Tyrosinemia Type Research Articles

Short-term nitisinone discontinuation of hereditary tyrosinemia type 1 mice causes metabolic alterations in glutathione metabolism/biosynthesis and multiple amino acid degradation pathways

Short-term nitisinone discontinuation of hereditary tyrosinemia type 1 mice causes metabolic alterations in glutathione metabolism/biosynthesis and multiple amino acid degradation pathways

The compound heterozygous mutations of c.607G>a and c.657delC in the FAH gene are associated with renal damage with hereditary tyrosinemia type 1 (HT1).

Hereditary tyrosinemia type 1 (HT1) is a rare inherited metabolic disease characterized by severe liver and renal dysfunction. Early identification in affected children is critical for improved treatment options and prognosis. In this study, we identified novel compound heterozygous mutations (NM_000137: c.657delC (p.K220Rfs*12) and c.607G>A (p.A203T)) in the fumarylacetoacetate hydrolase (FAH) gene in a family. We also characterized the clinical phenotype of the proband and verified the pathogenic effects of the mutations. Furthermore, we explored the pathogenic mechanism of renal injury through renal biopsy pathology and cell-based in vitro assays. Our study aims to verify the association between novel fumarylacetoacetate hydrolase (FAH) variants and HT1, confirm the pathogenic effects of the mutations and explore the pathogenic mechanism of renal injury. We showed these FAH mutations were inherited in an autosomal recessive manner and resulted in abnormal FAH protein expression and dysfunction, leading to fumarylacetoacetate (FAA) accumulation. The proband also showed apparent renal injury, including glomerular filtration barrier dysfunction and abnormal tubular protein reabsorption. These observations may provide deeper insights on disease pathogenesis and identify potential therapeutic approaches for HT1 from a genetic perspective. Similarly, we hope to provide valuable information for genetic counseling and prenatal diagnostics.

Initial presentation, management and follow-up data of 33 treated patients with hereditary tyrosinemia type 1 in the absence of newborn screening

Hereditary tyrosinemia type 1 (HT1) is a rare autosomal recessive disorder of phenylalanine and tyrosine catabolism due to a deficiency of fumarylacetoacetate hydrolase. HT1 has a large clinical spectrum with acute forms presenting before six months of age, subacute forms with initial symptoms occurring between age 6 and 12 months, and chronic forms after 12 months of age. Without treatment, HT1 results in the accumulation of toxic metabolites leading to liver disease, proximal tubular dysfunction, and porphyria-like neurological crises. Since the early nineties, the outcome of HT1 has dramatically changed due to its treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC, nitisinone). In some countries, HT1 is included in the newborn screening program based on the analysis of succinylacetone concentration on dried blood spots.In the present study, we report clinical and laboratory parameters data on 33 HT1 patients focusing on clinical presentation and therapeutic management at the time of diagnosis. Eighteen patients were diagnosed with the acute form (median age at presentation 2.5 months), 6 with the subacute form (median age at presentation 10 months), and 5 with the chronic form of HT1 (median age at presentation 15 months). Four patients were diagnosed pre-symptomatically in the setting of a family history of HT1. Among the 29 symptomatic patients, hepatomegaly was found in 83% of patients and prolonged coagulation times due to hepatocellular insufficiency was observed in 93% of patients. HT1 diagnosis was confirmed by increased urine succinylacetone in all patients. All patients but 2 were treated with nitisinone immediately at diagnosis. During follow-up, 2 patients received liver transplant for high grade dysplasia or hepatocellular carcinoma, 10 patients exhibited some form of neurocognitive impairments.Our data confirm that HT1 is a severe treatable liver disease that should be detected at the earliest, ideally by newborn screening and appropriately treated.

Comprehensive Evaluation of the NeoBase 2 Non-derivatized MSMS Assay and Exploration of Analytes With Significantly Different Concentrations Between Term and Preterm Neonates.

