ABSTRACT
Hepatic glycogen storage disease type IX (GSD IX) is due to a deficiency of phosphorylase kinase and is one of the most common types of GSD. We conducted a retrospective, observational cohort study on individuals with GSD IX from across the United Kingdom. We describe the natural history and long‐term outcomes for 89 individuals with GSD IX with a median age of 16.4 years (range 4 months to 73 years). This included 60 patients with IXα2, 12 with IXβ and 13 with IXγ2. We report 49 novel alleles in PHKA2, PHKB and PHKG2. The median age at initial presentation was 2.5 years, with 82% (n = 68) presenting with hepatomegaly and 46% (n = 38) presenting with ketotic hypoglycaemia. Steatosis was reported in 71% (n = 12) who had a liver biopsy. The mean Z‐score for height at initial presentation was −1.21, and this significantly improved over childhood. A spectrum of severity was seen in all subtypes, with some requiring more intensive dietary management after initial presentation and others requiring no formal dietary treatment at all. No patients developed adenomas or hepatocellular carcinomas, and 75% (n = 33) of adults were on no dietary therapy. Individuals with IXγ2 had a more severe disease course and had significantly worse biochemistry at initial presentation compared to other subtypes. They were diagnosed at a younger age and required more intensive dietary management across the lifespan. We believe that GSD IXγ2 is an ideal target for novel therapies. We recommend regular monitoring and multidisciplinary input in all patients with GSD IX and encourage more formal assessment of protein intake with each review.
Keywords: genotype, glycogen storage disease type IX, GSD IXα2, GSD IXβ, GSD IXγ2, steatosis
1. Introduction
Glycogen storage disease type IX (GSD IX) is due to a deficiency of the enzyme phosphorylase kinase (PhK), a protein kinase that converts glycogen phosphorylase to its active form [1]. PhK is a hexadecamer with four copies each of α, β, γ, and δ subunits, each with its own tissue specific isoform [2]. Hepatic GSD IX is due to deficiency in one of 3 of the subunits: (1) α subunit, encoded by PHKA2 (GSD IXα2, MIM #306000); (2) β subunit, encoded by PHKB (GSD IXβ, MIM #261750); and (3) γ subunit, encoded by PHKG2 (GSD IXγ2, MIM #261750). GSD IXβ and IXγ2 have autosomal recessive inheritance, whereas IXα2 is X‐linked.
GSD IX is the one of the most common hepatic GSDs, with an estimated incidence of 1 in 100, 000 [1, 3]. X‐linked GSD IXα2 is the most common subtype of GSD IX, accounting for 75% of cases and occurring almost exclusively in males, although there are reports of manifesting female carriers [4, 5]. Hepatic GSD IX typically presents in the first few years of life with hepatomegaly, short stature and ketosis with or without hypoglycaemia. Biochemically, there may be mixed hyperlipidaemia and elevated liver transaminases [1]. GSD IX is clinically indistinguishable from GSD type VI, and in those with GSD type III without elevations in creatine kinase (CK), and the diagnosis is confirmed either molecularly or with enzymology. PhK activity can be measured in liver for all 3 hepatic subtypes of GSD IX, and in blood for types IXα2 and IXβ. An elevated glycogen content and a low ratio of phosphorylase a (the active form) compared to total phosphorylase can also assist with interpretation [6].
Historically, GSD IX was felt to be a benign condition, with treatment not usually required due to decreasing glucose requirements with age and catch up growth described in individuals with IXα2 [7]. It is now becoming increasingly evident that GSD IX can have a spectrum of severity, and recent guidelines recommend multi‐disciplinary care with diet and medical therapy [6]. The objective of this observational, retrospective cohort study was to describe the natural history and long‐term outcomes of 89 individuals with a confirmed diagnosis of hepatic GSD IX from across the United Kingdom.
2. Methods
Pediatric and adult metabolic centers from across the UK were invited to participate in this retrospective observational cohort study. An Excel spreadsheet was used to collect de‐identified patient data on demographics, initial presentation, and long‐term outcomes, diet therapy, molecular testing, and enzymology. Data were collected between November 2023 and January 2026. All data were analysed using descriptive statistics, and Stata software was used to look at paired t‐tests and regression analysis.
All patients provided informed consent for genetic testing. Formal research ethics committee approval was not required for this study where no individually identifiable data is presented.
3. Results
3.1. Demographics
A total of 89 patients (71 male and 18 female) from 4 pediatric and 3 adult metabolic centers in the UK were included in this study; none of whom we believe have been previously reported. The age of transition from pediatric to adult care in the UK is 16 years. A total of 60 patients had GSD IXα2 (2 females), 12 had IXβ (7 females) and 13 had IXγ2 (7 females). The median age of the patients was 16.4 years (range 4 months to 73 years). This included data for 44 adult patients (age 16 and older: 25 IXα2, 10 IXβ, 7 IXγ2, 2 undefined). Ethnicity was recorded for 66 patients, with 56% White British, 24% Caucasian or ‘other White’, 19% Asian and 2% Arab.
A total of 85 patients had a confirmed genetic diagnosis, with an additional 4 patients (3 female, 1 male) diagnosed clinically and biochemically and confirmed to have low phosphorylase kinase activity on enzymology testing on either red cells, white cells or liver tissue [6]. The male patient had recently had GSD panel testing with no causative variant found, and the 3 female patients had been tested in childhood, with no causative variants found. The variants observed in our cohort of patients is shown in Table 1, with 49 novel alleles described.
TABLE 1.
Patient variants and references for PHKA2 (NM_000292.3), PHKB (NM_000293.3) and PHKG2 (NM_000294.3). Total refers to the number of times this variant was observed in our cohort.
