Publications by authors named "Martina Huemer"

53 Publications

Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision.

J Inherit Metab Dis 2021 Feb 17. Epub 2021 Feb 17.

Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.

Isolated methylmalonic acidaemia (MMA) and propionic acidaemia (PA) are rare inherited metabolic diseases. Six years ago, a detailed evaluation of the available evidence on diagnosis and management of these disorders has been published for the first time. The article received considerable attention, illustrating the importance of an expert panel to evaluate and compile recommendations to guide rare disease patient care. Since that time, a growing body of evidence on transplant outcomes in MMA and PA patients and use of precursor free amino acid mixtures allows for updates of the guidelines. In this article, we aim to incorporate this newly published knowledge and provide a revised version of the guidelines. The analysis was performed by a panel of multidisciplinary health care experts, who followed an updated guideline development methodology (GRADE). Hence, the full body of evidence up until autumn 2019 was re-evaluated, analysed and graded. As a result, 21 updated recommendations were compiled in a more concise paper with a focus on the existing evidence to enable well-informed decisions in the context of MMA and PA patient care.
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http://dx.doi.org/10.1002/jimd.12370DOI Listing
February 2021

Co-therapy with S-adenosylmethionine and nicotinamide riboside improves t-cell survival and function in Arts Syndrome (PRPS1 deficiency).

Mol Genet Metab Rep 2021 Mar 20;26:100709. Epub 2021 Jan 20.

Department of Paediatrics, University Children's Hospital Basel and University of Basel, Basel, Switzerland.

Arts syndrome or phosphoribosyl-pyrophosphate-synthetase-1 (PRPS1) deficiency is caused by loss-of-function mutations in the gene (Xq22.3). PRPS1 is an initial and essential step for the synthesis of the nucleotides of purines, pyrimidines, and nicotinamide. Classically, affected males present with sensorineural hearing loss, optic atrophy, muscular hypotonia, developmental impairment, and recurrent severe respiratory infections early in life. Treatment of a 3-year old boy with S-adenosylmethionine (SAM) replenished erythrocyte purine nucleotides of adenosine and guanosine, while SAM and nicotinamide riboside co-therapy further improved his clinical phenotype as well as T-cell survival and function.
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http://dx.doi.org/10.1016/j.ymgmr.2021.100709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823043PMC
March 2021

Cystathionine β-synthase deficiency in the E-HOD registry-part I: pyridoxine responsiveness as a determinant of biochemical and clinical phenotype at diagnosis.

J Inherit Metab Dis 2020 Dec 9. Epub 2020 Dec 9.

Division of Metabolism and Children's Research Center, University Children's Hospital, Zurich, Switzerland.

Cystathionine β-synthase (CBS) deficiency has a wide clinical spectrum, ranging from neurodevelopmental problems, lens dislocation and marfanoid features in early childhood to adult onset disease with predominantly thromboembolic complications. We have analysed clinical and laboratory data at the time of diagnosis in 328 patients with CBS deficiency from the E-HOD (European network and registry for Homocystinurias and methylation Defects) registry. We developed comprehensive criteria to classify patients into four groups of pyridoxine responsivity: non-responders (NR), partial, full and extreme responders (PR, FR and ER, respectively). All groups showed overlapping concentrations of plasma total homocysteine while pyridoxine responsiveness inversely correlated with plasma/serum methionine concentrations. The FR and ER groups had a later age of onset and diagnosis and a longer diagnostic delay than NR and PR patients. Lens dislocation was common in all groups except ER but the age of dislocation increased with increasing responsiveness. Developmental delay was commonest in the NR group while no ER patient had cognitive impairment. Thromboembolism was the commonest presenting feature in ER patients, whereas it was least likely at presentation in the NR group. This probably is due to the differences in ages at presentation: all groups had a similar number of thromboembolic events per 1000 patient-years. Clinical severity of CBS deficiency depends on the degree of pyridoxine responsiveness. Therefore, a standardised pyridoxine-responsiveness test in newly diagnosed patients and a critical review of previous assessments is indispensable to ensure adequate therapy and to prevent or reduce long-term complications.
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http://dx.doi.org/10.1002/jimd.12338DOI Listing
December 2020

When to measure plasma homocysteine and how to place it in context: The homocystinurias.

Authors:
Martina Huemer

J Mother Child 2020 Oct 2;24(2):39-46. Epub 2020 Oct 2.

Division of Metabolism, Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland.

This review presents clinical patterns that should trigger homocysteine measurement in blood, as well as the further diagnostic work-up focused on inborn errors of metabolism and disorders of vitamin B12 (cobalamin) absorption and supply. The numerous conditions (e.g. cardiovascular disease, Alzheimer's disease) for which mild-to-moderate hyperhomocysteinaemia caused by genetic polymorphisms or acquired reasons is considered a risk factor are beyond the scope of this review.Homocysteine is a sulphur-containing amino acid, which is derived from the amino acid methionine. Homocysteine is either trans-sulphurated to form cystathionine and then cysteine, or re-methylated to methionine. The trans-sulphuration reaction depends on the enzyme cystathionine beta synthase and its cofactor vitamin B6. The re-methylation reaction not only involves the enzymes methionine synthase and methionine synthase reductase but also depends on the cofactor cobalamin and on the provision of methyl groups from the folate cycle. Because the homocysteine-methionine cycle provides for the vast majority of methyl groups in the body, it is central to numerous pathways that depend on methyl group supply, such as creatine synthesis or DNA methylation. Based on this premise, the severity of clinical presentations of inborn errors of metabolism, such as classical homocystinuria or the cobalamin C (cblC) defect, affecting this pathway is unsurprising.
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http://dx.doi.org/10.34763/jmotherandchild.20202402si.2016.000007DOI Listing
October 2020

Clinical and molecular characterization of adult patients with late-onset MTHFR deficiency.

