Diagnostic and therapeutic strategies for porphyrias.

Porphyrias are rare metabolic disorders. Lack of awareness and knowledge about the clinical features of porphyrias results in diagnostic and therapeutic delays for many patients. Delays in diagnosing and treating porphyrias can result in severe, progressive morbidity (and mortality) and psychological distress for patients. This review discusses the pathophysiology, diagnosis, treatment, and follow-up of the most prevalent porphyrias: acute intermittent porphyria, porphyria cutanea tarda, and erythropoietic protoporphyria.

Osteoporosis in patients with erythropoietic protoporphyria.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare metabolic disease with painful photosensitivity due to protoporphyrin IX accumulation. OBJECTIVES: To evaluate bone mineral density (BMD) and known osteoporosis risk factors in patients with EPP. METHODS: Patients with EPP attending the Erasmus MC outpatient clinic who had undergone BMD measurements were included. Plasma 25 hydroxy (OH) vitamin D, alkaline phosphatase, parathyroid hormone and total protoporphyrin IX levels were measured; information on lifestyle, sunlight exposure and a bone-relevant physical exercise index [Bone Physical Activity Questionnaire (BPAQ) score] was obtained via questionnaires. BMD scores and the prevalence of osteopenia and osteoporosis in the EPP population were compared with a reference population. RESULTS: Forty-four patients with EPP (23 female, 21 male; mean age 37·6 years) were included. The mean SDs of the T-scores were -1·12 for the lumbar spine and -0·82 for the femoral neck (both P < 0·001). Osteopenia was present in 36%; osteoporosis in 23%. Based on the reference population the expected prevalence was 15% and 1%, respectively. Prevalence of vitamin D deficiency was 50% (defined as a 25-OH vitamin D level < 50 nmol L-1 ). Mean self-reported BPAQ score was 19·4 units (reference interval 19-24). Multiple linear regression analysis showed a significant influence of vitamin D deficiency and bone-relevant physical exercise score on BMD in patients with EPP. CONCLUSIONS: The prevalence of osteoporosis and osteopenia is greatly increased in patients with EPP. Alkaline phosphatase (related to vitamin D deficiency) and amount of weight-bearing exercise are significantly correlated with low BMD in this population.

Decreased cellular uptake and metabolism in Allan-Herndon-Dudley syndrome (AHDS) due to a novel mutation in the MCT8 thyroid hormone transporter.

We report a novel 1 bp deletion (c.1834delC) in the MCT8 gene in a large Brazilian family with Allan-Herndon-Dudley syndrome (AHDS), an X linked condition characterised by severe mental retardation and neurological dysfunction. The c.1834delC segregates with the disease in this family and it was not present in 100 control chromosomes, further confirming its pathogenicity. This mutation causes a frameshift and the inclusion of 64 additional amino acids in the C-terminal region of the protein. Pathogenic mutations in the MCT8 gene, which encodes a thyroid hormone transporter, results in elevated serum triiodothyronine (T3) levels, which were confirmed in four affected males of this family, while normal levels were found among obligate carriers. Through in vitro functional assays, we showed that this mutation decreases cellular T3 uptake and intracellular T3 metabolism. Therefore, the severe neurological defects present in the patients are due not only to deficiency of intracellular T3, but also to altered metabolism of T3 in central neurones. In addition, the severe muscle hypoplasia observed in most AHDS patients may be a consequence of high serum T3 levels.

Thyroid hormone transporters.

Thyroid hormone is important for development of various tissues, in particular brain, and for regulation of metabolic processes throughout life. The follicular cells of the thyroid gland produce predominantly T4 (thyroxine), but the biological activity of thyroid hormone is largely exerted by T3 (3,3',5-tri-iodothyronine). The deiodinases involved in T4-to-T3 conversion or T4 and T3 degradation, as well as the T3 receptors, are located intracellularly. Therefore the action and metabolism of thyroid hormone require transport of iodothyronines across the cell membrane via specific transporters. Recently, a number of transporters capable of cellular uptake of iodothyronines have been identified. The most specific transporters identified so far are OATP1C1 and MCT8, which appear to be involved in T4 transport across the blood-brain barrier, and in T3 transport into brain neurons, respectively. The MCT8 gene is located on human chromosome Xq13, and mutations in MCT8 are associated with X-linked severe psychomotor retardation and elevated serum T3 levels.