• Gorka Fernández-Eulate, Christophe Carreau, Jean-François Benoist, Foudil Lamari, Benoit Rucheton, Natalia Shor, and Yann Nadjar.
• Neuro-Metabolism Unit, Reference Center for Lysosomal Diseases, Neurology Department, Pitié-Salpêtrière University Hospital, APHP, Paris, France.
• J. Neurol. Neurosurg. Psychiatr. 2022 Apr 1; 93 (4): 413-421.

AbstractNeurometabolic diseases are a group of individually rare but numerous and heterogeneous genetic diseases best known to paediatricians. The more recently reported adult forms may present with phenotypes strikingly different from paediatric ones and may mimic other more common neurological disorders in adults. Furthermore, unlike most neurogenetic diseases, many neurometabolic diseases are treatable, with both conservative and more recent innovative therapeutics. However, the phenotypical complexity of this group of diseases and the growing number of specialised biochemical tools account for a significant diagnostic delay and underdiagnosis. We reviewed all series and case reports of patients with a confirmed neurometabolic disease and a neurological onset after the age of 10 years, with a focus on the 36 treatable ones, and classified these diseases according to their most relevant clinical manifestations. The biochemical diagnostic approach of neurometabolic diseases lays on the use of numerous tests studying a set of metabolites, an enzymatic activity or the function of a given pathway; and therapeutic options aim to restore the enzyme activity or metabolic function, limit the accumulation of toxic substrates or substitute the deficient products. A quick diagnosis of a treatable neurometabolic disease can have a major impact on patients, leading to the stabilisation of the disease and cease of repeated diagnostic investigations, and allowing for familial screening. For the aforementioned, in addition to an exhaustive and clinically meaningful review of these diseases, we propose a simplified diagnostic approach for the neurologist with the aim to help determine when to suspect a neurometabolic disease and how to proceed in a rational manner. We also discuss the place of next-generation sequencing technologies in the diagnostic process, for which deep phenotyping of patients (both clinical and biochemical) is necessary for improving their diagnostic yield.© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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