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This summary reviews the evidence linking biallelic variants in AASS (HGNC:17366) with hyperlysinemia (MONDO:0009388). Hyperlysinemia is an autosomal recessive disorder characterized by an abnormal lysine degradation pathway, typically identified through biochemical screening. Initial case reports, such as the one identified in a urine newborn screening program, demonstrated the presence of biallelic AASS variants with biochemical confirmation, supporting a role for AASS in the pathogenesis of the disorder (PMID:37927488). In this case, the patient presented with a cystinuria‐like profile and markedly elevated urinary lysine without severe clinical deterioration.
Subsequently, multi‐patient studies have expanded the phenotypic spectrum of hyperlysinemia. Systematic reviews reporting 23 patients across several independent articles (PMID:38991296) have revealed heterogeneity in clinical presentation, ranging from benign biochemical findings to neurological features such as intellectual disability, spastic tetraparesis, and seizures. This variability reinforces the need for careful clinical and biochemical assessment when interpreting AASS variants. In some families, segregation studies have identified homozygous or compound heterozygous mutations, further substantiating the autosomal recessive inheritance pattern.
Genetic evidence is robust with multiple distinct AASS variants reported. Notably, a coding variant, c.436C>T (p.Arg146Trp), was consistently observed across different reports (PMID:37927488). Other reports have identified additional variants such as c.799C>T (p.Arg267Cys) and truncating mutations like c.709G>T (p.Glu237Ter) that contribute to the overall genetic burden. The combined identification of these variants in unrelated probands, along with supportive familial segregation data, provides strong genetic support for the association.
Functional studies further reinforce the pathogenicity of AASS variants. Experimental assays, including splice acceptor analyses (e.g., c.1767-1G>A), reveal that these mutations disrupt the normal function of the lysine-2-oxoglutarate domain, leading to impaired lysine degradation (PMID:33100873). Although hyperlysinemia is frequently considered to be a benign biochemical variant, the demonstration of altered enzyme function and perturbations in lysine metabolism in model systems offers mechanistic insight. Together, these findings corroborate the genetic evidence and highlight the relevance of functional testing in resolving genotype-phenotype relationships.
While a majority of cases emphasize a benign clinical course, a subset of patients exhibit neurological abnormalities such as intellectual disability, spastic tetraparesis, and seizures. Conflicting evidence, particularly regarding the clinical impact of hyperlysinemia, underscores a heterogeneous disease presentation. Some patients remain asymptomatic beyond the biochemical derangement, whereas others show a multisystem involvement that may require more comprehensive clinical management. These observations indicate that while the biochemical defect is consistent, additional modifiers or environmental factors may influence the overall disease severity.
In summary, the convergence of genetic, segregation, and functional data strongly supports a robust association between biallelic AASS variants and hyperlysinemia. The evidence indicates that autosomal recessive inheritance of pathogenic AASS mutations leads to disruptions in lysine metabolism, manifesting in a spectrum of clinical presentations. Key take‑home message: Comprehensive genetic evaluation combined with biochemical and functional assays provides high clinical utility in diagnosing and counseling patients with hyperlysinemia.
Gene–Disease AssociationStrong23 probands (PMID:38991296) across multiple families, with supportive segregation and functional assays, substantiate a strong association. Genetic EvidenceStrongMultiple biallelic variants including c.436C>T (p.Arg146Trp) (PMID:37927488) and c.799C>T (p.Arg267Cys) have been identified in unrelated patients, confirming autosomal recessive inheritance. Functional EvidenceModerateFunctional assays, such as the demonstration of disrupted splicing (c.1767-1G>A) (PMID:33100873), indicate a pathogenic mechanism affecting lysine degradation. |