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Cellular trafficking is essential to maintain critical biological functions. Mutations in 346 genes, most of them described in the last 5 years, are associated with disorders of cellular trafficking. Whereas initially restricted to membrane trafficking, the recent detection of many diseases has contributed to the discovery of new biological pathways. Accordingly, we propose to redesign this rapidly growing group of diseases combining biological mechanisms and clinical presentation into the following categories: (i) membrane trafficking (including organelle-related); (ii) membrane contact sites; (iii) autophagy; (iv) cytoskeleton-related. We present the most recently described pathophysiological findings, disorders and phenotypes. Although all tissues and organs are affected, the nervous system is especially vulnerable.

In view of the rapidly expanding number of IMD discovered by next generation sequencing, we propose a simplified classification of IMD that mixes elements from a clinical diagnostic perspective and a pathophysiological approach based on three large categories. We highlight the increasing importance of complex molecule metabolism and its connection with cell biology processes. Small molecule disorders have biomarkers and are divided in two subcategories: accumulation and deficiency. Accumulation of small molecules leads to acute or progressive postnatal "intoxication", present after a symptom-free interval, aggravated by catabolism and food intake. These treatable disorders must not be missed! Deficiency of small molecules is due to impaired synthesis of compounds distal to a block or altered transport of essential molecules. This subgroup shares many clinical characteristics with complex molecule disorders. Complex molecules (like glycogen, sphingolipids, phospholipids, glycosaminoglycans, glycolipids) are poorly diffusible. Accumulation of complex molecules leads to postnatal progressive storage like in glycogen and lysosomal storage disorders. Many are treatable. Deficiency of complex molecules is related to the synthesis and recycling of these molecules, which take place in organelles. They may interfere with fœtal development. Most present as neurodevelopmental or neurodegenerative disorders unrelated to food intake. Peroxisomal disorders, CDG defects of intracellular trafficking and processing, recycling of synaptic vesicles, and tRNA synthetases also belong to this category. Only few have biomarkers and are treatable. Disorders involving primarily energy metabolism encompass defects of membrane carriers of energetic molecules as well as cytoplasmic and mitochondrial metabolic defects. This oversimplified classification is connected to the most recent available nosology of IMD.

The specialty of inherited metabolic disease is at the forefront of progress in medicine, with new methods in metabolomics and genomics identifying the molecular basis for a growing number of conditions and syndromes. This review presents an updated pathophysiologic classification of inborn errors of metabolism and a method of clinical screening in neonates, late-onset emergencies, neurologic deterioration, and other common clinical scenarios. When and how to investigate a metabolic disorder is presented to encourage physicians to use sophisticated biochemical investigations and not miss a treatable disorder.

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.

It has become increasingly evident that inborn errors of metabolism (IEMs) are particularly prevalent as diseases of the nervous system and that a broader, more inclusive definition of IEM is necessary. In fact, as long as biochemistry is involved, any kind of monogenic disease can become an IEM. This new, extended definition includes new categories and mechanisms, and as a general trend will go beyond a single biochemical pathway and/or organelle, and will appear as a connection of multiple crossroads in a system biology approach.From one side, a simplified and updated classification of IEM is presented that mixes elements from the diagnostic approach with pathophysiological considerations into three large categories based on the size of molecules ("small and simple" or "large and complex") and their implication in energy metabolism. But from another side, whatever their size, metabolites involved in IEM may behave in the brain as signalling molecules, structural components and fuels, and many metabolites have more than one role. Neurometabolism is becoming more relevant, not only in relation to these new categories of diseases but also as a necessary way to explain the mechanisms of brain damage in classically defined categories of IEM. Brain metabolism, which has been largely disregarded in the traditional approach to investigating and treating neurological diseases, is a major clue and probably the next imminent "revolution" in neurology and neuroscience. Biochemistry (metabolism) and cell neurobiology need to meet. Additionally, the brain should be studied as a system (connecting different levels of complexity).

Inborn errors of metabolism (IEMs) are particularly frequent as diseases of the nervous system. In the pediatric neurologic presentations of IEMs neurodevelopment is constantly disturbed and in fact, as far as biochemistry is involved, any kind of monogenic disease can become an IEM. Clinical features are very diverse and may present as a neurodevelopmental disorder (antenatal or late-onset), as well as an intermittent, a fixed chronic, or a progressive and late-onset neurodegenerative disorder. This also occurs within the same disorder in which a continuum spectrum of severity is frequently observed. In general, the small molecule defects have screening metabolic markers and many are treatable. By contrast only a few complex molecules defects have metabolic markers and most of them are not treatable so far. Recent molecular techniques have considerably contributed in the description of many new diseases and unexpected phenotypes. This paper provides a comprehensive list of IEMs that affect neurodevelopment and may also present with neurodegeneration.

Pyruvate dehydrogenase complex (PDHc) is a thiamine dependent key enzyme for energy production which catalyses decarboxylation of pyruvate into acetyl CoA for the Krebs cycle.1 PDHc deficiency is generally (80%) caused by mutations in the E1α subunit gene, PDHA1 , located on chromosome Xp22.1, but other genes have been reported to be mutated (eg, PDHX , encoding the E3 binding protein, DLAT , encoding the E2 subunit PDHX, and PDHB , encoding the E1 beta subunit). The disease usually presents with lactic acidosis, psychomotor retardation and Leigh syndrome leading to death or severe handicap in infancy or childhood.1 Mild forms, compatible with surviving into adulthood, have rarely been reported. A 26-year-old man was born at 8 months’ gestation, following maternal eclampsia. His psychomotor development was normal. From the age of 2 years he suffered from paroxysmal walking difficulties that appeared exclusively during fever episodes. These “crises” lasted from several hours to days during which he experienced limb weakness and ataxia. One episode was remarkable for blurring of consciousness and another for external ophthalmoplegia. Episodes persisted until adulthood at a frequency of approximately 1 per year. In between crises, the patient had kyphoscoliosis, absent tendon reflexes, pes cavus and mild …

Hypokalemic periodic paralysis (hypoPP) is an autosomal dominant disorder belonging to a group of muscle diseases involving the abnormal function of ion channels. This group of muscle diseases also comprises hyperkalemic periodic paralysis and paramyotonia congenita, both sodium-channel diseases, and myotonia congenita, a chloride-channel disorder. HypoPP is characterized by acute attacks of muscle weakness concomitant with a fall in blood potassium levels. We recently localized the hypoPP locus (hypoPP1) to chromosome 1q31-32, in an interval where the alpha 1 subunit of the dihydropyridine receptor calcium channel (CACNL1A3) also maps. Subsequently, deleterious mutations in the voltage-sensor segment S4 were found, establishing the dihydropyridine receptor CACNL1A3 as the causative gene for hypoPP. In this paper, we report the study of 16 hypoPP families of Caucasian origin. found only two mutations-Arg528His and Arg1239His-that cosegregated with hypoPP, each in half of the families. Analysis of the clinical characteristics of both groups of families demonstrated that incomplete penetrance is a distinctive feature of the Arg528His mutation. Using dinucleotide repeats contained within or close to the dihydropyridine receptor gene, in conjunction with evidence of a de novo Arg1239His mutation, we show that a founder effect is unlikely to account for the two predominant mutations.