We investigate rare and informative inborn errors of metabolism, including Hermansky-Pudlak syndrome, cystinosis, and alkaptonuria. These rare diseases offer insight into biochemical and cellular mechanisms. Both gene discovery and mutation analysis assist in elucidating normal pathways and functions as well as provide a measure of genotype-phenotype correlation. In addition, we care for affected patients, providing expertise in largely abandoned diseases and thereby improving diagnosis, offering prognosis, and developing therapies for disorders that have none. Members of the section are considered the world’s experts in cystinosis, Hermansky-Pudlak syndrome, and disorders of free sialic acid metabolism.

Hermansky-Pudlak Syndrome
Gahl, Huizing, Anikster, Anderson, Claassen, Bernardini; in collaboration with Boissy, White, Brantly, Gochuico, Avila
We continue to discover mutations in the four known genes causing Hermansky-Pudlak syndrome (HPS) and to search for new genes responsible for the disease. We have described the murine gene corresponding to the human HPS3 gene. In collaboration with other scientists, we have developed an assay to detect serotonin in platelets, evaluated a clotting analyzer for humans with platelet defects, and delineated the radiographic features of HPS patients with pulmonary fibrosis. We have examined, cared for, and investigated 120 HPS patients to date. In separate studies, we found that the anti-inflammatory drug, pirfenidone, helped retard the pulmonary fibrosis of HPS in patients who initially had at least 50 percent of the expected forced vital capacity.

Cystinosis
Gahl, Bernardini, Kleta, Lynch, Anikster, Phornphutkul; in collaboration with Thoene, Schneider, Kaiser-Kupfer, Skovby
We follow approximately 60 patients with cystinosis, some before and some after renal transplantation. We perform mutation analysis on patients new to the protocol, accumulate longitudinal data on treatment regimens, and detect early and late complications of cystinosis. We have described the CTNS mutations identified in African American patients and, in collaboration with Danish investigators, in Danish patients. In collaboration with physicians in the National Eye Institute, we have helped to describe anterior segment complications of cystinosis and retinal visualization in cystinosis by using indocyanine green videoangiography. We also conducted a study of a new formulation of cysteamine eyedrops. Members of the section are helping to bring cysteamine eyedrops to New Drug Approval by the Food and Drug Administration.

Alkaptonuria
Gahl, Phornphutkul, Bernardini
Alkaptonuria results from the accumulation of homogentisic acid, an intermediate in tyrosine degradation that results from a deficiency of homogentisate 1,2-dioxygenase. The symptoms include joint and cardiac valve deterioration beginning in mid-life. We have now examined and investigated more than 60 alkaptonuria patients from a clinical, biochemical, and molecular perspective. We have identified 90 percent of the genetic mutations causing alkaptonuria in our patients and have described a man with alkaptonuria and diabetic nephropathy whose renal disease exacerbated his ochronosis. We also found three individuals with darkened ear cartilage as a consequence of prolonged use of the antibiotic minocycline, who carried the diagnosis of alkaptonuria. Two women with alkaptonuria were given low doses of nitisinone, a drug that inhibits the enzyme producing homogentisic acid. Although their plasma tyrosine levels rose dramatically, the lowering of homogentisic acid production provides proof of principle for the use of nitisinone in alkaptonuria.

Other Metabolic Disorders
Gahl, Huizing, Anikster, Bernardini, Lalor, Kleta; in collaboration with Skovby
We also investigate a variety of other rare disorders of human metabolism. Members of the section have identified the gene and the mutations responsible for type III 3methylglutaconic aciduria in Iraqi-Jewish and non–Iraqi-Jewish patients. A family with gray platelet syndrome has been described and characterized. Members of the section have reported a patient with Griscelli syndrome and neurological involvement caused by mutations in rab27a rather than the expected gene, myosin 5A. In collaboration with other investigators, we have reported patients with lysosomal free sialic acid storage due to mutations in the gene encoding the lysosomal sialic acid transporter. The section remains the world’s premier referral laboratory for diagnosing sialuria and other disorders of free sialic acid metabolism.