Investigacines (CSUR/MetabERN)

Betaine anhydrous in homocystinuria: results from the RoCH registry
Vassili Valayannopoulos1,2* , Manuel Schiff3, Nathalie Guffon4, Yann Nadjar5, Angels García-Cazorla6, Mercedes Martinez-Pardo Casanova7, Aline Cano8, Maria L. Couce9, Jaime Dalmau10, Luis Peña-Quintana11, Vincent Rigalleau12, Guy Touati13, Luis Aldamiz-Echevarria14, Pascal Cathebras15, Didier Eyer16, Dominique Brunet17, Léna Damaj18, Dries Dobbelaere19, Claire Gay15, Sylvie Hiéronimus20, Virginie Levrat21 and François Maillot22

Background: The Registry of Adult and Paediatric Patients Treated with Cystadane® – Homocystinuria (RoCH) is a non-interventional, observational, multi-centre, post-authorization safety study that aimed to identify safety of betaine anhydrous (Cystadane®) in the treatment of patients with inborn errors of homocysteine metabolism (homocystinuria) in order to minimise the treatment associated risks and establish better knowledge on its clinical use. The registry included patients of all ages with homocystinuria who were treated with betaine anhydrous in conjunction with other therapies. Clinical data were collected retrospectively from 2007 to 2013, then prospectively up to February 2014. All adverse events (AEs) reported during the study were recorded. The clinical and biological status of patients was monitored at least once a year.

Results: A total of 125 patients with homocystinuria (adults [> 18 years]: 50; paediatric [≤18 years]: 75) were enrolled at 29 centres in France and Spain. Patients were treated with betaine anhydrous for a mean duration of 7.4 ± 4.3 years. The median total daily dose of betaine anhydrous at the first and last study visits was 6 g/day for cystathionine β-synthase (CBS)-deficient vitamin B6 responders and 9 g/day for methylenetetrahydrofolate reductase deficient patients, while the median daily dose increased in CBS-deficient B6 non-responders (from 6 to 9 g/day) and cobalamin metabolism-defective patients (from 3 to 6 g/day) between the first and last visits. Treatment caused a mean overall reduction of 29% in plasma homocysteine levels in the study population. A total of 277 AEs were reported during the study, of which two non-serious AEs (bad taste and headache) and one serious AE (interstitial lung disease) were considered to be drug related. Overall, betaine anhydrous was well tolerated with no major safety concerns.

Conclusions: Data from the RoCH registry provided real-world evidence on the clinical safety and efficacy of betaine anhydrous in the management of homocystinuria in paediatric and adult patients. Keywords: Betaine anhydrous, Efficacy, Homocystinuria, RoCH registry, Safety

Valayannopoulos et al. Orphanet Journal of Rare Diseases (2019) 14:66

The natural history of classic galactosemia: lessons from the GalNet registry

M. E. Rubio-Gozalbo1* , M. Haskovic1, A. M. Bosch2, B. Burnyte3, A. I. Coelho1, D. Cassiman4, M. L. Couce5, C. Dawson6, D. Demirbas7, T. Derks8, F. Eyskens9, M. T. Forga10, S. Grunewald11, J. Häberle12, M. Hochuli13, A. Hubert14,15, H. H. Huidekoper16, P. Janeiro17, J. Kotzka18, I. Knerr19, P. Labrune14,15, Y. E. Landau20, J. G. Langendonk21, D. Möslinger22, D. Müller-Wieland23, E. Murphy24, K. Õunap25, D. Ramadza26, I. A. Rivera27, S. Scholl-Buergi28, K. M. Stepien29, A. Thijs30, C. Tran31, R. Vara32, G. Visser33, R. Vos34, M. de Vries35, S. E. Waisbren36, M. M. Welsink-Karssies2, S. B. Wortmann37, M. Gautschi38, E. P. Treacy20,39† and G. T. Berry7†

Background: Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients.

Methods: Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018.

Results: Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome.

Conclusion: This study describes the natural history of classic galactosemia based on the hitherto largest data set.