| Gene | Variant | Amino acid change | Variant type | Classification (Minimum ACMG criteria) | Total | References |
|---|---|---|---|---|---|---|
| PHKA2 | c.256C>T | p.(Arg86*) | Nonsense | Likely Pathogenic (PVS1, PM2_Supporting) | 1 | This study |
| c.271T>C | p.(Cys91Arg) | Missense | Likely Pathogenic (PS2, PM2_Supporting, PP3_Moderate) | 1 | This study | |
| c.301_303del | p.(Lys101del) | In‐frame deletion | VOUS (PM4, PP4) | 1 | This study | |
| c.379delG | p.(Asp127fs*22) | Frameshift | Likely Pathogenic (PVS1, PM2_Supporting) | 1 | This study | |
| c.556C>T | p.(Arg186Cys) | Missense | Likely Pathogenic (PS4_Moderate, PM2_Supporting, PM5, PP3_Moderate) | 1 | [8] | |
| c.557G>A | p.(Arg186His) | Missense | Pathogenic (PS4_Moderate, PM2_Supporting, PM5, PP3_Strong, PP4) | 1 | [3, 8, 9, 10] | |
| c.559G>A | p.(Gly187Arg) | Missense | Likely Pathogenic (PS4_Moderate, PM2_Supporting, PM5, PP3_Strong) | 1 | [10] | |
| c.602C>A | p.(Ser201Tyr) | Missense | Likely Pathogenic (PM2_Supporting, PP3_Strong, PP4) | 2 | This study | |
| c.677_689del | p.(Ser226Phefs*44) | Frameshift | Likely Pathogenic (PVS1, PM2_Supporting) | 1 | This study | |
| c.740C>T | p.(Pro247Leu) | Missense | Pathogenic (PS2, PM2_Supporting, PP3_Strong, PP4_Moderate) | 1 | This study | |
| c.750_752del | p.(Thr251del) | In‐frame deletion | Likely Pathogenic (PS2, PM2_Supporting, PM4) | 1 | [11] | |
| c.874G>A | p.(Gly292Arg) | Missense | Likely Pathogenic (PM2_Supporting, PP3_Strong, PP4) | 1 | This study | |
| c.884G>A | p.(Arg295His) | Missense | Likely Pathogenic (PS4_Moderate, PM2_Supporting, PM5, PP3_Strong) | 1 | [12, 13, 14, 15, 16, 17] | |
| c.899G>T | p.(Gly300Val) | Missense | Likely Pathogenic (PS4_Moderate, PM2_Supporting, PP3_Strong) | 1 | [10] | |
| c.919‐1G>C | p.(?) | Non‐coding | Likely Pathogenic (PVS1_Moderate, PS1_Moderate, PM2_Supporting, PP4) | 1 | This study | |
| c.963C>A | p.(Phe321Leu) | Missense | Likely Pathogenic (PS2, PM2_Supporting, PP3_Moderate, PP4_Moderate) | 1 | This study | |
| c.1005delT | p.(Phe335Leufs*2) | Deletion | Likely Pathogenic (PVS1, PM2_Supporting) | 3 | This study | |
| c.1174C>G | p.(Arg392Gly) | Missense | VOUS (PM2_Supporting, PP3_Moderate, PP4) | 1 | This study | |
| c.1275delC | p.(Leu426*) | Nonsense | Likely Pathogenic (PVS1, PM2_Supporting, PP3_Moderate) | 2 | This study | |
| c.1412_1416del | p.(Ile471Serfs*8) | Frameshift | Likely Pathogenic (PVS1, PM2_Supporting) | 3 | This study | |
| c.1459 + 1G>T. | p.(?) | Non‐coding | VOUS (PVS1_Moderate, PM2_Supporting) | 1 | This study | |
| c.1499G>A | p.(Arg500Gln) | Missense | VOUS (PS4_Moderate, PM2_Supporting, PP3_Moderate) | 1 | This study | |
| c.1561A>G | p.(Thr521Ala) | Missense | VOUS (BS1) | 1 | [18] | |
| c.2332G>A | p.(Asp778Asn) | Missense | VOUS (PM2_Supporting, PP3_Moderate) | 1 | This study | |
| c.2470C>T | p.(Arg824Cys) | Missense | Likely Pathogenic (PS4_Moderate, PM1, PM2_Supporting, PP3_Moderate, PP4) | 3 | [3] | |
| c.2470C>G | p.(Arg824Gly) | Missense | Likely Pathogenic (PM1, PM2_Supporting, PM5, PP3_Moderate, PP4) | 1 | This study | |
| c.2518‐4_2523dup | p.(Thr842Alafs*103) | Frameshift | Likely Pathogenic (PVS1, PM2_Supporting) | 1 | This study | |
| c.2597 + 2dup | p.(?) | Non‐coding | VOUS (PM2_Supporting, PP3, PP4) | 1 | This study | |
| c.2645_2646del | p.(Gly882Alafs*59) | Frameshift | Likely Pathogenic (PVS1, PM2_Supporting) | 1 | This study | |
| c.2746C>T | p.(Arg916Trp) | Missense | Likely Pathogenic (PS4_Moderate, PM2_Supporting, PP3_Moderate, PP4) | 1 | [10, 14, 19, 20] | |
| c.2989_2990del | p.(Arg997Glufs*4) | Deletion | Likely Pathogenic (PVS1, PM2_Supporting) | 1 | This study | |
| c.3190C>T | p.(Gln1064*) | Nonsense | Likely Pathogenic (PVS1, PM2_Supporting) | 1 | [21] | |
| c.3224G>A | p.(Gly1075Glu) | Missense | Likely Pathogenic (PM1, PM2_Supporting, PP3_Moderate, PP4) | 1 | This study | |
| c.3230_3232del | p.(Ile1077del) | In‐frame deletion | Likely Pathogenic (PM1, PM2_Supporting, PM4, PP4) | 1 | This study | |
| c.3313C>T | p.(Leu1105Phe) | Missense | VOUS (PP3_Moderate) | 1 | This study | |
| c.3340A>C | p.(Thr1114Pro) | Missense | Likely Pathogenic (PM2_Supporting, PM5, PP3_Strong) | 1 | This study | |
| c.3368A>G | p.(His1123Arg) | Missense | VOUS (scores no criteria) | 1 | This study | |
| c.3373G>A | p.(Glu1125Lys) | Missense | Pathogenic (PS4, PM2_Supporting, PP3_Strong) | 4 | [8, 19] | |
| c.3410_3421dup | p.(Leu1140_Val114ins4) | In‐frame duplication | VOUS (PM2_Supporting, PM4, PP4) | 1 | This study | |
| c.3614C>G | p.(Pro1205Arg) | Missense | Likely Pathogenic (PS4_Moderate, PM2_Supporting, PM5, PP3_Moderate) | 2 | This study | |
| c.3614C>T | p.(Pro1205Leu) | Missense | Likely Pathogenic (PS4, PM2_Supporting, PP3_Moderate) | 3 | [3, 10, 19, 22, 23, 24] | |
| c.3632C>G | p.(Thr1211Arg) | Missense | Likely Pathogenic (PS4_Moderate, PM2_Supporting, PP3_Moderate, PP4) | 3 | This study | |
