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Showing papers in "Journal of Inherited Metabolic Disease in 2007"


Journal ArticleDOI
TL;DR: It is demonstrated that in spite of the considerable burden of disease in both sexes that begins to manifest in childhood or adolescence, the recognition of the underlying diagnosis is delayed by 14 years in males and 19 years in females.
Abstract: The Fabry Registry is a global observational research platform established to define outcome data on the natural and treated course of this rare disorder. Participating physicians submit structured longitudinal data to a centralized, confidential database. This report describes the baseline demographic and clinical characteristics of the first 1765 patients (54% males (16% aged < 20 years) and 46% females (13% < 20 years)) enrolled in the Fabry Registry. The median ages at symptom onset and diagnosis were 9 and 23 years (males) and 13 and 32 years (females), respectively, indicating diagnostic delays in both sexes. Frequent presenting symptoms in males included neurological pain (62%), skin signs (31%), gastroenterological symptoms (19%), renal signs (unspecified) (17%), and ophthalmological signs (11%). First symptoms in females included neurological pain (41%), gastroenterological symptoms (13%), ophthalmological (12%), and skin signs (12%). For those patients reporting renal progression, the median age at occurrence was 38 years for both sexes, but onset of cerebrovascular and cardiovascular events was later in females (median 43 and 47 years, respectively) than in males (38 and 41 years, respectively). This paper demonstrates that in spite of the considerable burden of disease in both sexes that begins to manifest in childhood or adolescence, the recognition of the underlying diagnosis is delayed by 14 years in males and 19 years in females. The Fabry Registry provides data that can increase awareness of common symptoms in all age groups, as well as insight into treated and untreated disease course, leading to improved recognition and earlier treatment, and possibly to improved outcomes for affected individuals.

299 citations


Journal ArticleDOI
TL;DR: This study conducted a study in which MPS IVA patients were asked to fill out a questionnaire with inquiries regarding family history, diagnosis, signs and symptoms, height, weight, surgical history, physical activity, and general complaints to provide a reference for assessment of efficacy for studies of novel therapies.
Abstract: Mucopolysaccharidosis IVA (MPS IVA; Morquio A disease) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase. The natural history of this disease is incompletely understood. To study which variables influence the clinical outcome, we conducted a study in which MPS IVA patients were asked to fill out a questionnaire with inquiries regarding family history, diagnosis, signs and symptoms, height, weight, surgical history, physical activity, and general complaints. A total of 326 patients (172 male, 154 female) from 42 countries enrolled in the Morquio A Registry programme. The mean age of patients enrolled was 14.9 years for males and 19.1 years for females, with a wide range of 1–73 years. Sixty-four per cent of the patients were under 18 years. Initial symptoms were recognized between 1 and 3 years of age (mean age 2.1 years) and mean age at diagnosis for the patients was 4.7 years. A progressive skeletal dysplasia was commonly observed among the MPS IVA patients. Fifty per cent of patients underwent surgical operations to improve their quality of life. The most frequent surgical sites include neck (51%), ear (33%), leg (26%) and hip (25%). The birth length for affected males and females was 52.2 ± 4.7 cm and 52.2 ± 4.5 cm, respectively. The final adult height for affected males and females was 122.5 ± 22.5 cm and 116.5 ± 20.5 cm, respectively. The results of this study provide a reference for assessment of efficacy for studies of novel therapies.

289 citations


Journal ArticleDOI
TL;DR: 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.
Abstract: 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.

238 citations


Journal ArticleDOI
TL;DR: The Danish NBS-Biobank has been used in several research projects for aetiological studies of a number of disorders, recently employing new sensitive multiplex technologies and genetic analyses utilizing whole-genome amplified DNA.
Abstract: After routine newborn screening, residual dried blood spot samples (DBSS) are stored at −20°C in the Danish Newborn Screening Biobank (NBS-Biobank), which contains DBSS from virtually all newborns in Denmark since 1982—about 18 million samples The purpose of the storage is: (1) diagnosis and treatment of congenital disorders including documentation, repeat testing, quality assurance, statistics and improvement of screening methods; (2) diagnostic use later in infancy after informed consent; (3) legal use after court order; (4) the possibility of research projects after approval by the Scientific Ethical Committee System in Denmark, The Danish Data Protection Agency and the NBS-Biobank Steering Committee The operation and use of the NBS-Biobank has until recently been regulated by an executive order of 1993 from the Danish Ministry of Health The Ethical Council, the Central Scientific Ethical Committee and the National Board of Health were also involved in the regulations These regulations have now been replaced by detailed general operational guidelines for biobanks in Denmark according to Acts on Processing of Personal Data, Patient’s Rights, Health 546/2005 and the Biomedical Research Ethics Committee System No specific Act on biobanks per se has been made in Denmark, but the new regulations and guidelines make the operations of the Danish NBS-Biobank even more clear-cut and safe The Danish NBS-Biobank has been used in several research projects for aetiological studies of a number of disorders, recently employing new sensitive multiplex technologies and genetic analyses utilizing whole-genome amplified DNA

233 citations


Journal ArticleDOI
TL;DR: Patients with types A and B Niemann–Pick disease (NPD) have an inherited deficiency of acid sphingomyelinase (ASM) activity, which appears to be more frequent in individuals of Middle Eastern and North African descent.
Abstract: 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.