Despite the popularity of the NeoBase 2 Non-derivatized MSMS assay (PerkinElmer, Turku, Finland), there are no reports of its comprehensive evaluation, including the ability to distinguish transient tyrosinemia of the newborn (TTN) from tyrosinemia type 1 (TYR 1) using succinylacetone (SUAC). No newborn screening (NBS) cutoffs for preterm neonates in the Korean population have been suggested. We evaluated the NeoBase 2 assay and identified analytes requiring different cutoffs in preterm neonates. Residual NBS dried blood spot samples and proficiency testing (PT) materials of the Newborn Screening Quality Assurance Program and the Korean Association of External Quality Assessment Service were used. Precision, accuracy, limit of detection (LOD), lower limit of quantification (LLOQ), linearity, recovery, carryover, and performance of SUAC were evaluated. Cutoffs were determined, and analytes requiring different cutoffs in preterm neonates were investigated. Mean CVs for within-run and between-day precision were within 15%. Accuracy analysis indicated high agreement with in-house derivatized assay results and results of other PT participants. All analytes demonstrated acceptable LOD, LLOQ, and linearity. Recoveries were acceptable, except for SUAC. Carryover was negligible. Cutoffs were established for all analytes; Tyr, adenosine, and C20:0-lysophosphatidylcholine required different cutoffs in preterm neonates. Differential diagnosis of TYR 1 and TTN was successful with simultaneous Tyr and SUAC measurement. The NeoBase 2 assay demonstrated satisfactory performance. The additional analytes provide a wider diagnostic coverage, and the simultaneous measurement of Tyr and SUAC is efficient in excluding TYR 1. The new cutoffs for preterm neonates may decrease false-positive rates, without compromising diagnostic sensitivity.

Activation of homology-directed DNA repair plays key role in CRISPR-mediated genome correction.

Gene editing for the cure of inborn errors of metabolism (IEMs) has been limited by inefficiency of adult hepatocyte targeting. Here, we demonstrate that in utero CRISPR/Cas9-mediated gene editing in a mouse model of hereditary tyrosinemia type 1 provides stable cure of the disease. Following this, we performed an extensive gene expression analysis to explore the inherent characteristics of fetal/neonatal hepatocytes that make them more susceptible to efficient gene editing than adult hepatocytes. We showed that fetal and neonatal livers are comprised of proliferative hepatocytes with abundant expression of genes involved in homology-directed repair (HDR) of DNA double-strand breaks (DSBs), key for efficient gene editing by CRISPR/Cas9. We demonstrated the same is true of hepatocytes after undergoing a regenerative stimulus (partial hepatectomy), where post-hepatectomy cells show a higher efficiency of HDR and correction. Specifically, we demonstrated that HDR-related genome correction is most effective in the replicative phase, or S-phase, of an actively proliferating cell. In conclusion, this study shows that taking advantage of or triggering cell proliferation, specifically DNA replication in S-phase, may serve as an important tool to improve efficiency of CRISPR/Cas9-mediated genome editing in the liver and provide a curative therapy for IEMs in both children and adults.