| g.18802936_19107270del | p.(?) | Large deletion | Pathogenic (PVS1, PM2_Supporting, PP4) | 2 | This study | |
| PHKB | c.238C>T | p.(Gln80*) | Nonsense | Likely Pathogenic (PVS1, PM2_Supporting, PP4) | 1 | This study |
| c.555G>T | (p.Met185Ile) | Missense | Benign (BA1) | 1 | [20] | |
| c.711‐?_1458 +?del | p.(?) | Large deletion | Pathogenic (PVS1, PM2_Supporting, PM3_Supporting, PP4_Moderate) | 1 | This study | |
| c.1090G>T | p.(Glu364*) | Nonsense | Likely Pathogenic (PVS1, PM2_Supporting, PM3) | 1 | [25] | |
| c.1127‐2A>G | p.(?) | Splice site | Likely Pathogenic (PVS1_Moderate, PM2_Supporting, PM3, PP4) | 4 | [20, 26] | |
| c.1257 T>A | p.(Tyr419*) | Nonsense | Likely Pathogenic (PVS1, PM2_Supporting, PP4) | 1 | [20] | |
| c.1285C>T | p.(Arg429*) | Nonsense | Likely Pathogenic (PVS1, PM2_Supporting, PM3_Supporting, PP4) | 2 | This study | |
| c.1546C>T | p.(Gln516*) | Nonsense | Likely Pathogenic (PVS1, PM2_Supporting) | 1 | This study | |
| c.1631A>G | (p.Asn544Ser) | Missense | VOUS (scores no criteria) | 1 | This study | |
| c.1797 + 1G>C | p.(?) | Intronic duplication | Likely Pathogenic (PVS1_Moderate, PM2_Supporting, PM3, PP4_Moderate) | 1 | This study | |
| c.1819C>T | p.(Gln607*) | Nonsense | Likely Pathogenic (PVS1, PM2_Supporting) | 2 | This study | |
| c.1969C>T | p.(Gln657*) | Nonsense | Pathogenic (PVS1, PM2_Supporting, PM3, PP4_Moderate) | 2 | This study | |
| c.2316‐2A>C | p.(?) | Non‐coding | Likely Pathogenic (PVS1, PM2_Supporting) | 1 | This study | |
| c.2326C>T | p.(Gln776*) | Nonsense | Pathogenic (PVS1, PM2_Supporting, PM3_Supporting, PP4) | 2 | This study | |
| c.2459_2461del | p.(Glu820del) | In‐frame deletion | Benign (BA1) | 1 | This study | |
| c.2783G>A | p.(Arg928His) | Missense | Likely Pathogenic (PM1, PM2_Supporting, PP3_Moderate, PP4) | 1 | This study | |
| PHKG2 | c.96‐11G>A | p.(?) | Non‐coding | Likely Pathogenic (PM2_Supporting, PM3, PP3, PP4_Moderate) | 1 | [27] |
| c.112G>A | p.(Val38Ile) | Missense | Likely Pathogenic (PM1_Supporting, PM2_Supporting, PM3, PP4_Moderate) | 1 | This study | |
| c.144delC | p.(His48GlnInfs*5) | Frameshift | Pathogenic (PVS1, PM2_Supporting, PM3, PP4) | 4 | [20] | |
| c.226C>T | p.(Arg76*) | Nonsense | Pathogenic (PVS1, PM2_Supporting, PM3_Supporting, PP4) | 2 | [28] | |
| c.247C>T | p.(Gln83*) | Nonsense | Likely Pathogenic (PVS1, PM2_Supporting) | 1 | [27, 28] | |
| c.371C>A | p.(Ala124Asp) | Missense | VOUS (PM1_Supporting, PM2_Supporting, PM3_Supporting, BP4_Moderate) | 2 | This study | |
| c.434A>T | p.(His145Leu) | Missense | Likely Pathogenic (PM2_Supporting, PM5, PP3_Moderate, PP4_Moderate) | 1 | This study | |
| c.458A>T | p.(Asp153Val) | Missense | Likely Pathogenic (PM2_Supporting, PP3_Strong, PP4) | 1 | This study | |
| c.469G>A | p.(Glu157Lys) | Missense | Likely Pathogenic (PM1_Supporting, PM2_Supporting, PM3, PP4_Moderate) | 2 | [3, 29, 30] | |
| c.478_480del | p.(Leu160del) | In‐frame deletion | VOUS (PM2_Supporting, PM4, PP4) | 1 | This study | |
| c.513 T>A | p.(Asp171Glu) | Missense | Likely Pathogenic (PM1_Supporting, PM2_Supporting, PM3_Supporting, PP3_Moderate, PP4) | 2 | This study | |
| c.677 T>G | p.(Leu226Arg) | Missense | Likely Pathogenic (PM2_Supporting, PM3, PP3, PP4_Moderate) | 5 | [31] | |
| c.698 T>C | p.(Phe233Ser) | Missense | Pathogenic (PS3_Supporting, PM2_Supporting, PM3_Strong, PP3_Moderate, PP4_Moderate) | 2 | [32, 33] | |
| c.925C>T | p.(Arg309Trp) | Missense | Likely Pathogenic (PM1, PM2_Supporting, PM3, PP3_Moderate, PP4) | 1 | [3] |
3.2. Initial Presentation
Table 2 reports the main findings of our cohort and is further broken down into each GSD IX subtype. The median age at diagnosis was 2.5 years (range 1 month to 11 years) with the median age at diagnosis for the different subtypes: 2.6 years (range 1 month to 11 years) for GSD IXα2, 3.4 years (range 1.1 to 6 years) for GSD IXβ, and 1.2 years (range 1 month to 6 years) for GSD IXγ2. The most common initial presenting symptoms were hepatomegaly in 82% (68/83), episodes of ketotic hypoglycaemia in 46% (38/83), and abnormal liver function tests in 24% (20/83). Other presenting symptoms included growth concerns in 24% (20/83), hypoglycaemic episodes in 17% (14/83), and episodes of ketosis without hypoglycaemia in 10% (8/83). A total of 16% (13/83) were diagnosed due to a positive family history. A total of 2% of patients (2/83) presented with an initial hypoglycaemic seizure, and data on initial presentation was unknown for 7% (6/89) of patients. A total of 17 patients were documented to have developmental delay at initial presentation: 1 with global developmental delay, 4 with motor delay, 1 with speech delay, 3 with delay in the context of autism, 2 with delay in the context of a secondary genetic diagnosis, 1 with delay in the context of cerebral palsy, and the remainder undefined.
TABLE 2.
