Spastic paraplegia and psychomotor retardation with or without seizures caused by HACE1 gene mutation:a case report and literature review
Objective To investigate the clinical and genetic features of patients with spastic paraplegia and psychomotor retardation with or without seizures(SPPRS)caused by HACE1 gene mutation.Methods Clinical data,auxiliary examination and genetic test results of a child with SPPRS caused by HACE1 gene mutation who was admitted to Henan Children's Hospital in April 2019 were collected.The clinical and genotypic characteristics of children with SPPRS were summarized by searching the relevant literature up to June 2024,retrieved from CNKI,Wanfang and PubMed databases with the terms of"HACE1""SPPRS""seizures""spastic paraplegia".Results The patient was a 11 months and 20 days old male,with a clinical phenotype including global developmental delay,leg spastic tremor,frequent epileptic seizures,obesity,and concurrent urethral malformation.Brain magnetic resonance imaging(MRI)showed enlarged bilateral ventricles,hypoplastic corpus callosum,delayed myelination.Genetic test results revealed compound heterozygous variants c.994C＞T(p.R332*)and c.1679-2A＞G in the HACE1 gene(according to the transcript NM_020771),respectively inherited from his mother and father,with c.1679-2A＞G being a newly reported variant.A total of 6 English literatures reported 21 SPPRS patients in 11 families,and HACE1 gene mutations were mainly characterized by nonsense mutations.The main clinical manifestations included global developmental delay(21 cases),movement disorders(21 cases),intellectual disabilities(18 cases),seizures(13 cases),obesity(13 cases),skeletal abnormalities(11 cases),microcephaly(9 cases),ocular abnormalities(9 cases),distinctive facial features(5 cases),sensorineural hearing loss(5 cases),and short stature(3 cases).MRI predominantly showed hypoplasia of the corpus callosum,ventricular dilation,paucity of white matter and cerebral atrophy.There were no clear genotype-phenotype correlations.A total of 13 HACE1 gene mutations were reported,including 9 nonsense mutations,2 frameshift mutations,1 in-frame mutation,and 1 missense mutation.Among the 11 families,only 2 families with 5 patients were caused by compound heterozygous mutations,c.1852_1853del(p.L832del)and c.454C＞T(p.Q152*),c.2242C＞T(p.R748*)and c.2019_2020insTTTAGGTATTTTTAGGTATT(p.P674fs).The other 16 patients in 9 families were caused by homozygous mutations of the remaining 9 mutations.Conclusions SPPRS is rare and usually occurs in infancy.The main clinical manifestations include comprehensive developmental delay,movement disorders,epilepsy,etc.Currently,no clear genotype-phenotype correlation has been found.The c.1679-2A＞G variant of the HACE1 gene is an unreported variant and enriches the mutation spectrum of the HACE1 gene.
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