Moving Beyond Syndromic Classifications in Neurodegenerative Disease: The Example of PLA2G6
2016-12-10

Clinical practice in neurodegenerative diseases commonly attempts to find a correct diagnosis and to predict underlying gene defects by grouping symptoms and patterns of neuronal systems damage into clinical syndromes. This way of neurological thinking in terms of clinical syndromes, however, is now increasingly challenged. Neurogenetic studies during the last 5 to 10 years not only have broadened the phenotypic spectrum of most diseases, they have also torn down the classification walls between many syndromes. Specifically, it has been realized that many clinical syndromes are not discrete entities but, rather, represent variably combined phenotypic clusters along a continuous spectrum. This change of concept is strongly driven by the wide-spread use of whole-exome sequencing (WES), which allows the genetic screening of many genes unbiased by prior clinical phenotype-based conjectures. In contrast, more targeted approaches, like Sanger or panel sequencing, are techniques constrained by pre-existing clinical conceptions, classifications, and diagnostic work flows. To put it simple, they largely allowed to find only what was already suspected based on prior phenotype assumptions. Two recent case series9, 10 have now demonstrated that syndromes caused by biallelic mutations in phospholipase A2 group VI (PLA2G6) (Online Mendelian Inheritance in Man no. 60360) also are examples of this general insight. From a clinical diagnostic standpoint, the 3 PLA2G6-associated syndromes appear as distinct, age-related syndromes (Fig. 1A): (1) Infantile neuroaxonal dystrophy (INAD) starts in early infancy before age 3 years and presents with psychomotor regression, ataxia, optic atrophy, and later spastic tetraparesis, with death usually in the first decade of life. (2) Atypical neuroaxonal dystrophy (atypical NAD), with onset in childhood or adolescence, presents with psychomotor regression, language and learning difficulties, ataxia, dystonia, and spasticity. (3) Dystonia-parkinsonism (PARK14) presents in early adulthood with (mildly) levodopa (l-dopa) responsive parkinsonism, dystonia, and cognitive decline but without prominent ataxia or sensory disturbances. Although it is known that all 3 syndromes are multisystemic and can include signs of brain iron accumulation on magnetic resonance imaging (thus also referred to as neurodegeneration with brain iron accumulation type 2 [NBIA2]), they were thus classified according to their most striking clinical features and their age of onset. Erro and colleagues have now demonstrated that disease courses do not respect the conceptual boundaries of these syndromes: 1 patient with a PLA2G6 mutation (Case 1) presented with infancy-onset ataxia, neurobehavioral features later on, and l-dopa-responsive parkinsonism in his teens, thus running across all 3 syndrome categories. The same is true for the other 2 patients. Case 2 had infancy-onset ataxia, with parkinsonism, spasticity, dystonia, and neuropathy developing in his late teens. Case 3 did not have ataxia or parkinsonism before the third decade life (although, interestingly, her brother had signs of the classic PARK14 syndrome). Pérez-Torre and colleagues further support this notion of a continuous phenotypic spectrum of PLA2G6-associated syndromes occurring not only between families, but also within families. In a family with 2 affected siblings, 1 presented with an atypical NAD, and the other presented with INAD. These reports on a continuous intrafamilial disease spectrum indicate that neither the biallelic PLA2G6 mutations per se nor the mutational class of PLA2G mutations (truncating, missense, etc.) alone can fully explain the phenotypic presentation. Rather, other genetic or environmental factors, acting as modifiers for disease onset, disease progression and disease phenotype, will need to be identified—a challenge that applies to both PLA2G6 as well as all of the other disease spectrum genes mentioned above. At the same time, PLA2G6 is a reminder not to define clinical syndromes too narrowly in the first place and to be more restrictive with coining distinct designations. On a closer look, at the conceptual level, all 3 PLA2G6 syndromes show not only a relatively constrained, overlapping age of onset (all are early onset, if the defined age of early onset is before 30 or 40 years) but also a substantial overlap in the brain systems they affect: cerebellum (ataxia), nigrostriatal and other basal ganglia systems (parkinsonism, dystonia), upper motor neuron (spasticity, hyperreflexia), and cerebral cortical/subcortical networks (psychomotor regression, cognitive decline, neuropsychiatric disturbances). There is certainly pragmatic clinical value in classifying neurodegenerative diseases according to their most striking feature as well as their age of onset, particularly to help guide management and symptomatic treatment. However, rigid diagnostic classification systems may hamper identification of the underlying genetic cause and development of disease-modifying therapies. A more descriptive, multidimensional depiction of the main features and the corresponding affected brain systems would allow a less biased and more systematic perspective, which is open to expansion of the phenotype. Such a perspective also prevents clinical engrams that are too narrowminded when looking for the right diagnosis in previously unexplained, complex neurodegenerative disease. Correspondingly, we suggest viewing PLA2G6-associated disease not in terms of the syndromes (Fig. 1A); rather, it should be conceptualized as a fluid, complex, multisystemic, early onset neurodegenerative disease affecting various regions and/or systems of the nervous system (cerebellar, extrapyramidal, pyramidal, cortical, visual, and peripheral) defined by disturbed PLA2G6 function that translates phenotypically into a multidimensional spectrum of variably associated signs and symptoms, including progressive cognitive impairment, ataxia, parkinsonism, spasticity, dystonia, visual loss, and peripheral neuropathy (Fig. 1B). We suggest using the same approach for the other neurodegenerative diseases listed above. One may go even 1 step further. Although it is increasingly appreciated that it is better to group clinical diseases not by the clinical presentations or syndromes but by the underlying defining gene, a novel classification might even try to group diseases by the molecular mechanism/pathway. Under the surface of the seemingly disparate clinical syndromic and diagnostic classifications lurk not only allelic genes, but also shared mechanisms and pathways. For example, PLA2G6 encodes calcium-independent group VI phospholipase A2 (iPLA2-VI), a calcium-independent phospholipase. It can be grouped with the disorders of phospholipid membrane remodeling or, in a broader sense, with complex lipid diseases.11 Here, it is joined by other membrane remodeling diseases and genes that, at first glance, seem to be relatively different, such as PNPLA6 (causing early onset ataxia, HSP/spastic paraplegia-39 [SPG39]) and/or retinal phenotypes5, 6, 12), DDHD domain containing 1 (DDHD1) and DDHD2 (causing HSP phenotypes/SPG5413), or abhydrolase domain containing 12 (ABHD12) (causing retinal and ataxia phenotypes14; for an overview, see Lamari et al.11). Regrouping PLA2G6 disease according to the molecular mechanism has important consequences for clinical and scientific thinking: It would no longer be grouped primarily as INAD/atypical NAD/PARK14 or as any type of NBIA. Rather, it would be grouped by but, by the same pathways, as clinically very different other diseases that may not exhibit any of these clinical features and may have no brain iron accumulation. Although the advantage might not be primarily on the clinical diagnostic level, it is certainly in the domain of developing targeted molecular treatments: the identification of mechanisms and pathways shared by various diseases will place stronger research priorities and extended possibilities on developing drugs for these mechanisms/pathways. It might then be possible to treat not only 1 type of disease with the developed compound, but also other diseases from this mechanism-based class of diseases. 1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. M.S.: 1A, 3A T.G.: 1A, 3B Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: The research by Matthis Synofzik is funded, in part, by the German Federal Ministry of Education and Research (BMBF) (ERARE JTC “PREPARE,” Kz. 01GM1607), which includes the general research background for preparing this manuscript. Thomas Gasser received no specific funding for this work. Financial Disclosures for the previous 12 months: Matthis Synofzik has received funding from the Robert Bosch Stiftung and the BMBF as well as honoraria from Actelion Pharmaceuticals, all unrelated to this article. Thomas Gasser has received speaker's honoraria from UCB and MedUpdate. He has received grant support from the German Research Foundation (DFG), the BMBF, the European Commission, the Helmholtz Association, the Michael J. Fox Foundation, and the Charitable Hertie-Foundation, all unrelated to this article.