Patient demographics and phenotype at initial presentation and last review. Growth measurements used UK‐WHO growth charts.
| All GSD IX | GSD IXα2 | GSD IXβ | GSD IXγ2 | |
|---|---|---|---|---|
| Number of patients (female) | 89 (18) | 60 (2) | 12 (7) | 13 (7) |
| Median current age, years (range) | 16.4 (0.3–73) | 14.5 (1.4–73) | 26 (6–37) | 17 (0.3–57) |
| Initial presentation | ||||
| Median age at diagnosis, years (range) | 2.5 (0.1–11), 79 | 2.6 (0.1–11), 55 | 3.4 (1.1–6), 9 | 1.2 (0.1–6), 12 |
| Mean Z‐score for height (SD) | −1.21 (1.71), 60 | −1.26 (1.79), 44 | −1.17 (1.05), 6 | −1.29 (1.67), 9 |
| Mean Z‐score for weight (SD) | −0.40 (1.19), 60 | −0.44 (1.14), 43 | −0.24 (1.01), 6 | −0.54 (1.37), 9 |
| Number who had a liver biopsy | 21 | 15 | 2 | 4 |
| Median age at liver biopsy, years (range) | 2 (0.6–10) | 2.3 (1.5–10) | 2.7 (2–3.4) | 0.95 (0.6–4) |
| Steatosis on biopsy | 12/17 (71%) | 6/10 (60%) | 1/2 (50%) | 4/4 (100%) |
| Fibrosis on biopsy | 10/17 (59%) | 6/11 (55%) | 0/2 (0%) | 4/4 (100%) |
| Cirrhosis on biopsy | 2/17 (12%) | 0/11 (0%) | 0/2 (0%) | 2/4 (50%) |
| Number with hepatomegaly | 68/83 (82%) | 45/55 (82%) | 10/11 (91%) | 12/13 (92%) |
| Number with ketotic hypoglycaemia | 38/83 (46%) | 26/55 (47%) | 1/11 (9%) | 8/13 (62%) |
| Hepatomegaly on ultrasound | 45/56 (80%) | 29/38 (76%) | 5/6 (83%) | 10/10 (100%) |
| Increased echogenicity on ultrasound | 21/56 (38%) | 17/38 (45%) | 0/6 (0%) | 4/10 (40%) |
| Steatosis on ultrasound | 13/56 (23%) | 8/38 (21%) | 2/6 (33%) | 3/10 (30%) |
| Coarse echotexture on ultrasound | 6/56 (11%) | 4/38 (11%) | 0/6 (0%) | 2/10 (20%) |
| Normal liver on ultrasound | 7/56 (13%) | 7/38 (18%) | 0/6 (0%) | 0/10 (0%) |
| Mean ALT U/L (SD) | 257 (297), 49 | 170 (174), 36 | 171 (45), 3 | 652 (463), 8 |
| Mean AST U/L (SD) | 490 (596), 12 | 395 (40), 7 | 234, 1 | 884 (745), 3 |
| Mean GGT U/L (SD) | 102 (128), 12 | 60 (41), 5 | 23 (5.6), 2 | 216 (176), 4 |
| Mean cholesterol mmol/L (SD) | 5.2 (2.3), 48 | 4.5 (1.4), 32 | 6.1 (1.6), 5 | 7.4 (3.6), 9 |
| Mean triglycerides mmol/L (SD) | 3.8 (3.4), 49 | 3.0 (2.2), 33 | 3.5 (1.3), 5 | 7.2 (5.5), 9 |
| Mean CK U/L (SD) | 135 (61), 19 | 120 (35), 11 | 121 (68), 5 | 249 (86), 2 |
| Last review | ||||
| Number with hepatomegaly | 42/81 (52%) | 24/52 (46%) | 6/12 (50%) | 10/13 (77%) |
| Number with ketotic hypoglycaemia | 15/85 (18%) | 8/57 (14%) | 0/12 (0%) | 5/12 (42%) |
| Hepatomegaly on ultrasound or MRI | 43/71 (61%) | 32/47 (68%) | 5/11 (45%) | 8/11 (73%) |
| Increased echogenicity on ultrasound or MRI | 24/71 (34%) | 16/47 (34%) | 1/11 (9%) | 6/11 (55%) |
| Steatosis on ultrasound or MRI | 20/71 (28%) | 10/47 (21%) | 4/11 (36%) | 4/11 (36%) |
| Coarse echotexture on ultrasound or MRI | 9/71 (13%) | 3/47 (6%) | 2/11 (18%) | 3/11 (27%) |
| Normal liver on ultrasound or MRI | 11/71 (15%) | 7/47 (15%) | 3/11 (27%) | 0/11 (0%) |
| Mean ALT U/L (SD) | 101*** (146), 49 | 60*** (100), 54 | 82 (21), 3 | 270* (232), 8 |
| Mean AST U/L (SD) | 140* (148), 12 | 40 (14), 7 | 105, 1 | 370 (69), 3 |
| Mean GGT U/L (SD) | 41* (42), 12 | 32* (34), 5 | 15 (11), 2 | 68 (56), 4 |
| Mean cholesterol mmol/L (SD) | 4.7* (1.1), 48 | 4.5 (1.0), 32 | 5.9 (1.1), 5 | 4.7* (0.7), 9 |
| Mean triglycerides mmol/L (SD) | 2.0*** (1.5), 49 | 1.9** (1.5), 33 | 2.4 (1.8), 5 | 2.3* (1.3), 9 |
| Mean CK U/L (SD) | 137 (76), 19 | 124 (49), 11 | 110 (14), 5 | 139 (7.8), 2 |
Note: Denominators and small numbers in italics denote number of patients with available data. The grey shading separates the cohort as a whole, versus the individual subtypes. Statistically significant changes at last review are denoted by: *p < 0.05, **p < 0.01, ***p < 0.001.
Abbreviation: SD = Standard deviation.
Hepatomegaly was reported on liver ultrasound in 80% (45/56) of patients at initial presentation, with 38% (21/56) noted to have increased echogenicity, and 23% (13/56) reported to have steatosis. A coarse echotexture was reported in 11% (6/56) of patients, 4 with IXα2 and 2 with IXγ2, at a median age of 1.7 years (range 1 month to 2.5 years).
3.3. Liver Biopsy
A total of 21 patients had a liver biopsy at their initial presentation at a median age of 2 years (range 7 months to 10 years). Of these for whom data were available, 71% (12/17) had steatosis at a median age of 2.9 years (range 7 months to 10 years) and 59% (10/17) had fibrosis at a median age of 2.1 years (range 7 months to 4 years). Two patients with GSD IXγ2 had a formal diagnosis of cirrhosis on the initial biopsy at a median age of 12 months. No patients had liver biopsies following their initial diagnosis.