Hypophosphatemic rickets as a key presenting feature of tyrosinemia type 1

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

S3069 Lifesaving but Tiresome Treatment for Tyrosinemia Type 1

Introduction: Tyrosinemia type I (HT1) is a rare autosomal recessive condition caused by a genetic mutation disrupting proper functioning of the fumarylacetoacetate hydrolase (FAH) enzyme, the terminal enzyme in the tyrosine catabolism pathway. The below case exemplifies the difficulty for adherence as children transition to adulthood of the standard therapy that prolongs life and decreases need for orthotopic liver transplantation (OLT). Case Description/Methods: A 23-year-old male with known tyrosinemia type I presents with progressively worsening back, lower extremity, and abdominal pain over the last six months. He had been lost to follow-up from Genetics clinic for the last ten years. He adhered to nitisinone therapy and diet modifications until around five years ago. The patient was admitted to the hospital for neurological crises due to non-adherence to HT1 therapy. On admission, vital signs were stable and his physical exam significant for mild tenderness of abdomen at RUQ and tenderness in the lumbar and thoracic region of back. Pertinent lab findings were albumin of 3.2, alkaline phosphatase of 356. AST, ALT, Bili, CBC, BMP WNL. Amino acid panel found tyrosine level of 62. AFP level of 188. MRI Abdomen with and without contrast found cirrhotic liver morphology, developing portal hypertension (borderline enlarged spleen, collateral vasculature, but no ascites), and a lesion of hepatic segment 8 measuring 2.3cm x 1.4cm in diameter. Patient was planned to be restarted on nitisinone with pending further evaluation of liver lesion. (Figure) Discussion: The above case demonstrates a patient with the rare genetic disorder Tyrosinemia type 1 with non-adherence to nitisinone and diet modification therapies. The presentation of neurological crises and abdominal pain with development of hepatomas/hepatocellular carcinoma (HCC) is typical for untreated or non-adherent patients with HT1. Nitisinone has been shown to be highly effective for this condition with 4-year survival rates of 94% compared to 29% of diet modification alone. Prior to nitisinone therapy, most patients required OLT. Despite the clear benefits, recent evidence is finding increasing non-adherence as patients grow older into adolescence and adulthood. This is consistent with adherence problems with early diagnosis chronic diseases with long-term therapies. More research is needed to elucidate major barriers for non-compliance and to refine guidelines regarding frequency of follow-up and monitoring of serum AFP to screen for HCC and encourage compliance.Figure 1.: MRI Abdomen with contrast with findings of a hepatic lesion on segment 8.

In vivo quantitative photoacoustic evaluation of the liver and kidney pathology in tyrosinemia

Hereditary tyrosinemia type Ⅰ (HT1) is a severe autosomal recessive inherited metabolic disease, which can result in severe damage of liver and kidney. Photoacoustic imaging (PAI) uses pulsed laser light to induce ultrasonic signals to facilitate the visualization of lesions that are strongly related to disease progression. In this study, the structural and functional changes of liver and kidney in HT1 was investigated by cross-scale PAI. The results showed that the hepatic lobule and renal tubule were severely damaged during HT1 progression. The hemoglobin content, vessel density, and liver function reserve were decreased. The metabolic half-life of indocyanine green declined from 59.8 s in health to 262.6 s in the advanced stage. Blood oxygen saturation was much lower than that in health. This study highlights the potential of PAI for in vivo evaluation of the liver and kidney lesions in HT1.

The Discovery of the Mode of Action of Nitisinone.

This review briefly discusses the discovery of the mode of action of the triketone herbicide, 2-(2-nitro-4-trifluormethylbenzoyl)-1,3-cyclohexanedione and its use as a drug Nitisinone for the treatment of inborn errors of tyrosine metabolism. Nitisinone is a potent reversible tight-binding inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, involved in the catabolism of the amino acid tyrosine. Nitisinone is used to treat the rare disease hereditary tyrosinaemia type 1 where the last enzyme in the breakdown of tyrosine, fumarylacetoacetase is deficient. Nitisinone is also used to treat patients with alkaptonuria where the enzyme homogentisic acid oxidase is deficient. Articles in this issue discuss metabolites of tyrosine catabolism in healthy patients and those with alkaptonuria.

Biochemical and behavioural profile of NTBC treated Tyrosinemie type 1 mice.

Tyrosinemia type 1 (HT1) is a rare metabolic disorder caused by a defect in the tyrosine catabolic pathway. Since HT1 patients are treated with NTBC, outcome improved and life expectancy greatly increased. However extensive neurocognitive and behavioural problems have been described, which might be related to treatment with NTBC, the biochemical changes induced by NTBC, or metabolites accumulating due to the enzymatic defect characterizing the disease. To study the possible pathophysiological mechanisms of brain dysfunction in HT1, we assessed blood and brain LNAA, and brain monoamine neurotransmitter metabolite levels in relation to behavioural and cognitive performance of HT1 mice. C57BL/6 littermates were divided in three different experimental groups: HT1, heterozygous and wild-type mice (n = 10; 5 male). All groups were treated with NTBC and underwent cognitive and behavioural testing. One week after behavioural testing, blood and brain material were collected to measure amino acid profiles and brain monoaminergic neurotransmitter levels. Irrespective of the genetic background, NTBC treatment resulted in a clear increase in brain tyrosine levels, whereas all other brain LNAA levels tended to be lower than their reference values. Despite these changes in blood and brain biochemistry, no significant differences in brain monoamine neurotransmitter (metabolites) were found and all mice showed normal behaviour and learning and memory. Despite the biochemical changes, NTBC and genotype of the mice were not associated with poorer behavioural and cognitive function of the mice. Further research involving dietary treatment of FAH-/- are warranted to investigate whether this reveals the cognitive impairments that have been seen in treated HT1 patients.

