Urine organic acid as the first clue towards aromatic L-amino acid decarboxylase (AADC) deficiency in a high prevalence area.

BACKGROUND: Aromatic L-amino acid decarboxylase deficiency is a rare neurometabolic disease due to impaired decarboxylation of neurotransmitter precursors to its active form. CASE: We retrospectively reviewed 8 cases from 2008 to 2019 with cerebrospinal fluid neurotransmitter analysis performed at our centre. All cases had an elevated urine vanillactic acid and, in most cases, with N-acetylvanilalanine detected. Cerebrospinal fluid analysis showed low downstream metabolites vanillylmandelic acid, homovanillic acid but high 3-O-methyl-L-DOPA, 5-hydroxytryptophan. Cerebrospinal fluid pterins were normal. Genotyping in DDC confirms the diagnosis. Urine organic acid analysis provided the first clue to diagnosis in four of the cases, which then triggered cerebrospinal fluid neurotransmitter and genetic analysis. We also developed a diagnostic decision support system to assist the interpretation of the mass spectrometry data from urine organic acids. CONCLUSIONS: Urine organic acid could be essential in guiding subsequent investigations for the diagnosis of aromatic L-amino acid decarboxylase deficiency. We propose to screen suspected cases first with urine organic acids, specifically looking for vanillactic acid and N-acetylvanilalanine. Suggestive findings should be followed with target analysis for c.714 + 4A > T in ethnically Chinese patients. The assistive tool allowed expedite interpretation of profile data generated from urine organic acids analysis. It may also reduce interpreter's bias when peaks of interest are minor peaks in the spectrum.

Novel PPOX exonic mutation inducing aberrant splicing in a patient with homozygous variegate porphyria.

INTRODUCTION: Variegate porphyria (VP; OMIM 176200) is one of the acute hepatic porphyrias, and it is characterized by the partial deficiency of protoporphyrinogen oxidase (PPOX). The unusual homozygous variant with mutations on both alleles of PPOX is distinguished with general heterozygous VP by several typical points such as severe defect in PPOX enzyme activity, early onset of photosensitivity before puberty, and skeletal deformity. MATERIAL AND METHOD: In this study, we describe a very rare case of autosomal recessive form of true homozygous VP found in a Chinese patient with consanguineous parents. Sanger sequencing of the PPOX gene showed a novel homozygous variant located at the first base of exon 8 of the gene, i.e., NM_000309.3c.808G > T. To investigate aberrant splicing induced by the mutant, wild-type exon 8 and mutant exon 8 were expressed in pET01 vector as minigene in cultured-cells and analyzed by RT-PCR. RESULTS: The wildtype PPOX showed an expected band in the gel electrophoresis after RT-PCR. The PPOX c.808G > T only showed a band similar to the band size of the vector only control. This result suggested c.808G > T mutant is an exonic mutation inducing aberrant splicing of pre-mRNA of the PPOX gene. CONCLUSION: This study showed a very rare case of homozygous VP with autosomal recessive homoallelic pattern. In comparison with previous cases of homozygous VP presenting brachydactyly, it is notable that our patient did not have any skeletal deformities.

NMR-based urinalysis for rapid diagnosis of ß-ureidopropionase deficiency in a patient with Dravet syndrome.

BACKGROUND: Beta-ureidopropionase deficiency is a rare inborn error of metabolism (IEM) affecting pyrimidine metabolism. To-date, about 30 genetically confirmed cases had been reported. The clinical phenotypes of this condition are variable; some patients were asymptomatic while some may present with developmental delay or autistic features. In severe cases, patients may present with profound neurological deficit including hypotonia, seizures and mental retardation. Using NMR-based urinalysis, this condition can be rapidly diagnosed within 15 min. CASE: An 11-month-old Chinese boy had dual molecular diagnoses, ß-ureidopropionase deficiency and Dravet syndrome. He presented with intractable and recurrent convulsions, global developmental delay and microcephaly. Urine organic acid analysis using GC-MS and NMR-based urinalysis showed excessive amount of ß-ureidopropionic acid and ß-ureidoisobutyric acid, the two disease-specific markers for ß-ureidopropionase deficiency. Genetic analysis confirmed homozygous known disease-causing mutation UPB1 NM_016327.2: c.977G>A; NP_057411.1:p.R326Q. In addition, genetic analysis for Dravet syndrome showed the presence of heterozygous disease-causing mutation SCN1A NM_001165963.1:c.4494delC; NP_001159435.1:p.F1499Lfs*2. CONCLUSIONS: The differentiation between Dravet syndrome and ß-ureidopropionase deficiency is clinically challenging since both conditions share overlapping clinical features. The detection of urine ß-ureidoisobutyric and ß-ureidopropionic acids using NMR or GC-MS is helpful in laboratory diagnosis of ß-ureidopropionase deficiency. The disease-causing mutation, c.977G>A of ß-ureidopropionase deficiency, is highly prevalent in Chinese population (allele frequency=1.7%); ß-ureidopropionase deficiency screening test should be performed for any patients with unexplained neurological deficit, developmental delay or autism.