215 citations


Journal ArticleDOI
TL;DR: Second-tier tests are developed to reduce false-positive results in the screening for congenital adrenal hyperplasia, tyrosinaemia type I, methylmalonic acidaemias, homocystinuria, and maple syrup urine disease.
Abstract: The continued expansion of newborn screening programmes to include additional conditions increases the responsibility of newborn screening laboratories to provide testing with the highest sensitivity and specificity to allow for identification of affected patients while minimizing the false-positive rate. Some assays and analytes are particularly problematic. Over recent years, our laboratory tried to improve this situation by developing second-tier tests to reduce false-positive results in the screening for congenital adrenal hyperplasia (CAH), tyrosinaemia type I, methylmalonic acidaemias, homocystinuria, and maple syrup urine disease (MSUD). Beginning in 2004, this approach was applied to Mayo's newborn screening programme and resulted in a false-positive rate of 0.09%, a positive predictive value of 41%, and a positive detection rate of 1 affected case in 1672 babies screened.

182 citations


Journal ArticleDOI
TL;DR: Therapy of acute hyperammonaemia has relied on ammonia-lowering agents but in recent years there has been considerable interest in neuroprotective strategies, and both strategies are intriguing areas for potential investigation in human urea cycle disorders.
Abstract: The urea cycle disorders constitute a group of rare congenital disorders caused by a deficiency of the enzymes or transport proteins required to remove ammonia from the body. Via a series of biochemical steps, nitrogen, the waste product of protein metabolism, is removed from the blood and converted into urea. A consequence of these disorders is hyperammonaemia, resulting in central nervous system dysfunction with mental status changes, brain oedema, seizures, coma, and potentially death. Both acute and chronic hyperammonaemia result in alterations of neurotransmitter systems. In acute hyperammonaemia, activation of the NMDA receptor leads to excitotoxic cell death, changes in energy metabolism and alterations in protein expression of the astrocyte that affect volume regulation and contribute to oedema. Neuropathological evaluation demonstrates alterations in the astrocyte morphology. Imaging studies, in particular 1H MRS, can reveal markers of impaired metabolism such as elevations of glutamine and reduction of myoinositol. In contrast, chronic hyperammonaemia leads to adaptive responses in the NMDA receptor and impairments in the glutamate–nitric oxide–cGMP pathway, leading to alterations in cognition and learning. Therapy of acute hyperammonaemia has relied on ammonia-lowering agents but in recent years there has been considerable interest in neuroprotective strategies. Recent studies have suggested restoration of learning abilities by pharmacological manipulation of brain cGMP with phosphodiesterase inhibitors. Thus, both strategies are intriguing areas for potential investigation in human urea cycle disorders.

181 citations


Journal ArticleDOI
TL;DR: Analysis of the characteristics of the Dutch Fabry cohort has revealed that a limited relationship between various disease manifestations exists and that individual symptoms do not correlate with elevated urinary or plasma Gb3 levels, limiting their value as surrogate disease markers.
Abstract: Background: Fabry disease (OMIM 301500) is an X-linked lysosomal storage disorder with characteristic vascular, renal, cardiac and cerebral complications. Globotriaosylceramide (Gb3) accumulates in Fabry patients as a result of α-galactosidase A deficiency. The phenotypic variability is high, but the relationship between clinical symptoms in individual Fabry patients has not been uniformly documented. Also, the relation between the most prominent biochemical abnormalities, elevated Gb3 levels in plasma and urine, and clinical symptoms is not firmly established. Methods: Clinical and biochemical characteristics of 96 (25 deceased) Dutch Fabry patients were collected retrospectively and before the initiation of enzyme therapy. Results: Clinical assessment revealed that median life expectancy was 57 years for male and 72 years for female patients. Cerebral complications, acroparaesthesias and gastrointestinal complications, but not cardiac and auditory complications, were all seen more frequently in male than female patients. Glomerular filtration rate (GFR) was highly variable in male patients, including 2 patients with GFR < 30 ml/min, but median GFR did not differ between males and females (103 and 101 ml/min, respectively). Hyperfiltration was more frequently observed in the female patient group. Microalbuminuria was present in 60% of males and 45% of females. No specific pattern of combined symptoms existed except for a relationship between left ventricular hypertrophy (LVH) and cerebral complications (males 36%, females 32%), or proteinuria (males 35%, females 31%). Gb3 was found to be more elevated in plasma samples from male (n = 26; median 6.27 μmol/L (1.39–9.74)) than female Fabry patients (n = 37; median 2.16 (0.77–4.18)). This was also observed for urinary Gb3: males (n = 22) median 1851 nmol/24 h (40–3724); females (n = 29) median 672 (86–2052). Plasma and urinary Gb3 levels correlated with each other in both males (r = 0.4, p = 0.05) and females (r = 0.4, p = 0.03), but no correlation between elevated Gb3 levels and clinical symptoms could be detected. Conclusion: Analysis of the characteristics of the Dutch Fabry cohort has revealed that a limited relationship between various disease manifestations exists and that individual symptoms do not correlate with elevated urinary or plasma Gb3 levels, limiting their value as surrogate disease markers.

