| Objective: To summarize and analyze the clinical and genetic characteristics of adult adrenoleukodystrophy(ALD)patients and evaluate the potential of serum neurofilament light chain proteins(NFL)to assess the severity of disease.Methods: Clinical,imaging,biochemical and genetic data of adult ALD patients diagnosed by genetic testing who were admitted to Shanghai Sixth People’s Hospital between May 2008 and September 2022 were analyzed retrospectively.Clinical characteristics of AMN patients with different types of gene mutations were compared.The motor function of the AMN patients was assessed using the Extended Disability Scale(EDSS),and the association between EDSS scores and the course of disease were analyzed.Loe score was used to evaluate the severity of white matter demyelinating,serum levels of Very Long-Chain Fatty Acids(VLCFA)in patients with AMN simple,AMN converted to cerebral and adult cerebral ALD(ACALD)were compared.Whole exome sequencing was performed on the proband,and the genetic characteristics of Chinese adult ALD patients were summarized and analyzed.The single molecule array(Simoa)technology was used to detect the serum NFL levels of patients,and the correlation between the NFL levels and the classification,disease duration,biochemical abnormalities and disease severity of ALD in patients was analyzed separately.Results: A total of 31 male ALD patients were collected,23 in the AMN group and 8 in the ACALD group.All AMN patients started with lower limb abnormalities,with 17 cases starting with stiffness and weakness and 6 cases starting with numbness and soreness in the lower limb.The occurrence of symptoms was not related to the type of gene mutation.The patient’s motor function EDSS score was positively correlated with duration of disease(r = 0.57,P= 0.006).White matter demyelination occurred in 33.3%(7/21)of patients over a disease duration of(7.67±4.46)years.In the ACLAD group,memory loss and cognitive dysfunction were the most common initial symptoms,and the course of the disease varied greatly.There was no significant difference in serum VLCFA level among patients with AMN alone,AMN converted to cerebral type and ACALD group.(H=1.691 for C26,F=1.906 for C24 / C22,F=0.603 for C26 / C22;P> 0.05 respectively).A total of22 ABCD1 mutations were identified in the study.Four probands belonging to different families carried the c.1415＿1416del(p.Q472Rfs*83)variant.Serum NFL levels were significantly increased in the ALD patient group compared to controls(Z = 5.112,P<0.0001).The NFL concentration in the serum showed superior correlation to EDSS and Loes scores(r=0.581 for EDSS,r=0.662 for Loes,P<0.05respectively).Serum NFL levels were significantly lower in patients with AMN than in patients with ACALD(Z =-3.693,P= 0.0002).Serum NFL concentration was a significant factor to distinguish AMN and CALD,the area under the ROC curve(AUC)was 0.967(95%CI: 0.895-1.000,P<0.001)and the optimal cut-off was 46.95pg/m L,the sensitivity,specificity and Yoden index were 1.00,0.917 and 0.917,respectively.Conclusions: Adult ALD is a clinically highly heterogeneous disease that ranges from slowly progressive bilateral lower limb spasticity to rapidly fatal cerebral white matter demyelination,with patient phenotypes independent of genotype and plasma very long chain level.AMN is at risk for conversion to brain type,phenotype conversion is independent of serum VLCFA levels,symptom incidence is independent of ABCD1 gene mutation type,and patient disability is positively correlated with disease duration.Early symptoms of ACALD are insidious and variable,with cognitive and psychiatric abnormalities gradually emerging as the disease progresses.The mutation c.1415＿1416del is a hot mutation at home and abroad.NFL,a non-specific marker of axonal damage,is significantly elevated in the serum of ALD patients and correlates with the severity of their disease.Serum NFL quantification could be a very promising biomarker for monitoring disease progression.Figure 8 Table 10 Reference 154... |
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