3.4. Growth
At initial presentation, the mean Z‐score for height for all individuals was −1.21 (SD = 1.71) and the mean Z‐score for weight was −0.40 (SD = 1.19), which corresponds to the 11th and 34th centiles using UK‐WHO growth charts. There were no significant differences for height and weight at initial presentation between the 3 subtypes. Figure 1 compares Z‐scores for height at initial presentation (mean = −1.15, SD = 1.63) and at last review up to the age of 18 years (mean = −0.44, SD = 1.15) for all individuals with these 2 measurements (n = 47), which showed a statistically significant increase (p < 0.001). Individuals with follow up of less than 2 years following diagnosis were excluded from this analysis. The mean Z‐score for weight at initial presentation (mean = −0.39, SD = 1.22) also significantly increased at the last review up to the age of 18 years (mean = 0.12, SD = 0.17, p < 0.01).
FIGURE 1.
Height Z‐score in childhood at initial presentation and last review using UK‐WHO growth charts up to age 18. Colored circles represent height Z‐score at initial presentation for each GSD IX subtype, and diamonds represent height Z‐score at the last review for each GSD IX subtype. Each individual circle has a corresponding diamond for the same patient, and fitted values represent the trend for the group as a whole.
Adult growth measurements are typically recorded as body mass index (BMI): 25 adult patients with IXα2 (range 16–73 years) had a median BMI of 23.5 kg/m2 (range 17.5–36.9). A total of 10 adult patients with IXβ (range 17–37 years) had a median BMI of 26.4 kg/m [2] (range 20.4–45.2). Seven adult patients with IXγ2 (range 17–57 years) had a median BMI of 22.5 kg/m2 (range 19.3–32.1). When the adult heights at last review were matched with the corresponding Z‐score for age 18, the mean Z‐score for the adult cohort was 0.12 (SD = 2.15).
3.5. Biochemistry
Table 2 shows that the mean ALT significantly improved (p < 0.001) from initial presentation (mean = 257 U/L, SD = 297) to the last review (mean 101 U/L, SD = 146). Mean ALT at presentation was much higher in individuals with IXγ2 (652 U/L, SD = 463), compared to those with IXα2 (170 U/L, SD = 174) and IXβ (171 U/L, SD = 45). Regression analysis of ALT at initial presentation showed a significant difference (p < 0.01) between individuals with IXγ2 compared to IXα2.
Significant improvements were seen in GGT from initial presentation (mean = 102 U/L, SD = 128) to last review (mean = 41 U/L, SD = 42, p < 0.05), and in AST at initial presentation (490 U/L, SD = 596) and last review (140 U/L, SD = 148, p < 0.05). The change in GGT from initial presentation to last review was statistically significant in the IXα2 group. Regression analysis found that GGT was significantly higher (p < 0.001) at initial presentation in individuals with IXγ2 compared to IXα2, as was AST (p < 0.05).
A significant improvement was seen in triglycerides from initial presentation (3.8 mmol/L, SD = 3.4) to last review (2 mmol/L, SD = 1.5, p < 0.001), and in cholesterol at initial presentation (mean = 5.2 mmol/L, SD = 2.3) and last review (mean = 4.7 mmol/L, SD = 1.1, p < 0.05). The cholesterol and triglyceride levels at initial presentation were significantly higher (p < 0.001) in individuals with IXγ2 compared to those with IXα2 on regression analysis. The improvements in triglyceride levels were statistically significant in those with IXα2 and IXγ2, and the decrease in cholesterol was significant for the IXγ2 group, as shown in Table 2.
Reference ranges can vary by age for creatine kinase (CK) with a level less than 200 U/L considered normal in adult females and less than 320 U/L considered normal in adult males. The CK was normal at baseline (mean = 135 U/L, SD = 61) and no significant change was seen at last review (mean = 137 U/L, SD = 76) in patients for whom 2 corresponding measurements were available.
3.6. Diet
Table 3 reports the key dietary details of our cohort for whom data were available. Following initial presentation, 20% (15/75) were treated with continuous overnight enteral feeds (COFs) at a median age of 1.9 years (range 1 month to 5.3 years): 10 children with IXα2, 1 child with IXβ and 4 with IXγ2. COFs were started due to more significant hypoglycaemia and the need for frequent feeds overnight. Treatment with uncooked cornstarch (UCCS) was commenced after initial presentation in 52% (43/82), with 8 of these patients also receiving COFs. Data on the frequency of UCCS delivery was available for 28 patients, with 64% (18/28) receiving multiple doses of UCCS per day and 36% (10/28) receiving only a single dose at night. Of the 7 patients who commenced COFs following IP but who did not commence UCCS immediately, the majority of these were less than 12 or 24 months of age and UCCS was slowly introduced over time. One patient had an intolerance to cornstarch due to a secondary medical condition. One centre additionally reported that 3 patients with IXγ2 (27%) and 2 patients with IXα2 (4%) were treated with neither COF nor UCCS after initial presentation but received regular oral or enteral bolus feeds throughout the night.
TABLE 3.
Dietary data at initial presentation and last review.
| All GSD IX | GSD IXα2 | GSD IXβ | GSD IXγ2 | |
|---|---|---|---|---|
| Initial presentation | ||||
| Median age at diagnosis, years (range) | 2.5 (0.1–11) | 2.6 (0.1–11) | 3.4 (1–1.6) | 1.2 (0.1–6) |
| Continuous overnight enteral feeds | 15/75 (20%) | 10/51 (20%) | 1/7 (14%) | 4/12 (33%) |
| Multiple doses of UCCS day/night | 18/28 (64%) | 15/22 (68%) | 1/2 (50%) | 2/4 (50%) |
| Single dose of UCCS at night only | 10/28 (36%) | 7/22 (32%) | 1/2 (50%) | 2/4 (50%) |
| No dietary treatment when well | 30/82 (37%) | 22/57 (39%) | 6/10 (60%) | 1/11 (9%) |
| Last review for children < 16 years | ||||
| Median age, years (range) | 9.2 (0.3–15.8) | 10.4 (1.4–15.8) | 7 (6–8) | 7 (0.3–13.7) |
| Continuous overnight enteral feeds | 5/45 (11%) | 3/35 (9%) | 0/2 (0%) | 2/6 (33%) |
| Multiple doses of UCCS day/night | 13/25 (52%) | 11/22 (50%) | 0/0 (0%) | 3/3 (100%) |
| Single dose of UCCS at night only | 12/25 (48%) | 11/22 (50%) | 0/0 (0%) | 0/3 (0%) |
| Prescribed protein products | 10/45 (22%) | 6/35 (17%) | 0/2 (0%) | 3/6 (50%) |
| No dietary treatment when well | 17/45 (38%) | 13/35 (37%) | 2/2 (100%) | 2/6 (33%) |
| Last review for adults ≥ 16 years | ||||
| Median age, years (range) | 21.5 (16.1–73) | 21.8 (16.1–73) | 24.5 (17–37) | 25 (17–57) |
| Multiple doses of UCCS day/night | 6/11 (55%) | 4/6 (67%) | 1/2 (50%) | 1/3 (33%) |
| Single dose of UCCS at night only | 5/11 (45%) | 2/6 (33%) | 1/2 (50%) | 2/3 (66%) |
| Prescribed protein products | 2/44 (5%) | 0/25 (0%) | 1/10 (10%) | 1/7 (14%) |
| No dietary treatment when well | 33/44 (75%) | 19/25 (76%) | 8/10 (80%) | 4/7 (57%) |
Note: Denominators denote number of patients with available data. The grey shading separates the cohort as a whole, versus the individual subtypes.