165 citations


Journal ArticleDOI
TL;DR: An overview of IEMs potentially revealed by psychiatric problems in adolescence or adulthood is presented and a diagnostic strategy to guide metabolic investigations is provided.
Abstract: Inborn errors of metabolism (IEMs) may present in adolescence or adulthood as a psychiatric disorder. In some instances, an IEM is suspected because of informative family history or because psychiatric symptoms form part of a more diffuse clinical picture with systemic, cognitive or motor neurological signs. However, in some cases, psychiatric signs may be apparently isolated. We propose a schematic classification of IEMs into three groups according to the type of psychiatric signs at onset. Group 1 represents emergencies, in which disorders can present with acute and recurrent attacks of confusion, sometimes misdiagnosed as acute psychosis. Diseases in this group include urea cycle defects, homocysteine remethylation defects and porphyrias. Group 2 includes diseases with chronic psychiatric symptoms arising in adolescence or adulthood. Catatonia, visual hallucinations, and aggravation with treatments are often observed. This group includes homocystinurias, Wilson disease, adrenoleukodystrophy and some lysosomal disorders. Group 3 is characterized by mild mental retardation and late-onset behavioural or personality changes. This includes homocystinurias, cerebrotendinous xanthomatosis, nonketotic hyperglycinaemia, monoamine oxidase A deficiency, succinic semialdehyde dehydrogenase deficiency, creatine transporter deficiency, and α and β mannosidosis. Because specific treatments should be more effective at the ‘psychiatric stage’ before the occurrence of irreversible neurological lesions, clinicians should be aware of atypical psychiatric symptoms or subtle organic signs that are suggestive of an IEM. Here we present an overview of IEMs potentially revealed by psychiatric problems in adolescence or adulthood and provide a diagnostic strategy to guide metabolic investigations.

162 citations


Journal ArticleDOI
TL;DR: Variability in reduction of Phe indicates that the response to sapropterin dihydrochloride cannot be predicted by baseline Phe level, which is well tolerated and reduced blood Phe levels across all PKU phenotypes tested.
Abstract: This study aimed to evaluate the response to and safety of an 8-day course of sapropterin dihydrochloride (6R-tetrahydrobiopterin or 6R-BH4) 10 mg/kg per day in patients with phenylketonuria (PKU), who have elevated blood phenylalanine (Phe) levels, and to identify a suitable cohort of patients who would respond to sapropterin dihydrochloride treatment with a reduction in blood Phe level. Eligible patients were aged ≥ 8 years, had blood Phe levels ≥ 450 μmol/L and were not adhering to a Phe-restricted diet. Suitable patients were identified by a ≥30% reduction in blood Phe level from baseline to day 8 following sapropterin dihydrochloride treatment. The proportion of patients who met these criteria was calculated for the overall population and by baseline Phe level (<600, 600 to <900, 900 to <1200 and ≥1200 μmol/L). In total, 485/490 patients completed the study and 20% (96/485) were identified as patients who would respond to sapropterin dihydrochloride. A reduction in Phe level was observed in all subgroups, although response was greater in patients with lower baseline Phe levels. Wide variability in response was seen across all baseline Phe subgroups. The majority of adverse events were mild and all resolved without complications. Sapropterin dihydrochloride was well tolerated and reduced blood Phe levels across all PKU phenotypes tested. Variability in reduction of Phe indicates that the response to sapropterin dihydrochloride cannot be predicted by baseline Phe level.

149 citations


Journal ArticleDOI
TL;DR: Although national newborn screening policies do not exist in either Canada or the USA, there are intense efforts to provide uniform access to screening nationwide in both countries, particularly where new technologies and treatment therapies exist.
Abstract: Newborn screening in North America dates to the early work of Bob Guthrie in the USA. Screening programmes in both the USA and Canada began in the early 1960s, with documented programmes in both countries as early as 1962. Throughout the 1960s and 1970s, many of the screening tests that later became part of routine screening around the world were developed in US and Canadian laboratories, including tests for phenylketonuria, other inborn errors of metabolism, congenital hypothyroidism, congenital adrenal hyperplasia, and haemoglobinopathies. An automated punching machine developed in the USA facilitated screening expansion by significantly reducing sample preparation time and effort. US and Canadian programmes were leaders in applying computerized data management to newborn screening in the 1980s. In the 1990s, DNA and tandem mass spectrometry testing protocols were developed in the USA and applied to newborn screening. US programmes have continually expanded over time, while most Canadian programmes have not. With impetus from private laboratories and professional and consumer groups, many US programmes now screen for more than 50 conditions and there is increased expansion activity in Canada. NBS research in the USA is focused on improving system efficiency and translating other genetic testing to NBS, particularly where new technologies and treatment therapies exist. Although national newborn screening policies do not exist in either Canada or the USA, there are intense efforts to provide uniform access to screening nationwide in both countries. New partnerships between health professionals, consumers and politicians are benefiting the overall screening systems in both countries.

