Hereditary tyrosinaemia type II in a consanguineous Ashkenazi Jewish family: Intrafamilial variation in phenotype; absence of parental phenotype effects on the fetus

Summary We describe an Ashkenazi Jewish family in which two adults, offspring of consanguineous parents, have persistent hypertyrosinaemia (770–1110 µmol/L; normal < 110 µmol/L). The metabolic disorder in this family is apparently due to hepatic cytosolic tyrosine aminotransferase deficiency (hereditary tyrosinaemia, type II; McKusick, 276600), because it is associated with the oculocutaneous manifestations of Richner-Hanhart syndrome. The association of this syndrome with hereditary tyrosinaemia type II is presumed to be constant. It is not in this family. The affected female sib (age 41 years) has hypertyrosinaemia and oculocutaneous signs; the brother (age 39 years) has hypertyrosinaemia but no oculocutaneous disease. Both sibs have two children; none has signs of a metabolic fetopathy. Maternal hypertyrosinaemia and maternal hyperphenylalaninaemia evidently constitute different risk factors for the fetus. Paternal hypertyrosinaemia is apparently not a risk to male infertility.     

A new variant form of hypertyrosinaemia due to 4-hydroxyphenylpyruvic acid oxidase deficiency

Two types of hereditary hypertyrosinaemia have been described (La Du and Gjessing, 1978). In this paper we describe familial cases of hypertyrosinaemia, in one of whom detailed enzymatic studies were done on the liver obtained at autopsy. The results suggest the disease as being a new variant of tyrosinaemia.     

The control of 5-hydroxytryptamine and dopamine synthesis in the brain: A theoretical approach

Summary The transport of the eight amino acids (phenylalanine, tyrosine, tryptophan, valine, leucine, isoleucine, histidine and methionine) using the large neutral amino acid transporter of the blood-brain barrier (BBB) has been calculated using published kinetic data. The fate of the amino acids has been followed from blood to interstitial space, to cell and through metabolism which included, for tyrosine and tryptophan, the hydroxylases. The system was analysed in terms of flux control coefficients. Since the summation theorem did not hold, the system clearly behaved as a non-homogeneous system. At physiological levels of these eight amino acids, the largest contribution to the control of the flux of tyrosine is given by the hydroxylase step, followed by the diffusional component of the transport across the BBB. For tryptophan it is the hydroxylase step, followed by the carrier-mediated transport across the BBB. For the other amino acids it is the metabolism, followed by the diffusional component of the BBB transport.These parameters for tyrosine and tryptophan were determined at increased levels of blood phenylalanine, tyrosine or histidine. The flux through tryptophan hydroxylase can be affected by high blood levels of tyrosine and histidine to values also observed in hyperphenylalaninaemia. Since hypertyrosinaemia (type II) and hyperhistidinaemia are not associated with mental retardation, it is concluded that interference with transport across the BBB of tyrosine and tryptophan, as well as the flux through tryptophan hydroxylase leading to the synthesis of 5-hydroxytryptamine, do not contribute to the cause of permanent brain dysfunction in hyperphenylalaninaemia.It can be calculated that addition of tyrosine to the diet to raise the blood tyrosine level in phenylketonuria patients may have a beneficial effect for the synthesis of neurotransmitters derived from tyrosine.     

Tandem mass spectrometric determination of succinylacetone in dried blood spots enables presymptomatic detection in a case of hepatorenal tyrosinaemia

