Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency.

Cystathionine beta-synthase (CBS) deficiency is a rare inherited disorder in the methionine catabolic pathway, in which the impaired synthesis of cystathionine leads to accumulation of homocysteine. Patients can present to many different specialists and diagnosis is often delayed. Severely affected patients usually present in childhood with ectopia lentis, learning difficulties and skeletal abnormalities. These patients generally require treatment with a low-methionine diet and/or betaine. In contrast, mildly affected patients are likely to present as adults with thromboembolism and to respond to treatment with pyridoxine. In this article, we present recommendations for the diagnosis and management of CBS deficiency, based on a systematic review of the literature. Unfortunately, the quality of the evidence is poor, as it often is for rare diseases. We strongly recommend measuring the plasma total homocysteine concentrations in any patient whose clinical features suggest the diagnosis. Our recommendations may help to standardise testing for pyridoxine responsiveness. Current evidence suggests that patients are unlikely to develop complications if the plasma total homocysteine concentration is maintained below 120 µmol/L. Nevertheless, we recommend keeping the concentration below 100 µmol/L because levels fluctuate and the complications associated with high levels are so serious.

Recommendations for reporting results of diagnostic genomic testing.

Results of clinical genomic testing must be reported in a clear, concise format to ensure they are understandable and interpretable. It is important laboratories are aware of the information which is essential to make sure the results are not open to misinterpretation. As genomic testing has continued to evolve over the past decade, the European Society of Human Genetics (ESHG) recommendations for reporting results of diagnostic genetic testing (biochemical, cytogenetic and molecular genetic) published in 2014 have been reviewed and updated to provide the genomic community with guidance on reporting unambiguous results.

Relationship of octanoylcarnitine concentrations to age at sampling in unaffected newborns screened for medium-chain acyl-CoA dehydrogenase deficiency.

BACKGROUND: Although octanoylcarnitine (C8) concentrations measured from newborn screening dried blood spots are used to identify those at high risk of medium-chain acyl-CoA dehydrogenase deficiency (MCADD), age-related reference values are currently not available for unaffected newborn populations. Because age at sampling may vary within and between screening programs, variations in C8 concentrations by age may affect screening program performance. We determined whether C8 concentrations vary by age at sampling, sex, birth weight, or gestational age in unaffected newborns. METHODS: We analyzed C8 concentrations from 227,098 unaffected newborns, including 179,729 from 6 English laboratories participating in a multicenter study and 47,369 from the single laboratory serving the New South Wales (NSW) Newborn Screening Program in Australia. In England, the majority of samples were collected at age 5-8 days and analyzed underivatized by use of tandem mass spectrometry (MS/MS); in NSW, samples were obtained at a median age of 3 days and analyzed derivatized by MS/MS. Information on infants' sex, birth weight, gestation, hospitalization, and transfusion status was recorded at time of sampling. RESULTS: C8 concentrations did not vary significantly by age at sampling, sex, birth weight, or gestational age and remained relatively constant during the first 2 weeks of life in unaffected babies being screened for MCADD. CONCLUSIONS: Newborn MCADD screening programs using this biomarker for screening samples collected after the first day and during the first 14 days of life do not need to adjust cutoff values to account for postnatal age, prematurity, or size at birth.

A systematic review of cognitive functioning in early treated adults with phenylketonuria.

BACKGROUND: Even though early dietary management of phenylketonuria (PKU) successfully prevents severe neurological impairments, deficits in cognitive functioning are still observed. These deficits are believed to be the result of elevated levels of phenylalanine throughout life. Research on cognitive functioning in adults with PKU (AwPKU) often focuses on domains shown to be compromised in children with PKU, such as attention and executive functions, whereas other cognitive domains have received less attention. This systematic review aimed to provide an overview of cognitive functioning across domains examined in early treated (ET) AwPKU. METHODS: A systematic search was performed in Ovid MEDLINE(R), PsycINFO, Web of Science, Cochrane, Scopus, Embase, ScienceDirect, and PubMed for observational studies on cognitive performance in ET AwPKU. RESULTS: Twenty-two peer-reviewed publications, reporting on outcomes from 16 studies were reviewed. Collectively, the results most consistently showed deficits in vigilance, working memory and motor skills. Deficits in other cognitive domains were less consistently observed or were understudied. Furthermore, despite reports of several associations between cognitive performance and phenylalanine (Phe) levels throughout life the relationship remains unclear. Inconsistencies in findings across studies could be explained by the highly heterogeneous nature of study samples, resulting in large inter- and intra-variability in Phe levels, as well as the use of a variety of tests across cognitive domains, which differ in sensitivity. The long-term cognitive outcomes of early and continuous management of PKU remain unclear. CONCLUSIONS: To better understand the development of cognitive deficits in ET AwPKU, future research would benefit from 1) (inter)national multicentre-studies; 2) more homogeneous study samples; 3) the inclusion of other nutritional measures that might influence cognitive functioning (e.g. Phe fluctuations, Phe:Tyrosine ratio and micronutrients such as vitamin B12); and 4) careful selection of appropriate cognitive tests.

Delayed diagnosis of phenylketonuria - a case report of two siblings.

