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Review
. 2016 Feb;139(Pt 2):317-37.
doi: 10.1093/brain/awv371. Epub 2015 Dec 29.

Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism

Darius Ebrahimi-Fakhari  1 , Afshin Saffari  2 , Lara Wahlster  3 , Jenny Lu  4 , Susan Byrne  5 , Georg F Hoffmann  2 , Heinz Jungbluth  6 , Mustafa Sahin  4
Affiliations
Review

Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism

Darius Ebrahimi-Fakhari et al. Brain. 2016 Feb.

Abstract

Single gene disorders of the autophagy pathway are an emerging, novel and diverse group of multisystem diseases in children. Clinically, these disorders prominently affect the central nervous system at various stages of development, leading to brain malformations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration, among others. Frequent early and severe involvement of the central nervous system puts the paediatric neurologist, neurogeneticist, and neurometabolic specialist at the forefront of recognizing and treating these rare conditions. On a molecular level, mutations in key autophagy genes map to different stages of this highly conserved pathway and thus lead to impairment in isolation membrane (or phagophore) and autophagosome formation, maturation, or autophagosome-lysosome fusion. Here we discuss 'congenital disorders of autophagy' as an emerging subclass of inborn errors of metabolism by using the examples of six recently identified monogenic diseases: EPG5-related Vici syndrome, beta-propeller protein-associated neurodegeneration due to mutations in WDR45, SNX14-associated autosomal-recessive cerebellar ataxia and intellectual disability syndrome, and three forms of hereditary spastic paraplegia, SPG11, SPG15 and SPG49 caused by SPG11, ZFYVE26 and TECPR2 mutations, respectively. We also highlight associations between defective autophagy and other inborn errors of metabolism such as lysosomal storage diseases and neurodevelopmental diseases associated with the mTOR pathway, which may be included in the wider spectrum of autophagy-related diseases from a pathobiological point of view. By exploring these emerging themes in disease pathogenesis and underlying pathophysiological mechanisms, we discuss how congenital disorders of autophagy inform our understanding of the importance of this fascinating cellular pathway for central nervous system biology and disease. Finally, we review the concept of modulating autophagy as a therapeutic target and argue that congenital disorders of autophagy provide a unique genetic perspective on the possibilities and challenges of pathway-specific drug development.

Keywords: autophagy; inborn errors of metabolism; mammalian target of rapamycin (mTOR); neurodegeneration; neurodevelopment.