J Inherit Metab Dis 2020 Oct 22. Epub 2020 Oct 22.

APHP, La Pitié-Salpêtrière University Hospital, Department of Genetics, Paris, France.

5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency usually presents as a severe neonatal disease. This study aimed to characterize natural history, biological and molecular data, and response to treatment of patients with late-onset MTHFR deficiency. The patients were identified through the European Network and Registry for Homocystinuria and Methylation Defects and the Adult group of the French Society for Inherited Metabolic Diseases; data were retrospectively colleted. To identify juvenile to adult-onset forms of the disease, we included patients with a diagnosis established after the age of 10 years. We included 14 patients (median age at diagnosis: 32 years; range: 11-54). At onset (median age: 20 years; range 9-38), they presented with walking difficulties (n = 8), cognitive decline (n = 3) and/or seizures (n = 3), sometimes associated with mild mental retardation (n = 6). During the disease course, symptoms were almost exclusively neurological with cognitive dysfunction (93%), gait disorders (86%), epilepsy (71%), psychiatric symptoms (57%), polyneuropathy (43%), and visual deficit (43%). Mean diagnostic delay was 14 years. Vascular events were observed in 28% and obesity in 36% of the patients. One patient remained asymptomatic at the age of 55 years. Upon treatment, median total homocysteine decreased (from 183 μmol/L, range 69-266, to 90 μmol/L, range 20-142) and symptoms improved (n = 9) or stabilized (n = 4). Missense pathogenic variants in the C-terminal regulatory domain of the protein were over-represented compared to early-onset cases. Residual MTHFR enzymatic activity in skin fibroblasts (n = 4) was rather high (17%-58%). This series of patients with late-onset MTHFR deficiency underlines the still unmet need of a prompt diagnosis of this treatable disease.
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http://dx.doi.org/10.1002/jimd.12323DOI Listing
October 2020

Elevated Homocysteine after Elevated Propionylcarnitine or Low Methionine in Newborn Screening Is Highly Predictive for Low Vitamin B12 and Holo-Transcobalamin Levels in Newborns.

Diagnostics (Basel) 2020 Aug 24;10(9). Epub 2020 Aug 24.

Austrian Newborn Screening, Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria.

Early diagnostics and treatment of vitamin B12 deficiency (B12D) in infants, mainly maternally conditioned, is crucial in preventing possible developmental delay and neurological deficits. Currently, B12D is rarely listed in regular newborn screening panels and mostly regarded as an incidental finding. The aim of this study was to evaluate a targeted newborn screening strategy for detection of suspected B12D. A decision strategy based on the primary parameters propionylcarnitine and methionine for selection of samples to be analyzed for total homocysteine by mass spectrometry was established. Therefore, 93,116 newborns were initially screened. Concentrations of vitamin B12 and holotranscobalamin in serum were obtained from clinical follow-up analyses of recalled newborns. Moreover, an extremely sensitive mass spectrometric method to quantify methylmalonic acid from the dried blood spots was developed. Overall, 0.15% of newborns were screened positive for suspected B12D, of which 64% had vitamin B12 concentrations below 148 pM. We also determined a cutoff value for methylmalonic acid in dried blood spots indicative for B12D in infants. Overall, we calculated a prevalence of 92/100,000 for suspected B12D in the Austrian newborns. In conclusion, we present a screening algorithm including second-tier measurement of total homocysteine that allows detection of low B12 serum concentrations with a high detection rate and low false-positive rate.
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http://dx.doi.org/10.3390/diagnostics10090626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555675PMC
August 2020

Health-related quality of life in paediatric patients with intoxication-type inborn errors of metabolism: Analysis of an international data set.

J Inherit Metab Dis 2021 Jan 22;44(1):215-225. Epub 2020 Sep 22.

Division of Metabolism, Children's Research Center, University Children's Hospital, Zurich, Switzerland.

Acute intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders and non-acute IT-IEM such as phenylketonuria have a major impact on paediatric patients' life. Patients have to adhere to a strict diet but may face neurocognitive impairment and - in acute diseases - metabolic decompensations nevertheless. Research on the subjective burden of IT-IEM remains sparse. Studies with appropriate sample sizes are needed to make valid statements about health-related quality of life (HrQoL) in children and adolescents with IT-IEM. Six international metabolic centres contributed self-reports and proxy reports of HrQoL (assessed with the Paediatric Quality of Life Inventory) to the final data set (n = 251 patients; age range 2.3-18.8 years). To compare HrQoL of the patient sample with norm data and between acute and non-acute IT-IEM, t tests were conducted. To examine the influence of child age, sex, diagnosis and current dietary treatment on HrQoL, multiple linear regression analyses were conducted. Self-reports and proxy reporst showed significantly lower HrQoL total scores for children with IT-IEM compared to healthy children. Current dietary treatment significantly predicted lower proxy reported total HrQoL. Children with non-acute IT-IEM reported significantly lower psychosocial health and emotional functioning than children with acute IT-IEM. The patient sample showed significantly impaired HrQoL and a diet regimen remains a risk factor for lower HrQoL. Differences in HrQoL between acute and non-acute IT-IEM subgroups indicate that factors beyond symptom severity determine the perception of disease burden. Identifying these factors is of crucial importance to develop and implement appropriate interventions for those in need.
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http://dx.doi.org/10.1002/jimd.12301DOI Listing
January 2021

Diagnosis and Care of Infants and Children with Pompe Disease.