Diagnostic tardif de la tyrosinémie héréditaire de type I, le cas de deux faux jumeaux

AbstractHereditary tyrosinemia type 1 (TH1) is an autosomal recessive inherited aminoacidopathy caused by a deficiency of an enzyme involved in the last step of tyrosine catabolism called fumarylacetoacetate hydrolase (FAH). The accumulation of metabolites fumarylacetoacetate, succinylacetoacetate and succinylacetone generates renal and hepatic toxicity, hence the name hepatorenal tyrosinemia. In the context of targeted screening, two male fraternal twins of consanguineous parents and with a history of death in the siblings, as well as a cousin, were diagnosed for TH1. The dosage of urinary succinylacetone (SA) came back for the first twin in favor of tyrosinemia, but the dosage in the second twin was positive only after the fourth determination confirming the pathology diagnosis. Classically, the SA rate rises from the first days of life; the heterogeneity of the mutations affecting the FAH gene can explain this phenotypic fluctuation also the action of modulating factors still little known without any reported correlation between the genotype and the phenotype. The genetic study revealed a frequent genetic mutation of the FAH gene.

In vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions

Conventional therapy for hereditary tyrosinemia type-1 (HT1) with 2-(2-nitro-4-trifluoromethylbenzoyl)−1,3-cyclohexanedione (NTBC) delays and in some cases fails to prevent disease progression to liver fibrosis, liver failure, and activation of tumorigenic pathways. Here we demonstrate cure of HT1 by direct, in vivo administration of a therapeutic lentiviral vector targeting the expression of a human fumarylacetoacetate hydrolase (FAH) transgene in the porcine model of HT1. This therapy is well tolerated and provides stable long-term expression of FAH in pigs with HT1. Genomic integration displays a benign profile, with subsequent fibrosis and tumorigenicity gene expression patterns similar to wild-type animals as compared to NTBC-treated or diseased untreated animals. Indeed, the phenotypic and genomic data following in vivo lentiviral vector administration demonstrate comparative superiority over other therapies including ex vivo cell therapy and therefore support clinical application of this approach.

A tyrosine catabolic intermediate 4-hydroxyphenylpyruate attenuates murine endotoxic shock by blocking NLRP3 inflammasome activation

The metabolic alterations of amino acid metabolism are closely associated with inflammatory response. However, relatively little is known about the roles of phenylalanine (Phe)/tyrosine (Tyr) catabolites during inflammation. Nitisinone (NTBC) is an orphan drug used to treat hereditary tyrosinemia type I potentially by changing Phe/Tyr metabolic flow. In this study, we used NTBC as a tool to investigate the potential role of the Phe/Tyr catabolic pathway in inflammatory responses. We found that NTBC was effective in tempering the bacterial endotoxin lipopolysaccharide (LPS)-induced septic shock in mice. Mechanistically, the protective effect was related to the accumulation of a Phe/Tyr catabolic intermediate, 4-hydroxyphenylpyruvate (4-HPP), induced by the NTBC treatment. 4-HPP could inhibit NLRP3 inflammasome priming and activation processes and therefore reduce IL-1β release and pyroptosis. Like NTBC, 4-HPP was also effective in attenuating endotoxic shock in mice. Our results suggest the Phe/Tyr catabolic pathway as a potential immunoregulatory hub that may be exploited therapeutically to alleviate inflammation.

