Journal of Inherited Metabolic Disease

A late-onset presentation of lipoamide dehydrogenase (E3) deficiency is described in a North American Ashkenazi Jewish (AJ) family. Diagnosis was made by urine organic acid and molecular analyses.

The enzyme 5α-reductase (5αR), by virtue of its peripheral 5α-reduction of testosterone (T) to dihydrotestosterone (DHT), is believed to play a major role in the differentiation and the subsequent growth of the penis. However, recent studies have reported 5αR deficiency (5αRD) in patients with isolated micropenis and hypothesized that 5αRD is not invariably associated with genital ambiguity. In Egypt, 5αRD has been reported frequently among intersex patients. The aim of this study was to assess the role of 5αRD in the development of micropenis among Egyptian patients with abnormal sexual development. The study included 29 patients who were categorized into three groups (isolated micropenis, 9 patients; microphallus with genital ambiguity, 11 patients; genital ambiguity with normal-sized phallus, 9 patients). Activity of 5αR was assessed by estimating T/DHT ratios in the basal state in pubertal subjects and following human chorionic gonadotropin (HCG) stimulation test in prepubertals. The results showed that the incidence of 5αRD was much higher in cases of ambiguous genitalia with micropenis (5 families out of 10, 50%) than in those with isolated microphallus (1/9, 11·1%) or those with ambiguous genitalia and normal-sized phallus (1/8, 12.5%). In conclusion, the study showed that isolated micropenis is a heterogeneous disorder and that 5αRD, despite its relative prevalence in Egypt, has a minimal role in the aetiology. On the other hand, 5αRD seems to correlate with penile length in intersex cases.

The Berardinelli–Seip congenital lipodystrophy (BSCL) syndrome is characterized by a near-total congenital absence of fat and predisposition to develop diabetes mellitus. We have previously reported that 22 patients from 16 consanguineous pedigrees living in the northeastern region of Brazil had a homozygous 669insA mutation in the Seipin gene (BSCL2 locus), while all of the 10 investigated subjects from the southeastern region were homozygous for a 1036 bp deletion in the AGPAT2 gene (BSCL1 locus). In this study, we compared the serum insulin and insulin resistance (HOMA), leptin, triglyceride and fasting glucose levels in individuals of these two genetically distinct clusters of BSCL subjects. The onset of diabetes was also estimated. The fasting glucose and triglyceride levels were not significantly different in these groups. Significant differences were detected for leptin, insulin and insulin resistance. BSCL1 patients presented lower serum leptin levels compared to BSCL2 patients. BSCL2 subjects had earlier onset of diabetes and higher insulin levels. In agreement, BSCL2 patients were more insulin resistant, as detected by HOMA. These results indicate phenotypic heterogeneity between BSCL1 and BSCL2 Brazilian subjects.

The activities of 14 lysosomal enzymes in chorionic villi at gestational ages of 6–12 weeks were assayed. Arylsulphatases A and B, α-glucosidase and β-glucuronidase activities increased with advancing gestational age. When compared with the activity in cultured amniotic fluid cells, arylsulphatase A, β-galactosidase, α-glucosidase, heparan N-sulphatase, α-l-iduronidase, α-mannosidase, neuraminidase and sphingomyelinase showed significant differences. All except β-glucuronidase showed lower activity in chorionic villi than in cultured amniotic fluid cells. Prenatal diagnosis using chorionic villi was possible except for α-l-iduronidase. Storage at −20°C up to 42 days did not significantly affect activity. The results emphasize the importance of using fresh or frozen age-matched control tissue for diagnosis.

Rối loạn vận động bao gồm một nhóm các bệnh đa dạng với các kiểu hình lâm sàng thường phức tạp. Các triệu chứng chồng chéo và sự thiếu hụt các biomarker chẩn đoán có thể cản trở việc đưa ra chẩn đoán chính xác. Các kỹ thuật giải trình tự thế hệ mới đã đóng góp đáng kể vào việc tìm hiểu các nguyên nhân di truyền gây ra rối loạn vận động và do đó đã cải thiện khả năng chẩn đoán. Sự thiếu hụt trong tín hiệu dopamine ở các nơron gai giữa hậu synapse đang nổi lên như một cơ chế gây bệnh trong một số rối loạn vận động cường động mới được xác định. Một số gen gây bệnh mã hóa các thành phần của con đường cAMP, một con đường tín hiệu hậu synapse quan trọng trong các nơron gai giữa. Tại đây, chúng tôi xem xét sự trình bày lâm sàng, tìm kiếm di truyền và cơ chế bệnh tật đặc trưng cho các rối loạn vận động hậu synapse di truyền này.

Inappropriate diet may contribute to one third of cancer deaths. Folates, a group of water-soluble B vitamins present in high concentrations in green, leafy vegetables, maintain DNA stability through their ability to donate one-carbon units for cellular metabolism. Folate deficiency has been implicated in the development of several cancers, including cancer of the colorectum, breast, ovary, pancreas, brain, lung and cervix. Generally, data from the majority of human studies suggest that people who habitually consume the highest level of folate, or with the highest blood folate concentrations, have a significantly reduced risk of developing colon polyps or cancer. However, an entirely protective role for folate against carcinogenesis has been questioned, and recent data indicate that an excessive intake of synthetic folic acid (from high-dose supplements or fortified foods) may increase human cancers by accelerating growth of precancerous lesions. Nonetheless, on balance, evidence from the majority of human studies indicates that dietary folate is genoprotective against colon cancer. Suboptimal folate status in humans is widespread. Folate maintains genomic stability by regulating DNA biosynthesis, repair and methylation. Folate deficiency induces and accelerates carcinogenesis by perturbing each of these processes. This review presents recent evidence describing how these mechanisms act, and interact, to modify colon cancer risk.

Since the completion of the human genome map, genomics, proteomics and pharmacogenomics have become popular headings. In this review some 40 years of development in research and laboratory diagnosis of inborn errors of metabolism are summarized. It is shown that collaborative approaches of clinicians, geneticists, pathologists, biochemists and molecular biologists have contributed significantly to the (prenatal) diagnosis, genetic counselling and prevention of simple gene disorders, and in some instances to successful treatment. DNA technology widens the range to predictive risk testing for multifactorial disorders manifesting in adulthood. This offers new perspectives for potential patients and their close relatives, but also poses new psychosocial and ethical problems. Despite high expectations of new technologies in the development of new medicines for multifactorial disorders, examples of previous studies on the molecular etiology and pathogenesis of monogenic diseases indicate that a long way is ahead of us. Also the treatment of rare disorders and equal access to cure and care in the Third World need great attention.