2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Homozygous<em> ALDH18A1</em> Variant in Siblings Adds to Understanding of Early Disease Progression in Autosomal Recessive Hereditary Spastic Paraplegia Type 9B

Homozygous ALDH18A1 Variant in Siblings Adds to Understanding of Early Disease Progression in Autosomal Recessive Hereditary Spastic Paraplegia Type 9B

Back to course

Pdf Summary

This case report discusses two siblings with homozygous variants in the ALDH18A1 gene, presenting with features consistent with Autosomal Recessive Hereditary Spastic Paraplegia Type 9B (SPG9B). Hereditary Spastic Paraplegias (HSPs) are a group of neurodegenerative diseases characterized by progressive weakness and spasticity of the lower extremities. The HSPs caused by pathogenic variants in ALDH18A1 are classified as SPG9, with SPG9A being autosomal dominant and SPG9B being autosomal recessive. <br /><br />The physical exams and metabolic evaluations of the siblings were largely normal, with the exception of microcephaly, developmental delay, and other features consistent with SPG9B. Fragile X evaluation and Manganese levels were also normal. Genetic testing revealed homozygous variants of uncertain significance (VUS) in ALDH18A1 in both siblings. One sibling also had a homozygous VUS in SLC30A10, and another homozygous VUS in HIST3H3. The ALDH18A1 variant was predicted to have a disruptive effect and was not found in population databases. <br /><br />The siblings' phenotypes included developmental delay, intellectual disability, microcephaly, severe motor impairment, and dysmorphic facial features. Other features such as poor growth, hypotonia, and dysmorphic features have been previously reported in SPG9B and further affirm their association with the condition. Additional features such as autism, hip dysplasia, abnormal creasing, and stereotypic movements were observed in these siblings, potentially representing an expansion of the phenotype in this rare disease. <br /><br />Overall, this case adds to the understanding of the early disease progression in SPG9B and highlights the importance of considering ALDH18A1 variants in individuals with clinical features consistent with SPG9B. Further research and case reports are needed to unravel the full spectrum of phenotypic manifestations and molecular mechanisms underlying SPG9B.

Asset Subtitle

Co-Author - Lingying Liu, CGC; Presenting Author - Paul R. Hillman, MD/PhD;

Meta Tag

Clinical History

Exome sequencing

Intellectual disability

Musculoskeletal system

Neuroscience

Phenotype

Co-Author Lingying Liu, CGC

Presenting Author Paul R. Hillman, MD/PhD

Keywords

ALDH18A1 gene

SPG9B

neurodegenerative diseases

developmental delay

microcephaly

genetic testing

variants of uncertain significance

intellectual disability

motor impairment

phenotypic manifestations