Paula Sánchez‐Pintos

Instituto de Investigación Sanitaria de Santiago

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María L. Couce

Complejo Hospitalario Universitario de Santiago

Isidro Vitoria

Hospital Universitari i Politècnic La Fe

Javier de las Heras

BioCruces Health research Institute

Patricia Correcher Medina

Hospital Universitari i Politècnic La Fe

Luis Peña Quintana

Hospital Universitario Insular de Gran Canaria

José A. Cocho

Instituto de Investigación Sanitaria de Santiago

Elvira Cañedo Villarroya

Hospital Infantil Universitario Niño Jesús

Rosaura Leis

Universidade de Santiago de Compostela

José M. Fraga

Universidade de Santiago de Compostela

Juliana Serrano-Nieto

Hospital Regional Universitario de Málaga

Cooperative Institutions

Centre for Biomedical Network Research on Rare Diseases

Instituto de Salud Carlos III

Universidade de Santiago de Compostela

Centro de Investigación Biomédica en Red

Instituto de Investigación Sanitaria de Santiago

Complejo Hospitalario Universitario de Santiago

Instituto de Investigación de Enfermedades Raras

Hospital Sant Joan de Déu Barcelona

Complexo Hospitalario Universitario A Coruña

Servicio Gallego de Salud

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Lipid profile status and other related factors in patients with Hyperphenylalaninaemia

Orphanet Journal of Rare Diseases (2016)

María L. Couce Isidro Vitoria Luis Aldámiz‐Echevarría Ana Fernández‐Marmiesse Iria Roca

The mainstay of treating patients with phenylketonuria (PKU) is based on a Phe-restricted diet, restrictive in natural protein combined with Phe-free L-amino acid supplements and low protein foods. This PKU diet seems to reduce atherogenesis and confer protection against cardiovascular diseases but the results from the few published studies have been inconclusive. The aim of our study was to evaluate the relationship between the lipid profile and several treatment-related risk factors in patients with hyperphenylalaninaemia (HPA) in order to optimize their monitoring. We conducted a cross-sectional multicentre study. A total of 141 patients with HPA were classified according to age, phenotype, type of treatment and dietary adherence. Annual median blood phenylalanine (Phe) levels, Phe tolerance, anthropometric measurements, blood pressure (BP) and biochemical parameters [(triglycerides, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), apolipoprotein A (ApoA), apolipoprotein B (ApoB), vitamin B12, total homocysteine (tHcy), Methionine (Met), high sensitivity C-Reactive Protein (hsCRP)] were collected for each patient. Plasma TC levels were lower in patients with PKU than in the mild-HPA group (150 ± 31 vs. 164 ± 22 mg/dL), and there was a weak inverse correlation between plasma TC and Phe levels. HDL-C, LDL-C, ApoA and ApoB levels were lower in the PKU group than in mild-HPA. Patients with PKU had higher systolic BP than the mild-HPA group and there was found a quadratic correlation between median Phe levels and systolic BP (p = 6.42e-5) and a linear correlation between median Phe levels and diastolic BP (p = 5.65e-4). In overweight or obese PKU patients (24.11 %), biochemical parameters such as TC, triglycerides, LDL-C, tHcy, hsCRP and BP were higher. By contrast, HDL-C was lower in these patients. Our data show a direct correlation between lipid profile parameters and good adherence to the diet in PKU patients. However, lipid profile in overweight or obese patients displayed an atherogenic profile, in addition to higher hsCRP concentrations and BP. Our study contributes to a better understanding of the relationship between phenotype and treatment in patients with HPA, which could be useful in improving follow-up strategies and clinical outcome. Research Ethics Committee of Santiago-Lugo 2015/393. Registered 22 September 2015, retrospectively registered.

