Further evidence for allelic heterogeneity in Hartnup disorder

Abstract

Hartnup disorder is an autosomal recessive impairment of amino acid transport in kidney and intestine. Mutations in SLC6A19 have been shown to cosegregate with the disease in the predicted recessive manner; however, in two previous studies (Seow et al., Nat Genet 2004;36:1003-1007; Kleta et al., Nat Genet 2004;36:999-1002), not all causative alleles were identified in all affected individuals, raising the possibility that other genes may contribute to Hartnup disorder. We have now investigated six newly acquired families of Australian and Canadian (Province of Quebec) origin and resequenced the entire coding region of SLC6A19 in families with only a single disease allele identified. We also studied one American family in whom no mutations had been identified in a previous study (Kleta et al., Nat Genet 2004;36:999-1002). We have identified seven novel mutations in SLC6A19 that show functional obliteration of the protein in vitro, explaining Hartnup disorder in all reported families so far. We demonstrate that Hartnup disorder is allelically heterogeneous with two mutated SLC6A19 alleles, whether identical or not, necessary for manifestation of the characteristic aminoaciduria in affected individuals. This study resolves the previous hypothesis that other genes contribute to the Hartnup phenotype.

Novel Mutation in SLC6A19 Causing Late-Onset Seizures in Hartnup Disorder

“…On the other hand, he exhibited delayed development, including mental retardation, with abnormal cranial magnetic resonance findings and attention-deficit hyperactivity disorder. The manifestations of Hartnup disorder can vary, ranging from asymptomatic status to pellagra-like skin rashes, cerebellar ataxia, psychotic behavior, and mental and physical retardation [2]. In 43 cases of Hartnup disorder reviewed by Wilcken et al, 28 were reported to manifest a rash.…”

“…It is caused by an inborn error of neutral amino acid transporter in the apical brush border membrane of the intestines and proximal tubules of the kidneys [2]. Usually, Hartnup disorder takes a benign course.…”

Ataxia in children: early recognition and clinical evaluation

“…Some patients show an intermittent, unsteady, wide-based gait. Prognosis is usually benign [23–25]. Maple syrup urine disease (MSUD) is an AR disorder that involves branched-chain amino acids.…”

Photosensitivity disorders in children

“…Currently, 17 mutations have been described; the most common mutation is c.517G / A, which is found in 43% of affected patients. 42 Patients with Hartnup disease present with intermittent and recurrent symptoms with a variable spectrum. The onset of disease in children is 3 to 9 years of age.…”