NMR-based urinalysis for beta-ketothiolase deficiency.

BACKGROUND: Beta-ketothiolase deficiency is a rare inborn errors of metabolism (IEM) affecting the catabolism of isoleucine, characterized by severe ketoacidosis in children of 6 to 24months old. A prompt diagnosis is of paramount importance as the metabolic decompensation can be effectively reverted by glucose infusion and health outcomes are improved on a protein-restricted diet. Currently, majority of the laboratory diagnosis were made based on mass-spectrometry and molecular genetics while little is mentioned on the advancement of nuclear magnetic resonance (NMR) spectroscopy for the diagnosis of this condition. CASE: We report a case of beta-ketothiolase deficiency in a 1-y-old Chinese boy who presented with repeated vomiting, impaired consciousness and severe ketoacidosis. NMR urinalysis detected excessive amount of butanone (a disease specific marker of beta-ketothiolase deficiency), tiglylglycine, (intermediate of isoleucine catabolism) and ketones. Diagnosis of beta-ketothiolase deficiency was further established by molecular genetic studies of ACAT1 gene of the proband. CONCLUSIONS: This case illustrated that NMR-based urinalysis is complementary to organic acid analysis for diagnosis of beta-ketothiolase deficiency. The operation of NMR is simple and fast; sample preparation is a two-step procedure while the NMR acquisition is automatic and usually takes <15min. We envisage that NMR analysis will become more available in clinical laboratories and will play an important role in acute pediatric care.

Aconite poisoning over 5 years: a case series in Hong Kong and lessons towards herbal safety.

BACKGROUND: Aconite poisoning is a severe, life-threatening poisoning related to the use of traditional Chinese medicine (TCM). Despite current legislation, repeated poisoning cases are steadily encountered. OBJECTIVE: The aim of the study was to summarize the clinical features and to elucidate the causative and contributory factors leading to aconite poisoning. METHODS: This study was conducted within the Hospital Authority Toxicology Reference Laboratory, which is the sole tertiary referral clinical toxicology laboratory in Hong Kong. This retrospective study reviewed all confirmed aconite poisoning cases handled by a clinical toxicology laboratory between April 2004 and July 2009. The diagnosis in all cases was confirmed biochemically by detecting aconitum alkaloids in urine specimens. Additionally, herbal specimens were morphologically identified and herbal formulae were studied and transcribed. The cause of poisoning for each case was determined whenever possible. RESULTS: Fifty-two cases were examined in this aconite poisoning case series. Neurological, cardiovascular and gastrointestinal toxicities were encountered in 49 (94.2%), 46 (88.5%) and 31 (59.6%) patients, respectively. The poisoning was severe in 6 (11.5%) patients, moderate in 17 (32.7%) patients and mild in 29 (55.8%) patients. Amongst 44 patients (84.6%) in whom the underlying reasons of poisoning could be determined, four major causes were found. These included overdose - prescription of a higher than recommended dosage of aconite herbs in 17 (32.7%) cases; 'hidden' poisoning (the aconite herb was not prescribed but dispensed inadvertently) in 17 (32.7%) cases; usage of inadequately processed herbs in 7 (13.5%) cases; and dispensary error in 2 (3.9%) cases. No case fatality was recorded. CONCLUSION: In the majority of cases in this series, the causes of poisoning can be traced to poor-quality herbs, poor quality of prescription practice, or dispensary errors. The quality issues of TCM practice should be critically addressed to minimize this poisoning threat.

Non-invasive urinary screening for aromatic L-amino acid decarboxylase deficiency in high-prevalence areas: a pilot study.