Summary Tyrosinaemia type I, or fumarylacetoacetase deficiency, causes hepatorenal damage by accumulation of fumarylacetoacetate. Patients are generally in good condition at birth, but are at risk of developing serious metabolic crises with liver failure and hepatic coma. An early start of treatment with NTBC and a tyrosine-balanced diet can prevent harm to the patients. The application of tandem mass spectrometry to newborn screening allows for easy determination of tyrosine to detect the presence of hypertyrosinaemia in the neonate, but most patients with tyrosinaemia type I do not present with high tyrosine levels at the time of newborn screening. We report on a 7-week-old girl presenting with acute hepatopathy and severe coagulopathy due to tyrosinaemia type I. The metabolic screening, which was performed by tandem mass spectrometry at the age of 48 h, had revealed normal values for tyrosine and methionine that were well within ranges observed in the general population and equally normal ratios of methionine/tyrosine and tyrosine/serine. In this patient even lowering the cut-off levels for tyrosine and methionine would not have provided better sensitivity. Residual blood spots from the newborn screening filter paper were retrospectively analysed using a specific mass-spectrometric method for the detection of succinylacetone and revealed a 5-fold elevated succinylacetone concentration. This indicates that identification of all newborns with hepatorenal tyrosinaemia is only possible by determination of succinylacetone as part of the newborn screening process. Electronic Supplementary Material The online version of this article (doi: ) contains supplementary material, which is available to authorized users. Online citation: JIMD Short Report #069 (2007) Online     

TAT gene mutation analysis in three Palestinian kindreds with oculocutaneous tyrosinaemia type II; characterization of a silent exonic transversion that causes complete missplicing by exon 11 skipping

Summary Deficiency of the hepatic cytosolic enzyme tyrosine aminotransferase (TAT) causes marked hypertyrosinaemia leading to painful palmoplantar hyperkeratoses, pseudodendritic keratitis and variable mental retardation (oculocutaneous tyrosinaemia type II or Richner–Hanhart syndrome). Parents may therefore seek prenatal diagnosis, but this is not possible by biochemical assays as tyrosine does not accumulate in amniotic fluid and TAT is not expressed in chorionic villi or amniocytes. Molecular analysis is therefore the only possible approach for prenatal diagnosis and carrier detection. To this end, we sought TAT gene mutations in 9 tyrosinaemia II patients from three consanguineous Palestinian kindreds. In two kindreds (7 patients), the only potential abnormality identified after sequencing all 12 exons and exon–intron boundaries was homozygosity for a silent, single-nucleotide transversion c.1224G > T (p.T408T) at the last base of exon 11. This was predicted to disrupt the 5′ donor splice site of exon 11 and result in missplicing. However, as TAT is expressed exclusively in liver, patient mRNA could not be obtained for splicing analysis. A minigene approach was therefore used to assess the effect of c.1224G > T on exon 11 splicing. Transfection experiments with wild-type and c.1224G > T mutant minigene constructs demonstrated that c.1224G > T results in complete exon 11 skipping, illustrating the utility of this approach for confirming a putative splicing defect when cDNA is unavailable. Homozygosity for a c.1249C > T (R417X) exon 12 nonsense mutation (previously reported in a French patient) was identified in both patients from the third kindred, enabling successful prenatal diagnosis of an unaffected fetus using chorionic villous tissue. Competing interests: None declared References to electronic databases: tyrosinaemia type II (OMIM +276600); hepatic cytosolic tyrosine aminotransferase (EC 2.6.1.5); GenBank: accession number for TAT mRNA, NM_000353; accession number for TAT genomic DNA, NC_000016.     

Outcome of pregnancy in the rat with mild hyperphenylalaninaemia and hypertyrosinaemia: Implications for the management of “human maternal PKU”

In attempting to determine the effects of mildly elevated maternal phenylalanine (Phe) blood levels on the developing fetal rat brain, a dietary supplement of Phe was given, under taste cover of Aspartame. Phe and tyrosine (Tyr) levels were mildly elevated throughout pregnancy without evidence of malnutrition. Mild hyperphenylalaninaemia with concurrent hypertyrosinaemia induced in rats prior to conception resulted in microcephaly and lasting behavioural problems in the offspring, specifically hyperactivity and learning difficulties. Dams fed Tyr to produce Tyr levels equivalent to the Phe-fed animals showed only the learning difficulties among the offspring.-Methyl Phe, a Phe hydroxylase inhibitor, fed in conjunction with Phe, at the level relevant to these experiments, resulted in raised Tyr levels and does not provide a better method of determining whether mildly elevated maternal Phe levels alone, or Phe and Tyr in combination, cause the abnormality found in the offspring of Phe-supplemented dams.Therapeutic addition of Tyr to diets of mothers with even mild hyperphenylalaninaemia should be approached with caution as mild co-elevation of Phe and Tyr in the fetus may be harmful.In the face of such a possible therapeutic dilemma alternatives, such as dietary additions of other essential amino acids to limit fetal brain damage, need to be explored.     

