Clinical characteristics and genetic analysis of HPDL biallelic gene related neurodevelopmental disorders with progressive spasm and cerebral white matter abnormalities / 中华神经科杂志

ABSTRACT

Objective:To summarize the clinical phenotype and genetic characteristics of biallelic variation in HPDL leading to neurodevelopmental disorders with progressive spasticity and cerebral white matter abnormalities. Methods:The clinical and genetic data of 3 cases with neurodevelopmental disorders confirmed in the Department of Neurology of the Affiliated Children′s Hospital of Zhengzhou University from February 2018 to June 2022 were analyzed. The second-generation sequencing method was used to sequence the HPDL gene and the first-generation Sanger sequencing was used to verify the family members, and the characteristics of gene variants were summarized, and the 3 cases were treateds and followed-up. Results:Among the 3 children with neurodevelopmental disorders, 2 were females and 1 was male, and the age of onset was 25 days to 11 years of birth. In the clinical phenotypes, cases 1 and 2 were children with Leigh-like syndrome with infancy onset, with recurrent seizures, intelligent backwardness, language and motor delay, lactic acid increase, acidosis. Cranial magnetic resonance plain scan suggested deepening of the sulcus in the bilateral cerebral hemisphere, abnormal symmetrical signals in the basal ganglia, dorsal thalamus, cerebral peduncles and brainstem, expansion of the supratentorial ventricle, and thinning of the corpus callosum. And cranial magnetic resonance spectroscopy suggested visible lactate peaks in the measurement area of bilateral putamen lesions. Case 3 presented with spastic paraplegia, early motor retardation, and late spastic gait. The plain skull magnetic resonance imaging scan showed no abnormalities. In the 3 cases, the whole exon genome sequencing showed the heterozygous variant c.26_.28delGCC(p.Cys9_His10delinsTyr) and the parent missense heterozygous variant c.788C>T(p.Thr263Met), the paternal truncated variant c.1051C>T(p.Gln351 *) and the parent frameshift variant c.995de1C(p.Thr332Mfs * 9), the parent missense variant c.781C>G (p.Leu261Val) and the parent truncated variant c.721C>T (p.Gln241 *). The c.26_28delGCC(p.Cys9_His10delinsTyr) was an unreported site mutation. No abnormalities were found in chromosomal copy number variation and mitochondria-related genes. Cases 1 and 2 were treated with anti-seizure drugs and cocktail, and the seizure was under effective control; case 3 was treated with comprehensive treatment and rehabilitation function training, and exercise and intelligence were improved. Conclusions:The clinical phenotype of the biallelic variant in HPDL was Leigh-like syndrome and hereditary spastic paraplegia, characterized by compound heterozygous variant, including whole code, missense, frameshift, and truncated variants. Biallelic variation in HPDL was found to be the genetic etiology of the 3 probands.