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The mutation spectrum and ethnic distribution of non-hepatorenal tyrosinemia (types II, III)



Different types of non-hepatorenal tyrosinemia are among the rare forms of tyrosinemia. Tyrosinemia type II and III are autosomal recessive disorders caused by pathogenic variants in the tyrosine aminotransferase (TAT), and 4-hydroxyphenyl-pyruvate dioxygenas (HPPD) genes, respectively. There are still unclarified aspects in their clinical presentations, mutational spectrum, and genotype–phenotype correlation.

Main body

In this study, we evaluated the spectrum of TAT and HHPD gene mutations in patients with tyrosinemia type II and III. Moreover, biochemical and clinical findings are evaluated to establish a genotype–phenotype relationship in the above-mentioned patients. Thirty-three TAT variants have been reported in 42 families, consisting of 21 missense variants, 5 frameshift variants, 4 nonsense variants, 2 variants that primarily cause splicing site, and 1 skipping complete exon (large deletion). The most common variant is p.Arg57Ter, causing a splicing defect, and resulting in premature termination of translation, which was found in 10 patients from 3 families. In HPPD gene, eleven variants in 16 patients have been reported including 7 missense variants, 2 nonsense variants, 1 splice defect, and 1 frameshift variant so far. All variants are unique, except for p.Tyr160Cys, which is a missense variant found in two different patients. Regarding genotype–phenotype correlations, in 90% of tyrosinemia type II patients, positive clinical and biochemical correlations with a detected variant are observed. In HPPD gene, due to the small number of patients, it is not possible to make a definite conclusion.


This is the first large review of variants in TAT and HPPD, highlighting the wide spectrum of disease-causing mutations. Such information is beneficial for the establishment of a privileged mutation screening process in a specific region or ethnic group.


Catabolism of amino acids supplies necessary nitrogen for the synthesis of crucial compounds like neurotransmitters, hormones, and energy for the cell. The liver and kidneys are the main tissues for this enzymatic pathway that its involvement depends on the nature of the amino acid. Tyrosine is a non-essential amino acid, derived directly from diet or tissue proteins or the hydroxylation of phenylalanine, which is an essential amino acid. It is a precursor in the synthesis of catecholamines, thyroid hormones, and melanin [1]. Defect in the tyrosine metabolism pathway causes increased tyrosine level and several types of related disorders.

The two least common deficiencies of tyrosine metabolism pathway are non-hepatorenal tyrosinemia, which are called tyrosinemia type II and III. Tyrosinemia type II (OMIM 276600) or oculocutaneous tyrosinemia occurs secondary to a deficiency of the cytoplasmic enzyme, tyrosine aminotransferase (TAT: EC [2]. TAT gene contains 12 exons, which code an active protein containing 454 amino acids. The gene is located at chromosome 16q22 which is autosomal recessive. Main manifestations of this enzyme deficiency are corneal thickening, as well as palmar and plantar hyperkeratosis. Liver and kidney functions are generally normal [3].

Tyrosinemia type III (OMIM 276710) is the rarest type of deficiency in the tyrosine metabolism pathway due to a lack of enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD). The human 4-HPPD gene is located at 12q24-qter and contains 14 exons, which encode a protein containing 392 amino acids. The 4-HPPD enzyme is expressed mainly in the liver and kidney. This disorder is autosomal recessive [4]. The symptoms of tyrosinemia type III are varied, and not well characterized. Some asymptomatic patients never develop neurological signs while some patients suffer from severe neurological symptoms in childhood.

Regarding recent developments in the management of these patients, we think that it is crucial for clinicians and healthcare providers to be informed about metabolic diseases, which would be potentially beneficial for current and future mutation-targeted therapeutic options. There are some reports about Tyrosinemia type II and III, however, no clear analysis and comparison between mutations (genotype), and their phenotype has been reported so far. The objective of this review was to identify and summarize the reported mutations in the TAT and HPPD genes and their corresponding manifestations.


Tyrosine aminotransferase (TAT) gene

To date, 33 mutations in TAT from 42 families (74 patients) have been described to cause tyrosinemia type II (Table 1, Additional file 1: Fig. 1A) [5,6,7,8,9,10,11,12,13,14,15,16,17]. Missense variants illustrate the predominant variant type (n = 21) in the most recessively inherited autosomal diseases. Furthermore, 5 frameshift variants, 4 nonsense variants, 2 variants that primarily cause splicing site, and 1 skipping complete exon (large deletion) are reported (Fig. 1B). No deep intronic variants and a variant in exon 1 have been reported. The majority of variants are specific. The most frequently observed variant is p.Arg57Ter, which is a nonsense variant causing premature termination of translation, found in 10 patients from 3 families (Table 1). In all patients, this strongly inactivating variant is correlated with high-untreated plasma tyrosine levels. The variant was observed in different ethnicities including Italian, Scottish, and Native American patients. The second most frequently reported variant is p.Thr408Thr, which was found in 7 patients, of 2 unrelated Arab families (Table 1). It is a silent exonic transversion variant, which caused complete missplicing by exon 11 skipping. This skipping leads to the in-frame deletion of 99 nucleotides (33 amino acids). Therefore, the mRNA stability would be affected by this deletion. It is confirmed that this deleterious variant, is responsible for the severe manifestation in these two families. Other frequently seen missense variants are p.Cys151Tyr, p.Leu273Pro, and p.Pro406Leu, which were found in 4 patients with 2 different families, respectively (Table 1). In silico analysis of p.Cys151Tyr variant demonstrated a strong damaging effect corresponding to a deleterious impact on TAT proteins. In addition, p.Leu273Pro variant was reported to affect the stability of TAT protein either by less interaction of protein surface or the reduction of stability of tertiary structure of the protein. The rest of the variants identified in tyrosinemia type II are very rare and reported in one family (Table 1). Variants are found in all exons except exon 1, however, the distribution of missense variants across the TAT gene is not uniform (Fig. 1A). Interestingly, the check-in location of variants revealed that the first variant arises at residue 57 (p.Arg57Ter, Table 1, Fig. 1A). It is demonstrated that probably the amino acids of the N-terminal to this residue are poorly conserved. The most common accumulation of variants in this gene occurs in exon 11, which might be particularly due to the susceptibility of this region to mutation. See additional file 1 for the more information in reported patients with tyrosinemia type II and III.