A review of biochemical and molecular genetic aspects of tyrosine hydroxylase deficiency including a novel mutation (291delC)

An overview is given of the current knowledge on the human tyrosine hydroxylase gene and on the biochemical aspects of diagnosing defects in this gene. Diagnostic biochemical findings are described in four cases of genetically confirmed tyrosine hydroxylase deficiency. Decreased CSF levels of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), together with normal pterin and CSF tyrosine and 5-hydroxyindoleacetic acid (5-HIAA) concentrations are the diagnostic hallmarks of tyrosine hydroxylase deficiency. At the metabolite level the diagnosis can only be made reliably in CSF. Strict adherence to a standardized lumbar puncture protocol and adequate reference values are essential for diagnosis of this "new" treatable neurometabolic disorder. Measurements of HVA, vanillylmandelic acid (VMA) or catecholamines in urine are not relevant for diagnosing tyrosine hydroxylase deficiency. The diagnosis should be considered in all children with unexplained hypokinesia and other extrapyramidal symptoms. Three of our patients are homozygous for a mutation in exon 6 (698G>A) of the tyrosine hydroxylase gene and one patient was compound heterozygous for the same mutation and a novel truncating mutation in exon 3 (291delC). This revised version was published online in August 2006 with corrections to the Cover Date.     

Current clinical management of gastrointestinal stromal tumor

Gastrointestinal stromal tumors(GISTs) are the most common malignant subepithelial lesions(SELs) of the gastrointestinal tract. They originate from the interstitial cells of Cajal located within the muscle layer and are characterized by over-expression of the tyrosine kinase receptor KIT. Pathologically, diagnosis of a GIST relies on morphology and immunohistochemistry [KIT and/or discovered on gastrointestinal stromal tumor 1(DOG1) is generally positive]. The prognosis of this disease is associated with the tumor size and mitotic index. The standard treatment of a GIST without metastasis is surgical resection. A GIST with metastasis is usually only treated by tyrosine kinase inhibitors without radical cure; thus, early diagnosis is the only way to improve its prognosis. However, a GIST is usually detected as a SEL during endoscopy, and many benign and malignant conditions may manifest as SELs. Conventional endoscopic biopsy is difficult for tumors without ulceration. Most SELs have therefore been managed without a histological diagnosis. However, a favorable prognosis of a GIST is associated with early histological diagnosis and R0 resection. Endoscopic ultrasonography(EUS) and EUS-guided fine needle aspiration(EUSFNA) are critical for an accurate diagnosis of SELs. EUSFNA is safe and effective in enabling an early histological diagnosis and adequate treatment. This review outlines the current evidence for the diagnosis and management of GISTs, with an emphasis on early management of small SELs.     