MRNA-based therapy proves superior to the standard of care for treating hereditary tyrosinemia 1 in a mouse model

Hereditary tyrosinemia type 1 is an inborn error of amino acid metabolism characterized by deficiency of fumarylacetoacetate hydrolase (FAH). Only limited treatment options (e.g., oral nitisinone) are available. Patients must adhere to a strict diet and face a life-long risk of complications, including liver cancer and progressive neurocognitive decline. There is a tremendous need for innovative therapies that standardize metabolite levels and promise normal development. Here, we describe an mRNA-based therapeutic approach that rescues Fah-deficient mice, a well-established tyrosinemia model. Repeated intravenous or intramuscular administration of lipid nanoparticle-formulated human FAH mRNA resulted in FAH protein synthesis in deficient mouse livers, stabilized body weight, normalized pathologic increases in metabolites after nitisinone withdrawal, and prevented early death. Dose reduction and extended injection intervals proved therapeutically effective. These results provide proof of concept for an mRNA-based therapeutic approach to treating hereditary tyrosinemia type 1 that is superior to the standard of care.

Neurocognitive outcome and mental health in children with tyrosinemia type 1 and phenylketonuria: A comparison between two genetic disorders affecting the same metabolic pathway.

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine–tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age‐ and gender‐matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler‐subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach‐scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal–Wallis tests with post‐hoc Mann–Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions “working memory”, “plan and organize” and “monitor”, ASEBA dimensions “social problems” and “attention problems”, and for the SSRS “assertiveness” scale (all p values <0.001). To conclude, TT1 patients showed cognitive impairments on all domains studied, and appeared to be significantly more affected than PKU patients. More attention should be paid to investigating and monitoring neurocognitive outcome in TT1 and research should focus on explaining the underlying pathophysiological mechanism.

Update on pathogenesis, diagnosis and treatment of hereditary tyrosinemia type Ⅰ

遗传性酪氨酸血症Ⅰ型（HT-1）是一种罕见的常染色体隐性遗传病，因延胡索酰乙酰乙酸水解酶缺陷，引起体内酪氨酸分解代谢受阻，毒性代谢物蓄积，从而导致严重的肝、肾功能障碍及神经危象，且有较高的肝细胞癌风险。本病多见于2岁内婴儿，临床表现缺乏特异性，血琥珀酰丙酮检测有助于早期识别。尼替西农联合低酪氨酸饮食治疗可显著改善预后。对于肝功能严重衰竭且尼替西农治疗无效或疑有肝细胞癌患者，推荐肝移植。酶替代疗法及基因治疗仍处于临床研究阶段。.

Clinical and biochemical footprints of inherited metabolic diseases. VIII. Neoplasias.

Cancer, caused by multiple cumulative pathogenic variants in tumor suppressor genes and proto-oncogenes, is a leading cause of mortality worldwide. The uncontrolled and rapid cell growth of the tumors requires a reprogramming of the complex cellular metabolic network to favor anabolism. Adequate management and treatment of certain inherited metabolic diseases might prevent the development of certain neoplasias, such as hepatocellular carcinoma in tyrosinemia type 1 or hepatocellular adenomas in glycogen storage disorder type 1a. We reviewed and updated the list of known metabolic etiologies associated with various types of benign and malignant neoplasias, finding 64 relevant inborn errors of metabolism. This is the eighth article of the series attempting to create a comprehensive list of clinical and metabolic differential diagnosis by system involvement.

