Validity and reliability of the MetabQoL 1.0 and assessment of neuropsychiatric burden in organic acidemias: Reflections from Turkey.

OBJECTIVES: The MetabQoL 1.0 is the first disease-specific health related quality of life (HrQoL) questionnaire for patients with intoxication-type inherited metabolic disorders. Our aim was to assess the validity and reliability of the MetabQoL 1.0, and to investigate neuropsychiatric burden in our patient population. METHODS: Data from 29 patients followed at a single center, aged between 8 and 18 years with the diagnosis of methylmalonic acidemia (MMA), propionic acidemia (PA) or isovaleric acidemia (IVA), and their parents were included. The Pediatric Quality of Life Inventory (PedsQoL) was used to evaluate the validity and reliability of MetabQoL 1.0. RESULTS: The MetabQoL 1.0 was shown to be valid and reliable (Cronbach's alpha: 0.64-0.9). Fourteen out of the 22 patients (63.6%) formally evaluated had neurological findings. Of note, 17 out of 20 patients (85%) had a psychiatric disorder when evaluated formally by a child and adolescent psychiatrist. The median mental scores of the MetabQoL 1.0 proxy report were significantly higher than those of the self report (p = 0.023). Patients with neonatal-onset disease had higher MetabQoL 1.0 proxy physical (p = 0.008), mental (p = 0.042), total scores (p = 0.022); and self report social (p = 0.007) and total scores (p = 0.043) than those with later onset disease. CONCLUSIONS: This study continues to prove that the MetabQoL 1.0 is an effective tool to measure what matters in intoxication-type inherited metabolic disorders. Our results highlight the importance of clinical assessment complemented by patient reported outcomes which further expands the evaluation toolbox of inherited metabolic diseases.

Out-of-pocket health expenditures in patients living with inborn errors of metabolism.

AIM: The implementation of newborn screening programs for inborn errors of metabolism has advanced the diagnosis and management of affected infants and undoubtedly improved their outcomes. We aimed to determine out-of-pocket health expenditures of patients with inborn errors of metabolism during follow-up and treatment processes and to determine the economic burden on the families. MATERIALS AND METHODS: A total of 232 patients who voluntarily agreed to participate in the study and were regularly followed up in the Department of Pediatric Metabolism with the diagnosis of Inborn Errors of Metabolism between April 2022 and July 2022 were included. Questionnaires were asked about the demographic characteristics of patients, use of health services, follow-up, treatment procedures, frequency of controls and health expenditures. RESULTS: The average out-of-pocket expenditure of the households in the last month was 1039.22 ± 1030.08 (minimum: 20, maximum: 5000) Turkish Liras. When we consider the catastrophic health expenditure rate as expenditure exceeding 40% of household income, we found that 9.9% (23 people) of parents included in the study made catastrophic health expenditures. The rate of catastrophic expenditure of patients with a diagnosis of Amino Acid Metabolism Disorders was found to be higher than that of patients with a diagnosis of Vitamin and Cofactor Metabolism Disorders. Similarly, patients with a diagnosis of lysosomal storage diseases had more expenditures than patients with a diagnosis of vitamin and cofactor metabolism disorders. When we compared the rate of catastrophic health expenditure of the patients with urea cycle disorders and the patients with a diagnosis of vitamin and cofactor metabolism disorders, the former had more expenditure than the latter (p < 0.05). There was no significant difference between other disease groups in terms of catastrophic expenditure. The rate of catastrophic expenditures of the households living as large family type were higher than the families living as nuclear family type (p < 0.01). A statistically significant difference was found between the rates of catastrophic expenditures of the families living in Ankara and those who were admitted from other provinces for follow-up and treatment (p < 0.001). However, there was no difference between the rates of catastrophic expenditure of the patients who received any treatment and those who were followed up without treatment (p > 0.05). CONCLUSION: Due to the high rate of consanguineous marriages in our country, the development of newborn screening programs, the increase in awareness about metabolic diseases and the improvement in diagnostic methods, the frequency of metabolic diseases is increasing, and mortality and morbidity rates are significantly reduced with early diagnosis and treatment opportunities. It is necessary to carry out more comprehensive studies to determine and prevent the socioeconomic effects of out-of-pocket health expenditures of patients living with Inborn Errors of Metabolism.