NTBC treatment in tyrosinaemia type I: Long-term outcome in French patients

Summary We describe a retrospective study of long-term outcome of 46 patients treated and regularly followed in France with 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC) for tyrosinaemia type I. Most had initial good response with normalization of liver function and metabolic parameters. Only one infant had no response to treatment and required liver transplantation. Among the 45 long-term treated patients, three underwent secondary liver transplantation: one for cirrhosis and two because of hepatocellular carcinoma. One of the latter died of transplantation complications, so that the overall survival rate was 97.5%. However, 17 of 45 showed persistent abnormal liver imaging (heterogeneous liver) and 6 had cirrhosis. Furthermore, 15 had persistently elevated levels of alpha-fetoprotein, highlighting the question of the persistent risk of carcinoma. Quality of life was usually good but compliance problems were frequent, mainly regarding the low phenylalanine–tyrosine diet. Few adverse effects were observed. A main concern was the high frequency of cognitive impairment causing schooling problems, which may be related to persistent chronic hypertyrosinaemia. In conclusion, this series confirms that NTBC treatment has clearly improved the vital prognosis and quality of life of tyrosinaemia type I patients but that many late complications persist. Long-term studies are necessary to determine whether this drug may prevent or only delay liver complications, andto survey the possible risks of the drug. A more restricted diet could be necessary to prevent the neurological impact of the disease. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Competing interests: None declared References to electronic databases: Tyrosinaemia type I, OMIM 276700. Fumarylacetoacetase, EC 3.7.1.2.     

Mastocytosis: Advances in diagnosis and treatment

Mastocytosis is characterized by pathologic mast cell accumulation and activation in tissues. Establishment of objective histopathologic and molecular criteria for diagnosis of mastocytosis has allowed sensitive detection of mast cells with aberrant features in patients presenting with suspected mast cell activation symptoms. Frequent detection of the D816V c-kit tyrosine kinase mutation in mastocytosis has led to evaluation of small-molecular-weight tyrosine kinase inhibitors as mast cell cytoreductive agents. In vitro experiments, however, showed that mast cells carrying the D816V c-kit mutation were resistant to the prototypical tyrosine kinase inhibitor imatinib. Efficacy of newer generation tyrosine inhibitors in mast cell disease is currently being evaluated.     

Syndromes hyperéosinophiliques : actualités physiopathologiques et thérapeutiques

The hypereosinophilic syndromes (HES), defined by an unexplained and sustained hypereosinophilia, can be associated with heterogeneous hematological conditions. Several molecular mechanisms underlying the eosinophilia, which remained indeterminate for a long time, have been recently identified. These recent advances allowed a better classification of the various forms of HES and the development of targeted therapies. The role of tyrosine kinases, especially PDGFRA, and the efficacy of tyrosine kinases inhibitors dramatically improved the diagnosis and the treatment of myeloproliferative variant of HES. On the other side, eosinophilia can be driven by IL-5 secreting abnormal and often clonal T cell subsets (lymphocytic variant of HES). The crucial role of this cytokine in eosinophil development, activation and survival leads to the assessment of anti-IL-5 monoclonal antibodies which have recently shown to provide a significant corticosteroid sparing effect in FIP1L1-PDGFRA negative HES patients. Despite these major advances, half of HES remains unexplained (idiopathic HES). Some FIPL1-PDGFRA negative patients respond to imatinib, suggesting the role of other tyrosine kinases (or other partners than FIP1L1 in a fusion gene implicating PDGFRA). Development of new biomarkers is needed to help physicians in the diagnosis, classification of HES and in the choice of a targeted therapy.     

Aberrant phenylalanine metabolism in phenylketonuria heterozygotes

The wide variation in phenylalanine hydroxylating capacity observed among patients with phenylketonuria (PKU) is primarily due to allelic heterogeneity at the phenylalanine hydroxylase (PAH) locus. In this study, we examined phenylalanine metabolism after an oral phenylalanine load in 148 carriers of known PAH gene mutations. As a group, heterozygotes formed less tyrosine than normozygotes (p<0.001), and there was a tendency that carriers of a severe PAH mutation formed less tyrosine than carriers of a mild mutation. Nevertheless, the interindividual variation was extensive, and we identified a group of individuals who formed no or very little tyrosine after the phenylalanine load. This tyrosine response was accompanied by a decreased ability to eliminate the phenylalanine test dose but did not correlate with the intrinsic severity of the mutant PAH allele. Examination of the entire coding region of the PAH gene revealed no additional sequence alterations in these subjects. Our data suggest that a subset of PKU heterozygotes have reduced phenylalanine hydroxylating capacity approaching or equalling the levels observed in genetic compounds with non-PKU mild hyperphenylalaninaemia (MHP). Awareness of this phenotypic overlap between PKU carriers and genetic compounds with two mutant alleles may be useful for clinicians and paediatricians involved in diagnosis and genetic counselling.     

