Nuevos retos en enfermedades neurometabólicas

New insights in inborn errors of metabolism are leading to new paradigms in child neurology

A. García-Cazorla, J.M. Saudubray [REV NEUROL 2018;66 (Supl. 2):S37-S42] PMID: 29876911 DOI: https://doi.org/10.33588/rn.66S02.2018198

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Volumen 66 | Número S02 | Nº de lecturas del artículo 12.153 | Nº de descargas del PDF 417 | Fecha de publicación del artículo 05/06/2018

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Introduction What is new?: new IEMs and the proposal of an updated classification How can we integrate these new concepts into the clinical practice of child neurology Consider a spectrum or continuum of symptoms rather than focusing on individual signs Three major categories of clinical presentations can be delineated Conclusions

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RESUMEN

In the last recent years, the -omics era has already transformed child neurology. Next generation sequencing (NGS) has identified many novel disease causing genes and phenotypes. While genetics is of great importance as a diagnostic tool, it is less helpful when it comes to a comprehensive understanding of mechanisms of brain dysfunction. Child neurologists are at high risk of being lost in genomics if they do not face the necessity of a new approach in their clinical practice. The large amount of data provided by NGS is just one more element in a complex puzzle. Different levels of complexity should be integrated in the much-needed novel child neurology paradigm. Classically, the descriptions of neurological diseases have relied on neuroanatomy and neurophysiology. However, metabolism, which strongly orchestrates the regulation of neuronal functions, has been mostly neglected in the study of brain disorders. Paradoxically, inborn errors of metabolism (IEM) have moved in the opposite direction. With more than 1100 IEM, almost 80% of which exhibit neurological symptoms, they have evolved from being initially considered as mere anecdotes to be a fundamental requisite in neuropediatric educational programs. Additionally, new complex molecule defects are leading to integrate classic metabolism and cell biology into the specific compartmentalized structure of the nervous system («cellular neurometabolism»). This article is a brief summary of the updated IEM classification combined with major neurological presentations in a tentative towards a pathophysiology based clinical practice in child neurology. In particular we emphasize a clinical approach focused in a continuum/spectrum of symptoms. Palabras claveCellular neurometabolism Complex motor disorders Early complex encephalopathies IEM classification Inborn errors of metabolism Synaptopathies

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Introduction

More than 300 new inborn errors of metabolism (IEMs) have been described during the last 5 years and most of them have major neurological symptoms [1]. These disorders have changed paradigms transforming the concept and classification of inborn errors of metabolism and are enormously contributing to our understanding of mechanisms in neurological diseases. A pioneer initiative in this direction was the description of the vast new group of complex lipid synthesis and remodelling defects. Standing at the frontier between classical IEMs and cellular neurobiology, they target cell membranes and strongly involve trafficking related disorders [2]. The description of this category was the first challenge to the classical classification of IEMs largely based on the study of individual organelles. From a clinical point of view, they cause prominent motor manifestations due to upper and/or lower motoneuron degeneration [3]. More recently many other defects affecting systems involved in intracellular vesiculation, trafficking, processing and quality control of complex molecules (like protein folding and autophagy) [4] have been discovered using the next generation sequencing (NGS) technique. These diseases produce a wide repertoire of neurological symptoms including defects of the synaptic vesicle, which encompass a continuum of signs that characterize the ‘synaptopathies’. Clinical signs of synaptic dysfunction include intellectual disability, neuropsychiatric symptoms, epilepsy and movement disorders [5].

The knowledge based of the present article is a previous work of the same authors [6]. The concept of ‘cellular neurometabolism’ contains a paradigm shift to move towards a clinical approach based on pathophysiological groups that combine the specific functioning of neuronal cell compartments with their metabolic properties. Taking into account these former ideas, the authors aim to herein suggest a pathophysiology based clinical approach for child neurologists.

What is new?: new IEMs and the proposal of an updated classification

A recent updated classification of IEMs proposes three large categories based on the size of molecules (‘small and simple’ or ‘large and complex’) and their implication in energy metabolism [1,6]:

Disorders of small molecules and the novel diseases and concepts included in this category are summarized in figure 1. As a general message disorders linked to a deficiency of small molecules (amino acids, fatty acids, neurotransmitters...) disrupt neurodevelopmental functions, whereas the excess of them (intoxications) may stress the cellular quality control and repair mechanisms leading to apoptotic and eventually neurodegenerative related events.
Energy related defects are represented in figure 2. In this updated approach to energy defects, it is worth noting that mitochondrial disorders are not just diseases of mitochondrial/nuclear DNA that impair respiratory chain function. More than 100 defects described so far are linked to diverse functions of the mitochondrial machinery. Interestingly, they can interfere neurodevelopment but at the same time be also progressive (early lethal or leading to slow degeneration) [7]. Some of them lack the classical biomarkers (lactate, amino acids, organic acids…) and have phenotypes not previously linked to energy defects such as cranial dysostosis and progeria [8].
Disorders of complex molecules are summarized in figure 3. While catabolic defects lead to storage of abnormal compounds resulting in the classical lysosomal defects (i.e. sphingolipidoses, muchopolysaccharidoses), the most important transformation in the concept and classification of IEMs comes from the second subgroup in this category: the disorders of synthesis, remodelling, trafficking, processing and quality control of complex molecules. These diseases have a great impact in both child and adult neurology. They stand at the crossroad between traditional IEMs and genetic diseases, include classic organelle disorders, and diverse cell biology mechanisms. They represent a great challenge for classic neurology because they lead to the connection of clinical signs with metabolism and neuroscience [6].

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.

Disorders of nucleic acids are an emergent group of disorders, that include not only purine and pyrimidine defects, but also tRNA synthetases defects [9,10], ribosomopathies [11] such as UBTF mutations, a recently described cause of infantile neurodegeneration (UBTF is involved in ribosomal synthesis) [12], diseases affecting mechanisms of DNA/RNA damage reparation and those involved in DNA methylation such as in CHARGE and Kabuki syndromes [13].

How can we integrate these new concepts into the clinical practice of child neurology

The integration of metabolism, the new IEMs categories, and cell biology in child neurology may bring forward a renovated clinical approach towards the following ideas:

Consider a spectrum or continuum of symptoms rather than focusing on individual signs

Traditionally child neurology has been studied according to a collection of well-defined symptoms (i.e. epilepsy, intellectual disability, autism, movement disorders, spasticity...). While this is a very useful and logical approach, there isn’t always a pathophysiological thinking linked to this rationale. As a consequence, and despite sharing common neurobiological mechanisms, epilepsy and autism have been considered as completely different entities, and therefore studied and treated by different sub-specialists in neuropaediatrics. However, as we move towards a deeper knowledge of disease mechanisms in the developing brain, we are progressing into viewing this as a ‘spectrum-continuum of symptoms’ underlying a set of common biological processes. The predominance of one symptom versus another may depend on the particular defect but may also rely on individual idiosyncrasy and most importantly on patient’s age. In fact, the already mentioned fragmented clinical approach in paediatrics reflects the procedures of adult neurology, since symptoms of the mature brain tend to be well parcelled and less variable within the same genetic alteration.

Three major categories of clinical presentations can be delineated

In paediatrics, most of the recently described IEMs fit into these clinical forms, and this is particularly relevant in early infancy. Moreover, although isolated or predominant signs are the rule in some diseases, and these three clinical entries can also overlap, this approach enables an easier matching of the clinical signs with the pathophysiology. The table aims to illustrate this multi-level approach with some examples. We have included both classic and recently described IEMs to stress the similar approach that can be followed. In particular, we highlight the involvement of biochemical pathways even when biomarkers have not been detected yet.

Early complex encephalopathies

Early complex encephalopathies include genetic defects that lead to early disruption of fundamental biological processes that are required for a proper brain development. Functions such as neuronal precursor proliferation, migration, synapse and dendrite formation, astrocyte development, pruning, cytoskeleton guidance, signalling and experience-dependence synapse remodelling may be affected. They may disclose macroscopic malformations but also subtle abnormalities and normal brain configuration (normal brain MRI). Clinically, signs appear during the first year of life (most of them within the first few months) and all neurological functions (cognitive, motor, head size, excitability, behaviour) may be affected, although they can have different peculiarities depending on the particular defect. Some of the most relevant examples are in the categories of small and complex molecule defects. Severe forms of small molecule defects may display brain cortical malformations. This is the case of amino acid defects: serine synthesis defects cause Neu-Laxova syndrome (lyssencephaly) [14]; glutamine synthetase [15] and asparagine synthetase [16] deficiencies display almost complete agyria. Fatty acid defects such as MFSD2A deficiency results in defective transport of docosahexanoic acid, an essential fatty acid, and is the cause of a severe lethal brain malformation [17]. Complex molecule defects are also an important cause of these early encephalopathies due to the lack or deficient function of relevant brain lipids or due to abnormal processing of these complex molecules. This is the case of Vici syndrome, a disorder of autophagy [18]. There are also several examples in disorders related to synaptic vesicle cycle (trafficking at the synaptic terminal and along the axon; see table).