Abbreviation: UCCS = uncooked cornstarch.
A total of 36% of children for whom data were available (n = 28) were treated with a single dose of uncooked cornstarch at night only following initial presentation. Around 37% of children (30/82) were on no formal dietary treatment at all when well, following their initial presentation.
At the last review, 5 children remained on continuous overnight feeds at a median age of 8.8 years (age range 5–11.8 years), 3 with IXα2 and 2 with IXγ2. All others who had been on COFs had ceased this before adulthood, including one individual with IXβ who ceased COFs in late adolescence.
At the last review, 43% of patients were on UCCS (32 children, 11 adults) with 61% (n = 23) on cornflour and 21% (n = 8) on Glycosade, and the rest unrecorded. This group included 47% (28/60) with IXα2, 17% (2/12) with IXβ, and 54% (7/13) with IXγ2. Of those for whom data were available, 48% (12/25) of children and 45% of adults (5/11) were on a single bedtime dose of UCCS only.
Of the 57% (51/89) not on any dietary treatment when well at the last review (17 children, 33 adults), the majority of these for whom data were available (41%, 17/41) indicated that they had previously been on UCCS, but that this was either self‐ceased or ceased by the clinic due to them being asymptomatic, and this was documented to have occurred in childhood or adolescence in 76% (13/17). A further 39% (16/41) had never required treatment with uncooked cornstarch, and this included 58% of children (11/19) and 23% (5/22) of adults with available data. Several children had ceased UCCS following either a normal glucose and ketone profile (16%, 3/19) or normal continuous glucose monitor (CGM) data (5%, 1/19). One adult patient was recorded as being non‐compliant (5%, 1/22) and one child was unable to tolerate UCCS (5%, 1/19).
Data on prescribed protein products (PPP) were only collected at the last review. PPP were included in the diet for 22% (10/45) of children and 5% (2/44) of adults. This included 31% (4/13) of individuals with IXγ2, 10% (6/60) with IXα2 and 8% (1/12) with IXβ. Most centres encouraged protein in the diet, but this was not formalized, and no centres routinely collected macronutrient data on protein intake.
3.7. Long‐Term Outcomes
One patient died in childhood from sepsis. All other patients are alive. One patient with IXγ2 had a liver transplant at 5 years of age as they had a secondary gastrointestinal diagnosis which made dietary management of their GSD very difficult.
Hepatomegaly was documented in 41% (17/41) of adult patients. Ultrasound and MRI imaging of the abdomen confirmed hepatomegaly in 49% (19/39) of adults, with 15% (6/39) reported to have coarse echotexture of the liver, 28% (11/39) with steatosis, and 23% (9/39) with normal imaging. One adult patient was noted to have haemangiomas of the liver, but no other abnormal liver lesions were seen in either the adult or pediatric cohorts.
Episodes of ketotic hypoglycaemia were reported in 18% (15/85) of all patients at last review. This was reported in 22% of children (10/45), all of whom were taking UCCS. A total of 10% of adults (4/42) reported episodes of KH, only one of whom was taking UCCS.
A total of 25% of patients (15/60) reported monitoring of glucose at home, with only 13% monitoring ketones (8/60). This included 7 pediatric patients who would intermittently check their glucose and ketone levels as part of home profiling. An additional 28 children were having regular elective admissions to hospital for inpatient profiling of glucose and ketone levels. Many adult patients were asked to measure glucose and ketone levels at home prior to their clinic appointments but were non‐compliant with monitoring. Use of continuous glucose monitoring (CGM) was uncommon in our cohort, with only 5 adults using CGM daily and 4 patients (3 adults, 1 child) using CGM following a dietary change. Of the 5 adults using CGM daily, 4 of these had an additional diagnosis of diabetes mellitus (DM). One had a strong family history of type II DM, including their sibling who did not have GSD, and another was felt to have good control of their GSD and to have a phenotype consistent with maturity‐onset diabetes of the young (MODY). The other 2 patients were siblings who were felt to have a secondary DM due to recurrent pancreatitis from a secondary genetic diagnosis causing recurrent pancreatitis.
Two adults were described as having mild learning difficulties in school, with 2 additional adult siblings having intellectual disability and sensorineural deafness, which is felt to be attributable to an as yet undefined secondary genetic diagnosis. All 4 patients with gross motor delay at initial presentation had resolution of their delay. The 3 patients with a diagnosis of autism at initial presentation did not have a change in this diagnosis with time or treatment. Hypogonadism was reported in 3 adult males, all of whom required testosterone replacement. One adult female patient had a successful pregnancy, and another was reported to have irregular periods and subfertility in association with an elevated BMI and suspected polycystic ovarian syndrome (PCOS). One adult patient was reported to have disordered eating, alternating between restrictive eating and binge eating, and often using UCCS in place of food.
A total of 28 patients with a median age of 17 years (range 5.1–73 years) had dual‐energy X‐ray absorptiometry (DEXA) scans to assess bone density by the time of their last review, with 82% documented as normal (23/28), 14% with osteopaenia (4/28) and 4% with osteoporosis (1/28). The 5 patients with osteopaenia/osteoporosis ranged in age from 28–39 years, 4 with GSD IXα2 and 1 with IXβ. One patient had a healthy BMI, two were overweight/obese and data for the other 2 was unknown. The patient with osteoporosis was on a single dose of uncooked cornstarch at night, and the rest were not on any dietary treatment. At least 18 patients (12 GSD IXα2, 2 IXβ and 4 IXγ2) had an echocardiogram following initial presentation, with data unknown for the majority of the cohorts who are now adults. No patients had evidence of cardiomyopathy, 1 child IXγ2 had a mild atrial septal defect and 2 children with IXα2 were found to have a bicuspid aortic valve. At the time of the last review, seven adult patients (3 GSD IXα2, 2 IXβ and 2 IXγ2) with a median age of 30 years (range 17–39 years) had a documented normal echocardiogram with no cardiomyopathy or structural abnormalities.