BACKGROUND: The diagnosis of aromatic L-amino acid decarboxylase (AADC) deficiency, one of the pediatric neurotransmitter disorders, is classically made with plasma enzyme level or cerebrospinal fluid (CSF) neurotransmitter profile, while both are technically demanding and the latter requires the invasive lumbar puncture. So far less than 100 cases have been reported worldwide with 20% from Taiwan. It was postulated that the condition might have been under-diagnosed among Chinese populations and a non-invasive screening tool should be developed in areas with high prevalence. METHODS: Urine metabolic profiles performed by gas chromatography-mass spectrometry (GC-MS) in a 31-month period were retrospectively reviewed: those with vanilmandelic acid concentration lower than one percentile plus the presence of 3-o-methyldopa were defined as positive and the patients were further evaluated. RESULTS: Among 1046 metabolic profiles (from 845 patients) reviewed, 3 profiles from 2 patients were screened positive: both cases had compatible CSF neurotransmitter profiles and the diagnosis was further confirmed by genetic analysis of DDC gene. 13 negative urinary metabolic profiles from 7 patients who had CSF neurotransmitters analyzed were identified as controls: all 7 CSF neurotransmitter profiles were not compatible for AADC deficiency. CONCLUSIONS: The GC-MS-based urine metabolic profiling was shown to be a satisfactory screening tool for AADC deficiency. Further confirmation can be performed by mutation analysis in the DDC gene, thus avoiding risks of lumbar puncture. We advocate all ethnic Chinese patients presenting with dystonia have their urine organic acids analyzed before proceeding to CSF neurotransmitters analysis.

Phenylketonuria in Hong Kong Chinese: a call for hyperphenylalaninemia newborn screening in the Special Administrative Region, China.

Hyperphenylalaninemia is one of the commonest inborn errors of metabolism affecting approximately 1 in 15,000 livebirths. Among Chinese, BH4 deficiency leading to hyperphenylalaninemia is much commoner than in Caucasians. Exact diagnosis is important for the treatment and genetic counseling. In 2000, newborn screening for phenylketonuria is mandatory by law in China throughout the whole country. However, it is not yet included in the newborn screening program of the Hong Kong Special Administrative Region, China. Published data on hyperphenylalaninemia among HongKong Chinese are largely lacking. We report a 1-year-old Hong Kong Chinese girl with severe 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency. The patient presented with infantile hypotonia and was misdiagnosed as cerebral palsy. She had very mild hyperphenylalaninemia (95 µmol/L), significantly high phenylalnine-to-tyrosine ratio (3.1), and elevated prolactin of 1109 mIU/L. Genetic analysis confirmed a homozygous known disease-causing mutation PTS NM_000317.1:c.259C>T; NP_000308.1: p.P87S in the proband. In our local experience, while the estimated prevalence of hyperphenylalaninemia due to PTPS deficiency was reported to be 1 in 29,542 live births, not a single case of phenylalanine hydroxylase deficiency has been reported. Furthermore, there is a general lack of awareness of inherited metabolic diseases in the community as well as among the medical professionals. Very often, a low index of clinical suspicion will lead to delay in diagnosis, multiple unnecessary and costly investigations, prolonged morbidity and anxiety to the family affected. We strongly recommend that expanded newborn screening for hyperphenylalaninemia should be implemented for every baby born in the Hong Kong Special Administrative Region, China.

Fatal viral infection-associated encephalopathy in two Chinese boys: a genetically determined risk factor of thermolabile carnitine palmitoyltransferase II variants.

Influenza-associated encephalopathy (IAE) is a potentially fatal neurological complication of influenza infection usually in the presence of high and persistent fever. Thermolabile carnitine palmitoyltransferase II enzyme (CPT-II) predisposes IAE, so far only described in Japanese. As the genetic origins of Japanese and Chinese are alike, similar genetic risk factors in CPT-II are expected. We report the first two unrelated Chinese patients of thermolabile CPT-II variants that underlain the persistent high fever-triggered viral infection-associated encephalopathy, multi-organ failure and death. Elevated (C16:0+C18:1)/C2 acylcarnitines ratio and the CPT2 susceptibility variant allele [p.Phe352Cys; p.Val368Ile] were detected. The asymptomatic family members of one patient also had abnormal long-chain acylcarnitines. In our experience of biochemical genetics, the elevated (C16:0+C18:1)/C2 acylcarnitines ratio is unusual and specific for thermolabile CPT-II variants. Allele frequency of [p.Phe352Cys; p.Val368Ile] among Hong Kong Chinese was 0.104, similar to Japanese data, and [p.Phe352Cys] has not been reported in Caucasians. This may explain the Asian-specific phenomenon of thermolabile CPT-II-associated IAE. We successfully demonstrated the thermolabile CPT-II variants in patients with viral infection-associated encephalopathy in another Asian population outside Japanese. The condition is likely under-recognized. With our first cases, it is envisaged that more cases will be diagnosed in subsequent years. The exact pathogenic mechanism of how other factors interplay with thermolabile CPT-II variants and high fever leading to IAE, is yet to be elucidated. Fasting and decreased intake during illness may aggravate the disease. Further studies including high risk and neonatal screening are warranted to investigate its expressivity, penetrance and temperature-dependent behaviors in thermolabile CPT-II carriers. This may lead to discovery of the therapeutic golden window by aggressive antipyretics and L-carnitine administration in avoiding the high mortality and morbidity of IAE.

