Users Online: 105
Home Print this page Email this page
Home About us Editorial board Search Browse articles Submit article Ahead of Print Instructions Subscribe Contacts Login 


 
Previous article Browse articles Next article 
CASE REPORT
Adv Biomed Res 2018,  7:7

A Case of Tyrosinemia Type III with Status Epilepticus and Mental Retardation


1 Department of Pediatric Endocrinology and Metabolism, Ilam University of Medical Sciences, Ilam; Endocrine and Metabolism Research Center, University of Medical Sciences, Isfahan, Iran
2 Department of Pediatric Endocrinology, Endocrine and Metabolism Research Center, Isfahan, Iran
3 Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

Date of Web Publication22-Jan-2018

Correspondence Address:
Dr. Neda Mostofizadeh
Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan
Iran
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2277-9175.223740

Rights and Permissions
  Abstract 


Tyrosinemia type III is an autosomal recessive disorder caused by the deficiency of 4- hydroxyphenylpyruvate dioxygenase (4-HPPD). It is characterized by elevated levels of blood tyrosine and massive excretion of its derivatives into the urine. Clinical findings of tyrosinemia type III include neurological symptoms and mental retardation. Only a few patients presenting with this disease have been described, and the clinical phenotype remains variable and unclear. We present a case, who was admitted to the hospital at the age of 4 months for recurrent seizures. Two months later, she was admitted again with status epilepticus. Laboratory data showed increased level of tyrosine in the blood. She was treated with a diet low in tyrosine and phenylalanine and anamix formula that leading to catch-up growth and improvement of her symptoms. Plasma tyrosine level dropped to normal values. In any child who presents with the neurologic symptom, some rare diagnosis like tyrosinemia type III should be considered.

Keywords: Mental retardation, status epilepticus, tyrosinemia type III


How to cite this article:
Najafi R, Mostofizadeh N, Hashemipour M. A Case of Tyrosinemia Type III with Status Epilepticus and Mental Retardation. Adv Biomed Res 2018;7:7

How to cite this URL:
Najafi R, Mostofizadeh N, Hashemipour M. A Case of Tyrosinemia Type III with Status Epilepticus and Mental Retardation. Adv Biomed Res [serial online] 2018 [cited 2019 Nov 13];7:7. Available from: http://www.advbiores.net/text.asp?2018/7/1/7/223740




  Introduction Top


Tyrosinemia type III is a rare disorder. Only a few patients have been described. Tyrosine is a precursor of dopamine, norepinephrine, epinephrine, melanin, and thyroxine.[1] This autosomal recessive disease is caused by the deficiency of 4-hydroxyphenylpyruvate dioxygenase [2],[3],[4] that is mainly expressed in neurons, neutrophils, kidney, and liver cells.[5] It catalyzes the reaction of 4-hydroxyphenylpyruvic acid to homogentisic acid [Figure 1].[6],[7]
Figure 1: Tyrosine metabolism pathway

Click here to view


The disease is characterized by increased level of blood tyrosine and massive excretion of its derivatives into the urine.[8] Excessive NO release can also participate in neuronal damage.[2] Age of presentation is from 1 to 17 months.[1] The clinical phenotype remains variable and unclear.[5]

Neurological symptoms include developmental delay, behavioral disturbance, seizures, microcephaly, ataxia, tremor, hypotonia, absent deep tendon reflexes,[2],[5],[9],[10] here, we present a case of tyrosinemia type III with status epilepticus.


  Case Report Top


This patient was a 21-month-old girl, who was born at term with birth weight 2250 g and head circumference 33 cm following a pregnancy with polyhydramnios. The patient had no perinatal problem. She was the second child of No consanguineous parents. The first sibling was a 4-year-old boy who is healthy and normally developed. She was admitted to Pediatric Emergency Department at 4 months of age for recurrent seizure. Two months later she was admitted again with status epilepticus. Her seizure controlled with antiepileptic drugs. We did not find any reason for status epilepticus in routine lab tests, cerebrospinal fluid analysis; brain computed tomography scan, brain magnetic resonance imaging, and blood gas analysis. All of them were normal.