White cells 2: impact of understanding the molecular basis of haematological malignant disorders on clinical practice

The molecular basis of many leukaemias is now known, allowing precise diagnosis. Treatment of chronic myeloid leukaemia is now possible by targeting of the BCR-ABL tyrosine kinase. The underlying molecular abnormalities in acute leukaemias allow the outlook for individual patients to be assessed at diagnosis and therapy tailored accordingly. Analysis of V(H) genes in B-cell malignant disorders allows these to be placed in the hierarchy of B-cell development and may provide prognostically valuable information.     

Philadelphia-positive acute lymphoblastic leukemia patients already harbor BCR-ABL kinase domain mutations at low levels at the time of diagnosis

Background

In patients with Philadelphia-positive acute lymphoblastic leukemia, resistance to treatment with tyrosine kinase inhibitors is frequent and most often associated with the development of point mutations in the BCR-ABL kinase domain. We aimed to assess: (i) in how many patients BCR-ABL kinase domain mutations are already detectable at relatively low levels at the time of diagnosis, and (ii) whether mutation detection correlates with subsequent response to therapy.

Design and Methods

We retrospectively analyzed samples collected at diagnosis from 15 patients with Philadelphia-positive acute lymphoblastic leukemia who subsequently received tyrosine kinase inhibitor therapy (dasatinib) by cloning the BCR-ABL kinase domain in a bacterial vector and sequencing 200 independent clones per sample.

Results

Mutations at relatively low levels (2–4 clones out of 200) could be detected in all patients – eight who relapsed and seven who achieved persistent remission. Each patient had evidence of two to eight different mutations, the majority of which have never been reported in association with resistance to tyrosine kinase inhibitors. In two patients out of six who relapsed because of a mutation, the mutation (a T315I) was already detectable in a few clones at the time of diagnosis. On the other hand, a patient who was found to harbor an F317L mutation is in persistent remission on dasatinib.

Conclusions

Our results suggest that the BCR-ABL kinase domain is prone to randomly accumulate point mutations in Philadelphia-positive acute lymphoblastic leukemia, although the presence of these mutations in a relatively small leukemic subclone does not always preclude a primary response to tyrosine kinase inhibitors.     

Diagnosis and treatment of bronchioloalveolar carcinoma

PURPOSE OF REVIEW: Bronchioloalveolar carcinoma accounts for 5% of lung cancers, although histologically mixed bronchioloalveolar carcinoma and adenocarcinoma account for up to 20%. Bronchioloalveolar carcinoma histology is present in a majority of tumors found on lung-cancer screening by computed tomography. We review issues surrounding the diagnosis and treatment of bronchioloalveolar carcinoma, which often differs from other types of lung cancer. RECENT FINDINGS: A spectrum of disease from histologically pure bronchioloalveolar carcinoma to adenocarcinoma exists. The approach to treatment of diseases within this spectrum is still evolving. Evidence on the role of sub-lobar resection, resection of multifocal disease, and pulmonary transplantation is reviewed. We also discuss epidermal growth factor receptor tyrosine kinase inhibitors, and their role in patients with bronchioloalveolar carcinoma. SUMMARY: An understanding of recent developments in the diagnosis and treatment of patients with bronchioloalveolar carcinoma histology is important as early detection of lung cancer becomes more common. Ongoing clinical trials will provide important information on the role of limited resection. The use of epidermal growth factor receptor tyrosine kinase inhibitors should currently be limited to patients with advanced or recurrent disease who have failed cytotoxic chemotherapy. New targeted therapies are emerging for patients with bronchioloalveolar carcinoma histology.     