Klin Padiatr 2020 Feb 18. Epub 2020 Feb 18.

Kinderklinik 1, Universitätsklinik Essen, Essen, Germany.

Pompe disease is a rare metabolic myopathy caused by deficiency of lysosomal α-glucosidase. Reduced enzyme activity results in abnormal intra- and extralysosomal glycogen deposition as well as impaired cellular function and autophagy. Age at manifestation and severity of disease depend on residual enzyme activity. Enzyme replacement therapy (ERT) is available since 2006. In infantile onset Pompe disease, the most severe form, markedly prolonged survival has resulted in a new phenotype with symptoms and problems not encountered previously. In addition, it became apparent that antibody formation against the recombinant human enzyme may adversely affect the response to ERT. This review summarizes new knowledge gained in the last years concerning care of pediatric patients with Pompe disease and gives recommendations for diagnostics, treatment, and follow-up.
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http://dx.doi.org/10.1055/a-1110-7335DOI Listing
February 2020

Early onset facioscapulohumeral muscular dystrophy - Long-term follow-up of a patient with total facial diplegia.

Neuromuscul Disord 2019 12 1;29(12):973-976. Epub 2019 Oct 1.

Institute for Human Genetics, University of Würzburg, Germany.

We report a patient with early onset facioscapulohumeral muscular dystrophy type 1 (FSHD1) who was not diagnosed until 48 years of age. She developed progressive facial diplegia from the age of 4-5 years followed by limb muscle weakness. Motor nerve conduction was normal, myopathic changes were seen electromyographically. Creatine kinase activity was mildly increased at the beginning. Muscle biopsy at 8 years suggested a neurogenic pattern, a second biopsy at age 30 was chronic myopathic with fibre calibre variation. The patient lost the ability to walk at age 44. When last seen she had total facial diplegia, no active movements in her limbs, mild kyphoscoliosis and a rigid thoracic spine. Molecular studies revealed a shortened D4Z4 fragment confirming the diagnosis FSHD1. Her family history was unremarkable, suggesting a de novo mutation. This report is to illustrate the evolving phenotype of early onset FSHD1 with predominating facial palsy.
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http://dx.doi.org/10.1016/j.nmd.2019.09.015DOI Listing
December 2019

Reducing complexity: explaining inborn errors of metabolism and their treatment to children and adolescents.

Orphanet J Rare Dis 2019 11 8;14(1):248. Epub 2019 Nov 8.

Division of Metabolism, University Children's Hospital Zurich, Zurich, Switzerland.

Background: Inborn errors of metabolism (IEM) are a group of rare, heterogeneous and complex genetic conditions. Clinically, IEM often affect the central nervous system and other organs. Some carry the risk of progression and / or potentially life-threatening crises. Many patients have to adhere to lifelong dietary or drug treatment. The complexity of IEM makes it difficult for patients and caregivers to understand their pathophysiology, inheritance and therapy rationale. Especially patients reaching adolescence may have only limited knowledge of their condition since medical care has often entirely been handled by their parents. Knowledge about disease and treatment, however, constitute pillars of self-responsible disease management. Not many standardized patient education materials on IEM are available and their comprehensibility has not been systematically investigated.

Methods: We developed and tested patient education materials for school-aged children and adolescents with IEM. Informative texts and illustrations in paper form and as videos were developed by an international network of metabolic care professionals together with a graphic artist and experts for easy-to-read language. The materials were presented in standardized single or group training sessions to 111 individuals; first, to 74 healthy children and adolescents (recruited via public schools) and consecutively to 37 paediatric patients with IEM (phenylketonuria, galactosemia, urea cycle defects, lysosomal storage disorders) from six metabolic centres. Knowledge-gain was assessed by pre- and post-testing.

Results: Knowledge-gain was significant in healthy children and adolescents as well as in patients (p < .001, r =. -77 /. -70). Effect sizes were large in both groups (r = -.77 / -.70). This result was independent from family language and teacher-rated concentration or cognitive capacity in healthy children.

Conclusion: The newly developed patient education materials are a powerful tool to improve disease- and treatment-related knowledge. They facilitate communication between the medical team and children and adolescents with IEM and their caregivers.
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http://dx.doi.org/10.1186/s13023-019-1236-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842257PMC
November 2019

Extent, impact, and predictors of diagnostic delay in Pompe disease: A combined survey approach to unveil the diagnostic odyssey.

JIMD Rep 2019 Sep 17;49(1):89-95. Epub 2019 Jul 17.

Division of Metabolism and Children's Research Centre University Children's Hospital Zurich Switzerland.

Background: Early diagnosis is of substantial benefit for patients with Pompe disease. Yet underdiagnosing and substantial diagnostic delay are still frequent and the determinants of this are unknown. This study is the first to systematically investigate the diagnostic odyssey in Pompe disease from patients', parents', and physicians' perspectives.

Methods: Patients with infantile or late onset Pompe disease, their parents as well as their metabolic experts were invited to fill in respective surveys. The survey addressed perceived disease symptoms at onset and during the course of the disease, specialties of involved physicians, activities of patient-initiated search for diagnosis and the perceived impact of time to diagnosis on outcome. Results of experts' and patients'/parents' surveys were compared and expressed by descriptive statistics.