Keywords: Registry, Natural history, Galactosemia, GALT deficiency, Galactosemia network

Rubio-Gozalbo et al. Orphanet Journal of Rare Diseases (2019) 14:86

Discovery of Biomarker Panels for Neural Dysfunction in Inborn Errors of Amino Acid Metabolism

Alba-Aina Castells1,2, Daniela Gueraldi1, Rafel Balada2, Alba Tristán-Noguero1, Elisenda Cortès-Saladelafont1, Federico Ramos1, Silvia Meavilla1, Mariela De Los Santos1, Camila Garcia-Volpe1, Roser Colomé1, Maria Luz Couce3, Cristina Sierra1, Aida Ormazábal1, Marta Batllori1, Rafael Artuch 1, Judith Armstrong1, Soledad Alcántara2 & Àngels Garcia-Cazorla 1


Patients with inborn errors of amino acid metabolism frequently show neuropsychiatric symptoms despite accurate metabolic control. This study aimed to gain insight into the underlying mechanisms of neural dysfunction. Here we analyzed the expression of brain-derived neurotrophic factor (BDNF) and 10 genes required for correct brain functioning in plasma and blood of patients with Urea Cycle Disorders (UCD), Maple Syrup Urine Disease (MSUD) and controls. Receiver-operating characteristic (ROC) analysis was used to evaluate sensitivity and specificity of potential biomarkers. CACNA2D2 (α2δ2 subunit of voltage-gated calcium channels) and MECP2 (methyl-CpG binding protein 2) mRNA and protein showed an excellent neural function biomarker signature (AUC ≥ 0,925) for recognition of MSUD. THBS3 (thrombospondin 3) mRNA and AABA gave a very good biomarker signature (AUC 0,911) for executive-attention deficits. THBS3, LIN28A mRNA, and alanine showed a perfect biomarker signature (AUC 1) for behavioral and mood disorders. Finally, a panel of BDNF protein and at least two large neural AAs showed a perfect biomarker signature (AUC 1) for recognition of psychomotor delay, pointing to excessive protein restriction as central causative of psychomotor delay.

To conclude, our study has identified promising biomarker panels for neural function evaluation, providing a base for future studies with larger samples.

Sci Rep 9, 9128 (2019).

Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation

Anna Čechová1, Ruqaiah Altassan2, Delphine Borgel3, Arnaud Bruneel4,5, Joana Correia6, Muriel Girard7, Annie Harroche8, Beata Kiec-Wilk9, Klaus Mohnike10, Tiffany Pascreau3, Łukasz Pawliński9, Silvia Radenkovic11,12, Sandrine Vuillaumier-Barrot4,13, Luis Aldamiz-Echevarria14, Maria Luz Couce15, Esmeralda G. Martins6, Dulce Quelhas16, Eva Morava17, Pascale de Lonlay18, Peter Witters19,20, Tomáš Honzík1


Mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) deficiency is a rare subtype of congenital disorders of protein N-glycosylation. It is characterised by deficiency of MPI caused by pathogenic variants in MPI gene. The manifestation of MPI-CDG is different from other CDGs as the patients suffer dominantly from gastrointestinal and hepatic involvement whereas they usually do not present intellectual disability or neurological impairment. It is also one of the few treatable subtypes of CDGs with proven effect of oral mannose. This article covers a complex review of the literature and recommendations for the management of MPI-CDG with an emphasis on the clinical aspect of the disease. A team of international experts elaborated summaries and recommendations for diagnostics, differential diagnosis, management, and treatment of each system/organ involvement based on evidence-based data and experts’ opinions. Those guidelines also reveal more questions about MPI-CDG which need to be further studied.

Keywords AT deficiency; guidelines; hepatic fibrosis; hyperinsulinaemic hypoglycaemia; mannose phosphate isomerase; MPI-CDG; protein-losing enteropathy

Inherit Metab Dis. 2020 July ; 43(4): 671–693

Long-term safety and outcomes in hereditary tyrosinaemia type 1 with nitisinone treatment: a 15-year non-interventional, multicentre study

Ute Spiekerkoetter, Maria L Couce, Anibh M Das, Corinne de Laet, Carlo Dionisi-Vici, Allan M Lund, Manuel Schiff, Marco Spada, Erik Sparve,
Johan Szamosi, Roshni Vara, Mattias Rudebeck


Background Since the EU approval of nitisinone in 2005, prognosis for patients with hereditary tyrosinaemia type 1 has changed dramatically, with patients living with the disease now reaching adulthood for the first time in history. This study aimed to assess the long-term safety and outcomes of nitisinone treatment in patients with hereditary tyrosinaemia type 1.