Identification of novel pathogenic variants in the GCDH gene and assessment of neurodevelopmental outcomes in 24 children with glutaric aciduria type 1.

AIM: To evaluate the pathogenic variants in GCDH gene and to assess the neurodevelopmental outcomes in children with Glutaric aciduria type 1 (GA-1). METHOD: Cross-sectional observational study between January 2019 and June 2020 in consecutive North Indian children with a clinical and biochemical suspicion of GA-1. Variants in the coding regions of GCDH gene were identified through Sanger sequencing. Neurodevelopmental and quality of life assessment was done using standardized scales. RESULTS: 24 children with GA-1 were identified. The median age at diagnosis was 12 months and the median delay in diagnosis was 3 months. Genetic analysis was done in 14 cases. It revealed 12 variants (11 missense and one nonsense) from 13 patients. Most of the pathogenic variants were in exon 9 and exon 5. Three novel variants were identified in three patients: two missense variants c.169G > A (p.Glu57Lys), c.1048T > C (p.Cys350Arg) and one nonsense variant c.331C > T (p.Lys111Ter). On neurodevelopmental assessment, majority of children with GA-1 were non ambulatory (62.5%), had limited hand skills (58.3%) and impaired communication (58.3%). Overall, poor global development was noted in 43.7%. A pre-existing developmental delay was significantly associated with impaired communication skills (p = 0.03), and the number of episodes of encephalopathy were significantly associated with impaired gross motor skill (p = 0.02). Presence of encephalopathy was significantly associated with poor performance in social emotional (p = 0.01) and cognitive (p = 0.03) domains of Developmental Profile-III scale and development of severe dystonia (p = 0.01). CONCLUSION: Our findings highlight the clinical, biochemical, radiological and genetic spectrum of GA-1 in children in North India and report the presence of novel pathogenic variations.

Burden of illness of aromatic L-amino acid decarboxylase deficiency: a survey of physicians in Southern Europe.

BACKGROUND: Aromatic L-amino acid decarboxylase deficiency (AADCd) is an ultra-rare genetic neurometabolic disorder caused by mutations in the DDC gene. OBJECTIVE: This retrospective, noninterventional study was designed to describe the burden of AADCd including the associated healthcare resource utilization in Southern Europe. METHODS: Eleven clinicians completed a patient case study survey for patients with AADCd currently or previously under their care, followed by an interview with each clinician to assess healthcare resource utilization, patient characteristics, and symptoms. RESULTS: Clinicians provided data for 20 patients with AADCd, of whom 60% were male. All patients experienced movement disorders, 90% exhibited developmental delay, 85% reported sleeping problems, and 80% experienced gastrointestinal problems. The symptoms varied with disease severity. Patients with AADCd received care from more than 16 different specialists including both medical and paramedical healthcare professionals. Hospitalizations and visits to accident and emergency departments were also frequent. CONCLUSION: In terms of symptoms and healthcare resource utilization, the burden of illness of AADCd is substantial. This study provides insights into several aspects of the disease that are difficult to ascertain from published case reports.

Safety Assessment of L-ß-Aminoisobutyric Acid (L-BAIBA): Subchronic Toxicity Study in Sprague Dawley Rats.

L-3-Aminoisobutyric acid (L-BAIBA) is an endogenous compound in human metabolism when thymine and valine undergo catabolism. L-BAIBA represents one of the two isomers of BAIBA in biological systems. BAIBA has been shown to reduce body fat percentage via an increase in fatty acid oxidation and a decrease in hepatic lipogenesis. However, no toxicological effects of L-BAIBA in animals or humans have been established. The present study was designed to evaluate the safety and toxic potentials of this compound, where L-BAIBA was administered orally to Sprague Dawley rats at 100, 300, and 900 mg/kg/day for 90 days. No treatment-related adverse effects were observed in any of the treatment groups. Based on the results, the No-Observed-Adverse-Effect Level (NOAEL) of L-BAIBA was 900 mg/kg/day.