Results And Discussion: We collected data on 15 males and 17 females including 9 infantile and 23 late onset Pompe patients. All received the correct diagnosis at a metabolic or musculoskeletal expert center. Patients with direct referral to the expert center had the lowest diagnostic delay, while patients who were seen by several physicians, received the correct diagnosis after 44%-200% longer delay. The proportion of direct referral varied strongly between pediatricians (57%) and other disciplines (18%-36%).

Conclusion: Our study highlights a substantially larger diagnostic delay in Pompe patients that are not directly referred to expert centers for diagnostic work. Our findings may be used to develop more successful strategies for early diagnosis.

Synopsis: Diagnostic delay in Pompe disease is substantial particularly in patients that are not directly referred to expert centers for diagnostic workup, so facilitating direct referral may be a new strategy for early diagnosis.
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http://dx.doi.org/10.1002/jmd2.12062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718115PMC
September 2019

Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision.

J Inherit Metab Dis 2019 11 15;42(6):1192-1230. Epub 2019 May 15.

Division of Metabolism, Bambino Gesù Children's Hospital, Rome, Italy.

In 2012, we published guidelines summarizing and evaluating late 2011 evidence for diagnosis and therapy of urea cycle disorders (UCDs). With 1:35 000 estimated incidence, UCDs cause hyperammonemia of neonatal (~50%) or late onset that can lead to intellectual disability or death, even while effective therapies do exist. In the 7 years that have elapsed since the first guideline was published, abundant novel information has accumulated, experience on newborn screening for some UCDs has widened, a novel hyperammonemia-causing genetic disorder has been reported, glycerol phenylbutyrate has been introduced as a treatment, and novel promising therapeutic avenues (including gene therapy) have been opened. Several factors including the impact of the first edition of these guidelines (frequently read and quoted) may have increased awareness among health professionals and patient families. However, under-recognition and delayed diagnosis of UCDs still appear widespread. It was therefore necessary to revise the original guidelines to ensure an up-to-date frame of reference for professionals and patients as well as for awareness campaigns. This was accomplished by keeping the original spirit of providing a trans-European consensus based on robust evidence (scored with GRADE methodology), involving professionals on UCDs from nine countries in preparing this consensus. We believe this revised guideline, which has been reviewed by several societies that are involved in the management of UCDs, will have a positive impact on the outcomes of patients by establishing common standards, and spreading and harmonizing good practices. It may also promote the identification of knowledge voids to be filled by future research.
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http://dx.doi.org/10.1002/jimd.12100DOI Listing
November 2019

-Related Mitochondrial DNA Depletion Syndrome 13 (MTDPS13): A Case Report With a Comprehensive Mutation Review.

Front Genet 2019 5;10:39. Epub 2019 Feb 5.

Division of Pediatric Neurology, Department of Pediatrics, American University of Beirut Medical Center, Beirut, Lebanon.

Mitochondrial DNA depletion syndromes (MTDPS) are a group of rare genetic disorders caused by defects in multiple genes involved in mitochondrial DNA (mtDNA) maintenance. Among those, mutations result in the encephalomyopathic mtDNA depletion syndrome 13 (MTDPS13; OMIM #615471), which commonly presents as a combination of failure to thrive, neurodevelopmental delays, encephalopathy, hypotonia, and persistent lactic acidosis. We report here the case of a Lebanese infant presenting to us with profound neurodevelopmental delays, generalized hypotonia, facial dysmorphic features, and extreme emaciation. Whole-exome sequencing (WES) showed the girl as having MTDPS13 with an underlying missense mutation that has been previously reported only twice in unrelated individuals (c.1303C > T). Comprehensive literature search marked our patient as being the 94th case of MTDPS13 reported to date worldwide, and the first from Lebanon. We include at the end of this report a comprehensive mutation review table of all the pathological mutations reported in the literature, using it to highlight, for the first time, a possible founder effect of Arab origins to the disorder, being most prevalent in patients of Arab descent as shown in our mutation table. Finally, we provide a direct comparison of the disorder's clinical manifestations across two unrelated patients harboring the same disease-causing mutation as our patient, emphasizing the remarkable variability in genotype-to-phenotype correlation characteristic of the disease.
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http://dx.doi.org/10.3389/fgene.2019.00039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370620PMC
February 2019

Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry.

J Inherit Metab Dis 2019 03 17;42(2):333-352. Epub 2019 Feb 17.

Hospital Infantil Miguel Servet, Zaragoza, Spain.

Aim: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry.

Results: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities.

Conclusion: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.
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http://dx.doi.org/10.1002/jimd.12041DOI Listing
March 2019

The clinical presentation of cobalamin-related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways.

J Inherit Metab Dis 2019 07 13;42(4):686-705. Epub 2019 Feb 13.

Division of Metabolism and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland.

This review gives an overview of clinical characteristics, treatment and outcome of nutritional and acquired cobalamin (Cbl; synonym: vitamin B12) deficiencies, inborn errors of Cbl absorption and intracellular trafficking, as well as methylenetetrahydrofolate dehydrogenase (MTHFD1) and methylene tetrahydrofolate reductase (MTHFR) deficiencies, which impair Cbl-dependent remethylation. Acquired and inborn Cbl-related disorders and MTHFR deficiency cause multisystem, often severe disease. Failure to thrive, neurocognitive or psychiatric symptoms, eye disease, bone marrow alterations, microangiopathy and thromboembolic events are characteristic. The recently identified MTHFD1 defect additionally presents with severe immune deficiency. Deficient Cbl-dependent enzymes cause reduced methylation capacity and metabolite toxicity. Further net-effects of perturbed Cbl function or reduced Cbl supply causing oxidative stress, altered cytokine regulation or immune functions are discussed.
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http://dx.doi.org/10.1002/jimd.12012DOI Listing
July 2019

Newborn screening for homocystinurias: Recent recommendations versus current practice.