Methods We did a non-interventional, non-comparative, multicentre study in 77 sites across 17 countries in Europe and collected retrospective and prospective longitudinal data in patients with hereditary tyrosinaemia type 1 who were treated with oral nitisinone during the study period (Feb 21, 2005, to Sept 30, 2019). There were no specific exclusion criteria. Patients were followed-up with an investigator at least annually for as long as they were treated, or until the end of the study. The primary endpoints, occurrence of adverse events related to hepatic, renal, ophthalmic, haematological, or cognitive or developmental function, were assessed in the complete set (all patients already receiving treatment at the index date [Feb 21, 2005] or starting treatment thereafter) and the index set (the subset of patients who had their first dose on the index date or later only).

Findings 315 patients were enrolled during the study period (complete set). Additionally, data from 24 patients who had liver transplantation or died during the post-marketing surveillance programme were retrieved (extended analysis set; 339 patients). Median treatment duration was 11·2 years (range 0·7–28·4); cumulative nitisinone exposure was 3172·7 patient-years. Patients who were diagnosed by neonatal screening started nitisinone treatment at median age 0·8 months versus 8·5 months in those who presented clinically. Incidences of hepatic, renal, ophthalmic, haematological, or cognitive or developmental adverse events were low. Occurrence of liver transplantation or death was more frequent the later that treatment was initiated (none of 70 patients who started treatment at age <28 days vs 35 [13%] of 268 patients who started treatment at age ≥28 days). 279 (89%) of 315 patients were assessed as having either very good or good nitisinone treatment compliance. Treatment and diet compliance declined as patients aged. Suboptimal plasma phenylalanine and tyrosine levels were observed. The majority of patients were reported to have good overall clinical condition throughout treatment; 176 (87%) of 203 during the entire study, 98% following 1 year of treatment.

Interpretation Long-term nitisinone treatment was well tolerated and no new safety signals were revealed. Life-limiting hepatic disease appears to have been prevented by early treatment start. Neonatal screening was the most effective way of ensuring early treatment. Standardised monitoring of blood tyrosine, phenylalanine, and nitisinone levels has potential to guide individualised therapy.

Funding Swedish Orphan Biovitrum (Sobi).

Lancet Diabetes Endocrinol 2021

The LINCE Project: A Pathway for Diagnosing NCL2 Disease

Daniel Rodrigues 1,2, Maria José de Castro1, Pablo Crujeiras 1,2, Anna Duat-Rodriguez 3,
Ana Victoria Marco4, Mireia del Toro5, María L. Couce1,2* and Cristóbal Colón1*


Neuronal Ceroid Lipofuscinosis (NCL) comprises a clinically and genetically heterogeneous group of 13 neurodegenerative lysosomal storage disorders. Neuronal Ceroid lipofuscinosis type 2 disease (NCL2), caused by the deficient lysosomal enzyme tripeptidyl peptidase 1 (TPP1), is the only one with an approved enzyme replacement treatment (ERT). Early initiation of ERT appears to modify significantly the natural history of the disease. We aimed to shorten the time to diagnosis of NCL2.


In March 2017, we started per first time in Spain a selective screening program, the LINCE project, in pediatric patients with clinical symptoms compatible with NCL2 disease. The program covered the whole country. We distributed kits to pediatricians with the necessary material to assess patients. All samples in this study were received within one week of collection. Enzymatic activity determined on dried blood spots was the main method used to screen for TPP1 and palmitoyl protein thioesterase 1 (PPT1) for the differential diagnosis with neuronal ceroid lipofuscinosis type 1 (NCL1).


Over a period of three years, we received 71 samples. The analysis was minimally invasive, relatively cheap and fast-executing. Three cases identified as a direct result of the selective screening strategy were confirmed by genetic study of NCL2 disease with a median age of 4.5 years. Our screening method has a specificity of 100%, and, with the absence to date of false negatives. We did not detect any NCL1-positive cases.


LINCE proved to be a simple, useful, and reliable tool for the diagnosis of NCL2, enabling clinicians to diagnose NCL2 faster. The presence of NCL2-positive cases in our population and availability of treatment may facilitate the inclusion of NCL2 in neonatal screening programs for early diagnosis.

Frontiers in Pediatrics – March 2022

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