Table 1 Summary of reported variants in TAT gene of patients with tyrosinemia type II
Fig. 1
figure 1

Schematic illustration (not to scale) of the TAT gene and location of sequence variants associated with Tyrosinemia type II deficiency. A Exon (boxes)–intron (lines) structure of the human TAT gene. Coloring boxes are consistent with panel. B Pie chart summarizing types of TAT variants reported to date

Regarding the geographical distribution of variants, the majority of reported variants are patients from Europe, North America, Japan, Tunisia, and Palestinian Arabs. For the most prevalent variant in TAT gene, p.Arg57Ter, the founder effect is apparent in northern Italy, which should be analyzed in other populations of Mediterranean ancestry. Little information about the epidemiology and molecular defects in tyrosinemia type II patients from East Asia is available at this time. To the best of our knowledge, no mutation in the TAT gene has been reported from Central America, Africa, the Middle East, and the Oceania continent.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) gene

Eleven disease-causing variants in 16 patients are recently reported in HPPD gene [4, 18,19,20,21,22,23]. All 11 HPPD alleles are divided into 7 missense variants, 2 nonsense variants, 1 splice defect, and 1 frameshift variant (Table 2). Nine of them are in the exonic region and 2 out of 11 variants are intronic ones. All variants are unique, except p.Tyr160Cys, which is a missense variant found in 2 different patients from 2 families (Table 2). The analysis of the crystal structure of Pseudomonas enzyme demonstrated that the Tyr160 residue corresponds to a position in an alpha helix, which is involved in inter-subunit contacts. Therefore, the position of variant might be important for the stability of the enzyme, but this needs to be further elucidated. Three variants were reported in exon 11 and 2 variants in the intronic region of 10, and 11. Therefore, the largest accumulation of variants happens in this region, which is suggestive of its susceptibility to mutation.

Table 2 Summary of reported variants in HPPD gene of patients with tyrosinemia type III

Regarding the geographical distribution of variants, the majority of reported variants are patients from Europe, and Asia (Japan, China, and Iran). No information about the epidemiology and molecular defects in tyrosinemia type III patients from North and Central America, Africa, Australia, and the Oceania continent are available.

Genotype–phenotype correlation

The correlation between genotype and phenotype is described as the possibility of an association between a specific mutation and/or class of mutation with a special clinical abnormality. Therefore, finding genotype–phenotype correlations in inherited metabolic disorders as rare diseases are difficult and complicated by several factors, such as the absence of large cohorts of patients for analysis, the large phenotypic heterogeneity associated with the same mutation, and a high proportion of private mutations [24]. The great number of variants in TAT and HPPD genes are private variants, so, genotype–phenotype correlations or correlations between type or location of the mutation and clinical manifestation have not been established so far. Therefore, for this purpose, we present a comprehensive list of patients identified from the reported literature, along with clinical and biochemical data (Additional file 1: Table S1). This helped us not only to precisely estimate the number of published patients with tyrosinemia type II and III diseases but also helped to stratify patients for genotype–phenotype correlations.

Data on clinical and biochemical results of tyrosinemia type II were available for 70 patients. We have identified among them, only 7 patients had elevated levels of tyrosine along with detected pathogenic variants, however, clinical manifestations were asymptomatic (Additional file 1: Table S1). Approximately 90% of patients had correlated clinical and biochemical manifestations with the type of detected variant.

Nevertheless, 5 out of 16 patients from 4 different families and populations with tyrosinemia type III were asymptomatic even though they had elevated tyrosine levels and high urinary excretion of 4-HPL and 4-HPP. However, due to the small number of patients, it is not possible to conclude clearly. It needs further investigation.


In conclusion, this report allows a detailed identification of the variants causing non-hepatorenal tyrosinemia (tyrosinemia type II, III) for future carrier and prenatal screening. It would be useful for clinicians to focus on specific variants of definite regions, which facilitates the targeted detection of disease. Although not all cases of non-hepatorenal tyrosinemia are described in the literature, establishing a genotype–phenotype correlation is difficult. Although the pathophysiology of non-hepatorenal tyrosinemias is not completely explained, it seems that multicenter collection of data and further studies on these patients are necessary to understand the consequences of these deficiencies, the mechanisms of injuries, and the long-term outcome of these patients.

Availability of data and materials

The data generated for this study are available upon reasonable request from the corresponding author.



4-Hydroxyphenylpyruvate dioxygenase


Tyrosine aminotransferase


4-Hydroxyphenyllactic acid


4-Hydroxyphenylpyruvic acid


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ZB: helped to design the study, directed data collection, analyzed data and interpretation, created the first draft of the manuscript and edited the manuscript. SN and SK: Searched and collected the data. BG: senior author, created the idea of the project, coordinated data collection, critically revised the work, and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Bita Geramizadeh.

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Supplementary Information

Additional file 1. Table 1.

Summary of reported patients with tyrosinemia type. Table 2. Summary of reported patients with tyrosinemia type III.

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Beyzaei, Z., Nabavizadeh, S., Karimzadeh, S. et al. The mutation spectrum and ethnic distribution of non-hepatorenal tyrosinemia (types II, III). Orphanet J Rare Dis 17, 424 (2022).

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