J Inherit Metab Dis 2019 01;42(1):128-139

Unidad de Metabolismo, Hospital Infantil Miguel Servet, Zaragoza, Spain.

Purpose: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations.

Methods: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres.

Results: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns.

Conclusions: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.
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http://dx.doi.org/10.1002/jimd.12034DOI Listing
January 2019

A variant in MRPS14 (uS14m) causes perinatal hypertrophic cardiomyopathy with neonatal lactic acidosis, growth retardation, dysmorphic features and neurological involvement.

Hum Mol Genet 2019 02;28(4):639-649

Division of Human Genetics, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern CH, Switzerland.

Dysfunction of mitochondrial translation is an increasingly important molecular cause of human disease, but structural defects of mitochondrial ribosomal subunits are rare. We used next-generation sequencing to identify a homozygous variant in the mitochondrial small ribosomal protein 14 (MRPS14, uS14m) in a patient manifesting with perinatal hypertrophic cardiomyopathy, growth retardation, muscle hypotonia, elevated lactate, dysmorphy and mental retardation. In skeletal muscle and fibroblasts from the patient, there was biochemical deficiency in complex IV of the respiratory chain. In fibroblasts, mitochondrial translation was impaired, and ectopic expression of a wild-type MRPS14 cDNA functionally complemented this defect. Surprisingly, the mutant uS14m was stable and did not affect assembly of the small ribosomal subunit. Instead, structural modeling of the uS14m mutation predicted a disruption to the ribosomal mRNA channel.Collectively, our data demonstrate pathogenic mutations in MRPS14 can manifest as a perinatal-onset mitochondrial hypertrophic cardiomyopathy with a novel molecular pathogenic mechanism that impairs the function of mitochondrial ribosomes during translation elongation or mitochondrial mRNA recruitment rather than assembly.
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http://dx.doi.org/10.1093/hmg/ddy374DOI Listing
February 2019

The impact of ammonia levels and dialysis on outcome in 202 patients with neonatal onset urea cycle disorders.

J Inherit Metab Dis 2018 07 8;41(4):689-698. Epub 2018 Mar 8.

Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, 8032, Zurich, Switzerland.

Neonatal onset hyperammonemia in patients with urea cycle disorders (UCDs) is still associated with high morbidity and mortality. Current protocols consistently recommend emergency medical and dietary management. In case of increasing or persistent hyperammonemia, with continuous or progressive neurological signs, dialysis is performed, mostly as ultima ratio. It is presently unknown whether the currently defined ammonia threshold (e.g., at 500 μmol/L) to start dialysis is useful to improve clinical outcome. A systematic review of clinical and biochemical data from published neonatal onset UCD patients was performed to identify factors determining clinical outcome and to investigate in which clinical and biochemical setting dialysis was most effective. A total of 202 patients (118 proximal and 84 distal UCDs) described in 90 case reports or case series were included according to predefined inclusion/exclusion criteria. Median age at onset was three days and mean ammonia that triggered start of dialysis was 1199 μmol/L. Seventy-one percent of all patients received any form of dialysis. Total mortality was 25% and only 20% of all patients had a "normal" outcome. In general, patients with higher ammonia levels were more likely to receive dialysis, but this had for most patients no influence on outcome. In conclusion, in severe neonatal onset hyperammonemia, the current practice of dialysis, which effectively clears ammonia, had no impact on outcome. It may be essential for improving outcome to initiate all available treatment options, including dialysis, as early as possible.
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http://dx.doi.org/10.1007/s10545-018-0157-4DOI Listing
July 2018

Development and Psychometric Evaluation of the MetabQoL 1.0: A Quality of Life Questionnaire for Paediatric Patients with Intoxication-Type Inborn Errors of Metabolism.

JIMD Rep 2017 1;37:27-35. Epub 2017 Mar 1.

Division of Metabolism, Children's Research Center, University Children's Hospital, Zurich, Switzerland.

Introduction: This study is part of the "European network and registry for intoxication type metabolic diseases" (E-IMD) project. Intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders (UCD) and organic acidurias (OA) have a major impact on patients' lives. Patients have to adhere to strict diet and medication and may suffer from metabolic crises and neurocognitive impairment. Disease-specific health-related quality of life (HrQoL) assessment questionnaires are the method of choice to estimate the subjective burden of a disease. To date, no such instrument is available for IT-IEM.

Methods: Disease-specific patient- and parent-reported HrQoL questions were constructed in German based on focus group interviews with patients and parents. Questionnaires for patients from 8 to 18 years were piloted with 14 participants (n = 9 children and adolescents, n = 5 parents) by cognitive debriefing and tested psychometrically with 80 participants (n = 38 patients, n = 42 parents) for item characteristics, validity, and reliability to construct the first version of a disease-specific HrQoL questionnaire.

Results: Twenty-eight questions were selected based on item descriptives. Scales of self- and proxy questionnaires demonstrated acceptable to excellent reliability in terms of internal consistency (Cronbach's α = 0.70-0.93). Scales and total scores correlated with those of generic HrQoL questionnaires, showing convergent validity.