Newborn screening for inherited metabolic diseases using tandem mass spectrometry in China: Outcome and cost-utility analysis.

OBJECTIVES: Few studies in China have focused on the economic evaluation of newborn screening (NBS) for inherited metabolic disorders (IMDs) by tandem mass spectrometry (MS/MS). This study assesses the total costs, benefits, benefit-cost ratio (BCR), cost-utility ratio (CUR) and incremental cost-utility ratio (ICUR) of NBS using MS/MS compared to the non-screened group. METHODS: The NBS outcomes of newborns who underwent MS/MS screening for IMDs in 2009-2018 were retrospectively reviewed. Records were extracted from a screening management system at the NBS Center of Zhejiang province. A cost-benefit analysis of screening was conducted, assessing screening costs for each subject, and direct and indirect treatment costs for IMDs detected by screening. The putative benefit of clinical outcomes related to early diagnosis was assumed to be improvement in quality of life and prolonged life expectancy in the screened group, as compared to the non-screened group. RESULTS: Of the 3,040,815 newborns screened, 735 (2.86%) cases were diagnosed through gene sequence analysis. The most frequently occurring types of IMD were amino acid disorders (n = 276), then fatty acid oxidation disorders (n = 248), followed by organic acidaemias (n = 211). The difference in quality-adjusted life-years (QALYs) ranged from 0.78 to 15.4 in the screened group. The CUR was CNY¥ 116,183.89/QALY in the screened group and CNY¥ 3,078,823.65/QALY in the non-screened group. The ICUR was CNY¥ -768,428.76/QALY, and the BCR was 6.09. CONCLUSIONS: NBS using MS/MS can be considered cost-effective in China. The nationwide promotion of NBS using MS/MS deserves priority consideration and sufficient publicity.

Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants.

BACKGROUND: Cellular cobalamin defects are a locus and allelic heterogeneous disorder. The gold standard for coming to genetic diagnoses of cobalamin defects has for some time been gene-by-gene Sanger sequencing of individual DNA fragments. Enzymatic and cellular methods are employed before such sequencing to help in the selection of the gene defects to be sought, but this is time-consuming and laborious. Furthermore some cases remain undiagnosed because no biochemical methods have been available to test for cobalamin absorption and transport defects. RESULTS: This paper reports the use of massive parallel sequencing of DNA (exome analysis) for the accurate and rapid genetic diagnosis of cobalamin-related defects in a cohort of affected patients. The method was first validated in an initial cohort with different cobalamin defects. Mendelian segregation, the frequency of mutations, and the comprehensive structural and functional analysis of gene variants, identified disease-causing mutations in 12 genes involved in the absorption and synthesis of active cofactors of vitamin B12 (22 cases), and in the non-cobalamin metabolism-related genes ACSF3 (in four biochemically misdiagnosed patients) and SUCLA2 (in one patient with an unusual presentation). We have identified thirteen new variants all classified as pathogenic according to the ACGM recommendation but four were classified as variant likely pathogenic in MUT and SUCLA2. Functional and structural analysis provided evidences to classify them as pathogenic variants. CONCLUSIONS: The present findings suggest that the technology used is sufficiently sensitive and specific, and the results it provides sufficiently reproducible, to recommend its use as a second-tier test after the biochemical detection of cobalamin disorder markers in the first days of life. However, for accurate diagnoses to be made, biochemical and functional tests that allow comprehensive clinical phenotyping are also needed.

Renal involvement in lysinuric protein intolerance: contribution of pathology to assessment of heterogeneity of renal lesions.