Analysis of inborn errors of metabolism: disease spectrum for expanded newborn screening in Hong Kong.

BACKGROUND: Data of classical inborn errors of metabolism (IEM) of amino acids, organic acids and fatty acid oxidation are largely lacking in Hong Kong, where mass spectrometry-based expanded newborn screening for IEM has not been initiated. The current study aimed to evaluate the approximate incidence, spectrum and other characteristics of classical IEM in Hong Kong, which would be important in developing an expanded newborn screening program for the local area. METHODS: The laboratory records of plasma amino acids, plasma acylcarnitines and urine organic acids analyses from year 2005 to 2009 inclusive in three regional chemical pathology laboratories providing biochemical and genetic diagnostic services for IEM were retrospectively reviewed. RESULTS: Among the cohort, 43 patients were diagnosed of IEM, including 30 cases (69%) of amino acidemias (predominantly citrin deficiency, hyperphenylalaninemia due to 6-pyruvoyl-tetrahydropterin synthase deficiency and tyrosinemia type I), 5 cases (12%) of organic acidemias (predominantly holocarboxylase synthetase deficiency) and 8 cases (19%) of fatty acid oxidation defects (predominantly carnitine-acylcarnitine translocase deficiency). The incidence of classical IEM in Hong Kong was roughly estimated to be at least 1 case per 4122 lives births, or 0.243 cases per 1000 live births. This incidence is similar to those reported worldwide, including the mainland of China. The estimated incidence of hyperphenylalaninemia was 1 in 29 542 live births. CONCLUSIONS: Our data indicate that it is indisputable for the introduction of expanded newborn screening program in Hong Kong. Since Hong Kong is a metropolitan city, a comprehensive expanded newborn screening program and referral system should be available to serve the neonates born in the area.

Role of postmortem genetic testing demonstrated in a case of glutaric aciduria type II.

Glutaric aciduria type II, or multiple acyl-CoA dehydrogenase deficiency, is a rare metabolic disorder inherited in an autosomal recessive manner. The condition can be caused by mutations in at least 3 genes, including ETFA, ETFB, and ETFDH. When this potentially lethal disorder is known for its clinical and biochemical heterogeneity, mutation analysis will be an invaluable part of diagnosis. We here described a Chinese adolescent boy who enjoyed good health earlier and presented at the age of 14 years with severe vomiting. His condition deteriorated rapidly and he succumbed shortly after. With a travel history before presentation and the late age of onset, diagnosis was particularly difficult. Findings in perimortem biochemical investigations and postmortem autopsy were guiding but not diagnostic. The diagnosis of glutaric aciduria type II was finally confirmed by mutation analysis performed by direct sequencing on genomic DNA from peripheral blood, which identified 2 different unreported missense mutations, c.502G>T (p.V168F) and c.786A>G (p.Q262R), in ETFA. The father and the mother were found to be heterozygous for the 2 mutations in ETFA respectively. Subsequent molecular family screening also ruled out the disease in his elder sister, who had a history of convulsion and a suspicious plasma acylcarnitine profile, and freed her from life-long supplementation. The case showed that molecular autopsies should be part of routine postmortem examination of unexplained sudden death in all age groups and DNA-friendly samples should be routinely collected and archived. In the era of personalized medicine with the power of modern genetics, molecular diagnosis should be obtained for heterogeneous diseases with different genetic defects but sharing similar clinical and/or biochemical phenotypes.

