Recessive AFG3L2 Mutation Causes Progressive Microcephaly, Early Onset Seizures, Spasticity, and Basal Ganglia
Alaa Eskandrani1, Amal AlHashem2, El-Sayed Ali3
1Division of Pediatric Neurology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
Background:
Mutations in AFG3L2, a gene encoding a subunit of the mitochondrion m-AAA protease, cause spinocerebellar ataxia type 28 and recessive spastic ataxia type 5. Neuroimaging shows cerebellar atrophy.
Methods:
Retrospective review of the patient charts including their clinical evaluation and molecular genetic, neurodiagnostic, and neuroradiological investigations.
Results:
We describe five members of a large consanguineous family with a severe mitochondrial disease phenotype in the form of regression of the developmental milestones in the first year of life, refractory epilepsy, progressive microcephaly, increased blood lactate, basal ganglia involvement, and premature death. Exome sequencing showed homozygous mutation of the AFG3L2 gene in all individuals: c.1714G>A (p.Ala572Thr).
Conclusions:
Our findings add to the phenotypic, neuroradiological, genetic, and biochemical spectrum of AFG3L2 mutations.
Insights
This study identifies a severe mitochondrial disease in a family caused by a mutation in the AFG3L2 gene. The findings expand the known spectrum of AFG3L2-related disorders.
Area of Science:
- Genetics
- Neuroscience
- Mitochondrial Biology
Background:
- Mutations in AFG3L2, a gene encoding a subunit of the mitochondrion m-AAA protease, are associated with spinocerebellar ataxia type 28 and recessive spastic ataxia type 5.
- Neuroimaging in these conditions often reveals cerebellar atrophy.
Observation:
- A consanguineous family presented with a severe mitochondrial disease phenotype including developmental regression, refractory epilepsy, progressive microcephaly, elevated blood lactate, basal ganglia involvement, and early mortality.
- Five affected family members were identified.
Findings:
- Exome sequencing revealed a homozygous mutation, c.1714G>A (p.Ala572Thr), in the AFG3L2 gene in all affected individuals.
- This mutation was linked to the severe, early-onset mitochondrial disease observed in the family.
Implications:
- This research broadens the understanding of the phenotypic, neuroradiological, genetic, and biochemical spectrum associated with AFG3L2 mutations.
- The findings highlight the critical role of AFG3L2 in mitochondrial function and neurological health, particularly in early development.
More Related Videos
06:41In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
08:04Identification and Classification of Position-specific GABAA Receptor Subunit Missense Variants for Their Role In Hippocampal Pyramidal Neurons
Published on: June 6, 2025
Related Concept Videos
01:11Genetic Lingo
01:43Incomplete Dominance
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
01:20Inborn Errors of Metabolism