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Corneal Lesion as the Initial Manifestation of Tyrosinemia Type II

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Chun-Pin Tsai
Chun-Pin Tsai
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Pei-Yu Lin
Pei-Yu Lin
Pei-Yu Lin
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Ni-Chung Lee at National Taiwan University
Ni-Chung Lee
Dau-Ming Niu
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Dau-Ming Niu
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Abstract

Tyrosinemia type II (Richner-Hanhart syndrome) is a rare autosomal recessive disease with deficiency of tyrosine aminotransferase and subsequently increasing level of serum tyrosine. We report the case of a 2-year-old girl who was referred due to bilateral corneal lesions. Slit-lamp examination showed small granular white deposits arranged in a dendritic pattern in the superficial central cornea of both eyes. Physical examination revealed painful, non-pruritic, hyperkeratotic plaques on the soles, palms and fingertips. Mental evaluation demonstrated developmental delay for her age. Blood examination revealed serum tyrosine level to be 1868 microM (normal range, 30-110 microM), which decreased to 838 microM with 2-month diet on tyrosine and phenylalanine restriction. The corneal and skin lesions resolved completely. However, the corneal deposits recurred a month later as her mother failed to strictly control the diet because the little girl was losing weight and activity. With specific formula and adjusted diet regimen, the corneal lesions decreased again. Corneal pseudodendritic deposits may be the initial manifestation in patients with tyrosinemia type II. Early diagnosis and intervention with diet control are crucial for preventing permanent visual and developmental deficits. Corneal deposits can be one of the parameters in monitoring the efficacy of diet control.
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J Chin Med Assoc • June 2006 • Vol 69 • No 6
286
CASE REPORT
Introduction
Tyrosinemia type II was first described by Richner
1
in
1938 and later by Hanhart
2
in 1947 as an oculo-
cutaneous syndrome. It is characterized by bilateral
pseudodendritic keratitis, painful palmoplantar hyper-
keratotic lesions, mental retardation, and variable
manifestations of central nervous system involvement.
It is an inborn error of metabolism with deficiency of
hepatic cytosolic tyrosine aminotransferase (TAT),
the rate-limiting enzyme of tyrosine catabolism.
Patients have elevated tyrosine blood levels and an
increase in urinary tyrosine metabolites. The TAT
gene locus was assigned to chromosome 16q22.
3
Tyrosinemia type II can be detected by screening
in the newborn; however, the test is not routinely per-
formed because the disease is extremely rare. Delay in
Corneal Lesion as the Initial Manifestation
of Tyrosinemia Type II
Chun-Pin Tsai
1,3
, Pei-Yu Lin
1,3
*, Ni-Chung Lee
2
, Dau-Ming Niu
2,3
, Shui-Mei Lee
1,3
, Wen-Ming Hsu
1,3
Departments of
1
Ophthalmology and
2
Pediatrics, Taipei Veterans General Hospital,
and
3
National Yang-Ming University School of Medicine, Taipei, Taiwan, R.O.C.
Tyrosinemia type II (Richner–Hanhart syndrome) is a rare autosomal recessive disease with deficiency of tyrosine
aminotransferase and subsequently increasing level of serum tyrosine. We report the case of a 2-year-old girl who
was referred due to bilateral corneal lesions. Slit-lamp examination showed small granular white deposits arranged
in a dendritic pattern in the superficial central cornea of both eyes. Physical examination revealed painful,
non-pruritic, hyperkeratotic plaques on the soles, palms and fingertips. Mental evaluation demonstrated developmental
delay for her age. Blood examination revealed serum tyrosine level to be 1,868µM (normal range, 30–110µM),
which decreased to 838µM with 2-month diet on tyrosine and phenylalanine restriction. The corneal and skin lesions
resolved completely. However, the corneal deposits recurred a month later as her mother failed to strictly control
the diet because the little girl was losing weight and activity. With specific formula and adjusted diet regimen, the
corneal lesions decreased again. Corneal pseudodendritic deposits may be the initial manifestation in patients with
tyrosinemia type II. Early diagnosis and intervention with diet control are crucial for preventing permanent visual
and developmental deficits. Corneal deposits can be one of the parameters in monitoring the efficacy of diet control.
[J Chin Med Assoc 2006;69(6):286–288]
Key Words: cornea, pseudodendritic, Richner–Hanhart syndrome, tyrosinemia type II
diagnosis may result in permanent visual impairment
and mental retardation. Therefore, awareness of the
initial presentation of the disease in order to make an
early diagnosis is very important. We report a patient
who presented with ocular symptoms and signs as the
initial manifestation. Follow-up of the ocular signs can
help in monitoring the control of tyrosinemia.
