Figure 1. Schematic description of IEM of small molecules. Concepts and diseases that have appeared more recently are highlighted in grey.
Figure 2. Schematic description of IEM of energy related disorders. Concepts and diseases that have appeared more recently are highlighted in grey. Only some examples of mitochondrial machinery defects are provided.
Figure 3. Schematic description of IEM of complex molecules. Concepts and diseases that have appeared more recently are highlighted in grey.
Table. Some examples of the integrative approach metabolism, neurobiology and brain networks. |
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Group of IEMs |
Disease |
Main clinical signs (continuum of symptoms and severity) |
Biological dysfunction (metabolic pathway and cell neurobiology) |
Brain networks, connectivity |
Therapies |
Refs. |
|
Early onset complex encephalopathies |
Disorders of small molecules (linked to a deficiency) |
Classic IEM Amino acid defects, serine synthesis defects (PGDH and others) |
Severe letal encephalopathy with lyssencephaly Microcephaly, spastic tetraparesis, cataracts, epilepsy Mild forms: intellectual disability and epilepsy. Presents as ‘synaptopahties’ |
Metabolism. Biomarker: low serine concentration. Serine is a precursor of glycine and sphingolipid synthesis. Also a neurotransmitter acting at NMDA receptors (in particular D-serine) Cell neurobiology. Serine stimulates neuronal proliferation in early development. Has a general role as ‘trophic’ factor and signaling molecule, therefore acting at multiple cell compartments. Involved in brain size and connectivity, myelin and neuronal membranes function |
Glutamatergic pathways thalamocortical projections, pyramidal neurons of the cortico- limbic regions, temporal lobe circuit (development of new memories). The climbing fibers innervating the cerebellar cortex. The corticospinal tracks |
L-serine supplements |
[14,22] |
Disorders of complex molecules |
New category SNAP29 (synaptosomal associated protein, 29 kDa) |
Severe form: progressive microcephaly, severe psycho-motor delay, palmoplantar keratosis and ichthyosis. Optic nerve hypoplasia, deafness. Defects of the corpus callosum and cortical dysplasia with pachygyria and polymicro-gyria, peripheral neuropathy Mild form: ichthyosis and dysgenesis of the corpus callosum |
Metabolism. This disease is in the category of disorder of synthesis, remodelling, trafficking, processing and quality control of complex molecules. In particular, this is a trafficking defect (membrane trafficking of complex molecules) but also involved in autophagy. No biomarkers found so far Cell neurobiology. It has a role in the neuronal soma compartment (complex Golgi organelle trafficking) and at the synaptic terminal, in particular in the synaptic vesicle cycle (endo an exocitosys trafficking) |
Not well described yet. Found in temporal and visual cortex (human post-mortem tissue; Allen Brain Atlas) |
No therapies for this particular disorder have been developed so far |
[23,24] |
|
Synaptopathy spectrum |
Energy related defects |
Classic IEM Creatine transporter defect |
Intellectual disability, behavioural problems (autistic-like features), seizures, in any combination. Some patients have also movement disorders Neurological and psychiatric problems can be progressive in adulthood |
Metabolism. Biomarker: increased creatine/creatinine ratio in urine, low peak of creatine in the brain (brain MRS). Defect of creatine brain transport. Defect in the reuptake of creatine within the neurons Cell neurobiology. Creatine behaves also as a neurotransmitter regulating GABAergic neurotransmission. Although creatine is an energetic molecule, most of the neurological symptoms are a consequence of the impaired mechanisms of neurotransmission (‘synaptopathy’) |
Gabaergic pathways, cortex (interneurons), basal ganglia, amygdala, cerebellum |
High dose creatine supplementation, arginine, glycine and S-adenosylmethionine have been employed with the aim to enhance intracerebral creatine synthesis with poor response |
[25,26] |
New category NAPB (N-ethylmaleimide-sensitive factor attachment protein, beta) |
Early epileptic encephalopathy (multifocal seizures), progressive microcephaly, profound global developmental delay, hypotonia, limb tremulousness and stereotypies (kicking, hand, wrist twisting, and bringing to the midline) |
Metabolism. This disease is in the category of disorder of synthesis, remodelling, trafficking, processing and quality control of complex molecules. In particular, this is a disorder of trafficking and involved in protein-protein interaction. No biomarkers found so far Cell neurobiology. Synaptic vesicle cycle, SNARE protein. SNARE complex dissociation and recycling: synaptic vesicle docking |
Not well described yet |
No therapies for this particular disorder have been developed so far |
[27] |
||
PGDH: phosphoglycerate dehydrogenase deficiency. |
Nuevos conocimientos sobre errores congénitos del metabolismo están dando lugar a nuevos paradigmas en neuropediatría Resumen. En los últimos años, la era -ómica ya ha transformado la neuropediatría. La secuenciación de alto rendimiento –next generation sequencing (NGS)– ha permitido identificar numerosos genes y fenotipos nuevos que provocan enfermedades. Aunque la genética tiene indudablemente una gran importancia como herramienta diagnóstica, no es de tanta utilidad cuando se trata de obtener una comprensión más amplia de los mecanismos involucrados en la disfunción cerebral. Los neuropediatras corren el riesgo de perderse en la genómica si no asumen la necesidad de un nuevo enfoque en su práctica clínica. La gran cantidad de datos que arroja la NGS es simplemente un elemento más en un complejo rompecabezas. Se deberían integrar distintos niveles de complejidad en el nuevo paradigma de la neuropediatría que tanto se echa en falta. Tradicionalmente, las descripciones de las enfermedades neurológicas se han basado en la neuroanatomía y la neurofisiología. Sin embargo, el metabolismo, que tiene un papel crucial en la regulación de las funciones neuronales, se ha obviado en la mayoría de estudios sobre los trastornos cerebrales. Paradójicamente, los errores congénitos del metabolismo (ECM) han tomado la dirección contraria. Con un total de más de 1.100 ECM, casi el 80% de los cuales manifiestan síntomas neurológicos, han pasado de considerarse inicialmente como anecdóticos a constituir un elemento fundamental en cualquier programa de educación neuropediátrica. Además, los nuevos defectos hallados en las moléculas complejas están promoviendo la integración del metabolismo y la biología celular clásicos en la estructura compartimentada específica del sistema nervioso (‘neurometabolismo celular’). Este artículo constituye un breve resumen de la clasificación de los ECM actualizada en combinación con las principales presentaciones neurológicas en un intento de lograr una práctica clínica neuropediátrica basada en la fisiopatología. De manera particular, hacemos hincapié en un enfoque clínico centrado en un amplo continuo/espectro de síntomas. Palabras clave. Clasificación de ECM. Encefalopatías complejas precoces. Errores congénitos del metabolismo. Neurometabolismo celular. Sinaptopatías. Trastornos motores complejos. |