Journal ArticleDOI
TL;DR: Since approximately half of the births in the world occur in the Asia Pacific Region, it is important to continue the ongoing implementation and expansion efforts so that these children can attain the same health status as children in more developed parts of the world and their full potential can be realized.
Abstract: The success of blood spot newborn screening in the USA led to early screening efforts in parts of the Asia Pacific Region in the mid-1960s. While there were early screening leaders in the region, many of the countries with depressed and developing economies are only now beginning organized screening efforts. Four periods of screening growth in the Asia Pacific region were identified. Beginning in the 1960s, blood spot screening began in New Zealand and Australia, followed by Japan and a cord blood screening programme for G6PD deficiency in Singapore. In the 1980s, established programmes added congenital hypothyroidism and new programmes developed in Taiwan, Hong Kong, China (Shanghai), India and Malaysia. Programmes developing in the 1990s built on the experience of others developing more rapidly in Korea, Thailand and the Philippines. In the 2000s, with limited funding support from the International Atomic Energy Agency, there has been screening programme development around detection of congenital hypothyroidism in Indonesia, Mongolia, Sri Lanka, Myanmar and Pakistan. Palau has recently contracted with the Philippine newborn screening programme. There is little information available on newborn screening activities in Nepal, Cambodia, Laos and the other Pacific Island nations, with no organized screening efforts apparent. Since approximately half of the births in the world occur in the Asia Pacific Region, it is important to continue the ongoing implementation and expansion efforts so that these children can attain the same health status as children in more developed parts of the world and their full potential can be realized.

Journal ArticleDOI
TL;DR: The major aim of this guideline is to re-assess the common practice and to formulate recommendations for diagnosis and management of GCDH deficiency based on the best available evidence.
Abstract: Glutaryl-CoA dehydrogenase (GCDH) deficiency is an autosomal recessive disease with an estimated overall prevalence of 1 in 100 000 newborns Biochemically, the disease is characterized by accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine, which can be detected by gas chromatography-mass spectrometry of organic acids or tandem mass spectrometry of acylcarnitines Clinically, the disease course is usually determined by acute encephalopathic crises precipitated by infectious diseases, immunizations, and surgery during infancy or childhood The characteristic neurological sequel is acute striatal injury and, subsequently, dystonia During the last three decades attempts have been made to establish and optimize therapy for GCDH deficiency Maintenance treatment consisting of a diet combined with oral supplementation of L: -carnitine, and an intensified emergency treatment during acute episodes of intercurrent illness have been applied to the majority of patients This treatment strategy has significantly reduced the frequency of acute encephalopathic crises in early-diagnosed patients Therefore, GCDH deficiency is now considered to be a treatable condition However, significant differences exist in the diagnostic procedure and management of affected patients so that there is a wide variation of the outcome, in particular of pre-symptomatically diagnosed patients At this time of rapid expansion of neonatal screening for GCDH deficiency, the major aim of this guideline is to re-assess the common practice and to formulate recommendations for diagnosis and management of GCDH deficiency based on the best available evidence

Journal ArticleDOI
TL;DR: A sustained and significant growth in NBS activities has become evident during the last decade, highlighted by implementation of new programmes, increase in coverage, expansion of NBS panels, increasing involvement of governmental and public health authorities, and integration ofNBS teams through scientific societies and External Quality Assurance Schemes.
Abstract: Newborn screening (NBS) in Latin America took its first steps in the mid-1970s. Nevertheless, many years elapsed before it achieved its integration within the public health care system and its systematic and continuous implementation under a programme structure. Latin American countries can be characterized not only by their great geographic, demographic, ethnic, economic and health system diversity, but also by their heterogeneity in NBS activities, which gives rise to variation in degree of organization: countries with optimal fulfilment (Cuba, Costa Rica, Chile, Uruguay); others rapidly expanding their coverage (Brazil, Mexico, Argentina); some others in a recent implementation phase (Colombia, Paraguay, Venezuela, Nicaragua, Peru); others with minimal, isolated and non-organized activities (Guatemala, Dominican Republic, Bolivia, Panama, Ecuador); and finally others without any NBS activities at all (El Salvador, Honduras, Haiti). Despite this disparity, a sustained and significant growth in NBS activities has become evident during the last decade, highlighted by implementation of new programmes, increase in coverage, expansion of NBS panels, increasing involvement of governmental and public health authorities, and integration of NBS teams through scientific societies and External Quality Assurance Schemes. Currently, congenital hypothyroidism (CH) is the most widely screened disease, followed by phenylketonuria, with organized NBS programmes for CH in 14 countries. Other diseases usually included in NBS programmes are screened in a lower rate. Every year, around 11.2 million infants are born in Latin America. During 2005, 49.3% of newborns were screened for CH, indicating that around 5.7 million newborns still did not have access to the benefits of NBS.

