Journal of Inherited Metabolic Disease

Oxidative phosphorylation (OXPHOS) has a prominent role in energy metabolism of the cell. Being under bigenomic control, correct biogenesis and functioning of the OXPHOS system is dependent on the finely tuned interaction between the nuclear and the mitochondrial genome. This suggests that disturbances of the system can be caused by numerous genetic defects and can result in a variety of metabolic and biochemical alterations. Consequently, OXPHOS deficiencies manifest as a broad clinical spectrum. Complex I, the biggest and most complicated enzyme complex of the OXPHOS system, has been subjected to thorough investigation in recent years. Significant progress has been made in the field of structure, composition, assembly, and pathology. Important gains in the understanding of the Goliath of the OXPHOS system are: exposing the electron transfer mechanism and solving the crystal structure of the peripheral arm, characterization of almost all subunits and some of their functions, and creating models to elucidate the assembly process with concomitant identification of assembly chaperones. Unravelling the intricate mechanisms underlying the functioning of this membrane‐bound enzyme complex in health and disease will pave the way for developing adequate diagnostic procedures and advanced therapeutic treatment strategies.

N‐Butyldeoxynojirimycin (NB‐DNJ, miglustat ‘Zavesca’) is an orallyactive iminosugar which inhibits the biosynthesis of macromolecular substrates that accumulate pathologically in glycosphingolipidoses. Clinical trials of NB‐DNJ in patients with Gaucher's disease demonstrate the therapeutic potential of such substrate inhibitors in the glycolipid storage disorders. However, macrophage‐targetted enzyme replacement using intravenous mannose‐terminated human glucocerebrosidase (imiglucerase, Cerezyme) is highly effective in ameliorating many of the manifestations of Gaucher's disease and is a treatment in widespread use. Given that imiglucerase and miglustat are now both licensed for the treatment of Gaucher's disease, there is a need to review their therapeutic status. Here the treatment of type 1 (non‐neuronopathic) Gaucher disease is evaluated with particular reference to the emerging role of oral N‐butyldeoxynojirimycin (miglustat) as a substrate‐reducing agent. This position statement represents the consensus viewpoint of an independent international advisory council to the European Working Group on Gaucher Disease.

Summary: It has been shown that treatment with miglustat (Zavesca, N‐butyldeoxynojirimycin, OGT 918) improves key clinical features of type I Gaucher disease after 1 year of treatment. This study reports longer‐term efficacy and safety data. Patients who had completed 12 months of treatment with open‐label miglustat (100‐300 mg three times daily) were enrolled to continue with therapy in an extension study. Data are presented up to month 36. Liver and spleen volumes measured by CT or MRI were scheduled every 6 months. Biochemical and haematological parameters, including chitotriosidase activity (a sensitive marker of Gaucher disease activity) were monitored every 3 months. Safety data were also collected every 3 months. Eighteen of 22 eligible patients at four centres entered the extension phase and 14 of these completed 36 months of treatment with miglustat. After 36 months, there were statistically significant improvements in all major efficacy endpoints. Liver and spleen organ volumes were reduced by 18% and 30%, respectively. In patients whose haemoglobin value had been below 11.5 g/dl at baseline, mean haemoglobin increased progressively from baseline by 0.55 g/dl at month 12 (NS), 1.28 g/dl at month 24 (p=0.007), and 1.30 g/dl at month 36 (p=0.013). The mean platelet count at month 36 increased from baseline by 22×10⁹/L. No new cases of peripheral neuropathy occurred since previously reported. Diarrhoea and weight loss, which were frequently reported during the initial 12‐month study, decreased in magnitude and prevalence during the second and third years. Patients treated with miglustat for 3 years show significant improvements in organ volumes and haematological parameters. In conclusion, miglustat was increasingly effective over time and showed acceptable tolerability in patients who continued with treatment for 3 years.