Table. Some examples of the integrative approach metabolism, neurobiology and brain networks.
	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]
Early onset complex encephalopathies	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]
Synaptopathy spectrum	Energy related defects	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.

Synaptopathy spectrum

Diseases impairing synaptic communication often have epilepsy, intellectual disability, behavioural abnormalities (including autism) and movement disorders in any combination [5]. As an example, most patients harbouring MUNC18 mutations present with early epileptic encephalopathies, by contrast in some others epilepsy is a minor or absent sign but they exhibit intellectual disability and autistic signs as major clinical manifestations [19]. SSADH (succinil semialdehyde deshydrogenase deficiency) presents with intellectual disability and behavioural abnormalities as predominant signs. Nevertheless half of the affected individuals have epilepsy [20] which is more common in adults and may be progressive [21]. MUNC18 that codifies STXBP1 regulates synaptic vesicle exocytosis and therefore neurotransmission. SSADH is a defect of GABA metabolism leading to abnormal neuronal communication. Although every disease is unique in terms of clinical peculiarities and natural history, similar mechanisms tend to have similar spectrum of clinical signs. Synaptic vesicle disorders have been recently defined as a group of diseases which involve defects in the biogenesis, transport and synaptic vesicle cycle [5]. Interestingly, those disorders with a major expression at the pre-synaptic terminal (synaptic vesicle cycle of trafficking, exo-endocytosis) are more likely to encompass the ‘synaptopathy spectrum signs’, whereas trafficking and processing of the synaptic vesicle at the soma compartment are related to complex, early and often multisystem diseases. Synaptic vesicle axonal transport defects are linked to spastic paraparesis, axonal neuropathy and cortical malformations [5]. Finally, some synaptopathies lead to impaired quality control mechanisms, in particular abnormal autophagy, and neurodegeneration, such as some parkinsonism-related diseases [5,6].

Complex motor presentations (‘motor spectrum’)

Diseases leading to abnormal motor symptoms are related to brain structures and circuits that regulate voluntary and passive movements, strength and muscle tone. In paediatrics complex motor presentations are not rare. In fact, the younger the patients the higher likelihood of detecting combinations of different motor signs (dyskinetic movements, pyramidal signs, hypotonia, ataxia...). As an example around 80% of spastic paraparesis are complex, with other neurological signs associated, and in particular motor signs [Ortez et al, in preparation]. The opposite situation is observed in adults, where most spastic paraparesis (90%) are pure. The disorders of synthesis, remodelling, trafficking, processing and quality control of complex molecules are the most common within this group. In particular, complex lipid synthesis and remodelling defects, and axonal trafficking of organelles [6].

Conclusions

Currently, child neurology is undergoing a process of rapid transformation. The huge technological improvement of diagnostic tools as well as of the techniques of exploration of the nervous system are leading to continuous scientific breakthroughs. One of the major challenges for child neurologists in these times of change is to learn how to combine excellent clinical practice with enough knowledge about mechanism of disease, basic neuroscience and other technical skills. Recent advances in IEMs are bringing interesting ideas and procedures that will be rapidly extended to clinical neurology. Although every disease is unique in terms of clinical peculiarities, specific signs, and natural history, similar pathophysiological mechanisms and neuronal compartment location tend to have similar spectrum of symptoms. Metabolism and cell biology functions are very well compartmentalized in the nervous system and together with the definition of brain networks, will provide the main elements to construct new paradigms of clinical approach in child neurology.

Bibliografía

↵ 1. Saudubray JM, García-Cazorla A. Inborn errors of metabolism overview: pathophysiology, manifestations, evaluation, and management. Pediatr Clin North Am 2018; 65: 179-208.

↵ 2. Lamari F, Mochel F, Saudubray JM. An overview of inborn errors of complex lipid biosynthesis and remodelling. J Inherit Metab Dis 2015; 38: 3-18.

↵ 3. García-Cazorla A, Mochel F, Lamari F, et al. The clinical spectrum of inherited diseases involved in the synthesis and remodeling of complex lipids. A tentative overview. J Inherit Metab Dis 2015; 38: 19-40.

↵ 4. Ebrahimi-Fakhari D, Saffari A, Wahlster L, et al. Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism. Brain 2016; 139 (Pt 2): 317-37.