Discussion: The MetabQoL 1.0 questionnaire exhibits sound psychometric properties and is a promising step towards assessing patient-reported outcomes in research and clinical practice. It provides a solid basis for translation into other languages and further elaboration and psychometric exploration in larger populations.
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http://dx.doi.org/10.1007/8904_2017_11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740049PMC
March 2017

Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency.

J Inherit Metab Dis 2017 01 30;40(1):21-48. Epub 2016 Nov 30.

Division of Metabolism, Bambino Gesù Children's Research Hospital, Rome, Italy.

Background: Remethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions.

Objective: To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management.

Data Sources: Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach.

Key Recommendations: We strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early.
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http://dx.doi.org/10.1007/s10545-016-9991-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203859PMC
January 2017

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

J Inherit Metab Dis 2017 01 24;40(1):49-74. Epub 2016 Oct 24.

Division of Genetic and Metabolism, Children's National Health System, Washington, DC, USA.

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.
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http://dx.doi.org/10.1007/s10545-016-9979-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203861PMC
January 2017

Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency.

J Inherit Metab Dis 2016 05 1;39(3):331-340. Epub 2016 Apr 1.

Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria.

Background: Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD). This hypothesis-generating study explored clinical phenotypes, metabolic profiles, molecular genetics, and treatment approaches in a cohort of children and adults with ARG1 deficiency to add to our understanding of the underlying pathophysiology.

Methods: Clinical data were retrieved retrospectively from physicians using a questionnaire survey. Plasma aminoacids, guanidinoacetate (GAA), parameters indicating oxidative stress and nitric oxide (NO) synthesis as well as asymmetric dimethylarginine (ADMA) were measured at a single study site.

Results: Nineteen individuals with ARG1 deficiency and 19 matched controls were included in the study. In patients, paraparesis, cognitive impairment, and seizures were significantly associated suggesting a shared underlying pathophysiology. In patients plasma GAA exceeded normal ranges and plasma ADMA was significantly elevated. Compared to controls, nitrate was significantly higher, and the nitrite:nitrate ratio significantly lower in subjects with ARG1 deficiency suggesting an advantage for NO synthesis by inducible NO synthase (iNOS) over endothelial NOS (eNOS). Logistic regression revealed no significant impact of any of the biochemical parameters (including arginine, nitrates, ADMA, GAA, oxidative stress) or protein restriction on long-term outcome.

Conclusion: Three main hypotheses which must be evaluated in a hypothesis driven confirmatory study are delineated from this study: 1) clinical manifestations in ARG1 deficiency are not correlated with arginine, protein intake, ADMA, nitrates or oxidative stress. 2) GAA is elevated and may be a marker or an active part of the pathophysiology of ARG1 deficiency. 3) Perturbations of NO metabolism merit future attention in ARG1 deficiency.
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http://dx.doi.org/10.1007/s10545-016-9928-yDOI Listing
May 2016

Successful intrauterine treatment of a patient with cobalamin C defect.

Mol Genet Metab Rep 2016 Mar 4;6:55-9. Epub 2016 Feb 4.

University Children's Hospital Zürich, Switzerland.

Cobalamin C (cblC) defect is an inherited autosomal recessive disorder that affects cobalamin metabolism. Patients are treated with hydroxycobalamin to ameliorate the clinical features of early-onset disease and prevent clinical symptoms in late-onset disease. Here we describe a patient in whom prenatal maternal treatment with 30 mg/week hydroxycobalamin and 5 mg/day folic acid from week 15 of pregnancy prevented disease manifestation in a girl who is now 11 years old with normal IQ and only mild ophthalmic findings. The affected older sister received postnatal treatment only and is severely intellectually disabled with severe ophthalmic symptoms. This case highlights the potential of early, high-dose intrauterine treatment in a fetus affected by the cblC defect.
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http://dx.doi.org/10.1016/j.ymgmr.2016.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789385PMC
March 2016

Living with Intoxication-Type Inborn Errors of Metabolism: A Qualitative Analysis of Interviews with Paediatric Patients and Their Parents.

JIMD Rep 2017 13;31:1-9. Epub 2016 Aug 13.

Division of Metabolism and Children's Research Center, University Children's Hospital, Steinwiesstrasse 75, 8032, Zurich, Switzerland.

Introduction: Progress in diagnosis and treatment of patients with intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders, organic acidurias or maple syrup urine disease is resulting in a growing number of long-term survivors. Consequently, health-related quality of life (HrQoL) of patients is increasingly regarded as a meaningful outcome parameter. To develop the first validated, disease-specific HrQoL questionnaire for IT-IEM, patients and parents were interviewed as content experts to identify major physical and psychosocial constraints and resources.

Methods: Focus group interviews with 19 paediatric IT-IEM patients and 26 parents were conducted in four metabolic centres in Austria, Germany and Switzerland. Disease-specific HrQoL categories were established by qualitative content analysis.

Results: Fourteen disease-specific topics related to the three well-established generic HrQoL dimensions of physical, mental and social functioning were derived from the interview transcripts. Both patients and parents perceived dietary restrictions and social stigmatisation as major burdens. Dietary restrictions and emotional burdens were more important for young (<8 years) patients, whereas cognition, fatigue and social issues were more relevant to older patients (≥8 years). Treatment-related topics had a significant effect on social and emotional HrQoL.