Journal ArticleDOI
TL;DR: The weak activity of mMDH on α-ketoglutarate is sufficient to account for the amount of l-2-hydroxyglutarate that is excreted by patients deficient in FAD-linked l- 2-HydroxyglUTarate dehydrogenase, which appears to belong to the expanding class of ‘house-cleaning’ enzymes.
Abstract: L-2-hydroxyglutaric aciduria is a metabolic disorder in which L-2-hydroxyglutarate accumulates as a result of a deficiency in FAD-linked L-2-hydroxyglutarate dehydrogenase, a mitochondrial enzyme converting L-2-hydroxyglutarate to alpha-ketoglutarate. The origin of the L-2-hydroxyglutarate, which accumulates in this disorder, is presently unknown. The oxidation-reduction potential of the 2-hydroxyglutarate/alpha-ketoglutarate couple is such that L-2-hydroxyglutarate could potentially be produced through the reduction of alpha-ketoglutarate by a NAD- or NADP-linked oxidoreductase. In fractions of rat liver cytosolic extracts that had been chromatographed on an anion exchanger we detected an enzyme reducing alpha-ketoglutarate in the presence of NADH. This enzyme co-purified with cytosolic L-malate dehydrogenase (cMDH) upon further chromatography on Blue Sepharose. Mitochondrial fractions also contained an NADH-linked, 'alpha-ketoglutarate reductase', which similarly co-purified with mitochondrial L-malate dehydrogenase (mMDH). Purified mMDH catalysed the reduction of alpha-ketoglutarate to L-2-hydroxyglutarate with a catalytic efficiency that was about 10(7)-fold lower than that observed with oxaloacetate. For the cytosolic enzyme, this ratio amounted to 10(8), indicating that this enzyme is more specific. Both cMDH and mMDH are highly active in tissues and alpha-ketoglutarate is much more abundant than oxaloacetate and more concentrated in mitochondria than in the cytosol. As a result of this, the weak activity of mMDH on alpha-ketoglutarate is sufficient to account for the amount of L-2-hydroxyglutarate that is excreted by patients deficient in FAD-linked L-2-hydroxyglutarate dehydrogenase. The latter enzyme appears, therefore, to be responsible for a 'metabolite repair' phenomenon and to belong to the expanding class of 'house-cleaning' enzymes.

Journal ArticleDOI
TL;DR: There is a clear need to develop a specific treatment for this progressively debilitating neurodegenerative disorder, and a review of NPC patients in the UK confirms the phenotypic variability of this inherited lipid storage disorder.
Abstract: Niemann-Pick disease type C (NPC) is an autosomal recessive, neurovisceral lipid storage disorder. Mutations in two genes (NPC1 and NPC2) produce indistinguishable clinical phenotypes by biochemical mechanisms that have not yet been entirely clarified. The wide spectrum of clinical presentations of NPC includes hepatic and pulmonary disease as well as a range of neuropsychiatric disorders. Late-onset disease has been increasingly recognized as the biochemical diagnosis of NPC has been more widely applied in adult neurology clinics. The clinical presentation and follow-up of 94 patients with NPC is described, 58 of whom were still alive at the time this report was prepared. The age at diagnosis ranged from the prenatal period (with hydrops fetalis) up to 51 years. This review of NPC patients in the UK confirms the phenotypic variability of this inherited lipid storage disorder reported elsewhere. Although a non-neuronopathic variant has been described, most patients in this series who survived childhood inevitably suffered neurological and in some cases neuropsychiatric deterioration. While symptomatic treatment, such as anticholinergic and antiepileptic drugs, can alleviate some aspects of the disease, there is a clear need to develop a specific treatment for this progressively debilitating neurodegenerative disorder.

Journal ArticleDOI
TL;DR: The clinical features of NICCD (neonatal intrahepatic cholestasis caused by citrin deficiency) were clarified by retrospective review of symptoms, management and long-term outcome of 75 patients by using questionnaires to paediatricians in charge of the patients.
Abstract: We clarified the clinical features of NICCD (neonatal intrahepatic cholestasis caused by citrin deficiency) by retrospective review of symptoms, management and long-term outcome of 75 patients. The data were generated from questionnaires to paediatricians in charge of the patients. Thirty of the patients were referred to hospitals before 1 month of age because of positive results in newborn screening (hypergalactosaemia, hypermethioninaemia, and hyperphenylalaninaemia). The other 45, the screen-negative patients, were referred to hospitals with suspected neonatal hepatitis or biliary atresia because of jaundice or discoloured stool. Most of the screen-negative patients presented before 4 months of age, and 11 had failure to thrive. Laboratory data showed elevated serum bile acid concentrations, hypoproteinaemia, low levels of vitamin K-dependent coagulation factors and hypergalactosaemia. Hypoglycaemia was detected in 18 patients. Serum amino acid analyses showed significant elevation of citrulline and methionine concentrations. Most of the patients were given a lactose-free and/or medium-chain triglyceride-enriched formula and fat-soluble vitamins. Symptoms resolved in all but two of the patients by 12 months of age. The two patients with unresolved symptoms suffered from progressive liver failure and underwent liver transplantation before their first birthday. Another patient developed citrullinaemia type II (CTLN2) at age 16 years. It is important to recognize that NICCD is not always a benign condition.