Case Report
A 2-year-old girl was referred due to bilateral dendritic
corneal lesions. She was described by her mother as
being reluctant to open her eyes in the afternoon. The
patient was found to have photophobia and frequent
tearing since birth. Herpetic keratitis was diagnosed
but treatment was not effective.
©2006 Elsevier. All rights reserved.
*Correspondence to: Dr. Pei-Yu Lin, Department of Ophthalmology, Taipei Veterans General Hospital, 201,
Section 2, Shih-Pai Road, Taipei 112, Taiwan, R.O.C.
E-mail: pylin@vghtpe.gov.tw
•
Received: October 5, 2005
•
Accepted: February 6, 2006
Corneal lesion of tyrosinemia type II
J Chin Med Assoc • June 2006 • Vol 69 • No 6
287
Slit-lamp examination revealed small granular white
deposits arranged in a dendritic pattern in the super-
ficial central cornea of both eyes (Figure 1A). The le-
sions did not stain with fluorescein (Figure 1B). The
conjunctiva was not congested. The anterior chamber,
pupil, lens and fundus in both eyes were normal.
Physical examination showed painful, non-pruritic,
hyperkeratotic plaques on the soles, palms and fin-
gertips (Figure 2A). Blood examination revealed se-
rum tyrosine level to be 1,868µM (normal range, 30–
110µM). Urinary organic acid analysis showed marked
elevation of tyrosine metabolites, and the urine tyrosine
level was 1,765µM. No other significant laboratory
abnormalities were detected. Thus, the diagnosis of
tyrosinemia type II was made.
Brain magnetic resonance imaging (MRI) showed
suspected demyelination of white matter. According
to the Bayley Scales of Infant Development (2
nd
edition),
her mental developmental index score was 56 (normal
range, 85–114), which demonstrated significant delay
for her age. Both her parents and older sister were free
from any ocular or cutaneous lesions. There was no
consanguinity of the parents.
She immediately underwent a tyrosine and
phenylalanine restriction diet. Two months later, her
serum tyrosine level had decreased to 838µM, and
the corneal and skin lesions had resolved completely
(Figure 2B). Her mental status and language capabil-
ity had also improved. However, the corneal lesions
recurred 1 month later as her mother had failed to
keep strict diet control for fear of weight loss in the
already thin girl. By using a specific formula and
adjusting the diet regimen, the corneal deposits
progressively cleared.
Discussion
Inherited tyrosinemia is classified into type I (deficien-
cy of fumarylacetoacetate hydrolase) with hepato-
renal diseases, type II (deficiency of hepatic tyrosine
aminotransferase) with oculocutaneous diseases, and
Figure 1. (A) External photograph of the left eye showing dendritiform lesions in the central cornea. (B) The lesions stained negatively
with fluorescein.
Figure 2. (A) Painful, non-pruritic, hyperkeratotic plaques on the sole. (B) Two months after diet control, the skin lesions resolved
completely.
BA
BA
C.P. Tsai, et al
J Chin Med Assoc • June 2006 • Vol 69 • No 6
288
type III (deficiency of 4-hydroxyphenylpyruvate) with
normal liver function and intermittent neurologic
anomalies. All types demonstrate elevated blood
tyrosine levels, but only type II is associated with
corneal changes.
Tyrosinemia type II usually manifests in the first
month of life. A previous study reported that palm-
oplantar keratosis occurred in 80%, corneal lesions
in 75%, and mental retardation in 60% of reported
cases.
4
Ocular symptoms include photophobia, tearing,
redness and blepharospasm. A recent series described
9 patients: all presented with ocular manifestations but
only 56% had skin lesions at the time of diagnosis.
5
The corneal and skin lesions are thought to be an
inflammatory response secondary to the deposition of
tyrosine crystals.
6
The dendritiform corneal lesions are
frequently misdiagnosed as herpetic keratitis. Seven of
the 9 patients (78%) reported by Macsai et al
5
together
with the patient in this report were initially diagnosed
and treated for herpes simplex keratitis. The corneal
lesions may undergo spontaneous remission and
recurrence, giving the illusion of a clinical response to
antiviral treatment. These pseudodendrites may occur
without skin lesions, making the misdiagnosis of her-
pes simplex virus keratitis more likely. The lack of ter-
minal bulbs, poor staining with fluorescein, bi-
lateral involvement, poor response to antiviral agents,
persistent inferocentral location of the dendrites,
normal corneal sensation, and exacerbation of symp-
toms with increased dietary protein may help in the
differential diagnosis from viral dendritic lesions.