Phenylketonuria (PKU), is an autosomal recessive condition affecting the amino acid metabolism. The UK National newborn screening programme was commenced in 1969 and PKU is one among the five conditions included in the screening programme. We present the case history of two siblings of a family with a delayed diagnosis of PKU. This case history highlights such an occurrence. PKU should be considered as an important differential in the diagnosis of adult patients with learning difficulties, seizures and behavioural problems. It would be prudent to instigate plasma and urine amino/organic acid analyses in adult patients with unexplained neuropsychological manifestations.

Cystatin C in assessment of glomerular filtration rate in children and young adults suffering from cancer.

The study objective was to establish the diagnostic efficacy of cystatin C in the assessment of glomerular filtration rate (GFR) in paediatric oncology patients by investigating the relationships between serum cystatin C, serum creatinine and isotope clearance and determining whether these relationships are different from those seen in a group of patients of similar age with renal disease. This was a cohort study in which patients were divided into two groups: group A comprised renal patients and group B comprised oncology patients. All patients were referred for isotopic GFR assessment as part of routine clinical management and concurrently also had assessments made of their serum creatinine and cystatin C levels, together with height and weight measurements. Reciprocals of cystatin C correlate well with isotopic GFR; correlation coefficients from linear regression were 0.83 and 0.66 for the renal and oncology groups, respectively. However, when GFR was assessed from serum creatinine and cystatin C, levels of agreement were still very high (95% levels of agreement: -33 and 31 ml/min/1.73 m for cystatin C and -46 and 30 ml/min/1.73 m for the Counahan serum creatinine estimate). Receiver-operator characteristic curve analysis demonstrated that cystatin C has improved diagnostic utility for identifying patients with GFRs both below normal (90 ml/min/1.73 m) and below the point at which chemotherapy dose reduction may be considered (60 ml/min/1.73 m). Levels of intrapatient variability were similar for both tracers. Cystatin C was shown to be a better indicator of renal function compared with serum creatinine in oncology patients as demonstrated by receiver-operator characteristic curve and Bland-Altman analyses; however, sensitivity of the tracer to mild reductions in GFR is still low.

The Proline/Citrulline Ratio as a Biomarker for OAT Deficiency in Early Infancy.

Deficiency of ornithine-δ-aminotransferase (OAT) in humans results in gyrate atrophy. Early diagnosis may allow initiation of treatment before irreversible damage has occurred. However, diagnosis is commonly delayed well into adulthood because of the nonspecific character of initial symptoms. Here, we report findings in a neonate who was evaluated because of a positive family history of OAT deficiency. The reversed enzymatic flux in early infancy resulted in borderline low ornithine concentration - evoking urea cycle disturbances - and increased proline. In addition, plasma citrulline was low. Consequently, the proline/citrulline ratio in plasma was increased compared to controls. To find out whether amino acid profiling in neonatal dried blood spots is suitable to detect OAT deficiency, we evaluated the original newborn dried blood spots of two affected patients and compared it with a database of >450,000 newborns tested in Minnesota since 2004. Proline concentrations (777 and 1,381 µmol/L) were above the 99 percentile (776 µmol/L) of the general population, and citrulline concentrations (4.5 and 4.9 µmol/L) only just above the 1 percentile (4.37 µmol/L). The proline/citrulline ratio was 172.9 and 281.8, respectively. This ratio was calculated retrospectively in the normal population, and the 99 percentile was 97.6. Applying this ratio for NBS could lead to early and specific detection of neonatal OAT deficiency, with no additional expense to newborn screening laboratories quantifying amino acids. Given that early diagnosis of OAT disease can lead to earlier treatment and prevent visual impairment, further studies are indicated to evaluate whether newborn screening for OAT deficiency is warranted.

Newborn screening for medium chain acyl-CoA dehydrogenase deficiency in England: prevalence, predictive value and test validity based on 1.5 million screened babies.

BACKGROUND: Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare, life-threatening condition. Early diagnosis by screening asymptomatic newborns may improve outcome, but the benefit to newborns identified with variants not encountered clinically is uncertain. OBJECTIVE: To estimate, overall and by ethnic group: screen-positive prevalence and predictive value (PPV); MCADD prevalence; proportion MCADD variants detected of predicted definite or uncertain clinical importance. SETTING: All births in areas of high ethnic minority prevalence in England. METHODS: Prospective multicentre pilot screening service; testing at age five to eight days; standardized screening, diagnostic and management protocols; independent expert review of screen-positive cases to assign MCADD diagnosis and predicted clinical importance (definite or uncertain). RESULTS: Approximately 1.5 million babies (79% white; 10% Asian) were screened. MCADD was confirmed in 147 of 190 babies with a positive screening result (screen-positive prevalence: 1.20 per 10,000; MCADD prevalence: 0.94 per 10,000; PPV 77% [95% CI 71-83]), comprising 103 (70%) with MCADD variants of definite clinical importance (95 white [95%]; 2 Asian [2%]) and 44 (30%) with variants of uncertain clinical importance (29 white [67%]; 12 Asian [28%]). CONCLUSION: One baby in every 10,000 born in England is diagnosed with MCADD by newborn screening; around 60 babies each year. While the majority of MCADD variants detected are predicted to be of definite clinical importance, this varies according to ethnic group, with variants of uncertain importance most commonly found in Asian babies. These findings provide support for MCADD screening but highlight the need to take account of the ethnic diversity of the population tested at implementation.