Clinical manifestations associated with the domain-containing protein 2 (DDHD2) gene mutation in an Iranian family with Spastic Paraplegia 54

Introduction: Spastic paraplegia type 54 (SPG54) is an autosomal recessive disorder, caused by bi-allelic mutations in the DDHD2 gene. Worldwide, over 24 SPG54 families and 24 pathogenic variants have been reported. Our study aimed to describe the clinical and molecular findings of a pediatric patient from a consanguineous Iranian family with significant motor development delay, walking problems, paraplegia and optic atrophy.Methods: The patient was a 7-year-old boy with severe neurodevelopmental and psychomotor problems. Neurological examinations, laboratory tests, electroencephalography (EEG), computed tomography (CT) scan, and brain magnetic resonance scan (MRI) were carried out for clinical evaluation. Whole-exome sequencing (WES) and in silico analysis were undertaken to identify the genetic cause of the disorder.Results: The neurological examination showed developmental delay, spasticity in the lower extremities, ataxia, foot contractures and deep tendon reflexes (DTR) in the extremities. CT scan was normal, but MRI revealed corpus callosum thinning (TCC) with atrophic changes in the white matter. The genetic study reported a homozygous variant (c.856 C>T, p.Gln286Ter) in the DDHD2 gene. The homozygous state was confirmed by direct sequencing in the proband and his 5-year-old brother. This variant was not reported as a pathogenic variant in literature or genetic databases and was predicted to affect the function of the DDHD2 protein. Conclusion: The clinical symptoms in our cases were similar to the previously reported phenotype of SPG54. Our results deepen the molecular and clinical spectrum of SPG54 to facilitate future diagnoses.

Automated summary

This study describes the clinical and molecular findings of a pediatric patient from a consanguineous Iranian family with significant motor development delay, walking problems, paraplegia, and optic atrophy. Clinical evaluations included neurological examinations, laboratory tests, EEG, CT scan, and brain MRI. Whole-exome sequencing and in silico analysis identified a homozygous variant in the DDHD2 gene. The study deepens the understanding of SPG54 and provides valuable information for future diagnoses.