A low tyrosine and low phenylalanine diet is
currently the most effective treatment for tyrosinemia
type II to reverse the ocular and skin manifestations.
However, a strict low tyrosine and low phenylalanine
diet without a specific formula may sometimes lead to
protein intake deficiency, as occurred in our patient,
which makes dietary compliance difficult. There is no
consensus as to what is the optimal blood tyrosine
level, or at what age the diet should be started to
prevent neurologic impairment. The blood tyrosine
level is suggested to be < 500µM. Of the 9 cases
reported by Macsai et al,
5
all 3 cases with controlled
blood tyrosine < 500µM were normal in both ocular
and developmental conditions, 3 cases with peak
tyrosine level between 500 and 900µM were also
asymptomatic, but 1 patient with peak tyrosine level
> 1,000µM showed recurrence of corneal lesion and
low intelligence. Other reports have suggested the
initiation of dietary treatment in infancy to maintain
serum tyrosine concentrations between 300 and
800µM with occasional peaks < 1,000µM, which is
associated with normal psychomotor development.
7,8
Early dietary control is as important as serum
tyrosine levels in determining outcome. Strict dietary
control achieved as early as 40 months of age may be
inadequate to prevent some language disorders.
9
Delay
in dietary therapy as well as poor dietary compliance
may result in chronic keratitis and corneal scarring.
The corneal lesions can recur in a corneal transplant,
particularly if systemic steroids are used.
10
In conclusion, bilateral pseudodendritic keratitis
may be the initial manifestation of tyrosinemia type II.
Early screening of infants with this manifestation and
strict dietary intervention are vital for successful
treatment. Regular follow-up of the corneal lesions to
check blood tyrosine levels and adjust the dietary
regimen can help enhance dietary compliance and
prevent morbidity associated with inadequate protein
intake.
References
1. Richner H. Hornhautaffektion bei keratoma palmare et plantare
hereditarium. Klin Mbl Augenheilk 1938;100:580–8.
2. Hanhart E. Neue sonderformen von keratosis palmo-plantaris,
u.a. eine regelmässig-dominante mit systematisierten lipomen,
ferner 2 einfach-rezessive mit schwachsinn und z.T. mit
hornhautveränderungen des auges (ektodermalsyndrom).
Dermatologica 1947;94:286–308.
3. Natt E, Westphal EM, Toth-Fejel SE, Magenis RE, Buist NR,
Rettenmeier R, Scherer G. Inherited and de novo deletion
of the tyrosine aminotransferase gene locus at 16q22.1-q22.3
in a patient with tyrosinemia type II. Hum Genet 1987;77:
352–8.
4. Buist NR, Kennaway NG, Fellman JH. Tyrosinaemia type II.
In: Bickel H, Wachtel V, eds. Inherited Diseases of Aminoacid
Metabolism. Stuttgart: Georg Thieme Verlag, 1995:203–35.
5. Macsai MS, Schwartz TL, Hinkle D, Hummel MB, Mulhern
MG, Rootman D. Tyrosinemia type II: nine cases of ocular
signs and symptoms. Am J Ophthalmol 2001;132:522–7.
6. Ripple RE, Lohr KM, Twining SS, Hyndiuk RA, Caya JG. Role
of leukocytes in ocular inflammation of tyrosinemia II. Invest
Ophthalmol Vis Sci 1986;27:926–31.
7. Paige DG, Clayton P, Bowron A, Harper JI. Richner–Hanhart
syndrome (oculocutaneous tyrosinemia, type II). J R Soc Med
1992;85:759–60.
8. Rabinowitz L, Williams L, Anderson C, Mazur A, Kaplan P.
Painful keratoderma and photophobia: hallmarks of tyrosinemia
type II. J Pediatr 1995;126:266–9.
9. Bardelli AM, Borgogni P, Farnetani MA, Fois A, Frezzotti R,
Mattei R, Molinelli M, et al. Familial tyrosinemia with eye and
skin lesions. Presentation of two cases. Ophthalmologica 1977;
175:5–9.
10. Sayar RB, Von Domarus D, Schafer HJ, Beckenkamp G.
Clinical picture and problems of keratoplasty in Richner–
Hanhart syndrome (tyrosinemia type II). Ophthalmologica
1988;197:1–6.