Bệnh adrenoleukodystrophy liên liên gen X (ALD) là một rối loạn tương đối phổ biến, thể hiện sự biến thể hình thái lớn. Khoảng một nửa số bệnh nhân mắc dạng bệnh não nhanh tiến triển ở trẻ em, có liên quan đến phản ứng viêm trong não, dẫn đến tàn tật toàn phần hoặc tử vong trong thập kỷ đầu tiên. Hai mươi lăm phần trăm hoặc hơn trong số bệnh nhân có dạng adrenomyeloneuropathy (AMN), một dạng bệnh phát triển chậm, chủ yếu liên quan đến tủy sống, ít hoặc không có phản ứng viêm, xuất hiện trong độ tuổi trưởng thành và tương thích với tuổi thọ gần như bình thường. Hai dạng bệnh này thường xảy ra trong cùng một dòng họ và gia đình hạt nhân. Phân tích phân tách dựa trên 3862 cá nhân trong 89 dòng họ chỉ ra sự tồn tại của một locus biến thể tự động với tỉ lệ khả năng là 20:1. Ngoài ra, chúng tôi trình bày kết quả sơ bộ của ba loại liệu pháp. Hai trăm bốn bệnh nhân đã nhận một chế độ ăn kết hợp việc sử dụng dầu chứa axit béo không bão hòa đơn (axit oleic và erucic) với việc hạn chế tiêu thụ axit béo chuỗi rất dài. Chế độ này làm bình thường hóa mức độ axit béo chuỗi rất dài bão hòa trong huyết tương trong vòng 4 tuần. Nó dường như cải thiện chức năng dây thần kinh ngoại vi ở bệnh nhân AMN, và một thử nghiệm quy mô lớn đang diễn ra để xác định liệu nó có thể ngăn chặn sự khởi phát của tổn thương thần kinh ở những bệnh nhân có bất thường sinh hóa của ALD nhưng vẫn còn khỏe mạnh về mặt thần kinh hay không. Chúng tôi báo cáo kết quả sớm của việc cấy ghép tủy xương ở 14 bệnh nhân. Có những bằng chứng khuyến khích nhưng vẫn còn sơ bộ cho thấy việc cấy ghép có thể ngăn chặn sự tiến triển của bệnh ở những bệnh nhân có tổn thương thần kinh nhẹ. Cần phải phát triển khẩn cấp các phương pháp để chống lại sự tiến triển nhanh của các dạng bệnh não, được cho là đã kháng lại can thiệp điều trị, bao gồm cả sự ức chế miễn dịch hoặc việc sử dụng immunoglobulin.

This report outlines the status of neonatal screening in Europe in 2004. Out of the 45 member states of the Council of Europe plus the regions Scotland and Wales (in total 47 ‘countries’), no data at all were available from 3 (Albania, Azerbaijan and Georgia). From the other 44, varying amounts of data were received. Apart from Armenia, Finland and Malta, all countries have a national programme for phenylketonuria (PKU), although in some countries those programmes do not yet have 100% coverage. Moldova and Ukraine have no national programme for congenital hypothyroidism (CH), the other countries do. Twelve countries screen for congenital adrenal hyperplasia (CAH), 6 for cystic fibrosis (CF) and 7 for galactosaemia (GAL), 6 for biotinidase deficiency (BD) and 4 for medium‐chain acyl‐CoA dehydrogenase deficiency (MCAD). Some countries have pilot programmes for certain conditions or different programmes per screening laboratory. The prevalences for PKU vary from 1:3000 to 1:30 000, and for CH from 1:1300 to 1:13 000. Methodologies vary within and between countries. There appears to be no relationship between the cut‐off limits and the recall rate. A first priority is to help those countries where the basic screening programmes have less than 100% coverage. In addition, continuous monitoring of the European programmes will help to decrease the variation in design and methodology by making use of the knowledge and expertise available from the global membership of the International Society for Neonatal Screening (ISNS). The huge difference of recall rates illustrate one obvious and important area for improvement of programme performances that could be aided by strengthened European cooperation.

Niemann‐Pick disease type C (NPC) is an atypical lysosomal storage disease resulting from mutations in one of two genes, either NPC1 or NPC2. Although a neurovisceral disorder, it is above all a neurodegenerative disease in the vast majority of patients. Not an enzyme deficiency, it is currently conceived as a lipid trafficking disorder. Impaired egress of cholesterol from the late endosomal/lysosomal (LE/L) compartment is a specific and key element of the pathogenesis, but other lipids, more specially sphingolipids, are also involved, and there are indications for further abnormalities. The full function of the NPC1 and NPC2 proteins is still unclear. This review provides a reappraisal of lipid storage and lysosomal enzymes activities in tissues/cells from NPC patients and animal models. It summarizes the current knowledge on the NPC1 and NPC2 proteins and their function in transport of cholesterol within the late endosomal‐lysosomal compartment, with emphasis on differences between systemic organs and the brain; it also discusses regulation by membrane lipids of the NPC2‐mediated cholesterol trafficking, interplay between cholesterol and sphingomyelin, the metabolic origin of glycosphingolipids stored in brain, and the putative role of free sphingoid bases in pathogenesis. Brief mention is finally made of diseases affecting other genes that were very recently shown to impact the “NPC pathway”.