Lipid Profile

10.1186/s13023-016-0508-x

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Citations (30)

Clinical and biochemical evolution after partial dietary liberalization of two cases of galactosemia due to galactose mutarotase deficiency

BMC Pediatrics (2024)

Paula Sánchez‐Pintos María José Camba-Garea Beatriz Martin López-Pardo Jose A Cocho de Juan M. Dolores Bóveda

The recommended diet attitude in the recently described galactose mutarotase (GALM) deficiency is not yet established. We describe two 9-years twins who remain asymptomatic despite prolonged partial dietary liberalization from 18 months of age, after two periods of galactose-free diet. It represents the second report in Europe of GALM deficiency.

Galactosemia

10.1186/s12887-024-05074-6

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New variants expand the neurological phenotype of COQ7 deficiency

Journal of Inherited Metabolic Disease (2024)

María Alcázar‐Fabra Abraham J. Paredes‐Fuentes Manuel Torralba Carnerero Daniel J.M. Fernández‐Ayala Antonio Arroyo‐Luque

The protein encoded by COQ7 is required for CoQ

Pleiotropy

Human genetics

Pathophysiology

Proband

10.1002/jimd.12776

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Citations (1)

Beyond genetics: Deciphering the impact of missense variants in CAD deficiency

Journal of Inherited Metabolic Disease (2023)

Francisco del Caño‐Ochoa Bobby G. Ng Antonio Rubio‐del‐Campo Sonal Mahajan Matthew P. Wilson

Abstract CAD is a large, 2225 amino acid multienzymatic protein required for de novo pyrimidine biosynthesis. Pathological CAD variants cause a developmental and epileptic encephalopathy which is highly responsive to uridine supplements. CAD deficiency is difficult to diagnose because symptoms are nonspecific, there is no biomarker, and the protein has over 1000 known variants. To improve diagnosis, we assessed the pathogenicity of 20 unreported missense CAD variants using a growth complementation assay that identified 11 pathogenic variants in seven affected individuals; they would benefit from uridine treatment. We also tested nine variants previously reported as pathogenic and confirmed the damaging effect of seven. However, we reclassified two variants as likely benign based on our assay, which is consistent with their long‐term follow‐up with uridine. We found that several computational methods are unreliable predictors of pathogenic CAD variants, so we extended the functional assay results by studying the impact of pathogenic variants at the protein level. We focused on CAD's dihydroorotase (DHO) domain because it accumulates the largest density of damaging missense changes. The atomic‐resolution structures of eight DHO pathogenic variants, combined with functional and molecular dynamics analyses, provided a comprehensive structural and functional understanding of the activity, stability, and oligomerization of CAD's DHO domain. Combining our functional and protein structural analysis can help refine clinical diagnostic workflow for CAD variants in the genomics era.

10.1002/jimd.12667

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Citations (11)

[Evaluation and perspective of 20 years of neonatal screening in Galicia. Program results.]

PubMed (2020)

Paula Sánchez‐Pintos José Ángel Cocho de Juan Ma Dolores Bóveda Fontán Daisy E. Castiñeiras Ramos Cristóbal Colón Mejeras

Galician newborn screening program for early detection of endocrine and metabolic diseases began in 1978 and was a pioneer in expanded newborn screening in Spain with the incorporation of mass spectrometry in July 2000. As a primary objective, 28 diseases are screened, including those recommended SNS except sickle cell anemia which is in the inclusion phase. In its 20-year history, 404,616 newborns (nb) have been analyzed, identifying 547 cases affected by the diseases included, with a global incidence of 1: 739 newborns and 1: 1.237 of the screened inborn errors of metabolism (IEM) (1:1.580 nb if excluding benign hyperphenylalaninemia-HPA), with an average participation of 99.35%, progressively higher during the analyzed period. Among the pathologies screened, congenital hypothyroidism (1:2.211 nb), cystinuria (1:4.129 nb) and HPA (1:5.699 nb), followed by phenylketonuria and cystic fibrosis (1:10,936 nb) stand out for their incidence. Sixty-six cases of false positives were identified (seventeen of them in relation to maternal pathology) and five false negatives, being the overall PPV and NPV of the program respectively of 89.2% and 99.99%, with a sensitivity of 99.09% and a specificity of 99.98%. The mortality rate of diagnosed CME patients is 1.52%, with eleven cases presenting symptoms prior to the screening result (2%). The intelligence quotient of IEM patients at risk of neurological involvement is normal in more than 95% of cases.