Confirmation of gelsemium poisoning by targeted analysis of toxic gelsemium alkaloids in urine.

The gelsemium plants are highly poisonous but toxicological evaluation of suspected poisoning cases has been hampered by the chemical complexity of the gelsemium toxins involved. A novel liquid chromatography-tandem mass spectrometry protocol was optimized for the collective detection of gelsemine and related alkaloids from Gelsemium elegans. The screening protocol was applied to the clinical investigation of unexplained intoxications following the ingestion of seemingly nontoxic herbs. In three clusters of toxicological emergencies ranging from severe dizziness to respiratory failure, Gelsemium elegans mistaken for various look-alike therapeutic herbs was suspected to be the hidden cause of poisoning. Nine cases of gelsemium poisonings were thus ascertained by the diagnostic urine alkaloid profiles. Gelsemine was sustained as the main urinary marker of Gelsemium exposure.

Hepatitis induced by Teucrium viscidum.

INTRODUCTION: In Hong Kong, Chinese medicine is popular and coexists with orthodox Western medicine. Despite a long history of use, many herbs have not been submitted to rigorous scientific testing and there are reports of hepatotoxicity. We describe a woman who developed acute hepatitis after drinking an herbal remedy containing Teucrium viscidum. CASE REPORT: A previously healthy 51-year-old woman was admitted to a regional hospital because of jaundice, with complaints of nausea, vomiting, and tea-colored urine for three days prior to admission. She denied any recent ingestion of known hepatotoxins, but she had consumed an herbal remedy for low back pain for three days before the onset of symptoms. She was icteric and had a serum total bilirubin level of 11.4 mg/dL, alanine aminotransferase of 2620 U/L, aspartate aminotransferase of 1876 U/L, and alkaline phosphatase level of 186 U/L. Discontinuation of the herbal remedy resulted in normalization of the liver enzymes two months later. DISCUSSION: This is the first report of hepatitis probably related to use of Teucrium viscidum. The herb is infrequently used in Chinese medicine for treatment of rheumatic and bleeding disorders. T. viscidum contains teucvin, similar to other Teucrium species and is related to T. chamaedrys, commonly known as germander, which is a well documented cause of hepatotoxicity. CONCLUSIONS: Our findings suggest that Teucrium viscidum can cause hepatotoxicity similar to that of germander.

Identification of a novel vardenafil analogue in herbal product.

A new herbal health product marketed for enhancing erectile function, namely Power58 Platinum, was purchased over-the-counter in Hong Kong. The product was tested for adulteration with sildenafil, tadalafil, and vardenafil as well as their structurally modified analogues. A new analogue of vardenafil, in which the N-ethylpiperazine ring and the sulphonyl group were removed from the vardenafil structure, was identified in the product.

A report of two families with sarcosinaemia in Hong Kong and revisiting the pathogenetic potential of hypersarcosinaemia.

INTRODUCTION: Sarcosinaemia is a rare metabolic disorder which has not been reported in Asia. CLINICAL PICTURE: The urine samples of 2 patients were screened as a routine metabolic screening offered for patients with mental retardation in our hospital. We used gas chromatography-mass spectrometry (GC-MS) which is capable of detecting abnormal pattern in amino acids and organic acids. Plasma sarcosine level was further quantified by GC-MS. The same methods were used in the investigations of asymptomatic family members. Urine examination by GC-MS revealed excessive amount of sarcosine in urine (normally undetectable) and their plasma sarcosine levels were raised. The 2 differential diagnoses of presence of sarcosine in urine--glutaric aciduria type II and folate deficiency--were ruled out by the absence of abnormal organic acids in the initial urine screen and by normal serum folate level respectively. Screening of the 2 families identified excessive sarcosine in urine in 2 siblings, one from each family. However, these 2 siblings of indexed patients thus identified have no neurological or developmental problem. CONCLUSION: Our finding was consistent with the notion that sarcosinaemia is a benign condition picked up coincidentally during screening for mental retardation.

Hidden aconite poisoning: identification of yunaconitine and related aconitum alkaloids in urine by liquid chromatography-tandem mass spectrometry.