Лечение тирозинемии тип 1: практические аспекты

Лечение многих болезней, включенных в программу расширенного скрининга новорожденных, предусматривает обязательное применение диетотерапии. Рекомендуемые подходы к лечению тирозинемии 1 типа (ТИР1) включают в себя назначение специализированных пищевых продуктов, фармакологическое лечение препаратом нитизинон - пероральным ингибитором фермента FAH на пути катаболизма тирозина, и симптоматическое лечение. Диетическое вмешательство с ограничением фенилаланина и тирозина вместе с поддерживающими мерами может облегчить симптомы, но, учитывая высокий риск гепатоцеллюлярной карциномы, излечение этих пациентов до сих пор возможно только использованием трансплантации печени. В 2021 году в Российской Федерации опубликованы клинические рекомендации по лечению этого редкого заболевания. Для обеспечения своевременного лечения необходимо, чтобы практикующий врач, занимающийся лечением пациентов с таким редким заболеванием, как ТИР1, обладал знаниями принципов ведения, а также практических алгоритмов расчета диеты. В данной статье на клинических примерах рассмотрены вопросы, касающиеся ведения в период метаболической декомпенсации и правильного подбора диетотерапии пациентам разного возраста, страдающим ТИР1. Treatment of many of the diseases in the panel of expanded newborn screening includes dietary therapy. Hereditary tyrosinemia type I (HT-I) is inherited metabolic disease caused by defects in tyrosine metabolism and by a mutation in the gene coding for fumarylacetoacetate hydrolase (FAH). The main clinical features of HT-I are caused by hepatic involvement and renal tubular dysfunction. The recommended treatment approaches for HT-1 are the prescription of specialized nutrition products, pharmacologic treatment with nitisinone, a peroral inhibitor of FAH in the tyrosine catabolic pathway, and symptomatic management. Dietary intervention with restriction of phenylalanine and tyrosine together with supportive measures can ameliorate the symptoms, but given the high risk for hepatocellular carcinoma, a cure for these patients so far is possible only with liver transplantation. In 2021, clinical guidelines for the treatment of this rаre disease were published in Russian Federation. To provide for the timely treatment, it is essential for a practitioner involved in the care patients with such a rare disorder as НТ-1 to have the knowledge of the principles of management, as well as practical algorithms for diet calculation. The article gives a detailed case-based description of management during metabolic decompensation and the choice of dietary therapy for HT-1 patients of different age groups.

Клинический случай тирозинемии тип I у новорожденного ребенка

Представлен случай тирозинемии 1 типа (НТ1) у новорожденного ребенка с описание клинической картины, иллюстрирующей сложности диагностики заболевания у новорожденного. Особое внимание уделено описанием неврологических проявлений и результатов инструментального обследования. Включение НТ1 в расширенный неонатальный скрининг позволит сократить время диагностики заболевания у новорожденных и как можно раньше начать патогенетическое лечение. A case of type 1 tyrosinemia in a newborn is presented with a description of clinical signs illustrating the complexity of diagnosing the disease in a newborn. Particular attention is paid to the description of neurological manifestations and the results of instrumental examination. The inclusion of type 1 tyrosinemia in expanded neonatal screening will reduce the time for diagnosing the disease in newborns and start pathogenetic treatment as early as possible.

Clinical experience with hepatorenal tyrosinemia from a single Egyptian center.

Although very recently, in Egypt, sick newborn screening has included screening for hepatorenal tyrosinemia, yet, it is not yet included in nationwide neonatal screening and hence diagnosis may be delayed. The aim of this study was to analyze data of all cases presenting with hepatorenal tyrosinemia to the Pediatric Hepatology Unit, Cairo University, Egypt from 2006 to 2019. Data were retrieved from patients’ files including age of onset of symptoms, clinical signs, blood counts, liver functions, serum phosphorous, alpha-fetoprotein, succinylacetone and abdominal ultrasound. During this period, 76 patients were diagnosed with hepatorenal tyrosinemia if succinylacetone in dry blood spot was elevated above 1 μmol/L. These 76 cases came from 70 families; consanguinity was reported in 61 families. In our cohort we reported 30 affected siblings with a similar clinical presentation, who died undiagnosed. Presentation was acute in 26%, subacute in 30% and chronic in 43%. Abdominal distention was the commonest presenting symptom (52.6%). Coagulopathy was the commonest derangement in liver functions; hyperbilirubinemia and raised transaminases were less common. Ultrasound findings included hepatic focal lesions in 47% and enlarged echogenic kidneys in 39% and 45.3% respectively. Only 20 children were treated with Nitisinone because of unavailability and high costs; seven out of them underwent liver transplantation. In conclusion, although hepatorenal tyrosinemia is a rare inborn error of metabolism, in a large population country with high rate of consanguinity; this disease is not uncommonly diagnosed. The current treatment is not readily available because of the costs in a resource-limited country. Neonatal screening and subsidization of the costly medication need to be considered.