Extensive study of five affected families provides some answers and more questions

Severe loss or complete absence of ATG7, an enzyme regulated by the ATG7 gene that is critical for autophagy, is characterized by neurodevelopmental disorders—however, some individuals with these mutations can reach population life expectancy, according to results from a study published in The New England Journal of Medicine.

“Our data suggest that impaired autophagy resulting from biallelic deleterious ATG7 variants is a cause of neurodevelopmental disorders involving neurologic, muscular, and endocrine hypofunction,” wrote researchers led by Jack J. Collier, PhD, of Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle Upon Tyne, UK. “These findings strengthen our understanding of autophagy in human disease and expand the spectrum of clinical phenotypes and genetic loci associated with congenital autophagy-deficient syndromes.”

The study authors included 12 patients from five families with recessive and detrimental mutations in the core autophagy protein ATG7—included patients demonstrated impaired autophagic flux and profound effects including neurodevelopmental deficits, facial dysmorphism, and ataxia.

Through extensive genetic, clinical, and neuroimaging studies, Collier and colleagues found:

  • Family 1 was characterized by recessively inherited loss-of-function ATG7 variants with reduced ATG7 expression, with the c.2080-2A→G splice-site variant causing replacement of canonical exon 19 with intron 18. Two female siblings had learning difficulties and ataxia, tremor, and proximal muscle weakness, along with bilateral sensorineural hearing loss and eye abnormalities. Facial dysmorphisms included a high arched palate, bum hypertrophy, a long, narrow face, and retrognathia. Upon neuroimaging, one sibling had moderate cerebellar hypoplasia and a thin posterior corpus callosum.
  • Family 2 was shown to have biallelic missense ATG7 variants that caused highly conserved amino acid residue. Two female siblings were wheelchair-bound due to spastic paraplegia and severe developmental delay. Both demonstrated congenital encephalopathy, axial hypotonia, truncal ataxia, and facial dysmorphism. One sibling had tonic-clonic seizures with recurrent episodes of status epilepticus. Both siblings had retinopathy, and one had optic atrophy. Neuroimaging revealed complex brain abnormalities, including severe cerebellar hypoplasia, thin posterior corpus callosum, and bilateral optochiasmatic atrophy.
  • Family 3 included a wheelchair-bound member with moderate developmental delay and congenital ataxia, facial dysmorphism, cerebellar hypoplasia, and a thin posterior corpus callosum. Biallelic missense ATG7 variants were again identified in one member of the family.
  • Family 4 was also characterized by recessive missense ATG7 variants and included two siblings with mild-to-moderate intellectual disability with ataxia and tremor or dyskinesia. Again, cerebellar hypoplasia and a thin posterior corpus callosum was revealed upon neuroimaging in both siblings. Facial dysmorphism and psychiatric conditions were also present, and included schizophrenic psychosis, aggression, and self-mutilating behavior. One sibling had late-onset dementia and an acoustic neuroma.
  • Family 5 was characterized by a homozygous ATG7 variant and comprised of seven siblings, of whom five were affected. Optic atrophy, seizures, and brain atrophy occurred in an infant sibling, who developed seizures, exhibited severe global neurodevelopmental delay and diffuse brain atrophy, and died at age 2. Three other siblings also had strabismus, visual impairment, and optic atrophy in infancy. All siblings had a similar clinical course, which included mild-to-moderate intellectual disability, delays in motor and language development, and tremor.

They also found that all patients with available MRI data exhibited cerebellar hypoplasia and abnormalities in the corpus callosum. None had liver abnormalities, however. In those with distinctive facial dysmorphism, clinical features included hypertrophic cardiomyopathy, ocular abnormalities, and deafness.

“An interesting observation made by Collier et al is the absence of correlation between the severity of the ATG7-dependent biochemical phenotype and that of the clinical one. For example, the patients from Family 2 had a substantial disease burden despite having a milder autophagy impairment. Although exome sequencing did not reveal additional mutations, it cannot be ruled out that there are additional disease-modifying genetic variations to account for these differences,” wrote Ian Ganley, PhD, of the University of Dundee, Dundee, UK, in an accompanying editorial.

Yet, the reverse was also true, noted Collier and colleagues: “Our investigations indicate that patients with this condition can approach population life expectancy (affected members of Family 4 have reached 68 and 71 years of age) despite severe attenuation of autophagic flux.”

According to Ganley, these findings raise several questions. “How, then, have these patients survived in the apparent absence of a functional macroautophagy pathway? This question remains to be answered, and the result calls into question the essential nature of macroautophagy; clearly, however, protein and organelle turnover are still occurring to some degree, because accumulations of cellular ’junk’ was not observed. Thus, it can be assumed that compensatory pathways have been up-regulated,” he wrote.

“In one sense, this offers a glimmer of hope, and although it will be important to determine whether this is indeed the case, the identification of such pathways will be essential in formulating approaches to the treatment of syndromes in which autophagic degradation is impaired,” Ganley concluded.

  1. Severe loss or complete absence of ATG7, an enzyme regulated by the ATG7 gene that is critical for autophagy, is characterized by neurodevelopmental disorders and involves hypofunction of the neurologic, muscular, and endocrine systems.

  2. Some individuals with ATG7 mutations that cause impaired ATG7 production can reach population life expectancy.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

This study was supported by grants from the Wellcome Centre for Mitochondrial Research, the Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease, the Mitochondrial Disease Patient Cohort (United Kingdom), the Lily Foundation, and the NHS Specialised Commissioners, who fund the “Rare Mitochondrial Disorders of Adults and Children” Service in Newcastle Upon Tyne; PhD funding from the Barbour Foundation and an EMBO Short Term Fellowship; the Academy of Finland, Novo Nordisk Foundation, Sigrid Juselius Foundation, Finnish Cardiovascular Foundation, and University of Helsinki; grants from the French National Agency for Research and the “Association Française contre les Myopathies;” the European Union Horizon 2020 research and innovation program; grants from the European Union Horizon 2020 program and the Swiss National Science Foundation; and a Medical Research Council UK Clinician Scientist Fellowship.

Collier has reported receiving research grants from the Barbour Foundation and the European Molecular Biology Organization.

Ganley reported personal fees from Mitobridge Inc. and grants from GlaxoSmithKline, outside the submitted work.

Cat ID: 497

Topic ID: 495,497,497,730,130,138,192,925