gln1376 c.4126C>T p.Gln1376
P13 GSDIV GBE1 AR c.1492G>A p.Glu498Lys c.1492G>A p.Glu498Lys
P14 GSDIV GBE1 AR c.1054G>C p.Asp352His c.1054G>C p.Asp352His
P15 GSDV PYGM AR c.1A>G p.Met1Val c.1A>G p.Met1Val
P16 GSDV PYGM AR c.772+2_772+3delTG c.772+2_772+3delTG
P17 GSDVI PYGL AR c.1355G>T p.Gly452Val c.1355G>T p.Gly452Val
P18 GSDVI PYGL AR c.2380-1G>C IVS19_1G>C c.2380-1G>C IVS19_1G>C
P19 GSDVI PYGL AR c.2380+1G>C IVS19+1G>C c.2380+1G>C IVS19+1G>C
P20 GSDVI PYGL AR c.921_924del p.His308Leufs*8 c.921_924del p.His308Leufs*8
P21 GSDIXa PH KA2 XL c.3614C>T p.Pro1205Leu c.3614C>T p.Pro1205Leu
P22 GSDIXa PHKA2 XL c.1978C>T p.Leu660Phe c.1978C>T p.Leu660Phe
P23 GSDIXa PHKA2 XL c.3028-2A>G c.3028-2A>G
P24 GSDIXa PHKA2 XL c.3201G>T p.Trp1067Cys c.3201G>T p.Trp1067Cys
P25 GSDIXb PHKB AR Exon18_21 deletion Exon18_21 deletion
P26 GSDIXd PHKA1 XL c.1963C>T p.Arg655Cys c.1963C>T p.Arg655Cys
Abbreviations: AR: autosomal recessive, AD: autosomal dominant, XL: X-linked. The novel variants are shown in bold.

3. The phenotypic features and molecular diagnostic results of GSD

Another novel mutation of G6PC associated with GSDIa was detected in a patient; c.562+1G>A (P7, homozygous). The most striking finding was the bilateral sensorineural hearing impairment that was detected in two of the patients with different mutations (one with common, previously defined; c.247C>T and one with novel; c.562+1G>A, P6, P7, respectively) [7][8]. Iwanicka-Pronicka et al. [9] reported hearing impairment “at birth” in four (2 GSDIa; 2 GSDIb) out of 40 GSDI cases (20 patients with each subtype). The underlying mechanism has not been yet determined. Hearing impairment was determined when P6 was 6 months old and P7 was 18 months old; both of them passed newborn hearing screening tests and have normal brain MRI (magnetic resonance imaging), EEG (electroencephalogram), and neurocognitive development; they had a cochlear implant at the age of 1 and 2, respectively. Both have mild disarticulation and speech disturbance. As their hearing was normal at birth, auditory dysfunction gene panel or whole exome sequencing (WES) was not performed. For this reason, it would be appropriate to perform hearing evaluation in order to detect hearing loss early in GSD type 1 patients. Short stature and osteoporosis are remarkable findings among patients at any age, and may be due to inappropriate metabolic control, poor nutrition, the effects of lactic acidosis, or accompanying endocrinological problems (hypogonadism) [10][11][12]. The occurrence of osteoporosis in all of the patients, except the younger (P5), can be attributed to the above-mentioned factors.

Two missense mutations were identified in GBE1-related GSDIV (one previously defined; c.1492G>A p.E498K and one novel; c.1054G>C p.Asp352His, P13, P14, respectively). P14 typically presented with hypotonia, myopathy, and hepatopathy. There is no treatment for this case other than liver transplantation [13]. Apart from that, it also causes a complex neurological condition called “Adult Polyglucosan Body Disease” (APBD), which shows symptoms after the fifth decade of life. It presents a variable combination of cognitive impairment, pyramidal tetraparesis, peripheral neuropathy, cerebellar dysfunction, and extrapyramidal signs [14][15]. There is no reported case in the literature that has both severe hepatic and neuromuscular involvement at this age. Performing neurological follow-up of patients with GBE1 mutation from an earlier age will provide a chance for early detection of neurological findings.

GSDVI may present with different combinations of findings including hepatomegaly, mild-to-moderate hypoglycemia, hyperlactatemia, hyper-transaminasemia, and short stature [16][17]. Short stature with normal neuromotor development should be a warning sign for GSD type VI.

GSDIX is a group of glycogenoses caused by hepatic phosphorylase kinase deficiency, a hexadecameric enzyme comprising four copies each of four unique subunits encoded by four different genes; PHKA1, PHKA2, PHKB, and PHKG2 [16][18]. Five out of six patients had novel mutated genes as follows; in PHKA2 c.1978C>T (p.Leu660Phe) (P22, homozygous) c.3028-2A>G (p.) (P23, homozygous), c.3201G>T (p.Trp1067Cys) (P24, homozygous), in PHKB exon 18_21 deletion (p.) (P25, homozygous), in PHKA1 c.1963C>T (p.Arg655Cys) (P26, homozygous). The most common findings are hepatomegaly, short stature, delay in motor development, the elevation of transaminases, cholesterol, and triglyceride, fasting hyperketosis, and hypoglycemia. 

4. Conclusions

It seems difficult to establish phenotype–genotype correlations in all types of GSDIX. Hearing impairment in GSD I, early peripheral neuropathy after liver transplantation in GSD IV, and psychomotor retardation, seizure, autism signs and hypertrophic cardiomyopathy in GSD IXa can be considered as newly determined, rare and unexcepted findings.

This entry is adapted from the peer-reviewed paper 10.3390/genes12121987

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