Discussion: By exploring patients' and parents' perspectives, 14 HrQoL categories were identified. These new categories will allow the development of a disease-specific, standardised questionnaire to assess HrQoL in paediatric IT-IEM patients. Age-appropriate information on the disease and psychosocial support targeted to patients' individual burdens are essential to the delivery of personalised care that takes account of physical, mental and social dimensions of HrQoL.
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http://dx.doi.org/10.1007/8904_2016_545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388637PMC
August 2016

Mutation Update and Review of Severe Methylenetetrahydrofolate Reductase Deficiency.

Hum Mutat 2016 May 18;37(5):427-38. Epub 2016 Mar 18.

Division of Metabolism and Children's Research Center, University Children's Hospital, Zürich, CH-8032, Switzerland.

Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is caused by mutations in the MTHFR gene and results in hyperhomocysteinemia and varying severity of disease, ranging from neonatal lethal to adult onset. Including those described here, 109 MTHFR mutations have been reported in 171 families, consisting of 70 missense mutations, 17 that primarily affect splicing, 11 nonsense mutations, seven small deletions, two no-stop mutations, one small duplication, and one large duplication. Only 36% of mutations recur in unrelated families, indicating that most are "private." The most common mutation is c.1530A>G (numbered from NM_005957.4, p.Lys510 = ) causing a splicing defect, found in 13 families; the most common missense mutation is c.1129C>T (p.Arg377Cys) identified in 10 families. To increase disease understanding, we report enzymatic activity, detected mutations, and clinical onset information (early, <1 year; or late, >1 year) for all published patients available, demonstrating that patients with early onset have less residual enzyme activity than those presenting later. We also review animal models, diagnostic approaches, clinical presentations, and treatment options. This is the first large review of mutations in MTHFR, highlighting the wide spectrum of disease-causing mutations.
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http://dx.doi.org/10.1002/humu.22970DOI Listing
May 2016

Atypical Clinical Presentations of TAZ Mutations: An Underdiagnosed Cause of Growth Retardation?

JIMD Rep 2016 3;29:89-93. Epub 2016 Jan 3.

Department of Paediatrics, Nijmegen Center for Mitochondrial Disorders, Radboud UMC, Nijmegen, The Netherlands.

Barth syndrome is known as a highly recognizable X-linked disorder typically presenting with the three hallmarks: (left ventricular non-compaction) cardiomyopathy, neutropenia, and 3-methylglutaconic aciduria. Furthermore, growth retardation, mild skeletal myopathy, and specific facial features as well as mitochondrial dysfunction in muscle are frequently seen. Underlying mutations are found in TAZ and lead to defective cardiolipin remodeling.Here, we report atypical clinical manifestations of TAZ mutations in two male patients initially presenting with growth retardation and very mild skeletal myopathy. As other phenotypic hallmarks were missing, Barth syndrome had not been suspected in these patients. One of them has been incidentally diagnosed in the frame of an in-depth cardiolipin research analysis, while the underlying genetic defect was unexpectedly identified in the second one by exome sequencing.

Conclusion: These cases underline that TAZ mutations might well be an underdiagnosed cause of skeletal myopathy and growth retardation and do not necessarily manifest with the full clinical picture of Barth syndrome.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059176PMC
http://dx.doi.org/10.1007/8904_2015_525DOI Listing
January 2016

Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency.

J Inherit Metab Dis 2016 Jan 30;39(1):115-24. Epub 2015 May 30.

Laboratori de Malalties Metabòliques Hereditàrias, Hospital Sant Joan de Déu, Barcelona, Spain.

Background: Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn defect disturbing the remethylation of homocysteine to methionine (<200 reported cases). This retrospective study evaluates clinical, biochemical genetic and in vitro enzymatic data in a cohort of 33 patients.

Methods: Clinical, biochemical and treatment data was obtained from physicians by using a questionnaire. MTHFR activity was measured in primary fibroblasts; genomic DNA was extracted from cultured fibroblasts.

Results: Thirty-three patients (mean age at follow-up 11.4 years; four deceased; median age at first presentation 5 weeks; 17 females) were included. Patients with very low (<1.5%) mean control values of enzyme activity (n = 14) presented earlier and with a pattern of feeding problems, encephalopathy, muscular hypotonia, neurocognitive impairment, apnoea, hydrocephalus, microcephaly and epilepsy. Patients with higher (>1.7-34.8%) residual enzyme activity had mainly psychiatric symptoms, mental retardation, myelopathy, ataxia and spasticity. Treatment with various combinations of betaine, methionine, folate and cobalamin improved the biochemical and clinical phenotype. During the disease course, patients with very low enzyme activity showed a progression of feeding problems, neurological symptoms, mental retardation, and psychiatric disease while in patients with higher residual enzyme activity, myelopathy, ataxia and spasticity increased. All other symptoms remained stable or improved in both groups upon treatment as did brain imaging in some cases. No clear genotype-phenotype correlation was obvious.

Discussion: MTHFR deficiency is a severe disease primarily affecting the central nervous system. Age at presentation and clinical pattern are correlated with residual enzyme activity. Treatment alleviates biochemical abnormalities and clinical symptoms partially.
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http://dx.doi.org/10.1007/s10545-015-9860-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551224PMC
January 2016

Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations.

J Inherit Metab Dis 2015 Sep 14;38(5):905-14. Epub 2015 Apr 14.

