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Emerging role for sphingolipids in the genetics of amyotrophic lateral sclerosis
  1. Matthew C Kiernan1,2,
  2. Michelle Anne Farrar3,4
  1. 1 Bushell Chair of Neurology, Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia
  2. 2 Neurology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
  3. 3 Neurology, Sydney Children's Hospital Randwick, Randwick, New South Wales, Australia
  4. 4 School of Women's and Children's Health, UNSW Medicine, UNSW, Sydney, New South Wales, Australia
  1. Correspondence to Professor Matthew C Kiernan, Bushell Chair of Neurology, Brain and Mind Centre, University of Sydney, Sydney, Australia; matthew.kiernan{at}

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Neurodevelopmental contributions to disease causation

While the mechanisms that trigger the development of amyotrophic lateral sclerosis (ALS) remain to be determined, recent decades have witnessed a surge of clinical and community interest, and the emergence of a therapeutic pipeline. At the most basic level of interpretation, neurodegeneration in ALS reflects a complex interplay between genetic factors and the environment, with consequent dysfunction of molecular pathways and network circuitry.1 Of relevance to this expanding knowledge about disease pathogenesis, the present issue of JNNP includes scientific report of a childhood-onset form of the disease, marked by progressive weakness, with evidence of upper and lower motor neuron degeneration,2 in the presence of normal sensory function.3 In this particular cohort of patients, elevated levels of ceramides were identified, with abnormal sphingolipid synthesis linked to the SPTLC2 gene thought to underlie this monogenic form of juvenile ALS.3

With this most recent discovery, the list of ALS genes continues to expand, with up to 20% of ALS heritability linked to genetic variants.1 Separate to these genetic associations, cumulative environmental exposures and epigenetic modifications appear likely to promote an individual across the disease-onset threshold. Of relevance, ALS is being increasingly viewed as a multistep process, based on mathematical models that were originally adapted from the study of cancer.4 Specifically, studies across European, Asian, Australian and Oceanic cohorts have demonstrated linear relationships between the natural log of the incidence and the log age, indicative of a multistep process that underlies the onset of ALS.4 5 In the context of genetic causes of ALS, such as SOD1 and c9orf72, while these variants may be sufficient to account for up to half of the required steps, confirming that genes predispose to ALS, non-genetic factors also remain clearly important.4 5 Of further relevance to the genetic underpinnings of ALS, and even more so to the paediatric condition spinal muscular atrophy (SMA), directed genetic therapies are now available, with dramatic benefits, particularly for SMA, not just in terms of survival, but also reflecting improvements in general health and well-being.6 Finally, the study by Syeda and colleagues suggests that serine supplementation may exacerbate the excess sphingolipid synthesis in this specific cohort of serine palmitoyltransferase (SPT) -associated ALS, and thereby should be avoided in such individuals.2

If we accept the genetic-environmental interplay at the nidus of ALS, how can we best consider the significant variability around the age of onset of disease, from early childhood through to late adulthood. Of relevance, it has been hypothesised that the seeds for ALS may evolve during the neonatal period, a time during which complex neuronal activity drives neurogenesis, the establishment of neuronal circuitry, with cell migration and differentiation, and the sprouting of axonal connections.7 It has been established that insults such as inflammation and hypoxia, may induce physiological dysfunction, thereby altering cortical architecture. In particular, damage induced via GABAergic circuits may alter the balance between cortical excitation and inhibition, critical for normal brain function.8 Of specific relevance to ALS, conditions such as autism, bipolar disease and schizophrenia have been linked to perinatal insults, with those conditions also associated across large kindreds of genetic ALS, particularly those with variants involving c9orf72.9

Identification of neurodevelopmental factors potentially involved in disease causation would certainly be a complex undertaking, that in the least would require longitudinal assessment of brain function, linked to precise phenotyping, combined with profiling of genomic, proteomic and environmental exposures. The rare monogenic diseases provide insights into the causal pathways of neurodegeneration, with Syeda and colleagues drawing attention to the importance of sphingolipids in neurodevelopment, plasticity and neurodegeneration. This expands the role for impairments in sphingolipid metabolism, from the recognised disturbances in catabolism in the sphingolipidoses to also include excess synthesis. Farber and Tay-Sachs diseases are among the former group of rare monogenic lysosomal storage disorders and have some similarities to the juvenile ALS described by Syeda and colleagues, with presenting features including infant or childhood onset weakness, spasticity and neurocognitive regression.10

Taken further, the potential combination of neurodevelopmental and genetic considerations into a multistep process may critically underlie the variability in ALS phenotypes. Unravelling the preclinical phase of ALS represents a complex undertaking, particularly in apparently sporadic disease, to dissect potential interplays between genetic, neonatal and environmental factors.11 While prolonged exposure to environmental toxins, when combined with excessive physical activity and changes in diet appear to be associated with the development of ALS, it is also generally accepted that these factors may be insufficient to trigger disease in the majority12 Of interest to the environmental considerations, the identification of the new SPTLC2 gene associated with a monogenic form of juvenile ALS, may provide further background for the discussion about environmental exposures, particularly in relation to alterations in the biochemical pathways related to serine metabolism and sphingolipids.2

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  • Twitter @nervecentrals, @imichellefarrar

  • Contributors MCK and MAF authored the Editorial Commentary.

  • Funding This study was funded by National Health and Medical Research Council (Practitioner Fellowship #1156093).

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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