Patients with types A and B Niemann–Pick disease (NPD) have an inherited deficiency of acid sphingomyelinase (ASM) activity. The clinical spectrum of this disorder ranges from the infantile, neurological form that results in death by 3 years of age (type A NPD) to the non‐neurological form (type B NPD) that is compatible with survival into adulthood. Intermediate cases also have been reported, and the disease is best thought of as a single entity with a spectrum of phenotypes. ASM deficiency is panethnic, but appears to be more frequent in individuals of Middle Eastern and North African descent. Current estimates of the disease incidence range from ~0.5 to 1 per 100 000 births. However, these approximations likely under estimate the true frequency of the disorder since they are based solely on cases referred to biochemical testing laboratories for enzymatic confirmation. The gene encoding ASM (SMPD1) has been studied extensively; it resides within an imprinted region on chromosome 11, and is preferentially expressed from the maternal chromosome. Over 100 SMPD1 mutations causing ASM‐deficient NPD have been described, and some useful genotype–phenotype correlations have been made. Based on these findings, DNA‐based carrier screening has been implemented in the Ashkenazi Jewish community. ASM ‘knockout’ mouse models also have been constructed and used to investigate disease pathogenesis and treatment. Based on these studies in the mouse model, an enzyme replacement therapy clinical trial has recently begun in adult patients with non‐neurological ASM‐deficient NPD.

Organic acidurias comprise many various disorders. Methylmalonic aciduria (MMA) and propionic aciduria (PA) are the most frequent diseases and the two organic acidurias for which we have better knowledge of the long‐term outcome.

Comparing the outcome of patients born before and after 1990, it appears that better neonatal and long‐term management have improved the survival rate. Less than 20% of the patients died in either the neonatal period or before the age of 10 years. However, most surviving patients showed poor nutritional status with growth retardation and about 40% present some kind of visceral or neurological impairment. The developmental outcome may have improved in MMA patients, with IQ higher than 75 in about 40% patients aged more than 4 years. Conversely, poor intellectual development is the rule in PA patterns, with 60% having an IQ less than 75 and requiring special education. Successful liver and/or renal transplantations, in a few patients, have resulted in better quality of life but have not necessarily prevented neurological and various visceral complications. These results emphasize the need for permanent metabolic follow‐up whatever the therapeutic strategy.

A 5‐year‐old boy, excreting large amounts of 2‐hydroxyglutaric acid in the urine (3.3–7.6 mmol/l), is described. The patient presented with psychomotor retardation and dystrophy. His skeletal age was delayed. The EEG was not well differentiated; it resembled that observed in 2‐year‐old children. There was a severe anaemia, which reacted well to iron supplements. The 2‐hydroxyglutaric acid was found to have thel‐configuration, as analysed by capillary gas chromatography of theO‐acetylated di‐(‐)‐2‐butyl ester derivative. The relation ofl‐2‐hydroxyglutarate excretion to known metabolic pathways is discussed.

During 1967–1983, the Maternal and Child Health Division of the Public Health Services funded a collaborative study of 211 newborn infants identified on newborn screening as having phenylketonuria (PKU). Subsequently, financial support was provided by the National Institute of Child Health and Human Development (NICHD). The infants were treated with a phenylalanine (Phe)‐restricted diet to age 6 years and then randomized either to continue the diet or to discontinue dietary treatment altogether. One hundred and twenty‐five of the 211 children were then followed until 10 years of age. In 1998, NICHD scheduled a Consensus Development Conference on Phenylketonuria and initiated a study to follow up the participants from the original Collaborative Study to evaluate their present medical, nutritional, psychological, and socioeconomic status.

Fourteen of the original clinics (1967–1983) participated in the Follow‐up Study effort. Each clinic director was provided with a list of PKU subjects who had completed the original study (1967–1983), and was asked to evaluate as many as possible using a uniform protocol and data collection forms. In a subset of cases, magnetic resonance imaging and spectroscopy (MRI/MRS) were performed to study brain Phe concentrations.

The medical evaluations revealed that the subjects who maintained a phenylalanine‐restricted diet reported fewer problems than the diet discontinuers, who had an increased rate of eczema, asthma, mental disorders, headache, hyperactivity and hypoactivity. Psychological data showed that lower intellectual and achievement test scores were associated with dietary discontinuation and with higher childhood and adult blood Phe concentrations. Abnormal MRI results were associated with higher brain Phe concentrations. Early dietary discontinuation for subjects with PKU is associated with poorer outcomes not only in intellectual ability, but also in achievement test scores and increased rates of medical and behavioural problems.