Department of Pediatrics, Landeskrankenhaus Bregenz, Carl-Pedenz-Str. 2, 6900, Bregenz, Austria,

FBXL4 deficiency is a recently described disorder of mitochondrial maintenance associated with a loss of mitochondrial DNA in cells. To date, the genetic diagnosis of FBXL4 deficiency has been established in 28 individuals. This paper retrospectively reviews proxy-reported clinical and biochemical findings and evaluates brain imaging, morphological and genetic data in 21 of those patients. Neonatal/early-onset severe lactic acidosis, muscular hypotonia, feeding problems and failure to thrive is the characteristic pattern at first presentation. Facial dysmorphic features are present in 67% of cases. Seven children died (mean age 37 months); 11 children were alive (mean age at follow-up 46 months), three children were lost to follow-up. All survivors developed severe psychomotor retardation. Brain imaging was non-specific in neonates but a later-onset, rapidly progressive brain atrophy was noted. Elevated blood lactate and metabolic acidosis were observed in all individuals; creatine kinase was elevated in 45% of measurements. Diagnostic workup in patient tissues and cells revealed a severe combined respiratory chain defect with a general decrease of enzymes associated with mitochondrial energy metabolism and a relative depletion of mitochondrial DNA content. Mutations were detected throughout the FBXL4 gene albeit with no clear delineation of a genotype-phenotype correlation. Treatment with "mitochondrial medications" did not prove effective. In conclusion, a clinical pattern of early-onset encephalopathy, persistent lactic acidosis, profound muscular hypotonia and typical facial dysmorphism should prompt initiation of molecular genetic analysis of FBXL4. Establishment of the diagnosis permits genetic counselling, prevents patients undergoing unhelpful diagnostic procedures and allows for accurate prognosis.
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http://dx.doi.org/10.1007/s10545-015-9836-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841446PMC
September 2015

Newborn screening for homocystinurias and methylation disorders: systematic review and proposed guidelines.

J Inherit Metab Dis 2015 Nov 12;38(6):1007-19. Epub 2015 Mar 12.

Laboratory Clinical Biochemistry and Metabolism, Center for Pediatrics and Adolescent Medicine University Hospital, Freiburg, Freiburg, Germany.

Newborn screening (NBS) is justified if early intervention is effective in a disorder generally not detected early in life on a clinical basis, and if sensitive and specific biochemical markers exist. Experience with NBS for homocystinurias and methylation disorders is limited. However, there is robust evidence for the success of early treatment with diet, betaine and/or pyridoxine for CBS deficiency and good evidence for the success of early betaine treatment in severe MTHFR deficiency. These conditions can be screened in dried blood spots by determining methionine (Met), methionine-to-phenylanine (Met/Phe) ratio, and total homocysteine (tHcy) as a second tier marker. Therefore, we recommend NBS for cystathionine beta-synthase and severe MTHFR deficiency. Weaker evidence is available for the disorders of intracellular cobalamin metabolism. Early treatment is clearly of advantage for patients with the late-onset cblC defect. In the early-onset type, survival and non-neurological symptoms improve but the effect on neurocognitive development is uncertain. The cblC defect can be screened by measuring propionylcarnitine, propionylcarnitine-to-acetylcarnitine ratio combined with the second tier markers methylmalonic acid and tHcy. For the cblE and cblG defects, evidence for the benefit of early treatment is weaker; and data on performance of Met, Met/Phe and tHcy even more limited. Individuals homozygous or compound heterozygous for MAT1A mutations may benefit from detection by NBS using Met, which on the other hand also detects asymptomatic heterozygotes. Clinical and laboratory data is insufficient to develop any recommendation on NBS for the cblD, cblF, cblJ defects, glycineN-methyltransferase-, S-adenosylhomocysteinehydrolase- and adenosine kinase deficiency.
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http://dx.doi.org/10.1007/s10545-015-9830-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626539PMC
November 2015

Evaluation of Implementation, Adaptation and Use of the Recently Proposed Urea Cycle Disorders Guidelines.

JIMD Rep 2015 18;21:65-70. Epub 2015 Feb 18.

Division of Metabolism, University Children's Hospital Zurich, 8032, Zürich, Switzerland,

Background: Implementation of guidelines and assessment of their adaptation is not an extensively investigated process in the field of rare diseases. However, whether targeted recipients are reached and willing and able to follow the recommendations has significant impact on the efficacy of guidelines. In 2012, a guideline for the management of urea cycle disorders (UCDs) has been published. We evaluate the efficacy of implementation, adaptation, and use of the UCD guidelines by applying different strategies.

Methods: (i) Download statistics from online sources were recorded. (ii) Facilities relevant for the implementation of the guidelines were assessed in pediatric units in Germany and Austria. (iii) The guidelines were evaluated by targeted recipients using the AGREE instrument. (iv) A regional networking-based implementation process was evaluated.

Results: (i) Download statistics revealed high access with an increase in downloads over time. (ii) In 18% of hospitals ammonia testing was not available 24/7, and emergency drugs were often not available. (iii) Recipient criticism expressed in the AGREE instrument focused on incomplete inclusion of patients' perspectives. (iv) The implementation process improved the availability of ammonia measurements and access to emergency medication, patient care processes, and cooperation between nonspecialists and specialists.

Conclusion: Interest in the UCD guidelines is high and sustained, but more precise targeting of the guidelines is advisable. Surprisingly, many hospitals do not possess all facilities necessary to apply the guidelines. Regional network and awareness campaigns result in the improvement of both facilities and knowledge.
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http://dx.doi.org/10.1007/8904_2014_387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470941PMC
June 2015