Analysis Of Genetic,Clinical And Imaging Characteristics Of Adrenomyeloneuropathy

BackgroundX-linked adrenoleukodystrophy(ALD)is a rare peroxisome disease caused by ABCD1 gene located on the X chromosome,which is inherited in X-linked recessive pattern.The pathogenic mutations can result in abnormal accumulation of very long chain fatty acids(VLCFA)in plasma and tissues,especially in brain,spinal cord,adrenal gland and testis.The disease course is progressive with variable clinical spectrum that includes absolute adrenal insufficiency,cerebral ALD,adrenomyeloneuropathy(AMN),asymptomatic patients and female carriers.Among them,AMN is the most common subtype with onset at adulthood,characterized by progressive rigidity and weakness of lower limbs.The neuroimaging is usually normal or just abnormal signal in pyramidal tract,besides spinal cord atrophy is a common non-specific sign,which can be used as an indicator to assess the progress and prognosis of the disease.Because of the obvious overlap in clinical and imaging between AMN and other neurodegenerative diseases such as hereditary spastic paraplegia(HSP),it is difficult to diagnose according to the clinical manifestations alone.Recently,with development of the high-throughput next generation sequencing(NGS),the diagnosis of multiple genetic diseases is easier and more accurate.In this paper,whole exome sequencing was used to identify 10 patients with AMN in 156 pedigrees with spastic paraplegia.The clinical and biochemical characteristics of these patients were analyzed.Next,Quantitative MRI was used to characterize and quantify the changes of spinal cord structure in 5 patients and age-matched healthy controls.The correlation between MRI measurement results and clinical status of these patients were analyzed.Method1.The subjects were 156 patients presenting with spastic paraplegia.DNA was extracted from peripheral blood of the probands and family members.The whole exome sequencing was performed for the remaining patients lacking known HSP-causal genes.Variants were analyzed by mutation frequency in population,family co-segregation analysis,pathogenicity prediction and ACMG guidelines.2.The serum VLCFA level of patients and carriers was measured by gas chromatography mass spectrometry.3.The clinical characteristics and VLCFA level in each family were analyzed.4.Clinical scale evaluation and spinal cord MRI were performed in 5 patients and age-matched healthy controls.The cross-sectional area of each segment was calculated and analyzed statistically.Result1.10 AMN patients with ABCD1 variants were found in 156 pedigrees with spastic paraplegia,including 6 known variants(c.251 C>T,c.421 G>A,c.796 G>A,c.1849 C>T,c.1876G>A and c.521A>G)and 4 novel variants(c.217 C>T,c.497T> C,c.526＿528del TCC and c.1969＿1987delins T).The family co-separation verification was successful.2.All AMN patients were male with the age of onset in adulthood.All of them complained of slowly progressive spastic paraplegia,and four probands presented adrenocortical insufficiency,five probands presented sphincter dysfunction.The VLCFA level of all patients increased,with ratios of C24/C22 and C26/C22 rising obviously.VLCFA level of most carriers also increased to different degrees.3.Compared with healthy controls,the cervical and thoracic medulla segments of the patients showed obviously thinner,among which difference of C4 was the largest and T9 was the smallest.Conclusion1.The proportion of AMN in spastic paraplegia was as large as 10/156.2.As for the patients with spastic paraplegia,especially men,VLCFA and genetic analysis should be performed to identify ALD.3.All of the AMN patients presented spinal cord atrophy,and cerebral involvement indicates the poor prognosis.Therefore,MRI of brain and spinal cord should be performed regularly during follow-up to monitor the progress of the disease.