Analysis Of Clinical Feature Of 4 Cases With Acute Intermittent Porphyria And Literature Review

Objective:The attention to rare diseases is gradually increasing in China.Acute Intermittent Porphyria（AIP）,a kind of rare disease,is caused by loss-of-function mutation of the gene encoding hydroxymethylbilane synthase（HMBS）.There are limited studies about AIP in China,and most of them are case report.There is no systematic analysis of clinical data of patients with AIP in China.In this study,we collected the clinical data of4 AIP patients who visited the First Hospital of Shanxi Medical University,and reviewed the literatures about published Chinese AIP patients with HMBS gene mutation to summarize the clinical characteristics of AIP patients in China and improve the understanding of medical staffs on AIP.Methods:4 patients were diagnosed with AIP and treated at the First hospital of Shanxi medical university from January 1,2016 to February 28 th,2022 were enrolled in this study.Data including the basic information,medical history,symptoms,laboratory and imaging examinations,treatments,and gene mutations were collected and analysed;Long-term follow-up was conducted to evaluate the out-of-hospital condition;Summarized their clinical characteristics.Databases of Pubmed,CNKI,Wanfang Data and VIP were systematically searched for published literatures about Chinese AIP cases from inception to February 28 th,2022.Retrospectively summarized the clinical characteristics and treatment of AIP patients in China.Results:1.Case data of four patientsFour patients（Ⅰ,Ⅱ,Ⅲ and Ⅳ）,all young women,were included in the study.They all experienced multiple acute attacks of AIP,of which the acute attacks in three patients were menstruation-related.Clinical manifestation: All four patients started with acute abdominal pain,accompanied by autonomic symptoms such as hypertension and tachycardia,as well as peripheral nerve symptoms such as fatigue and limb numbness.Patients Ⅰ,Ⅲ and Ⅳwere relatively severe condition and suffered from epileptiform seizures,which was characterized as "neurological symptom type".Patient Ⅱ had a mild illness,mainly manifested as digestive system symptoms,and was classified as "abdominal pain type".Their urine turned red after the sun.Laboratory results: Except for anemia,liver dysfunction,and positive urinary porphobilinogen（PBG）,all four experienced hyponatremia at the time of onset,which was mainly considered to be due to syndrome of inappropriate antidiuretic hormone.Patients I,III,and IV experienced epileptiform seizures that occurred in the setting of severe hyponatremia,especially when their serum sodium levels rapidly decreased.Four patients also experienced the fluctuations of uric acid levels,which increased in the milder conditions and decreased in the more severe conditions,with a similar trend of changes in serum sodium levels.Treatment: All four patients were relieved after receiving carbohydrate loading therapy and corresponding symptomatic treatment.In addition to intravenous sodium,patients III and IV had short-term use of low-dose tolvaptan,which effectively corrected their refractory hyponatremia.Gene sequencing: All four patients carry HMBS gene mutation: Ⅰ（c.1078₁132del）,II（c.160+5g>C）and III（c.730₇31del CT）and IV（c.518G>C）.c.518G>C was a newly reported mutation in this study,which is a missense mutation（p.R173P）.It has been predicted by many software that it is harmful and classified as a “likely pathogenic”mutation according to ACMG.2.literature reviewA total of 32 literatures were included,containing 65 AIP patients（56 females and 9males）with the age mostly between 20³9 years old（83.1%,54/65）.Clinical features:（1）Clinical manifestations: Abdominal pain（96.9%,63/65）was the most common clinical manifestation.56.9%（37/65）of AIP patients suffered from central neuropathy;30.8%（20/65）of patients had autonomic neuropathy;13.8%（9/65）of patients experienced peripheral neuropathy;9.2%（6/65）of patients experienced spirit symptoms.33.8%（22/65）of patients had dark urine.35 patients had experienced multiple acute attacks of AIP.In some patients,the onset of AIP may have been related to menstruation（9 cases）,pregnancy and childbirth（4 cases）,fatigue（3 cases）,alcohol consumption（2 cases）,and dieting（1 case）.（2）Laboratory result: 25 patients developed hyponatremia.There were 11 cases of anemia and 11 cases of abnormal liver function.6patients were in abnormal renal function.4 case was caught in disorder of hormone level.Urine PBG test was performed in 25 cases and the results were all positive.（3）Treatment: 27 patients received carbohydrate loading therapy,and 25 of them were improved.2 patients were treated with carbohydrate loading therapy combined with heme,and 1 patient eventually improved.Gene mutations: A total of 26 HMBS gene mutations were included in the study,wherein R173 mutation was the most frequently reported（12 cases）: eight patients had the R173 W mutation（six neurological symptom type and two abdominal pain types）,and four patients had the R173 Q mutation（three neurological symptom type and one abdominal pain type）.Even with the same mutation,different patients may show different clinical phenotypes.Conclusion:1.AIP is more common in young women,with clinical manifestations including abdominal pain,neuropsychiatric symptoms and dark urine.2.Hyponatremia is a common laboratory abnormality in acute attack of AIP.Epileptic seizures in AIP patients may be associated with severe hyponatremia.3.Carbohydrate loading therapy is mainly applied to control the attack of AIP in China,but it may aggravate hyponatremia.Short-term application of low-dose tolvaptan is conducive to the correction of refractory hyponatremia in patients with AIP.4.R173 is the most common mutation site in clinical cases reported in China at present.We reported a novel mutation R173 P,which was predicted to be a harmful mutation.