The reported data on the natural history of alkaptonuria provide a basis for the evaluation of long-term therapies. Although nitisinone can reduce HGA production in humans with homogentisate 1,2-dioxygenase deficiency, the long-term safety and efficacy of this treatment require further evaluation.

The 16-bp duplication in exon 15 of HPS, which we found only in Puerto Rican patients, is associated with a broad range of pigmentation and an increased risk of restrictive lung disease in adults.

Alkaptonuria is a rare, autosomal recessive disorder of tyrosine degradation due to deficiency of the third enzyme in the catabolic pathway. As a result, homogentisic acid (HGA) accumulates and is excreted in gram quantities in the urine, which turns dark upon alkalization. The first symptoms, occurring in early adulthood, involve a painful, progressively debilitating arthritis of the spine and large joints. Cardiac valvular disease and renal and prostate stones occur later. Previously suggested therapies have failed to show benefit, and management remains symptomatic. Nitisinone, a potent inhibitor of the second enzyme in the tyrosine catabolic pathway, is considered a potential therapy; proof-of-principle studies showed 95% reduction in urinary HGA. Based on those findings, a prospective, randomized clinical trial was initiated in 2005 to evaluate 40 patients over a 36-month period. The primary outcome parameter was hip total range of motion with measures of musculoskeletal function serving as secondary parameters. Biochemically, this study consistently demonstrated 95% reduction of HGA in urine and plasma over the course of 3 years. Clinically, primary and secondary parameters did not prove benefit from the medication. Side effects were infrequent. This trial illustrates the remarkable tolerability of nitisinone, its biochemical efficacy, and the need to investigate its use in younger individuals prior to development of debilitating arthritis.

Hartnup disorder, an autosomal recessive defect named after an English family described in 1956 (ref. 1), results from impaired transport of neutral amino acids across epithelial cells in renal proximal tubules and intestinal mucosa. Symptoms include transient manifestations of pellagra (rashes), cerebellar ataxia and psychosis 1,2 . Using homozygosity mapping in the original family in whom Hartnup disorder was discovered, we confirmed that the critical region for one causative gene was located on chromosome 5p15 (ref. 3). This region is homologous to the area of mouse chromosome 13 that encodes the sodium-dependent amino acid transporter B 0 AT1 (ref. 4). We isolated the human homolog of B 0 AT1, called SLC6A19, and determined its size and molecular organization. We then identified mutations in SLC6A19 in members of the original family in whom Hartnup disorder was discovered and of three Japanese families. The protein product of SLC6A19, the Hartnup transporter, is expressed primarily in intestine and renal proximal tubule and functions as a neutral amino acid transporter.Despite molecular characterization of other proximal tubule transporters, the neutral amino acid carrier defective in Hartnup disorder (OMIM 2345000) has resisted genetic identification 2 . We carried out homozygosity mapping and fine mapping in ten members of two consanguineous families (the siblings in whom Hartnup disorder was originally discovered 1 ; family A; Fig. 1a) and in siblings from the US 5 (family B; Fig. 1a). We found linkage of Hartnup disorder to 5p15 only in family A, with a maximum combined multipoint lod score of 2.31 at 11.24 cM (P ¼ 0.01). This confirmed our previous results showing linkage to chromosome 5p15 (ref.3). In family B, we obtained a maximum multipoint lod score of À2.40 at 15.81 cM.We simultaneously pursued two mouse monoamine transporterrelated orphan genes, Slc6a18 (also called Xtrp2; ref. 6) and Slc6a19 (encoding B 0 AT1; ref. 4). These members of the SLC6 family of transporters map to the mouse chromosomal region that is homologous to human chromosome 5p15. Both Slc6a18 and Slc6a19 showed abundant expression in mouse kidney, as assessed by real time RT-PCR (Fig. 2a). Immunohistochemistry confirmed expression of mouse B 0 AT1 at the brush border of small intestine (data not shown) and kidney proximal tubule cells (Fig. 2b).The human homolog, B 0 AT1, is encoded by the predicted locus SLC6A19, with a 2,022-bp open reading frame. PCR amplification using human kidney cDNA produced a 1,905-bp product with 100% identity to SLC6A19 sequence. We next determined the genomic organization of SLC6A19, which has a stop codon 28 bases before the ATG in the 5¢ untranslated region. SLC6A19 has 12 coding exons. The B 0 AT1 protein contains 634 amino acids and 12 predicted transmembrane regions (Fig. 1b). In a panel of human cDNAs, we detected robust expression of SLC6A19 in kidney and small intestine, with minimal expression in pancreas (Fig. 2c). SLC6A19 was also expressed in stomach, liver, duodenum and ileocecum (data n...