Poisoning from aconite occurs worldwide as a result of misuse of the potent plant. Laboratory investigation into suspected intoxication cases is challenging because the content of toxic aconitum alkaloids varies depending on the plant source, market processing, dosing protocol, hydrolytic degradation, and metabolic transformation. Using a triple-quadrupole tandem mass spectrometer, a group screening method was developed based on the mass-fragmentographic scheme of common aconitum alkaloids. The precursor-ion scans of m/z 105 and 135 permitted selective profiling of 14-O-benzoyl-norditerpenoids and the 14-O-anisoyl-norditerpenoids, respectively. Gradient reversed-phase liquid chromatography minimized coelution of isobaric compounds. The screening protocol was applied to a clinical investigation of suspected herbal poisoning. In total, 15 urine samples were thus screened positive for aconitum alkaloid over 5 years. The diagnoses of aconite poisoning in 11 patients were firmly established based on the known prescription history and the positive urine finding. In four patients, without aconitum herbs being listed in the herbal prescriptions, contamination of the herbal remedies by aconite was suspected to be the hidden cause of their acute poisoning. Yunaconitne, a highly toxic aconitum alkaloid, was thus identified in human urine for the first time. The group screening method of aconitum alkaloids in urine is an important diagnostic aid for acute poisoning by aconites of an unclear origin.

Risk of vitamin A toxicity from candy-like chewable vitamin supplements for children.

Numerous vitamin supplements are available over-the-counter to the general public. Some such supplements are available as candy-like chewable preparations to encourage consumption by children. We report 3 cases of overdose of such preparations. Each patient had taken an estimated 200,000 to 300,000 IU of vitamin A. Their circulating vitamin A (retinol and retinyl palmitate) concentrations were monitored over a 6-month period. There were no clinical or biochemical complications noted. However, there were marked increases in both retinol and retinyl palmitate concentrations above age-related reference ranges. In particular, it took 1 to 3 weeks for the serum retinol concentrations to peak and many months for them to normalize. Parents should be warned about the dangers of excessive vitamin consumption. Clinicians should be aware of the late peak in serum retinol concentrations, which may lead to late complications of vitamin A overdose.

Detection of Herba Aristolochia Mollissemae in a patient with unexplained nephropathy.

The authors report a case of unexplained nephropathy 2 months after ingestion of Herba Aristolochia Mollissemae in a patient with long-standing Crohn's disease and recently diagnosed carcinoma of the colon. It presented as a relentlessly progressing hypocellular interstitial nephritis 5 months after cessation of an earlier course of mesalazine. The patient finally had end-stage renal failure 12 months after taking herbs and required hemodialysis. Aristolochic acid (AA) was detected in the herbal sample of Herba Aristolochia Mollissemae by high-performance liquid chromatography-diode array detection and electrospray ionization-tandem mass spectrometry. Specific AA-DNA adducts were detected in the renal biopsy by 32 P-postlabelling analysis. Transitional cell carcinoma was diagnosed 5 months after herb ingestion. It was found that the originally prescribed nonnephrotoxic herb had been substituted by AA-containing Herba Aristolochia Mollissemae at the wholesaler level. Although AA-associated nephropathy could not be proved conclusively, the current case contributed to the withdrawal of the AA-related herbs by the local health authority in Hong Kong. Physicians should be on the alert for herbal nephrotoxicity by possible replacement of nontoxic herbs by nephrotoxic herbs.

Novel mutations of the AGXT gene causing primary hyperoxaluria type 1.

BACKGROUND: Primary hyperoxaluria type 1 (PH1), an inherited cause of nephrolithiasis, is due to a functional defect of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). A definitive PH1 diagnosis can be established by analyzing AGT activity in liver tissue or mutation analysis of the AGXT gene. METHODS: The molecular basis of PH1 in three Chinese patients, two with adult-onset and one with childhood-onset recurrent nephrolithiasis, was established by analyzing the entire AGXT gene. RESULTS: Three novel mutations (c2T>C, c817insAG and c844C>T) and two previously reported mutations (c33insC and 679-IVS6+2delAAgt) were identified. c2T>C converts the initiation codon from ATG to ACG, which predicts significant reduction, if not complete abolition, of protein translation. c817insAG leads to a frameshift and changes the amino acid sequence after codon 274. c844C>T changes glutamine at codon 282 to a termination codon, resulting in protein truncation. CONCLUSIONS: This is the first report describing AGXT gene mutations in Chinese patients with PH1. AGXT genotypes cannot fully explain the clinical heterogeneity of PH1, and other factors involved in disease pathogenesis remain to be identified. Our experience emphasizes the importance of excluding PH1 in patients with recurrent nephrolithiasis to avoid delay or inappropriate management.