Metabolic investigations showed increased level of tyrosine in the blood (737 μmol/l and 915 μmol/l) in 2 consecutive time, (normal range 88–204 μmol/l). The levels of 4-hydroxyphenyl lactic acid (1710 mmol/mol creatinine with normal <5.3) and 4-hydroxyphenyl pyruvic acid (2184 mmol/mol creatinine with normal <4.9) in the urine were elevated, without marked elevation of succinylacetone. Kidney and liver functions were normal. Clinical findings and biological abnormalities were suggestive of tyrosinemia type III and were treated with a diet low in tyrosine, phenylalanine, and anamix formula plus ascorbic acid supplementation (50 mg/day in two doses) that leading to catch-up growth and improvement of her symptoms. Plasma tyrosine level dropped to normal values. Now her mental status is mildly delayed.


  Discussion Top


To our knowledge, only a few patients presenting with this disease have been described in the literature, and none of them presented with status epilepticus.

Most of the reported patients have had neurological symptoms after the neonatal period while others detected by neonatal screening have been asymptomatic. Like our patient all have had normal liver and renal function and none has skin or eye abnormalities.[11]

The most common long-term complication is intellectual impairment, found in 75% of patients. In 2008, a patient with tyrosinemia type III was described with autism and mental retardation.[11] Mild hypertyrosinemia may be offered as typical clinical features of the disease.[8]

Asymptomatic infants with 4-HPPD deficiency have been identified by neonatal screening for hypertyrosinemia.[1] Our patient presented with seizure and status epilepticus, and neurological abnormalities. Similar to our patient Endo et al. reported a patient with seizure, mental retardation, and neurological abnormalities. In another study, Cerone et al. reported a patient with intermittent ataxia.[3]

The high tyrosine concentration in an otherwise normal amino acid profile has been found in patients presenting with neurological symptoms.[12]

The diagnosis is suspected in children with sustained moderate increases in plasma levels of tyrosine (typically 350–700 μmole/L on a normal diet) and massive excretion of its derivatives, 4-hydroxyphenyl pyruvic acid, 4-hydroxyphenyl lactic, and 4-hydroxyphenyl acetic acid into in urine.[1] One of the important factors for definitive diagnosis is genetic study or assay the activity of a 4-HPPD enzyme in liver biopsy.[1] That is what we could not do it and can be a limitation of our study.

In 2001 on a review of 13 patients, five were detected by neonatal screening, two of which were free of any symptoms, with a normal development at 13 months, and 5.4 years, respectively, following a low tyrosine and phenylalanine diet; the three other patients showed mild intellectual impairment. Eight out of 13 patients were diagnosed after the neonatal period because of neurologic signs, that one of them showing a normal development at the age of 17 years,[13] in contrast to our patient that the first neurological signs were started at 4 months of age. Clinical and biochemical findings in patients with a 4-HPPD deficiency in previous and present studies illustrated in [Table 1].
Table 1: Clinical and biochemical findings in patients with 4-HPPD deficiency

Click here to view


In favor of our patient long-term treatment with a tyrosine-restricted diet led to control of seizure disorder.

In the last reported cases, improvement of signs, symptoms, and psychomotor function were observed with a restricted diet.[5] However, D'Eufemia et al. reported that their patient showed normal psychomotor development and no clinical signs in spite of a normal diet.[2]

In our patient, mild mental retardation remained, similar to the reported case by Heylen et al.[5] Their patient's language skills and autistic behavior improved by using a tyrosine-restricted diet while no changes were made in the mental retardation.[5]

The effects of therapeutic interventions by using a low-protein diet are still unknown, and it is not yet clear whether lowering plasma tyrosine levels is able to alter the natural history of the disease in spite of this fact that it is recommended to treat these patients with a tyrosine- and phenylalanine-restricted diet.[5]

As treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-ciclohexanedione (NTBC) in patients with tyrosinemia type I shifts the metabolic block from fumarylacetoacetate hydrolase to p-hydroxyphenylpyruvate dioxygenase or from tyrosinemia type I to tyrosinemia type III, treatment with NTBC must be supplemented by dietary treatment with a phenylalanine- and tyrosine-reduced diet, which is the rational approach to treatment in tyrosinemias type II and III.[14] NTBC do not approve for the treatment of tyrosinemia type III, for this reason, we did not apply it in our patient.[15]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Grant A, Rezvani I. Tyrosinemia. In: Kliegman RM, Behrman RE, Genson HB, Stanton BF, editors. Nelson Textbook of Pediatric. 19th ed. Philadelphia: Saunders; 2011.  Back to cited text no. 1
    