... While this clinical triad -ocular, cutaneous and neurodevelopmental abnormalities -outlines the usual findings in TYRII patients, it is worth noting that manifestations may occur in only 1 of these areas, namely on initial presentation [7,8,[10][11][12][13][14][15][16][17]. ...
... This should even further raise awareness among general pediatricians and primary care providers about the importance of ruling out TYRII in children with pseudodentritic keratitis alone, regardless of the initial clinical evolution. Several other authors have discussed the diagnostic confusion that may exist with HSV in the context of ocular pseudodentritic keratitis lesions, but all of these authors reported patients who eventually clinically deteriorated and/or did not respond to acyclovir, which differs from our case [3,[8][9][10][11]14,17]. ...
... This is consistent with the presentation of our patient, as typical palmoplantar lesions were not present. Indeed, similarly to the case we describe, previous reports also presented patients in which pseudodentritic keratitis was the first and sometimes the only clinical manifestation of TYRII [8,[10][11][12][13][14][15][16][17][18]. Moreover, it has been previously reported that skin lesions may at first be small, subtle, and difficult to differentiate from other keratotic lesions [4]. ...
An Infant with Bilateral Keratitis: From Infectious to Genetic Diagnosis
Article
Full-text available
  • Nov 2022
Patient: Male, 10-month-old Final Diagnosis: Tyrosinemia type 2 Symptoms: Decreased appetite • epiphora • irritability • photophobia Medication: — Clinical Procedure: — Specialty: Pediatrics and Neonatology Objective Challenging differential diagnosis Background Tyrosinemia Type II (TYRII) is a rare autosomal recessive inborn error of metabolism caused by deficiency of tyrosine aminotransferase (TAT), leading to hypertyrosinemia. TYRII patients often present in the first year of life with ocular and cutaneous findings, including corneal ulcers, pseudodendritic keratitis, and palmoplantar hyperkeratosis. The corneal involvement is often mistaken for herpes simplex virus (HSV) keratitis, which is a much commoner condition. Case Report A previously healthy 10-month-old male infant was referred to Ophthalmology for acute onset photophobia. Bilateral dendritiform corneal lesions raised the suspicion for herpetic keratitis. Additionally, a papular, crusted lesion was found on his thumb after a few days of hospitalization, also raising concerns about HSV. The patient’s clinical condition seemed to improve under intravenous acyclovir and supportive treatment. A conjunctival swab and crusted lesion on the thumb were tested for HSV using a polymerase chain reaction (PCR) technique, and both were negative. Nevertheless, given the clinical presentation and the favorable course of signs and symptoms, hospital discharge was planned with oral acyclovir. It was halted by an alternative diagnosis of autosomal recessive inborn error of metabolism, tyrosinemia type II, confirmed by elevated plasma tyrosine level and later by molecular analysis requested as a confirmatory investigation by the genetics medical team. Conclusions The corneal involvement in TYRII is often mistaken for HSV keratitis, and clinical course alone should not halt further investigations to rule out TYRII. Clinicians should suspect TYRII clinically when its characteristic ocular dendritiform lesions are present, namely in infancy or early childhood, and even in the absence of its typical cutaneous palmoplantar hyperkeratosis plaques.
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... This may lead to an ulcerated keratitis, which may be mistaken for herpes simplex keratitis. 3 Over time, peripheral vascularization, irregular epithelium and corneal haze may develop. These findings typically present months before hyperkeratotic skin lesions on hands and feet (palmoplantar keratosis) appear. ...
... 11 Ocular and cutaneous defects resolved completely if patients followed a strict modification of diet. [1][2][3][4][11][12][13][14][15][16] Recurrence has been documented following a lapse in dietary modification. 11 Similar to the present report, in most cases patients were suspected to have a diagnosis of herpes simplex keratitis, and treatment with acyclovir was given. ...
... 11 Similar to the present report, in most cases patients were suspected to have a diagnosis of herpes simplex keratitis, and treatment with acyclovir was given. [2][3][4][11][12][13][14] Some patients were found to have transient resolution of corneal findings following antiviral therapy, however only completely resolved with dietary therapy. 11 In all reported cases, corneal lesions were found bilaterally at initial presentation. ...