No observable differences were noted between male and female patients for the different GSD IX subtypes, which is likely due to the small number of female patients in our cohort.
4. Discussion
We describe the presentation and long‐term outcomes of 89 individuals with glycogen storage disease type IX in the United Kingdom. The majority are white, and the most common subtype in our cohort was GSD IXα2, representing 67% of our cohort. We report 49 novel alleles, with missense variants (n = 36) accounting for the majority of variants, followed by nonsense (n = 13) and frameshift (n = 6) variants. Our cohort included a number of variants of uncertain significance, with each of these individuals having a clinical and biochemical diagnosis of GSD.
The most common variant in PHKA2 in our cohort (n = 4) was the Glu1125Lys missense variant, which has been previously reported in UK and Chinese populations [19]. In PHKA2 we also saw the common Pro1205Leu variant (n = 3), which has a pan‐ethnic distribution [3, 10, 19, 22, 23, 24], and the Arg824Cys variant (n = 3), which was reported in Canada [3]. We report 2 novel alleles in PHKA2, Thr1211Arg and Phe335Leufs*2, each in 3 individuals from 2 families. The 3 individuals with the Phe335Leufs*2 variant, including one female, also carried a heterozygous Glu401Glu synonymous variant of uncertain significance in PHKB. A third novel allele, Ile471Serfs*8, was seen in 3 individuals of different ages from across the UK, and it is unclear whether they may be related. Our cohort also included 3 manifesting female carriers of variants in PHKA2, which highlights the fact that this information should not be withheld on the genomic reports for symptomatic female patients, and that clinician input into variant interpretation is crucial.
For PHKB, nonsense variants (n = 8) were seen most frequently, and the most common allele (n = 4) was the previously reported c.1127‐2A>G p.(?) splice site variant [20, 26], which was seen in the homozygous state in 2 siblings of Asian ethnicity. Two benign variants in PHKB were described in our cohort: Met185Ile and Glu820del. The Met185Ile variant has been previously reported in an individual in which a second variant was not detected [20]. This individual had borderline enzyme activity with a low ratio of activated to total phosphorylase. Our patient had a compound heterozygous VOUS and had low enzyme activity, but the ratio of active to total phosphorylase was borderline, and the glycogen content was low, which made interpretation difficult. The Glu820del variant has not been previously reported but has an allele frequency of around 1 in 300. Our patient had a compound heterozygous likely pathogenic variant but has not had enzymology performed. Clinically and biochemically, both of our patients had a diagnosis of GSD, and so these findings possibly reflect a second undetected variant.
For PHKG2, the most frequent variants were the Leu226Arg (n = 5) and the His48GlnInfsTer5 (n = 4) variants, both previously reported in individuals of White British and Pakistani backgrounds respectively [20, 31].
Diagnosis in our cohort typically occurred in the first few years of life, although it is unclear if this was a clinical diagnosis or a diagnosis made following liver biopsy or genetic testing. The oldest age at diagnosis was 11 years for an individual with IXα2, who had hepatomegaly and short stature. Given the rarity of GSD IX and the spectrum of severity, it is likely that there may be delays in diagnosis, even within specialist metabolic centres. Some children may be falsely labeled as having idiopathic ketotic hypoglycaemia [5].
Hepatomegaly was a consistent feature at initial presentation, with 82% noted on examination and 80% reported on ultrasound. Almost half of the cohort was also reported as having ketotic hypoglycaemia at their initial presentation, although it was not clear from our data collection tool whether this was seen during an acute presentation to hospital, or whether this was found during an elective admission for profiling of glucose and ketone levels following the suspicion of a GSD. A number of children were reported to present with hypoglycaemia only, or with ketosis without hypoglycaemia, as described in the literature [22]. Abnormal liver function tests and poor growth were also common presenting features seen in our cohort. Biochemical features at initial presentation included elevated cholesterol and triglycerides and abnormal liver function tests. These findings are all consistent with what is reported in the literature [1, 3, 4].
Almost 40% of our cohort had the finding of increased echogenicity on their initial liver ultrasound report, with an additional 23% reported to have steatosis. The most common cause of increased echogenicity on liver ultrasound is steatosis [36], and so this is a useful diagnostic clue, particularly in children who are non‐overweight or obese. Steatosis was also a frequent feature on liver biopsy (71%). More concerningly, over half of those biopsied had features of fibrosis, which included 6 patients with IXα2, 4 with IXγ2 and 1 with an undetermined subtype. Two infants with IXγ2 already had cirrhosis on their initial liver biopsy. This correlates with a literature review by Fernandes et al. (2020), which found that almost all reported individuals with IXγ2 who have had a liver biopsy had evidence of fibrosis and/or cirrhosis [1].
The mean Z‐score for height at initial presentation for the entire cohort corresponded to the 11th centile on UK‐WHO growth charts. We looked at growth up until the age of 18 for all individuals, including our adult patients who had a documented growth measurement before age 18. We chose to exclude those who had follow up measurements less than 2 years post initial presentation, to allow time for catch up growth. Figure 1 shows a significant improvement in height across childhood. This is encouraging, although it is difficult to completely attribute causation to effective dietary treatment as over a third of patients did not require any formal dietary treatment after their initial diagnosis. The median BMI in the adults for all subtypes was in the healthy range (between 18.5 and 24.9) and the mean Z‐score for height in adults (0.12, SD 2.15) corresponds to the 55th centile, which indicates adequate growth with age.
Dietary management of GSD type IX in childhood highlights the spectrum of severity, with a fifth of all subtypes requiring treatment with continuous overnight enteral feeds (COFs), while some in each subtype required a nocte dose of UCCS only and others needed no formal dietary treatment when well. Unfortunately, our data collection tool failed to capture all children who were not on COFs but who were on frequent oral or bolus tube feeds overnight, which is often preferred in younger children and may also be a family preference. As the IXγ2 group were diagnosed at a younger age, it is likely that this group on the whole had a more intensive feeding regimen at initial presentation. Although one patient with IXβ required COFs following their initial presentation, the majority did not require any formal dietary treatment when well.