↵ 5. Cortès-Saladelafont E, Tristán-Noguero A, Artuch R, et al. Diseases of the synaptic vesicle: a potential new group of neurometabolic disorders affecting neurotransmission. Semin Pediatr Neurol 2016; 23: 306-20.

↵ 6. García-Cazorla A, Saudubray JM, Cellular neurometabolism: a tentative to connect cell biology and metabolism in neurology. JIMD 2018 [in press].

↵ 7. Frazier AE, Thorburn DR, Compton AG. Mitochondrial energy generation disorders: genes, mechanisms and clues to pathology. J Biol Chem 2017; Dec 12. [Epub ahead of print].

↵ 8. Ehmke N, Graul-Neumann L, Smorag L, et al. De novo mutations in SLC25A24 cause a craniosynostosis syndrome with hypertrichosis, progeroid appearance, and mitochondrial dysfunction. Am J Hum Genet 2017; 101: 833-43.

↵ 9. Wallen RC, Antonellis A. To charge or not to charge: mechanistic insights into neuropathy-associated tRNA synthetase mutations. Curr Opin Genet Dev 2013; 23: 302-9.

↵ 10. Smits P, Smeitink J, Van den Heuvel L. Mitochondrial translation and beyond: processes implicated in combined oxidative phosphorylation deficiencies. J Biomed Biotechnol 2010; 2010: 737385.

↵ 11. Mills E, Green R. Ribosomopathies: there’s strength in numbers. Science 2017; 358: 608-16.

↵ 12. Edvardson S, Nicolae CM, Agrawal PB, et al. Heterozygous de novo UBTF gain-of-function variant is associated with neurodegeneration in childhood. Am J Hum Genet 2017; 101: 267-73.

↵ 13. Butcher DT, Cytrynbaum C, Turinsky AL, et al. CHARGE and Kabuki syndromes: gene-specific DNA methylation signatures identify epigenetic mechanisms linking these clinically overlapping conditions. Am J Hum Genet 2017; 100: 773-88.

↵ 14. Acuña-Hidalgo R, Schanze D, Kariminejad A, et al. Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway. Am J Hum Genet 2015; 95: 285-93.

↵ 15. Häberle J, Görg B, Rutsch F, et al. Congenital glutamine deficiency with glutamine synthetase mutations. N Engl J Med 2005; 353: 1926-33.

↵ 16. Ruzzo EK, Capo-Chichi JM, Ben-Zeev B, et al. Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy. Neuron 2013; 80: 429-41.

↵ 17. Guemez-Gamboa A, Nguyen LN, Yang H, et al. Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome. Nat Genet 2015; 47: 809-13.

↵ 18. Cullup T, Kho AL, Dionisi-Vici C, et al. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat Genet 2013; 45: 83-7.

↵ 19. Stamberger H, Nikanorova M, Willemsen MH, et al. STXBP1 encephalopathy: a neurodevelopmental disorder including epilepsy. Neurology 2016; 86: 954-62.

↵ 20. Pearl PL, Gibson KM, Acosta MT, et al. Clinical spectrum of succinic semialdehyde dehydrogenase deficiency. Neurology 2003; 60: 1413-7.

↵ 21. Lapalme-Remis S, Lewis EC, De Meulemeester C, et al. Natural history of succinic semialdehyde dehydrogenase deficiency through adulthood. Neurology 2015; 85: 861-5.

↵ 22. De Koning TJ. Amino acid synthesis deficiencies. J Inherit Metab Dis 2017; 40: 609-20.

↵ 23. Sprecher E, Ishida-Yamamoto A, Mizrahi-Koren M, et al. A mutation in SNAP29, coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma. Am J Hum Genet 2005; 77: 242-51.

↵ 24. Fuchs-Telem D, Stewart H, Rapaport D, et al. CEDNIK syndrome results from loss-of-function mutations in SNAP29. Br J Dermatol 2011; 164: 610-6.

↵ 25. Hahn KA, Salomons GS, Tackels-Horne D, et al. X-linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-gene (SLC6A8) located in Xq28. Am J Hum Genet 2002; 70: 1349-56.

↵ 26. Kleefstra T, Rosenberg EH, Salomons GS, et al. Progressive intestinal, neurological and psychiatric problems in two adult males with cerebral creatine deficiency caused by an SLC6A8 mutation. Clin Genet 2005; 68: 379-81.

↵ 27. Conroy J, Allen NM, Gorman KM, et al. NAPB –a novel SNARE– associated protein for early-onset epileptic encephalopathy. Clin Genet 2016; 89: E1-3.

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.

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