ABSTRACT
BACKGROUND: Mutations in AIMP1, which plays an important role in the development and maintenance of axon-cytoskeleton integrity and regulating neurofilaments, cause neurodegeneration of variable severity and white matter abnormalities. METHODS: From the patient records we analyzed the clinical evaluation, molecular genetics, neurodiagnostic, and neuroradiological investigations. RESULTS: We describe six members of a large consanguineous family with a phenotype of severe neurodegeneration in the form of developmental delays, progressive microcephaly, epilepsy, and failure to thrive. MRI showed callosal atrophy and T2 hyperintensity in the superficial white matter. The periventricular and deep white matter structures were, however, preserved. MR spectroscopy demonstrated N-acetylaspartate preservation without evidence of neuroinflammation. Exome sequencing showed a novel homozygous mutation of the AIMP1 gene in all individuals: c.917A>G (p.(Asp306Gly)). CONCLUSIONS: This novel homozygous mutation of the AIMP1 gene is characterized by preserved development of the periventricular and deep white matter structures as demonstrated by MRI and MR spectroscopy correlation.
Subject(s)
Aspartic Acid/analogs & derivatives , Cytokines/genetics , Neoplasm Proteins/genetics , Neurodegenerative Diseases , RNA-Binding Proteins/genetics , White Matter/pathology , Adolescent , Adult , Aspartic Acid/metabolism , Child , Consanguinity , Developmental Disabilities/etiology , Developmental Disabilities/genetics , Epilepsy/etiology , Epilepsy/genetics , Failure to Thrive/etiology , Failure to Thrive/genetics , Female , Humans , Magnetic Resonance Imaging , Male , Microcephaly/etiology , Microcephaly/genetics , Mutation , Neurodegenerative Diseases/complications , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Pedigree , Phenotype , White Matter/diagnostic imaging , Young AdultABSTRACT
Both malformations of the central nervous system and neurometabolic disorders are common, mainly in highly consanguineous populations. Both metabolic pathways and developmental pathways are closely related and interact with each other. Neurometabolic disorders can lead to disturbances in brain development through multiple mechanisms that include deficits in energy metabolism, critical nutrient deficiency, accumulation of neurotoxic substrates, abnormality in cell membrane constituents, and interference in cell-to-cell signaling pathways. The anomalies observed include absent or hypoplastic corpus callosum, midline brain defects, and malformations of the cortex, the cerebellum and the brain stem. Early diagnosis of an underlying inherited neurometabolic disorders is critical for the institution of treatment, which may positively influence prognosis, and allow for proper genetic counseling. In this review, we discuss those disorders in which the structural brain malformation is a dominant feature, and propose a practical approach that will permit a physician to investigate, and treat these disorders.