Lysinuric protein intolerance (LPI) is a rare autosomal recessive disease caused by mutations in the SLC7A7 gene encoding the light subunit of a cationic amino acid transporter. Symptoms mimic primary urea cycle defects but dysimmune symptoms are also described. Renal involvement in LPI was first described in the 1980s. In 2007, it appeared that it could concern as much as 75% of LPI patients and could lead to end-stage renal disease. The most common feature is proximal tubular dysfunction and nephrocalcinosis but glomerular lesions are also reported. However, very little is known regarding histological lesions associated with LPI. We gathered every kidney biopsy of LPI-proven patients in our highly specialized pediatric and adult institution. Clinical, biological, and histological information was analyzed. Five LPI patients underwent kidney biopsy in our institution between 1986 and 2015. Clinically, 4/5 presented with proximal tubular dysfunction and 3/5 with nephrotic range proteinuria. Histology showed unspecific tubulointerstitial lesions and nephrocalcinosis in 3/5 biopsies and marked peritubular capillaritis in one child. Glomerular lesions were heterogeneous: lupus-like-full house membranoproliferative glomerulonephritis (MPGN) in one child evolved towards monotypic IgG1κ MPGN sensitive to immunomodulators. One patient presented with glomerular non-AA non-AL amyloidosis. Renal biopsy is particularly relevant in LPI presenting with glomerular symptoms for which variable histological lesions can be responsible, implying specific treatment and follow-up.

An Economic Evaluation of Neonatal Screening for Inborn Errors of Metabolism Using Tandem Mass Spectrometry in Thailand.

BACKGROUND: Inborn errors of metabolism (IEM) are a rare group of genetic diseases which can lead to several serious long-term complications in newborns. In order to address these issues as early as possible, a process called tandem mass spectrometry (MS/MS) can be used as it allows for rapid and simultaneous detection of the diseases. This analysis was performed to determine whether newborn screening by MS/MS is cost-effective in Thailand. METHOD: A cost-utility analysis comprising a decision-tree and Markov model was used to estimate the cost in Thai baht (THB) and health outcomes in life-years (LYs) and quality-adjusted life year (QALYs) presented as an incremental cost-effectiveness ratio (ICER). The results were also adjusted to international dollars (I$) using purchasing power parities (PPP) (1 I$ = 17.79 THB for the year 2013). The comparisons were between 1) an expanded neonatal screening programme using MS/MS screening for six prioritised diseases: phenylketonuria (PKU); isovaleric acidemia (IVA); methylmalonic acidemia (MMA); propionic acidemia (PA); maple syrup urine disease (MSUD); and multiple carboxylase deficiency (MCD); and 2) the current practice that is existing PKU screening. A comparison of the outcome and cost of treatment before and after clinical presentations were also analysed to illustrate the potential benefit of early treatment for affected children. A budget impact analysis was conducted to illustrate the cost of implementing the programme for 10 years. RESULTS: The ICER of neonatal screening using MS/MS amounted to 1,043,331 THB per QALY gained (58,647 I$ per QALY gained). The potential benefits of early detection compared with late detection yielded significant results for PKU, IVA, MSUD, and MCD patients. The budget impact analysis indicated that the implementation cost of the programme was expected at approximately 2,700 million THB (152 million I$) over 10 years. CONCLUSION: At the current ceiling threshold, neonatal screening using MS/MS in the Thai context is not cost-effective. However, the treatment of patients who were detected early for PKU, IVA, MSUD, and MCD, are considered favourable. The budget impact analysis suggests that the implementation of the programme will incur considerable expenses under limited resources. A long-term epidemiological study on the incidence of IEM in Thailand is strongly recommended to ascertain the magnitude of problem.

Delineating the spectrum of impairments, disabilities, and rehabilitation needs in methylmalonic acidemia (MMA).