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Automated therapy preparation of isoleucine formulations using 3D printing for the treatment of MSUD: First single-centre, prospective, crossover study in patients

International Journal of Pharmaceutics (2019)

Álvaro Goyanes Christine M. Madla Aysha Umerji Goretti Duran Jose Maria Giraldez Montero

Isoleucine

Crossover study

10.1016/j.ijpharm.2019.118497

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Citations (223)

Odimet®: A Pioneering Tele-Health Tool to Empower Dietary Treatment and the Acute Management of Inborn Errors of Metabolism—An Assessment of Its Effectiveness during the COVID Pandemic

Nutrients (2024)

Paula Sánchez‐Pintos María José Camba-Garea Beatriz Martin López-Pardo María L. Couce

Strict adherence to a diet is an essential pillar of long-term treatment for many inborn errors of metabolism (IEMs). Tools that educate patients about dietary management can positively condition adherence and prevent morbidity. We designed a free online dietary calculation program (Odimet®, version 2.1.) for IEMs patients in 2008, updated in 2022, that provides detailed information on the content of amino acids, protein, lipids, carbohydrates, vitamins and minerals in >3000 food products, including specific medical foods for IEM. We analyzed the statistics on visits to Odimet® to evaluate its usefulness for long-term dietary management during a 5-year period focusing on three periods: pre-pandemic (15 March 2018–14 March 2020); pandemic 1 (15 March 2020–14 March 2021); and pandemic 2 period (15 March 2021–15 March 2023), in 120 patients with the following distribution: 84 patients with phenylketonuria (PKU); 12 with maple syrup urine disease (MSUD); 11 with urea cycle disorders (UCDs); and 13 with classical galactosemia. The evolutionary levels of their specific metabolic markers were evaluated, showing that globally, both pediatric and adult patients maintain a good metabolic control, even during a pandemic (median levels of phenylalanine in pediatric PKU patients 213.4 µmol/L and 482.3 µmol/L in adults; of leucine in MSUD patients: 144.2 µmol/L; of glutamine in UCDs: 726.8 µmol/L; and of galactose 1-phosphate levels in galactosemia: 0.08 µmol/L). The proportion of patients using Odimet® ranges from 78–100%. An increase in the number of diets being calculated was observed during COVID-19 pandemic. Currently, 14,825 products have been introduced (3094 from the general database, and 11,731 added by users to their own profiles). In 2023 63 emergency dietary adjustments in the studied intoxication-type pathologies were calculated in Odimet®. Our results suggest that its regular use contributes to maintaining metabolic stability in IEMs patients, allowing them to adapt their menus to their lifestyle, and represents a powerful complementary tele-health tool which can be used to perform remote real-time dietary follow-up.

Galactosemia

Dietary management

Pandemic

10.3390/nu16030423

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Citations (2)

Carbohydrate status in patients with phenylketonuria

Orphanet Journal of Rare Diseases (2018)

María L. Couce Paula Sánchez‐Pintos Isidro Vitoria María-José de Castro Luis Aldámiz‐Echevarría

