Glycogen storage disease, type II

Glycogen storage disease, type II is a metabolic/muscular genetic disease caused by autosomal recessive variants in GAA, acting through loss-of-function (biallelic; recessive). Within this volume's rankable burden cohort it sits at residual rank 10 of 23, where established therapy is substantially disease-modifying. That order is a provisional [H]-grade prioritisation device, not a registry-locked ranking.

Glycogen storage disease, type II is inherited as autosomal recessive and acts by loss-of-function (biallelic; recessive) ([H]). Its pre-treatment burden proxy is 0.8125 and, after the established therapy's efficacy offset e = 0.5500 is applied, its residual burden score is 0.3656 ([H]), placing it at residual rank 10 of 23.

Gene, inheritance, and molecular mechanism

Glycogen storage disease, type II is inherited as Autosomal recessive inheritance [L] and is classified mechanistically as loss-of-function (biallelic; recessive) [H]. GAA encodes acid alpha-glucosidase, the lysosomal enzyme that degrades glycogen. Its deficiency traps glycogen in the lysosomes of cardiac and skeletal muscle (Pompe disease).

Inheritance source: medgen:esummary:ModeOfInheritance:2026-06-17. Mechanism source: inference:recessive=>loss_of_function; basis=medgen_inheritance(recessive). These are observed, cited inputs; the inheritance and mechanism classification is the reproducible analysis layer (C-D1).

In-scope clinical involvement

Infantile-onset disease combines a hypertrophic cardiomyopathy with profound hypotonia; late-onset disease presents as a slowly progressive limb-girdle and respiratory-muscle weakness.

Organ systems [L] from HPO phenotype.hpoa v2026-06-06 (OMIM 232300); P-aspect terms rolled up to HP:0000118 organ-system categories via hp.obo.

Reproducible burden position

Of the five axes, 4 are scored (the rankability cut is ≥ 3 of 5); the pre-treatment composite is the renormalised mean over the scored axes, raw_burden = 0.8125. The registry-grade [L] axes here are onset, progression, and disability (onset from the Orphanet AverageAgeOfOnset register / HPO; disability from the GBD 2013 disability-weights table). Mortality remains an [H] inference from the cited clinical definition.

Because those axes carry [H] inferences, this position is a provisional [H] prioritisation device, not a registry-locked ranking.

The natural-history registry passes have been run against Orphanet/Orphadata (CC BY 4.0, R6) and the openly published GBD 2013 disability-weights table (Salomon et al., CC BY, R7). R6 lifts onset to registry-grade [L] across most of the cohort (earliest AverageAgeOfOnset category, entity-anchored per ORPHAcode, Exact OMIM↔ORPHA only); R7 lifts disability to [L] where one dominant untreated sequela maps to a named GBD health state (published disability weight binned by declared cut-points), and independently corroborates a mortality axis from PMC survival literature where a quantitative disease-typical figure exists. Severity now lifts to registry [L] for the one disease whose dominant sequela carries a cited HPO Severity-modifier annotation (the HP:0012824 subtree, R8); for the rest the open HPO severity annotations are feature-level (using one feature as the disease tier would be a category error), so severity stays [H]/[O] with the obstacle named. Progression lifts to registry [L] where a cited PMC open-access source states a disease-level magnitude for the dominant untreated sequela and the frozen R3 tier function derives the tier from that verbatim sentence (R9, curated dominant-sequela join, non-spectrum); for the rest progression stays [H]/[O]. The OMIM clinical synopsis (the disease-level alternative) is API-key-gated and the key is unobtainable for an individual researcher — that path is removed, not guessed.

Established treatment and residual burden

The established disease-directed approach is enzyme replacement therapy (alglucosidase alfa / avalglucosidase alfa). Mechanistically: ERT replaces acid alpha-glucosidase, clearing lysosomal glycogen [L].

Its effect on natural history is classified disease-modifying (substantial), mapping to an efficacy offset e = 0.5500 and a residual factor R_treat = 0.4500. Applied to the pre-treatment proxy this gives the residual burden score 0.3656, moving the disease from raw rank 4 to residual rank 10 (shift -6).

Evidence tier: accession-dated to the GeneReviews NBK1261 Management section [L] (initial posting August 31, 2007; last revision August 21, 2025; retrieved 2026-06-18; corroborating term(s): “enzyme, replacement, alglucosidase, alfa”). The natural-history axis grades remain a mix of [L] (GeneReviews-corroborated) and [H] (definition-only), so the burden order is still provisional.