Methylmalonic acidemia patients have complex rehabilitation needs that can be targeted to optimize societal independence and quality of life. Thirty-seven individuals with isolated MMA (28 mut, 5 cblA, 4 cblB), aged 2-33 years, were enrolled in a natural history study, and underwent age-appropriate clinical assessments to characterize impairments and disabilities. Neurological examination and brain imaging studies were used to document movement disorders and the presence of basal ganglia injury. A range of impairments and disabilities were identified by a team of physical medicine experts. Movement disorders, such as chorea and tremor, were common (n = 31, 83%), even among patients without evidence of basal ganglia injury. Joint hypermobility (n = 24, 69%) and pes planus (n = 22, 60%) were frequent and, in many cases, under-recognized. 23 (62%) patients required gastrostomy feedings. 18/31 patients >4 years old (58%) had difficulties with bathing and dressing. 16 of 23 school-aged patients received various forms of educational support. Five of the 10 adult patients were employed or in college; three lived independently. Unmet needs were identified in access to rehabilitation services, such as physical therapy (unavailable to 14/31), and orthotics (unavailable to 15/22). We conclude that patients with MMA are challenged by a number of functional limitations in essential activities of mobility, self-care, and learning, in great part caused by movement disorders and ligamentous laxity. Early assessment, referral, and implementation of age-appropriate rehabilitation services should significantly improve independence and quality of life.

Cost-effectiveness of liver transplantation in methylmalonic and propionic acidemias.

Propionic acidemia (PA) and classical methylmalonic acidemia (MMA) are rare inborn errors of metabolism that can cause early mortality and significant morbidity. The mainstay of disease management is lifelong protein restriction. As an alternative, liver transplantation (LT) may improve survival, quality of life, and prevent further neurological deterioration. The aim of our study was to estimate the incremental costs and outcomes of LT versus nutritional support in patients with early-onset MMA or PA. We constructed a Markov model to simulate and compare life expectancies, quality-adjusted life years (QALYs), and lifetime direct and indirect costs for a cohort of newborns with MMA or PA who could either receive LT or be maintained on conventional nutritional support. We conducted a series of 1-way and probabilistic sensitivity analyses. In the base case, LT on average resulted in 1.5 more life years lived, 7.9 more QALYs, and a savings of $582,369 for lifetime societal cost per individual compared to nutritional support. LT remained more effective and less costly in all 1-way sensitivity analyses. In the probabilistic sensitivity analysis, LT was cost-effective at the $100,000/QALY threshold in more than 90% of the simulations and cost-saving in over half of the simulations. LT is likely a dominant treatment strategy compared to nutritional support in newborns with classical MMA or PA.

Newborn screening by tandem mass spectrometry for glutaric aciduria type 1: a cost-effectiveness analysis.

BACKGROUND: Glutaric aciduria type I (GA-I) is a rare metabolic disorder caused by inherited deficiency of glutaryl-CoA dehydrogenase. Despite high prognostic relevance of early diagnosis and start of metabolic treatment as well as an additional cost saving potential later in life, only a limited number of countries recommend newborn screening for GA-I. So far only limited data is available enabling health care decision makers to evaluate whether investing into GA-I screening represents value for money. The aim of our study was therefore to assess the cost-effectiveness of newborn screening for GA-I by tandem mass spectrometry (MS/MS) compared to a scenario where GA-I is not included in the MS/MS screening panel. METHODS: We assessed the cost-effectiveness of newborn screening for GA-I against the alternative of not including GA-I in MS/MS screening. A Markov model was developed simulating the clinical course of screened and unscreened newborns within different time horizons of 20 and 70 years. Monte Carlo simulation based probabilistic sensitivity analysis was used to determine the probability of GA-I screening representing a cost-effective therapeutic strategy. RESULTS: Within a 20 year time horizon, GA-I screening averts approximately 3.7 DALYs (95% CI 2.9 - 4.5) and about one life year is gained (95% CI 0.7 - 1.4) per 100,000 neonates screened initially . Moreover, the screening programme saves a total of around 30,682 Euro (95% CI 14,343 to 49,176 Euro) per 100,000 screened neonates over a 20 year time horizon. CONCLUSION: Within the limitations of the present study, extending pre-existing MS/MS newborn screening programmes by GA-I represents a highly cost-effective diagnostic strategy when assessed under conditions comparable to the German health care system.

Impact of inborn errors of metabolism on admission in a neonatal intensive care unit--a prospective cohort study.