In patients with phenylketonuria (PKU), a low-phenylalanine (Phe) diet supplemented with low-protein foods and a Phe-free amino acid mixture favors a dietary intake rich in carbohydrates, but little is known about how these molecules are metabolized in this setting. The objective of the present study was to analyze carbohydrate metabolism in patients with hyperphenylalaninemia. We conducted a multicenter cross-sectional study to investigate biochemical markers of basal and postprandial carbohydrate metabolism in PKU patients according to age, Phe tolerance, waist circumference and body mass index (BMI), diet, tetrahydrobiopterin (BH4) supplementation, and adherence to treatment. Basal biomarkers and anthropometric parameters were also evaluated in patients with mild hyperphenylalaninemia (MHPA) and in healthy controls. A total of 83 patients aged 4–52 years were studied; 68.7% had PKU and 31.3% had MHPA. 68 healthy controls of similar sex and age were also evaluated Metabolic control was adequate in 71.9% of PKU patients. Fasting glucose levels (mean 80.77 ± 8.06 mg/dL) were high in just one patient, but fasting insulin levels, with a mean of 12.74 ± 8.4 mIU/L, were altered in 15 PKU patients (26.3%) and markedly higher than in patients with MPHA (p = 0.035). Fasting insulin levels and Homeostasis Model Assessment Insulin Resistance (HOMA-IR) were significantly higher than in healthy controls and correlated with body mass index, waist circumference, age, and also showed statistically significant differences according to diagnosis and Phe tolerance (p < 0.05). Patients under BH4 therapy had lower insulin levels and HOMA-IR. A higher mean carbohydrate intake from AA mixtures was observed in classic PKU patients. The caloric intake in the form of carbohydrates was also higher in PKU than MHPA patients (p = 0.038) and it was correlated with basal insulin (rho = 0.468, p = 0.006), HOMA-IR (rho = 0.423, p = 0.02), BMI (rho 0.533, p = 0.002), and waist circumference (rho 0.584, p = 0.0007). This study shows that PKU patients are at risk of carbohydrate intolerance and insulin resistance, more evident in adults and overweight patients, probably related to their higher caloric intake in form carbohydrate content. A higher dependency of AA mixtures was demonstrated in PKU patients.

Hyperphenylalaninemia

Basal (medicine)

Carbohydrate Metabolism

10.1186/s13023-018-0847-x

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Citations (43)

FRI-153 High prevalence of steatotic liver disease and systemic inflammation in hereditary fructose intolerance (HFI) patients independent of age, BMI and the presence of metabolic syndrome

Journal of Hepatology (2024)

Teresa C. Delgado Ainara Cano María Mercado-Gómez Xabier Buqué Cristina N. Alonso

10.1016/s0168-8278(24)01976-7

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Practical Recommendations for the Diagnosis and Management of Lysosomal Acid Lipase Deficiency with a Focus on Wolman Disease

Nutrients (2024)

Javier de las Heras Carolina Almohalla Javier Blasco‐Alonso Mafalda Bourbon María L. Couce

Lysosomal acid lipase deficiency (LAL-D) is an ultra-rare lysosomal storage disease with two distinct phenotypes, an infantile-onset form (formerly Wolman disease) and a later-onset form (formerly cholesteryl ester storage disease). The objective of this narrative review is to examine the most important aspects of the diagnosis and treatment of LAL-D and to provide practical expert recommendations. The infantile-onset form occurs in the first weeks of life and is characterized by malnourishment and failure to thrive due to gastrointestinal impairment (vomiting, diarrhea, malabsorption), as well as systemic inflammation, hepatosplenomegaly, and adrenal calcifications. Mortality is close to 100% before one year of life in the absence of specific treatment. The later-onset form can be diagnosed in childhood or adulthood and is characterized by chronic liver injury and/or lipid profile alterations. When LAL-D is suspected, enzyme activity should be determined to confirm the diagnosis, with analysis from a dried blood spot sample being the quickest and most reliable method. In infantile-onset LAL-D, the initiation of enzyme replacement therapy (sebelipase α) and careful nutritional management with a low-lipid diet is very urgent, as prognosis is directly linked to the early initiation of specific treatment. In recent years, our knowledge of the management of LAL-D has increased considerably, with improvements regarding the initial enzyme replacement therapy dose and careful nutritional treatment with a low-lipid diet to decrease lipid deposition and systemic inflammation, leading to better outcomes. In this narrative review we offer a quick guide for the initial management of infantile-onset LAL-D.

Hepatosplenomegaly

Failure to Thrive

10.3390/nu16244309

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