Clinical Characteristics Of Childhood Onset Acute Intermittent Porphyria And Correlation Analysis Of HMBS Genotypes And Phenotypes

Part Ⅰ Analysis of clinical characteristics of childhood onset of acute intermittent porphyriaObjectivesTo explore the clinical features of acute intermittent porphyria in childhood by analyzing the clinical data of 3 children diagnosed by gene and reviewing the literature,the clinical characteristics in childhood were discussed.To guide clinical pediatricians in the diagnosis and treatment of childhood-onset acute intermittent porphyria.MethodsThe clinical data of 3 pediatric patients with acute intermittent porphyria who were admitted to the Department of Pediatrics of Qilu Hospital of Shandong University from January 2019 to July 2021 were collected.At the same time,the clinical characteristics,auxiliary examination results,treatment and prognosis of this rare disease were summarized and analyzed through literature retrieval.Results1.Results of three casesAll of 3 patients admitted to Qilu Hospital of Shandong University were diagnosed as AIP carrying pathogenic variations of HMBS,including 2 females and 1 male.The ages were 1 year and 7 months,1 year and 5 months,and 5 years when seeing doctors.The onset ages were 6 months,5 months and 5 years.Among the 3 patients,2 patients presented with epilepsy as the first symptom,and there were no abnormalities in laboratory examination,craniocerebral imaging and genetic metabolic disease screening.Both patients took 3 kinds of oral antiepileptic drugs to control their seizures.Case 1 was poorly controlled and accompanied with severe psychomotor retardation.Case 2 remained asymptomatic for one and a half years.The main symptoms of case 3 were fever and abdominal pain.And anemia,hyponatremia and impaired liver function were found in laboratory examination.The symptoms were improved by the treatment of sodium supplementation,liver protection and hemofiltration.All 3 patients carried HMBS gene mutations,including 1 frameshift mutation（p.Q194H fs*13）,1 missense mutation（p.R 167W）,and 1 splicing mutation（c.422+1G>A）.2.Literature retrieval resultsA total of 43 AIP patients with childhood onset were collected,including 19 males and 24 females.The most common onset age was from 12 to 18 years old.In 23 patients,the causes of acute attack were clear,including drugs,acute upper respiratory tract infection,lack of energy,alcohol and estrogen,among which drugs and infection were the two main factors.46.5%of 43 patients were diagnosed with delay.Among the 43 patients,the three most common symptoms were gastrointestinal symptoms（93.0%）,epileptic seizures（60.5%）and psychiatric symptoms（46.5%）.The most common form of seizure is a generalized tonic-clonic seizure.Hyponatremia was the most common abnormal laboratory tests.Of the 18 patients with craniocerebral imaging findings,44.4%（8/18）had abnormalities and 27.8%（5/18）was posterior reversible encephalopathy syndrome.Urinary porphyrin was elevated in 43 patients at acute stage,12 of whom carried mutations of HMBS,and 31 of whom had no genetic results.Among the 43 patients,38 patients received treatment except 5 with spontaneous remission of symptoms,of which 32 patients improved after treatment,4 patients died,and 2 patients with unknown treatment and prognosis.The most common treatments in the 38 patients were hyperglycemic fluids,anticonvulsants and heme respectively.Twenty-two of the 43 patients received anticonvulsant therapy.Symptoms worsened in 9 patients treated with phenytoin and 6 with phenobarbital.Of the 8 patients treated with valproate,symptoms worsened in 6 patients.Symptoms improved in 8 patients treated with gabapentin and 5 with levetiracetam.5 patients improved treated with diazepam,lorazepam,propofol or midazolam in the acute phase.Conclusions1.We found that there are more female than male in children with acute intermittent porphyria,and the most common onset age was from 12 to 18 years old.2.The most common inducing factors of acute intermittent porphyria are drugs（anticonvulsant drugs and antituberculotic drugs）and acute upper respiratory tract infection.3.The main clinical manifestation of acute attacks in childhood are abdominal pain and seizures during acute attack period.It’s difficult to differ from other diseases in early period and easy to be misdiagnosed.Acute intermittent porphyria should be considered when patients presented with unexplained abdominal pain,acute nervous system injury（acute encephalopathy,epileptic seizures）with hyponatremia,or rhabdomyolysis with no apparent cause.4.Anticonvulsant drugs should be used carefully in acute intermittent porphyria accompanied with seizures.Phenobarbital and phenytoin are forbidden,while gabapentin and levetiracetam are preferred.Part Ⅱ Correlation between genotype and phenotype of acute intermittent porphyriaObjectivesIn this study,genotypes and phenotypes of patients carrying HMBS mutations were summarized and analyzed to find the correlation between genotypes and phenotypes,and to further elaborate the possible potential mechanisms of phenotypes and severity of different genotypes,so as to guide clinical diagnosis,treatment and prognosis assessment.MethodsA total of 3 AIP patients admitted to Qilu Hospital of Shandong University from January 2019 to July 2021 were collected,and the genotypes and phenotypic characteristics of AIP patients carrying HMBS gene mutations were analyzed retrospectively through literature retrieval.ResultsA total of 88 previously reported and 3 patients（69 females,22 males）,45 domestic patients and 46 foreign patients were included in this study.49.5%of 91 patients carried missense mutations.A total of 62 variants were carried in 91 patients and most of which were located in exon 15.Among the 62 variants,23 were located in domain 1,16 in domain 2 and 23 in domain 3.Fifteen patients carried the variant of R173W.Of the 91 patients,14 had only gastrointestinal symptoms,11 had only nervous system involvement,and 66 had both systems involved.The mutation carried by patients with simple gastrointestinal symptoms was most common in domain 3（41.7%）,and most of the symptoms improved by treatment of hyperglycemia or heme,except for one patient with E250Q who died of cardiac arrest.The central nervous system was most often involved in the 11 patients presenting only with neurological symptoms,mainly epileptiform seizures.Four patients presented with psychomotor retardation,carrying variants of L81P,R167W,R321H and 579₅83del.The patient carrying R167W died at 40 months.Among 66 patients with both digestive and nervous symptoms,65.2%had central nervous system symptoms,and 8 patients carried the mutation of R173W.59.1%had peripheral nerve symptoms.42.4%had autonomic symptoms（hypertension and tachycardia）,among which patients with R167Q variant developed symptomatic sinus bradycardia and died after 10 days.21.2%had psychiatric symptoms,and 7 of them had depression.About 40%of the variation involving the nervous system was in domain 1.Among the 91 patients,9 patients had poor prognosis,and 7 of them died,carrying 7 different mutation sites including R173W,R167W,R167Q,E250Q,L137P,W283X and R173Q.Two patients had neurological sequelae（R167Q,Q181X）.Conclusion1.R173W mutation is the most common mutation site of AIP.2.Patients carrying R173W,R167W,R167Q and R173Q variants had severe clinical phenotypes.3.Most of the variations involving abdominal pain were in domain 3,while most of the variations involving nervous system were in domain 1.