OBJECTIVE: To estimate the incidence of Inborn errors of metobolism (IEM) in Neonatal intensive care unit (NICU) using tandem mass spectrometry and to determine the impact that these disorders have on NICU resources. METHODS: During the period of study, 724 (81% eligible cases) dried blood filter-paper samples were collected from a NICU. The samples were analysed using tandem mass spectrometry. The diagnosis was further confirmed through clinical symptoms and by gas chromatography-mass spectrometry. The results were also confirmed by clinical follow-up of all positive patients in an overall interval of 1 year. The mean observation period was 11 months per neonate. RESULTS: In total, 22 cases were screen positive and 8 cases of inborn errors of metabolism were detected. The incidence of IEM in the population of patients admitted to the authors' NICU was 1.1%. The most common inborn error found was methylmalonic acidemia (3 cases, 37.5%), and all of the cases needed aggressive treatment and invasive mechanical ventilation. There were two cases of Tyrosinemia type 1, one case each of Maple Syrup Urine Disease, Propionic Acidemia, and Multiple Acyl-CoA dehydrogenase deficiency (MADD). Five of the eight patients required invasive mechanical ventilation. The median length of NICU stay was 3 days (1~7 days) and early therapeutic intervention was effective for four of them and other four patients (50%) died. CONCLUSIONS: The incidence of IEM in NICU was 1.1%, indicating an underestimation of the incidence of metabolic disorders prior to implementing screening. Most patients with IEM in the NICU required invasive mechanical ventilation and the mortality was increased due to underlying IEM.

Extended newborn screening: an update for the general paediatrician.

Extended newborn screening (ENBS) with the use of tandem mass spectrometry technology is well established in all Australian states and in New Zealand. ENBS has afforded a marked reduction in morbidity and mortality in select conditions such as medium-chain acyl-CoA dehydrogenase deficiency. While this technology has been of great benefit to newborn screening, it comes with many inherent and unforeseen challenges. In this review, we discuss the successes and challenges associated with ENBS.

Long-term needs of adult patients with organic acidaemias: outcome and prognostic factors.

BACKGROUND: With improvements in the treatment of children with organic acidaemias (OA), the number surviving to adulthood is increasing. To plan appropriate services for their care it is important to know what their needs are. OBJECTIVE: To describe the clinical and social problems affecting adult patients with OA. PATIENTS AND METHODS: We reviewed the medical records of 15 adult patients diagnosed with OA. Social attainment (housing, schooling and occupation) was analysed. Nutritional status was evaluated by body mass index (BMI) and laboratory studies. Neurological and visceral complications were noted. Cognitive outcome was evaluated by psychometric testing and/or educational attainment. RESULTS: Seven had methylmalonic acidaemia (MMA), 4 isovaleric acidaemia (IVA) and 4 propionic acidaemia (PA). Ten were female, and median age was 23.5 years (range 18-48). All but three had late-onset disease. Two patients became pregnant during follow up. Four patients had obtained university degrees and were working. Three-quarters of the patients required some kind of social support. All had a good nutritional status. Height was normal in IVA and 3 PA patients. Osteoporosis was present in 2 out of 8 patients assessed. A variety of neurocognitive or visceral complications were seen in two-thirds of the patients. Metabolic decompensations were unusual. CONCLUSIONS: The approach to adult patients with OA has to be multidisciplinary, with the clinician and dietician as the core of the team, but with the collaboration of clinical nurses specialists, social workers and other specialist services and the support of a biochemical and molecular laboratory.

Fractional anisotropy for assessment of white matter tracts injury in methylmalonic acidemia.

BACKGROUND: Methylmalonic acidemia (MMA) is a multifactorial autosomal recessive inborn error of organic acid metabolism, often presenting with neurological symptoms. As neurological disorders are often related to white matter injury, diffusion tensor imaging (DTI) is an excellent tool for assessment of white matter injury and possibly for diagnosing this disorder. METHODS: We retrospectively analyzed DTI images of 12 patients with MMA (7 males, 5 females, age range: 7 - 12 months, mean age: 9.25 +/- 1.70 months) with negative MRI findings. And another 12 age-matched and gender-matched infants were enrolled as control subjects. Fractional anisotropy (FA) of different white matter tracts of the brain was measured in both groups. RESULTS: For patients with negative MRI findings, compared with healthy infants, a statistically significant reduction in DTI FA value of the frontal white matter, temporal white matter, and occipital white matter was observed (P < 0.01). CONCLUSIONS: In addition to conventional T1W and T2W MR Image, Brain DTI presents a useful, sensitive and complementary tool for the assessment of brain damage in patients with MMA.