2.
D'Eufemia P, Finocchiaro R, Celli M, Raccio I, Properzi E, Zicari A. Increased nitric oxide release by neutrophils of a patient with tyrosinemia type III. Biomed Pharmacother 2009;63:359-61.  Back to cited text no. 2
    
3.
Cerone R, Holme E, Schiaffi no MC, Caruso U, Maritano L, Romano C. Tyrosinemia type III: Diagnosis and ten-year follow-up. Acta Paediatr 1997;86:1013-5.  Back to cited text no. 3
    
4.
Scott CR. The genetic tyrosinemias. Am J Med Genet C Semin Med Genet 2006;142C:121-6.   Back to cited text no. 4
[PUBMED]    
5.
Heylen E, Scherer G, Vincent MF, Marie S, Fischer J, Nassogne MC. Tyrosinemia Type III detected via neonatal screening: Management and outcome. Mol Genet Metab 2012;107:605-7.  Back to cited text no. 5
[PUBMED]    
6.
Lindstedt S, Holme E, Lock EA, Hjalmarson O, Strandvik B. Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet 1992;340:813-7.  Back to cited text no. 6
[PUBMED]    
7.
Nakamura K, Tanaka Y, Mitsubuchi H, Endo F. Animal models of tyrosinemia. J Nutr 2007;137:1556S-60.  Back to cited text no. 7
[PUBMED]    
8.
Endo F, Kitano A, Uehara I, Nagata N, Matsuda I, Shinka T, et al. Four-hydroxyphenylpyruvic acid oxidase deficiency with normal fumarylacetoacetase: A new variant form of hereditary hypertyrosinemia. Pediatr Res 1983;17:92-6.  Back to cited text no. 8
[PUBMED]    
9.
Awata H, Endo F, Matsuda I. Structure of the human 4-hydroxyphenylpyruvic acid dioxygenase gene (HPD). Genomics 1994;23:534-9.  Back to cited text no. 9
[PUBMED]    
10.
Giardini O, Cantani A, Kennaway NG, D'Eufemia P. Chronic tyrosinemia associated with 4-hydroxyphenylpyruvate dioxygenase deficiency with acute intermittent ataxia and without visceral and bone involvement. Pediatr Res 1983;17:25-9.  Back to cited text no. 10
    
11.
Ellaway CJ, Holme E, Standing S, Preece MA, Green A, Ploechl E, et al. Outcome of tyrosinaemia type III. J Inherit Metab Dis 2001;24:824-32.   Back to cited text no. 11
[PUBMED]    
12.
Holme E. Disorders of tyrosine degradation. In: Blau N, Duran M, Blaskovics M, Gibson K, editors. Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases. 2nd ed. Berlin: Chapman and Hall; 1996.  Back to cited text no. 12
    
13.
Tahiroglu AY, Mungan NÖ, Firat S, Avci A. Autism symptoms related to tyrosinaemia type III: A case report. Turk J Endocrinol Metab 2008;12:55-6.  Back to cited text no. 13
    
14.
Hoffmann GF, Engelmann G. Liver disease. In: Hoffmann F, Zschocke J, Nyhan W, editors. Inherited Metabolic Diseases, A Clinical Approach. Heidelberg: Springer; 2010.  Back to cited text no. 14
    
15.
Preece MA, Rylance GW, MacDonald A, Green A, Gray RGF. A new case of tyrosinemia type I11 detected by neonatal screening. J Inher Metab Dis 1996;19 Suppl 1:32.  Back to cited text no. 15
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]


This article has been cited by
1 Acquired thrombotic thrombocytopenia purpura associated with severe ADAMTS13 deficiency in a 3-year-old boy: a case report and review of the literature
Hamidah Alias,Woon Lee Yong,Farah Azima Abdul Muttlib,Ho Wai Koo,C-Khai Loh,Sie Chong Doris Lau,Hafiza Alauddin,Raja Zahratul Azma
Journal of Medical Case Reports. 2018; 12(1)
[Pubmed] | [DOI]
2 Antibodies towards Tyrosine Amyloid-Like Fibrils Allow Toxicity Modulation and Cellular Imaging of the Assemblies
Dor Zaguri,Topaz Kreiser,Shira Shaham-Niv,Ehud Gazit
Molecules. 2018; 23(6): 1273
[Pubmed] | [DOI]



 

Top
Previous article  Next article
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Case Report
Discussion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed1205    
    Printed23    
    Emailed0    
    PDF Downloaded145    
    Comments [Add]    
    Cited by others 2    

Recommend this journal