Rare Disease Biomarkers & Computational Phenotyping
rare diseases, cerebrospinal fluid, CSF, amino acids, copper, paediatric, reference intervals, neurometabolic, epilepsy, biogenic amines, Sant Joan de Déu, UPC, Ministerio de Ciencia
| Funding | Ministerio de Ciencia e Innovación (AEI) |
| Programme | Proyectos de Generación de Conocimiento / Proyectos I+D+i |
| Status | Active |
| Clinical partner | Hospital Sant Joan de Déu, Barcelona |
| Key collaborator | Dr. Rafael Artuch Iriberri |
| Doctoral student | Helena Rodríguez-González (co-advised by Perera-Lluna and Artuch) |
| B2SLab PI | Alexandre Perera Lluna |
Context: rare neurometabolic disease and the biomarker gap
Inherited neurometabolic disorders are individually rare but collectively significant — they affect thousands of children across Europe, often presenting in infancy or early childhood with seizures, developmental delay, movement disorders, or unexplained metabolic crises. Diagnosing them requires precise biochemical measurement: amino acids, biogenic amines, organic acids, trace elements, and their metabolic intermediates in cerebrospinal fluid (CSF) and blood.
The clinical problem is deceptively simple: to know whether a patient’s result is abnormal, you need to know what normal looks like — for a child of that age, in that biological context. In adults, this is hard enough. In children, it is substantially harder: concentrations of neurochemicals in CSF shift dramatically across the first years of life, driven by brain maturation, myelination, nutritional requirements, and the changing activity of metabolic pathways. Reference intervals derived from a single age group, from a small convenience sample, or from adults translated downward are systematically misleading.
B2SLab addresses this problem at its computational root — building statistically rigorous, age-continuous reference intervals for paediatric biomarkers using the large, carefully collected clinical datasets that only a centre of excellence like Hospital Sant Joan de Déu can accumulate.
A long-standing collaboration with Dr. Rafael Artuch
The intellectual and clinical engine of this research line is a sustained collaboration between B2SLab and Dr. Rafael Artuch Iriberri, Head of Clinical Biochemistry and Neurometabolism at Hospital Sant Joan de Déu (SJD) in Barcelona.
Dr. Artuch is one of Europe’s foremost experts in the biochemical diagnosis of neurometabolic diseases. Under his leadership, the SJD Clinical Biochemistry Service has built one of the largest and most carefully annotated collections of paediatric CSF and blood samples in the world, accumulated over decades of diagnostic activity for children referred with neurological disease from across Catalonia and beyond.
This is a collaboration built on genuine mutual need: the clinical datasets at SJD require sophisticated statistical and computational methods that the clinical laboratory cannot provide alone; the computational methods require clinical data and expert interpretation that B2SLab cannot generate independently. The result is a programme in which methodology and biology advance together.
CSF amino acids: reference intervals for a diagnostic gold standard
Why CSF amino acids matter
Cerebrospinal fluid amino acid profiling is the diagnostic gold standard for a range of inherited neurometabolic conditions: disorders of amino acid transport across the blood-brain barrier, neurotransmitter synthesis defects, urea cycle disorders with CNS involvement, and the nutritional consequences of severe gastrointestinal disease. It is also increasingly used to monitor treatment response in conditions such as phenylketonuria and non-ketotic hyperglycinaemia.
The challenge is interpretive: CSF is collected by lumbar puncture, which limits sampling to patients with clinical indication. The “healthy reference population” from which reference intervals should ideally be derived is therefore never truly healthy — it consists of children who underwent lumbar puncture for a clinical reason but were found to have no metabolic disease. Managing this systematic selection bias, alongside the strong age-dependence of amino acid concentrations, is the central methodological problem.
Study: CSF amino acid profiling in a large paediatric cohort
Serum copper: when inflammation confounds the measurement
The diagnostic importance of copper
Copper is an essential trace element — cofactor for key enzymes in electron transport, antioxidant defence, iron metabolism, and neuropeptide synthesis. Both deficiency (Menkes disease, nutritional deprivation, malabsorption) and excess (Wilson disease, toxic exposure) cause serious disease, with neurological consequences prominent in both directions. In children, the biochemical diagnosis and monitoring of copper metabolism disorders depends critically on reliable reference intervals for serum copper and its carrier protein ceruloplasmin.
The confounding effect of inflammation
A complication rarely addressed in existing reference interval studies is that copper is an acute-phase reactant: inflammation drives increased hepatic synthesis of ceruloplasmin, the main copper-carrying protein in blood, raising measured serum copper independently of true copper status. A child with an ongoing infection, autoimmune condition, or chronic inflammatory disease will appear copper-replete on a standard reference range comparison even if their true functional copper status is compromised.
Study: age- and inflammation-adjusted copper reference intervals
Helena Rodríguez-González: doctoral thesis
Both research papers above are primary outputs of the doctoral thesis of Helena Rodríguez-González, jointly supervised by Prof. Alexandre Perera-Lluna (UPC / B2SLab) and Dr. Rafael Artuch Iriberri (Hospital Sant Joan de Déu).
Helena’s thesis sits at the boundary between clinical biochemistry and computational methods. The unifying thread across her work is the problem of clinical reference interval computation for paediatric biomarkers: how to derive, validate, and communicate normal ranges from complex observational data, accounting for age-dependence, biological confounders, sampling bias, and the particular challenges of rare disease populations.
The co-supervision model reflects the nature of the problem: the statistical and computational methodology is developed at B2SLab; the clinical datasets, biological interpretation, and validation against diagnostic outcomes are provided by Dr. Artuch’s team at SJD. The collaboration ensures that methodological advances are grounded in real clinical need and that clinical datasets are analysed with the rigour that complex observational data demands.
Broader context
This research line connects directly to B2SLab’s wider rare disease work:
- Share4Rare — the European patient data platform for rare diseases, where B2SLab designed the HPO-based phenotype standardisation infrastructure used to characterise patients across 50+ countries
- Metabolomics for Metabolic Disease — the complementary line using untargeted LC-MS to discover novel biomarkers for common metabolic diseases