Cardiac dysfunction induced by novel targeted anticancer therapy: An emerging issue

Increasing use of targeted anticancer agents that inhibit tyrosine kinase signaling (monoclonal antibodies or tyrosine kinase inhibitors) has dramatically improved the survival of patients with malignancies. However, cardiotoxicity, including heart failure, left ventricular dysfunction, hypertension, myocardial infarction, and thromboembolism, has occurred. Importantly, these cardiotoxicities are at least partially reversible and responsive to medical management. Early recognition of cardiovascular side effects is vital to allow long-term, continuous therapy with these life-prolonging agents. This article reviews potential cardiovascular side effects of frequently used inhibitors of tyrosine kinase activity (eg, trastuzumab, sunitinib) and discusses the diagnosis and management of cardiotoxicity associated with targeted therapy.     

Circulating angiogenic factors in the pathogenesis and prediction of preeclampsia

Preeclampsia is a major cause of maternal, fetal, and neonatal mortality worldwide. Although the etiology of preeclampsia is still unclear, recent studies suggest that its major phenotypes, high blood pressure and proteinuria, are due in part to excess circulating soluble fms-like tyrosine kinase-1 concentrations. Soluble fms-like tyrosine kinase-1 is an endogenous antiangiogenic protein that is made by the placenta and acts by neutralizing the proangiogenic proteins vascular endothelial growth factor and placental growth factor. High serum soluble fms-like tyrosine kinase-1 and low serum free placental growth factor and free vascular endothelial growth factor have been observed in preeclampsia. Abnormalities in these circulating angiogenic proteins are not only present during clinical preeclampsia but also antedate clinical symptoms by several weeks. Therefore, this raises the possibility of measuring circulating angiogenic proteins in the blood and the urine as a diagnostic and screening tool for preeclampsia. The availability of a test to predict preeclampsia would be a powerful tool in preventing preeclampsia-induced mortality, especially in developing nations, where high-risk specialists are limited. This review will summarize our current understanding of the role of circulating angiogenic proteins in the pathogenesis and clinical diagnosis/prediction of preeclampsia.     

Gastrointestinal stromal tumors: the role of the gastroenterologist in diagnosis and risk stratification

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that are best classified as sarcomas with variable aggressiveness. They are typically treated with surgical resection and adjuvant tyrosine kinase inhibitors or, for advanced/metastatic GISTs, with tyrosine kinase inhibitors alone. Gastroenterologists are often the first to detect GISTs and are, therefore, tasked with diagnosis and facilitation of early intervention. Diagnostic tools including various imaging techniques such as endoscopic ultrasound (EUS) and EUS-assisted tissue sampling are critical for an accurate diagnosis. In the case of small tumors, EUS-assisted resection or ligation techniques to treat asymptomatic small tumors have been described. This paper reviews current evidence for the diagnosis and management of GISTs, with an emphasis on the role of the gastroenterologist.     

胃肠道间质瘤的诊断治疗

胃肠道间质瘤(gastrointestinal stromal tumors,GIST)是消化系最常见的间叶组织源性肿瘤,是一种潜在恶性的肿瘤.其临床表现缺乏特异性,术前诊断上存在较大困难.近几年其发病机制已经逐渐被人们所认识,诊断及治疗水平上也有了很大的提高.原癌基因kit突变是其主要发病机制之一.以CD117为代表的免疫织化学染色在其诊断中作为一个重要的决定性因素.治疗上目前注重于综合治疗,手术完整切除仍然是其首选治疗,包括新辅助治疗及术后辅助治疗在内的分子靶向治疗的出现成为GIST治疗上的一次巨大进步,甲磺酸伊马替尼等选择性酪氨酸激酶抑制剂制剂的出现,给GIST患者的治疗带来了新的希望.     

胃肠道间质瘤的诊治新进展

胃肠道间质瘤（GIST）是胃肠道最常见的间叶源性肿瘤,原癌基因c—kit突变是其主要发病机制之一。以CD117为代表的免疫织化学染色在其诊断中是一个重要的决定性因素。手术完整切除仍然是其首选治疗,分子靶向治疗是进展期GIST治疗上的一次飞跃,本文对GIST的诊治新进展进行综述。