Assessment of mitochondrial respiratory chain function in hyperphenylalaninaemia.

Phenylketonuria (PKU) is an autosomal recessive disorder resulting in neurological and intellectual disability when untreated. However, even in treated patients there may be residual neurological impairment such as tremor. It has been suggested that the hyperphenylalaninaemia in patients with PKU reduces complex I (NADH:ubiquinone reductase) activity of the mitochondrial respiratory chain (MRC) and/or biosynthesis of coenzyme Q(10) (CoQ(10)), which acts as an electron carrier in the MRC, leading to impaired energy metabolism in the brain of patients with PKU and hence the neurological pathology. The aim of this study was to elucidate the mechanism of phenylalanine (Phe) toxicity on the MRC. We compared mean plasma and blood-spot Phe and mononuclear CoQ(10) levels in 17 patients with PKU and a tremor compared to 22 patients without tremor. Human 1321N1 astrocytoma cells were exposed to hyperphenylalaninaemia by the addition of 300 or 900 micromol/L of Phe to the cell culture medium. Following 96 h of culture we measured complex I and citrate synthase activities and CoQ(10) level. Results showed no significant difference in Phe or CoQ(10) levels in patients with tremor compared to those without tremor. Further, hyperphenylalaninaemia did not cause a significant reduction in complex I activity or CoQ(10) biosynthesis, even when taking into account the mitochondrial enrichment of the cell samples by expressing complex I and CoQ(10) as a ratio to citrate synthase. In conclusion, the results of this study suggest that hyperphenylalaninaemia does not contribute to the pathophysiology of PKU by causing a decrease in MRC complex I activity and/or CoQ(10) biosynthesis.

Essential fatty acid profiling for routine nutritional assessment unmasks adrenoleukodystrophy in an infant with isovaleric acidaemia.

We report a 16-month-old asymptomatic male with enzyme confirmed isovaleric acidaemia (IVA; isovaleryl-CoA dehydrogenase deficiency; OMIM 243500) who, upon routine nutritional follow-up, presented evidence of peroxisomal dysfunction. The newborn screen (2 days of life) revealed elevated C(5)-carnitine (2.95 µmol/L; cutoff <0.09 µmol/L) and IVA was subsequently confirmed by metabolic profiling and in vitro enzymology. Plasma essential fatty acid (EFA) analysis, assessed to evaluate nutritional status during protein restriction and L: -carnitine supplementation, revealed elevated C(26:0) (5.0 µmol/L; normal <1.3). Subsequently, metabolic profiling and molecular genetic analysis confirmed X-linked adrenoleukodystrophy (XALD). Identification of co-inherited XALD with IVA in this currently asymptomatic patient holds significant treatment ramifications for the proband prior to the onset of neurological sequelae, and critically important counselling implications for this family.

Newborn screening in North Carolina: the evolution of policy and practice.

Newborn screening policies in North Carolina are due to the efforts of skilled and knowledgeable state officials, clinicians, and scientists who are able to develop effective newborn screening procedures. A newborn screening that was developed in North Carolina is the first automated method for diagnosing phenylketonuria. This process was later adopted in many other states. The use of tandem mass spectrometry in newborn screening was also pioneered in North Carolina, and it is being used in an increasing number of states. Newborn screening is more than testing, however; follow-up and specialized care are essential. State-level policies should recognize the multiple links necessary to make newborn screening effective and efficient.

Energy expenditure in patients with propionic and methylmalonic acidaemias.

Resting energy expenditure (REE) was investigated in 8 children with propionic and methylmalonic acidaemias because a lowered REE has been reported in the literature. We observed a marginally elevated REE and think that adequate caloric intake and the use of a synthetic amino acid mixture are responsible for this.