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Figures

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Mutations in autophagy genes cause childhood-onset multisystem diseases with predominant nervous system involvement and provide a ‘genetic window’ into autophagy's role in neurobiology and disease. In this review, Ebrahimi-Fakhari et al. examine the clinical and molecular spectrum of ‘congenital disorders of autophagy’, a novel class of inborn errors of metabolism.
Figure 1
Figure 1
The three main subtypes of autophagy and their implications for multiple tissues and organ systems. Autophagy mainly comprises of three subtypes: microautophagy, chaperone-mediated autophagy and macroautophagy. These are distinguished based on the route and mechanism of cargo delivery to lysosomes, the final degrading organelles. Research over the last decades has elucidated a number of cell and tissue-specific functions that depend on or are critically influenced by autophagy. These functions are present in many organ systems, including the nervous system. The variety of functions of autophagy in different organ systems under physiological conditions is emphasized by the broad clinical manifestations in congenital disorders of autophagy, which manifest as multisystem diseases with prominent CNS pathology. CMA = chaperone-mediated autophagy.
Figure 2
Figure 2
Macroautophagy: an overview of the molecular pathway and mutations associated with congenital disorders of autophagy. Macroautophagy is a step-wise process resulting in the formation of double-membrane-bound autophagic vesicles that engulf their cargo before fusing with lysosomes. The principle stages of macroautophagy include: (I) initiation; (II) nucleation of an isolation membrane (also called phagophore); (III) elongation of evolving autophagic vesicles; (IV) engulfment of cargo and closure of the autophagosomal membrane; (V) autophagosome maturation; (VI) fusion with late endosomes or lysosomes; and finally (VII) degradation of cargo through lysosomal hydrolases. The last step yields basic metabolites that are then recycled. Mutations in congenital disorders of autophagy and single gene disorders associated with deficits in the regulation of autophagy impair different stages of the pathway. Through interfering with the beclin 1 complex, hereditary spastic paraplegia-associated recessive mutations in ZFYVE26 (SPG15) impair early stages such as the formation of the isolation membrane. Mutations in TECPR2 (SPG49) were recently shown to be critically involved in maintaining endoplasmic reticulum exit sites that may serve as scaffolds for the formation of early autophagosome intermediates. X-linked WDR45 mutations cause beta-propeller protein-associated neurodegeneration (BPAN) and have been found to potentially interfere with the elongation of nascent autophagic vesicles. Autosomal-recessive EPG5 mutations in Vici syndrome as well as SNX14 mutations in SNX14-associated autosomal-recessive cerebellar ataxia and intellectual disability syndrome impact the late stages of the autophagy pathway through impairing autophagosome-lysosome fusion. Mutations in SPG11 (SPG11) lead to a defect in autophagic lysosome reformation. Autophagy-associated diseases also affect different stages of autophagy regulation. An example for mTOR-associated neurodevelopmental diseases, loss-of-function mutations in TSC1 or TSC2 in tuberous sclerosis complex lead to constitutive activation of mTORC1 and thus block autophagic flux at multiple stages. Locating the defect to the late stages of the pathway, lysosomal storage diseases impact lysosomal metabolism and thus block upstream steps in the autophagy pathway. Impaired crosstalk between the lysosomal pathway and autophagosome biogenesis might also impact the coordinated regulation of both compartments. AR-CAID = autosomal-recessive cerebellar ataxia and intellectual disability syndrome; LSD = lysosomal storage disease; TSC = tuberous sclerosis complex.
Figure 3
Figure 3
Vici syndrome: a multisystem disease. Mutations in the autophagy gene EPG5 cause Vici syndrome, a paradigm for multisystem diseases associated with defective autophagy. The eight cardinal features of Vici syndrome consist of agenesis of the corpus callosum, acquired microcephaly, bilateral cataracts, hypertrophic or dilated cardiomyopathy, combined immunodeficiency, and skin, hair or retinal hypopigmentation, failure to thrive and profound developmental delay. CNS manifestations are manifold and include congenital brain malformations such as agenesis of the corpus callosum with colpocephaly, cerebellar hypoplasia, hypoplasia/atrophy of the brainstem, abnormalities of the septum pellucidum, opercular hypoplasia and probably age-dependent abnormal T2 signal in the thalami. Dysgenesis of the falx, non-lissencephalic cortical dysplasia, polymicrogyria of the cerebral hemispheres, or bilateral schizencephaly have also been reported in a few individuals. Delayed myelination and diffuse white matter atrophy are commonly reported. Pointing to the potential presence of a neurodegenerative phenotype in addition to prominent deficits in brain development, dilated ventricles, Purkinje cell loss, and diffuse cerebral atrophy have been described in a subset of patients.
Figure 4
Figure 4
BPAN: natural history of a biphasic disease. Patients with WDR45-mutation associated BPAN commonly present with a distinct biphasic clinical course. Initial manifestations in infancy or early childhood consist of global developmental delay, intellectual disability, and seizures, which tend to progress in the later stages of the disease. Cerebellar ataxia, spasticity, Rett-like hand stereotypies, and autistic features have also been reported in a subset of patients. The disease advances in adolescence or early adulthood when dystonia, parkinsonism, and progressive cognitive decline become prominent. Other manifestations often include bladder and bowel incontinence, disordered sleep, and visual and auditory deficits.
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