Journal ArticleDOI
TL;DR: In this paper, the pyridoxal 5'-phosphate (PLP) was used to treat infants with PNPO deficiency in neonatal epileptic encephalopathy.
Abstract: Neonatal epileptic encephalopathy can be caused by inborn errors of metabolism. These conditions are often unresponsive to treatment with conventional antiepileptic drugs. Six children with pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency presented with neonatal epileptic encephalopathy. Two were treated with pyridoxal 5'-phosphate (PLP) within the first month of life and showed normal development or moderate psychomotor retardation thereafter. Four children with late or no treatment died or showed severe mental handicap. All of the children showed atypical biochemical findings. Prompt treatment with PLP in all neonates and infants with epileptic encephalopathy should become mandatory, permitting normal development in at least some of those affected with PNPO deficiency.

Journal ArticleDOI
TL;DR: An overview of the current status of expanded newborn screening programmes in Europe and the reasons for the differences observed appear arbitrary and contrary to the optimal benefit of this important preventive health measure are presented.
Abstract: By January 2007 seven European countries had expanded, and more are considering the expansion of their newborn screening programmes by inclusion of ESI tandem mass spectrometry. We present an overview of the current status of expanded newborn screening programmes in Europe. While the first pilot programmes were initiated in 1998 in Germany, most countries started within the last 3 years. The number of disorders screened for by MS/MS ranges from two disorders (phenylketonuria and medium-chain acyl-CoA dehydrogenase deficiency) in some countries to 20 in others. The number of live births investigated per screening centre varies from 18 000 to 77 000. Few programmes have reported the number of positively identified cases and technical data, although many participate in quality assurance and proficiency test schemes. Given the relatively common genetic background of most European populations and similar health care systems, the reasons for the differences observed appear arbitrary and contrary to the optimal benefit of this important preventive health measure. Harmonization of disease screening panels, spectrum of metabolites analysed, sizes of screening laboratories, analytical procedures, follow-up management and proficiency and quality testing is urgently warranted on the European level. This will hopefully occur before screening by novel applications of tandem mass spectrometry for additional groups of disorders including lysosomal storage disorders and X-linked adrenoleukodystrophy are implemented.

Journal ArticleDOI
TL;DR: Interference of AFD symptoms with individuals-lives (particularly acroparaesthesiae or anhidrosis) showed the largest odds of association with depression, and relationship and financial status proved strong predictors of depression.
Abstract: Background Anderson–Fabry disease (AFD), an X-linked lysosomal storage disorder, leads to multi-organ dysfunction and premature mortality. Depression in adults with AFD has been reported, but no large study has been done. We have examined the adult Fabry population in the United Kingdom to describe the prevalence, associated factors and frequency of diagnosis of depression.

Journal ArticleDOI
TL;DR: Large neutral amino acids (LNAA) have been used on a limited number of patients with phenylketonuria with the purpose of decreasing the influx of phenylalanine (Phe) to the brain, establishing proof of principle of the role of orally administered LNAA in lowering blood Phe concentrations in patients with PKU.
Abstract: Large neutral amino acids (LNAA) have been used on a limited number of patients with phenylketonuria (PKU) with the purpose of decreasing the influx of phenylalanine (Phe) to the brain. In an open-label study using LNAA, a surprising decline of blood Phe concentration was found in patients with PKU in metabolic treatment centres in Russia, the Ukraine, and the United States. To validate the data obtained from this trial, a short-term double-blind placebo control study was done using LNAA in patients with PKU, with the participation of three additional metabolic centres – Milan, Padua and Rio de Janeiro. The results of the short trial showed significant lowering of blood Phe concentration by an average of 39% from baseline. The data from the double-blind placebo control are encouraging, establishing proof of principle of the role of orally administered LNAA in lowering blood Phe concentrations in patients with PKU. Long-term studies will be needed to validate the acceptability, efficacy and safety of such treatment.

Journal ArticleDOI
TL;DR: The Middle East and North Africa region needs to take big steps towards developing national strategies for prevention and should learn from experiences of regional and international screening programmes.
Abstract: This review presents the current experiences with newborn screening in the Middle East and North Africa region. The population in the region is about 400 million, with high birth rate and an estimated 10 million newborns per year. The majority of the population is of the Islamic faith and mostly Arab. The population is characterized by a high consanguinity (25-70%) and a high percentage of first-cousin marriages. Haemoglobin disorders, inherited metabolic disorders, neurogenetic disorders and birth defects are relatively common among the population. There is a rather slow progress in developing and implementing preventive genetic programmes owing to legal, cultural, political and financial issues. Although research spending is rather soft in the region, there are numerous pilot studies that highlighted the high incidence of genetic defects and the need for newborn screening programmes. Currently, there are only four countries that are executing national newborn screening but they vary from one disease to 23 and coverage is not complete. The region needs to take big steps towards developing national strategies for prevention and should learn from experiences of regional and international screening programmes.

