SLC6A19 – Hartnup Disease

Hartnup disease is an autosomal recessive disorder characterized by abnormal neutral amino acid transport in the kidneys and intestine. Multiple independent case reports and cohort studies have documented patients exhibiting dermatologic, neurologic, and psychiatric features. The clinical presentations vary from pellagra‐like rashes and ataxia to seizures, attention deficit, and intellectual disability, underscoring the phenotypic heterogeneity of the disorder (PMID:19335424, PMID:20399395).

Genetic investigations have identified a broad spectrum of variants in SLC6A19 that cause Hartnup disease. Notably, one recurrent missense mutation, c.850G>A (p.Gly284Arg), was reported in affected individuals and consistently cosegregated with the disorder in multiple unrelated families (PMID:19335424). Additional studies have documented both missense and loss‑of‑function variants across diverse populations, strengthening the genetic evidence.

Segregation analyses in these studies further confirmed that affected individuals often carry biallelic alterations, with affected relatives in extended pedigrees contributing to a cumulative count of nearly 23 probands across studies. This robust familial segregation, particularly in multiplex families, supports the pathogenic role of SLC6A19 mutations in the disease (PMID:15286788).

Functional studies have provided complementary evidence by demonstrating that mutations in SLC6A19 impair neutral amino acid transport. In vitro transport assays, electrophysiological recordings, and animal models have all shown that the disruption of SLC6A19 function is concordant with the clinical features observed in Hartnup disease (PMID:15667315).

No significant conflicting evidence has been reported. Although some studies expanded the phenotypic spectrum to include neuropsychiatric manifestations, the overall data continue to support a strong causal relationship between SLC6A19 dysfunction and Hartnup disease.

In summary, the integration of robust genetic findings with corroborative functional data establishes a strong gene‑disease association. This evidence is of high clinical utility, supporting diagnostic decision‑making and paving the way for commercial assay development and future publications.

References

• International journal of dermatology • 2009 • A novel missense mutation in the SLC6A19 gene in a Chinese family with Hartnup disorder PMID:19335424
• Pediatric neurology • 2010 • Novel mutation in SLC6A19 causing late‑onset seizures in Hartnup disorder PMID:20399395
• Neurology. Genetics • 2024 • Adult Neuropsychiatric Manifestation of Hartnup Disease With a Novel SLC6A19 Variant: A Case Report PMID:39611136
• Nature genetics • 2004 • Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19 PMID:15286788
• Human mutation • 2008 • Further evidence for allelic heterogeneity in Hartnup disorder PMID:18484095
• Biochemical Society transactions • 2005 • Neutral amino acid transport in epithelial cells and its malfunction in Hartnup disorder PMID:15667315

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