Researchers discover new phenotypic characteristics in inherited disorders of neurotransmitter metabolism

The study co-led by Dr Àngels Garcia-Cazorla, Institut de Recerca Sant Joan de Déu (IRSJD), has studied more than 270 patients with ultra-rare neuro-metabolic diseases to describe and evaluate their initial clinical and biochemical characteristics improve their diagnosis.

The study, published in Nature Communications, is the result of the "International Working Group on Neurotransmitter Related Disorders (I-NTD)", a registry that collects clinical data from patients with inherited disorders of neurotransmitter metabolism from more than 25 different countries. I-NDT was co-founded by Dr. Angels Garcia Cazorla's group along with Dr. Thomas Opladen (Heidelberg) and Dr Manju Kurian (London).

Neurotransmitters are chemical messengers that carry, drive, and balance signals between neurons and target cells throughout the body. There are more than 100 and each one has its specific function. Lack of its synthesis, transport or processing, or lack of its essential co-factors, such as tetrahydrobiopterin (BH4), can cause what are called inherited disorders of neurotransmitter metabolism.

These disorders are a group of rare neurometabolic diseases that are associated with movement problems and global developmental delay, affecting the central or autonomic nervous system and the hematological or the cardiovascular ones. These diseases, according to the chemical structure of the neurotransmitter or cofactor affected, are classified into two major groups.

 "One of the main problems in diagnosing these rare neurometabolic diseases is that their symptoms are unspecific and sometimes they overlap with symptoms seen in other neurological conditions such as cerebral palsy or epileptic encephalopathies. As a result, many of these diseases are often under-recognized or directly misdiagnosed" says Dr. Àngels Garcia Cazorla, leader of the research group "Pediatric neurometabolism: neural communication mechanisms and personalized therapies".

In fact, within these rare neurometabolic diseases, only a small group can be detected by the newborn's heel prick. However, other diseases of this type require selective diagnostic tests leading to prolonged diagnosis work-up and therefore a delayed treatment initiation. Generally, the outcome depends on the specific disease, the timing of diagnosis, the start and type of specific treatment, as well as the long-term compliance to treatment. In addition, as they are rare diseases, very few cases have been described or there are even unique cases in the world, which makes it even more difficult to study, diagnose and treat them.

New phenotypic characteristics to improve diagnosis

With this study, researchers aim to overcome these limitations and expand current knowledge about these disorders. Therefore, more than 270 patients with inherited disorders from the monoamine group (one of the two major groups) have been studied to perform the first standardized evaluation of the iNTD patient registry.

The singularity of this network has allowed characterizing and evaluating thoroughly the initial clinical and biochemical aspects in the diagnostic process. The results obtained reveal:

• an increased rate of prematurity
• a high risk for being small for gestational age and for congenital microcephaly in some disorders
• age at diagnosis and the diagnostic delay are influenced by the diagnostic methods applied and by disease-specific symptoms
• the presence of new symptoms of neonatal presentation such as hypoxia or jaundice

The results emphasize the importance of recognizing early symptoms and also highlight the need for a careful and systematic clinical evaluation to improve diagnosis in these rare neurodevelopmental diseases.

Reference paper

Kuseyri Hübschmann, O., Horvath, G., Cortès-Saladelafont, E. et al. Insights into the expanding phenotypic spectrum of inherited disorders of biogenic amines. Nat Commun 12, 5529 (2021). https://doi.org/10.1038/s41467-021-25515-5