Journal ArticleDOI
TL;DR: MRI abnormalities in phenylketonuria are the result of a distinctive alteration of white matter suggesting the intracellular accumulation of a hydrophilic metabolite, which leaves unaffected white matter architecture and structure.
Abstract: Objective: To gain insights into the nature and pathogenesis of white matter (WM) abnormalities in PKU Methods: Thirty-two patients with phenylalanine hydroxylase deficiency (21 with early and 11 with late diagnosis and treatment) and 30 healthy controls underwent an integrated clinical, neuroimaging (30 T MRI, diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI)) and neurochemical (1H MRS) investigation Results: All patients had white matter abnormalities on T2-weighted (T2W) and fluid-attenuated inversion recovery (FLAIR) scans; parietal white was consistently affected, followed by occipital, frontal and temporal white matter T1-weighted hypointense alterations were also found in 8 of 32 patients DWI hyperintense areas overlapped with those detected on T2W/FLAIR The apparent diffusion coefficient (ADC) was reduced and correlated inversely with severity of white matter involvement Fractional anisotropy index, eigenvalues λmin, λmiddle, λmax obtained from DTI data, and the principal brain metabolites assessed by 1H MRS (except brain phenylalanine (Phe)) were normal Brain Phe peak was detected in all but two subjects Brain and blood Phe were strictly associated Blood Phe at the diagnosis, patient’s age, and concurrent brain Phe independently influence white matter alteration (as expressed by conventional MRI or ADC values) Conclusions: (a) MRI abnormalities in phenylketonuria are the result of a distinctive alteration of white matter suggesting the intracellular accumulation of a hydrophilic metabolite, which leaves unaffected white matter architecture and structure (b) White matter abnormalities do not seem to reflect the mechanisms involved in the derangement of mental development in PKU (c) Our data do not support the usefulness of conventional brain MRI examination in the clinical monitoring of phenylketonuria patients

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TL;DR: In this paper, the authors evaluated peak bone mass in adult PKU patients and compared BMD to nutritional parameters using dual-energy x-ray absorptiometry in 31 adults (18 female, mean age 25 ± 53 years).
Abstract: Objective: Several studies have suggested a compromised bone mass in phenylketonuria patients but most reported on heterogeneous or small patient groups Our aim was to evaluate peak bone mass in adult PKU patients and to relate BMD to nutritional parameters Patients and methods: BMD was measured by dual-energy x-ray absorptiometry in 31 adult PKU patients (18 female), mean age 25 ± 53 years Nutritional intake was calculated based on food diaries Diet adherence was determined based on patients’ report Results: Mean blood phenylalanine (Phe) concentration was 968 ± 526 μmol/L (16 ± 87 mg/dl) Eight patients (322%) met the recommended blood Phe concentration of <726 μmol/L (<12 mg/dl), and there was no significant difference in Phe concentrations between diet-adherent and non-adherent patients Osteopenia was detected in 11 patients (387%), while osteoporosis was detected in 2 patients (65%) No correlation was found between BMD and age, blood minerals, Phe, vitamin D and alkaline phosphatase levels, calcium and protein intake, body mass index, and body fat percentage Conclusions: Peak bone mass is decreased in PKU patients Possible explanations include long-standing dietary deficiency in protein, calcium, vitamin D or trace elements, or a primary defect in bone turnover inherent to the disease itself Our data do not favour any of these hypotheses Further studies are needed to elucidate the cause of low bone density in PKU patients

Journal ArticleDOI
TL;DR: These data indicate longer duration of euglycaemia and better short-term metabolic control in the majority of GSD patients with WMHM20 compared to cornstarch.
Abstract: Objective: To determine whether a new starch offers better short-term metabolic control than uncooked cornstarch in patients with glycogen storage diseases (GSDs).

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TL;DR: The significant correlation of FFM (representing muscle mass) with intake of natural protein—rather than total protein—indicates that the enhancement of tolerance to natural protein may be of value in PKU patients.
Abstract: Treatment of phenylketonuria (PKU, OMIM 261600) means a diet restricted in natural protein and supplemented with phenylalanine (Phe)-free l-amino acid mixtures. Growth impairment has been described even in patients with a total protein intake at or above the recommended dietary allowance (RDA). In the present study, growth and body composition (fat-free mass (FFM) and fat) were recorded over 12 months in 34 treated PKU patients (mean age 8.7 years at baseline). Measurements were compared with those of healthy peers and with general population standard (Z-) scores calculated using the LMS method. In 28 PKU patients, data on birth weight and birth length were available and related to measurements at baseline of the study. Mean total protein intake in PKU patients was 124% (range 77–193%) of the RDA (DACH 2000). No significant differences in growth and body composition were present between PKU patients and healthy populations either at birth or during the study period. The significant correlation of FFM (representing muscle mass) with intake of natural protein—rather than total protein—indicates that the enhancement of tolerance to natural protein may be of value in PKU patients.