Interestingly, only 26% of patients using UCCS at their last review were using Glycosade, compared with 74% using cornstarch. Recent published results from the Glyde study in patients with ketotic GSDs showed a 20% increase in fasting tolerance before the development of ketones [37]. We therefore feel that Glycosade should be considered in patients with GSD IX, particularly those on a single bedtime dose of UCCS. Prescribed protein products were included in the diet of 22% of children and 5% of adults, with a high proportion of these (31%) being individuals with IXγ2. The drive for a high protein diet has been well established for glycogen storage disease type III, and the literature suggests that we do the same for the other ketotic GSD subtypes [6, 38]. A higher protein intake in the ketotic GSDs is felt to be beneficial due to offsetting the carbohydrate intake and providing fuel for muscles as well as precursors for gluconeogenesis [6]. A recommendation from our findings is that a more robust assessment of protein intake should be undertaken at each review, with supplementation with PPP if required to maintain 2–3 g of protein per kilogram.
Encouragingly, no adults remained on COFs and most (75%) are on no formalized treatment at all when well. We feel that this is a good indication that the disease burden lessens with age and less intensive dietary management is required. Only a very small number of patients were monitoring glucose and ketone levels at home and/or using CGM. Unfortunately, access to CGM is quite difficult in the UK. We believe that further studies in adult patients are required to better understand the natural history of GSD IX.
Poor metabolic control in GSD IX may be associated with osteopaenia and osteoporosis, and guidelines suggest a baseline scan post puberty and as clinically indicated [6]. Most of the DEXA scans reported in our cohort were normal, although further longitudinal data is required to understand how frequently monitoring is required. Hypertrophic cardiomyopathy was reported in 5 cases of GSD IX in the 1990s, although the subtypes were unknown [39]. Since this time, only 2 cases have been reported, once in a patient with IXα2 and once in a patient with IXβ. None of the 25 patients who had echocardiograms had evidence of cardiomyopathy, and we therefore don't see the utility of monitoring this unless clinically indicated.
It is unclear why 3 male patients had hypogonadism, and this may be related to their underlying liver disease and/or obesity [40]. We would recommend awareness of these complications and testing where clinically indicated. One adult female patient was suspected to have PCOS, which has also been reported in GSD IX [6]. Further studies are required in adult GSD IX patients to better understand the role of treatment in preventing health complications.
Our findings correlate with the literature, in that GSD IXγ2 is more severe than the other subtypes [1, 27, 31]. This is believed to be because PHKG2 encodes the catalytic site of the enzyme [1]. In our cohort, children with GSD IXγ2 were diagnosed at a younger age and also had significantly higher levels of liver transaminases, cholesterol and triglycerides at initial presentation compared to the other subtypes. Two of the cohort had established cirrhosis at the time of diagnosis. Their long‐term outcome is uncertain as they are both still in early childhood. The improvements in biochemistry in those with IXγ2 were less marked at last review compared to the other subtypes, and they tended to require more intensive dietary management both at initial presentation and last review, which extended into adulthood. There is a paucity of literature on long‐term outcomes in GSD type IX, particularly for type IXγ2. Of our 7 adult patients with IXγ2, most are in early adulthood. Our oldest individual with IXγ2 is 57 years of age and is not on any dietary treatment but has abnormal biochemistry and imaging, as well as diabetes mellitus. Our adult IXγ2 patients had more pathology on liver imaging compared to the other subtypes, which correlates with findings from a murine model whereby the mice had a progression in fibrosis over time [41]. This makes GSD IXγ2 an ideal target for new therapeutic interventions, such as gene therapy.
Our study further supports growing evidence that GSD IXα2 can have a spectrum of severity, with 55% having fibrosis on liver biopsy at diagnosis, and 20% requiring COFs in childhood [1]. Interestingly, while most of our GSD IXβ group tended to have a milder disease course, 1 young adult patient in this group required COF in childhood and is now managed with PPP and multiple doses of UCCS over the day. This suggests that there may also be a spectrum of severity in GSD IXβ.
Reassuringly, none of our cohort developed adenomas or hepatocellular carcinoma. Adenomas have been reported in all of the GSD IX subtypes, albeit in small numbers for GSD IXα2 and IXβ [1]. We believe that this lends further support to the need for regular multidisciplinary review and good dietary management.
Our study has several limitations, including that it involved multiple centres and was retrospective in nature. Data were missing for many patients, particularly those who had transitioned from pediatric to adult services. Small numbers for some of the biochemical data did not allow for statistical analysis. Original reports for liver biopsies and genomic testing were not available for many individuals. Nevertheless, we feel that our large sample size and detailed dietary data will add to the understanding of the natural history of hepatic GSD IX.
5. Conclusion
Our findings illustrate that individuals with GSD IX in the United Kingdom display a spectrum of severity. They normally present in the first few years of life, and hepatomegaly with steatosis is a consistent feature. There is an improvement in growth across childhood, and dietary management eases in adulthood. GSD IXγ2 has a more severe disease course and is an ideal target for novel therapies.
Author Contributions
Rebecca K. Halligan: study design, data analysis, manuscript initial draft, manuscript revision. Michael T. Sanders: data analysis. Arthavan Selvanathan: collection of data, manuscript revision, variant interpretation. Nirubhan Veeraghavan, Isaac Bernhardt, Joanna Gribben, Radha Ramachandran, Fiona J. White, Bernd C. Schwahn, Karolina M. Stepien, Preeya Rehsi, Elaine Murphy, Sarah L. Hulley: collection of data, manuscript revision. Helen R. Mundy: study design, manuscript revision. All authors approved the final version of the manuscript.
Funding
The authors have nothing to report.
Ethics Statement
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5).
Consent
All patients provided informed consent for genetic testing and inclusion in the study. Formal research ethics committee approval was not required for this study where no individually identifiable data is presented. The project has been registered as a service evaluation study at Salford Royal Hospital (Reference number 26SE0014) in addition to a written and/or verbal consent from all cases included from this site.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
We would like to acknowledge all of the clinicians, dietitians, and clinical nurse consultants involved in the care of these GSD patients. Due to author limits, we have only included those who had a direct role in the study and manuscript. We would also like to acknowledge our patients and their families for their involvement in this study.
Halligan R. K., Sanders M. T., Selvanathan A., et al., “Hepatic Glycogen Storage Disease Type IX: Long‐Term Outcomes in the UK From 89 Patients,” Journal of Inherited Metabolic Disease 49, no. 4 (2026): e70228, 10.1002/jimd.70228.
Academic Editor: Peter Witters
Data Availability Statement
The data that supports the findings are available upon request from the corresponding author. The data are not publicly available due to privacy restrictions.
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Associated Data
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Data Availability Statement
The data that supports the findings are available upon request from the corresponding author. The data are not publicly available due to privacy restrictions.