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TL;DR: PKU subjects need special attention in the definition of optimal supplementation of nutrients, which may be insufficient in relation to the type of diet and may otherwise manifest symptoms of deficit.
Abstract: PKU subjects need special attention in the definition of optimal supplementation of nutrients, which may be insufficient in relation to the type of diet and may otherwise manifest symptoms of deficit. In particular, it is necessary to pay great attention to the long-chain polyunsaturated fatty acid (LC-PUFA) levels in relation to correct development of the central nervous system. On the basis of numerous beneficial effects currently known, a permanent supplementation with LC-PUFAs, in particular with docosahexaenoic acid, should be considered. Moreover, new formulas, Phe-free peptides, and ‘modulated’ amino acid preparations might help in preventing nutritional deficiencies and imbalances, with the ultimate aim of improving growth. New strategies—such as supply of tetrahydrobiopterin—need to be optimized in terms of targets, patients and expected outcomes.

Journal ArticleDOI
TL;DR: This review summarizes the recent advances in the understanding of the physiopathology of MLD and the new therapeutic perspectives currently under preclinical investigation, including enzyme replacement therapy, gene therapy and cell therapy.
Abstract: Metachromatic leukodystrophy (MLD) is a demyelinating storage disease caused by deficiency of the lysosomal enzyme arylsulfatase A (ARSA). Lack of ARSA activity leads to the accumulation of galactosylceramide-3-O-sulfate (sulfatide) in the central and peripheral nervous systems. Based on the age at onset, the disease is usually classified into three forms: the late-infantile form, which manifests in the second year of life; the juvenile variants (onset between 4 and 12 years), which are subdivided into early-juvenile (EJ, onset before 6 years) and late-juvenile (LJ, onset after 6 years); and the adult form (onset after 12 years of age). Currently, there is no efficient therapy for the late-infantile form of MLD (50% of the patients), death occurring within a few years after onset of neurological symptoms. Allogeneic haematopoietic cell transplantation (HCT), when performed at a very early stage of the disease, may improve selected patients with juvenile or adult forms of MLD. As with other lysosomal storage diseases, the physiopathology of MLD is poorly understood. Demyelination is the main pathological finding, but substantial storage of sulfatides in neurons also occurs, and may contribute to the clinical phenotype. The physiopathological process leading to neuronal and glial cell degeneration and apoptosis involves accumulation of undegraded sulfatides but also secondary abnormalities (storage/mislocalization of unrelated lipids, inflammatory processes). This review summarizes the recent advances in the understanding of the physiopathology of MLD and the new therapeutic perspectives currently under preclinical investigation, including enzyme replacement therapy, gene therapy and cell therapy.

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TL;DR: The disease panels covered by newborn blood spot screening vary greatly from country to country, and there are great disparities between the value judgements applied in screening and in routine clinical practice.
Abstract: The disease panels covered by newborn blood spot screening vary greatly from country to country. There are different interpretations of the Wilson and Jungner principles and of underlying data in the scientific literature, and great disparities between the value judgements applied in screening and in routine clinical practice.

Journal ArticleDOI
Lianshu Han1, J Ye1, Wenjuan Qiu1, Xueren Gao1, Ying Wang1, X F Gu1 
TL;DR: It is suggested that tandem mass spectrometry is useful for selective screening of clinically suspected patients and fatty acid oxidation disorders are relatively rare in the Chinese, but medium-chain acyl-CoA dehydrogenase deficiency should be further investigated.
Abstract: We have initiated clinical selective screening for inborn errors of metabolism in China by analysing amino acids and acylcarnitines in a dried blood filter-paper samples using tandem mass spectrometry. Samples from a total of 3070 children suspected of inborn errors of metabolism were collected through a study network which covered most provinces of China. The diagnoses were further confirmed through clinical symptoms, by gas chromatography-mass spectrometry and other biochemistry studies, and in a few cases by DNA analysis. In all, 212 cases were diagnosed (6.6%) including 92 (43.4%) with amino acids disorders (48 with phenylketonuria, 12 with ornithine carbamoyltransferase deficiency, 7 with tyrosinaemia type I, 9 with maple syrup urine disease, 5 with citrullinaemia type I, 8 with citrullinaemia type II, 2 with homocystinuria, and 1 with argininaemia); 107 (50.5%) with organic acid disorders (including 58 with methylmalonic acidaemia, 13 with propionic acidaemia, 6 with isovaleric acidaemia, 7 with glutaric acidaemia type I, 6 with 3-methylcrotonyl-CoA carboxylase deficiency, 2 with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, 10 with multiple carboxylase deficiency, and 5 with beta-ketothiolase deficiency); and 13 (6.1%) with fatty acid oxidation disorders (including 1 with carnitine palmitoyltransferase deficiency type I, 1 with carnitine palmitoyltransferase deficiency type II, 1 with short-chain acyl-CoA dehydrogenase deficiency, 5 with medium-chain acyl-CoA dehydrogenase deficiency, 3 with very long-chain acyl-CoA dehydrogenase deficiency, and 2 with multiple acyl-CoA dehydrogenase deficiency). It is suggested that tandem mass spectrometry is useful for selective screening of clinically suspected patients. The majority of diseases (94%) in this study were amino acid disorders and organic acid disorders. Fatty acid oxidation disorders are relatively rare in the Chinese, but medium-chain acyl-CoA dehydrogenase deficiency should be further investigated.