A child with dendritiform eye lesions and developmental delay
Article
Full-text available
  • Sep 2022
Purpose Tyrosinemia Type II (Richner-Hanhart syndrome) is a rare autosomal recessive disease that occurs due to deficiency in the enzyme tyrosine aminotransferase and can result in an ulcerated keratitis. We present a case of a young patient with oculocutaneous tyrosinemia despite a negative newborn screen. Observations A 15 month old boy with an uncomplicated birth history and negative newborn screen presented with a unilateral central irregular epithelial defect and hyperkeratotic lesions on his fingertips and soles. A month later, the patient developed bilateral dendritiform epithelial erosions. Following a series of antiviral, antibiotic, and lubricating treatments, there was a waxing and waning course of epithelial healing. After the patient was lost to follow up for one year, the patient presented with a new global developmental delay prompting further workup. Tyrosine and phenylalanine levels were ordered which confirmed a diagnosis of Tyrosinemia Type II, and the patient was started on a low-protein diet. A month later, the patient's epithelial defects and ocular symptoms were resolved. Conclusion and Importance: Presentation of a dendritiform epithelial erosion, whether unilateral or bilateral, accompanied by symptoms of developmental delay and palmoplantar hyperkeratotic lesions should prompt measurement of tyrosine and phenylalanine levels. As dermatologic lesions and variable developmental delay may not appear until later in the course of disease, diagnosis may depend on early recognition of ocular signs and symptoms even with negative newborn screening. Prompt diagnosis and diet modification is necessary to prevent developmental delay in this disease. To our knowledge, this is the first Tyrosinemia Type II case in the literature manifesting as an asynchronous bilateral eye disease.
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... This threshold level for presentation of keratitis is lower than previously reported. [89][90][91][92][93][94] Patients with tyrosinemia type II usually develop severe corneal disease when plasma tyrosine levels are higher than 1000 μmol/L. 89 In contrast, individual cases of corneal pathology related to hypertyrosinemia have been reported in HT-1 patients on NTBC with plasma tyrosine levels ranging from 600 to 900 μM. ...
... [89][90][91][92][93][94] Patients with tyrosinemia type II usually develop severe corneal disease when plasma tyrosine levels are higher than 1000 μmol/L. 89 In contrast, individual cases of corneal pathology related to hypertyrosinemia have been reported in HT-1 patients on NTBC with plasma tyrosine levels ranging from 600 to 900 μM. However, average tyrosine levels preceding presentation are not always reported in these studies. ...
Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations
Article
Full-text available
  • Aug 2017
Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive condition resulting in hepatic failure with comorbidities involving the renal and neurologic systems and long term risks for hepatocellular carcinoma. An effective medical treatment with 2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione (NTBC) exists but requires early identification of affected children for optimal long-term results. Newborn screening (NBS) utilizing blood succinylacetone as the NBS marker is superior to observing tyrosine levels as a way of identifying neonates with HT-1. If identified early and treated appropriately, the majority of affected infants can remain asymptomatic. A clinical management scheme is needed for infants with HT-1 identified by NBS or clinical symptoms. To this end, a group of 11 clinical practitioners, including eight biochemical genetics physicians, two metabolic dietitian nutritionists, and a clinical psychologist, from the United States and Canada, with experience in providing care for patients with HT-1, initiated an evidence- and consensus-based process to establish uniform recommendations for identification and treatment of HT-1. Recommendations were developed from a literature review, practitioner management survey, and nominal group process involving two face-to-face meetings. There was strong consensus in favor of NBS for HT-1, using blood succinylacetone as a marker, followed by diagnostic confirmation and early treatment with NTBC and diet. Consensus recommendations for both immediate and long-term clinical follow-up of positive diagnoses via both newborn screening and clinical symptomatic presentation are provided.
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... Noteworthy changes are also present in the ratio of several amino acids suggesting that the availability of amino acids for neurotransmitter biosynthesis and liver function may be altered [22]. Due to the aforementioned effects of NTBC therapy, concerns exist for patients to develop ocular, cutaneous and possible neurological complications including mood changes, lower IQ and depression as observed in hereditary tyrosinemia type 2 (HT2,OMIM #276600) and type 3 (HT3, OMIM #276710) patients as a consequence of hypertyrosinemia [24][25][26]. Corneal keratopathy, with the risk of developing blindness, has been detected even with low dose NTBC in TIMD patients [27]. NTBC therapy, due to the concomitant hypertyrosinemia, requires therefore lifelong dietary adjustment by a tyrosine-and phenylalanine-restricted diet in order to reduce the debilitating side-effects of the drug. ...
Oxidative Stress, Glutathione Metabolism, and Liver Regeneration Pathways Are Activated in Hereditary Tyrosinemia Type 1 Mice upon Short-Term Nitisinone Discontinuation
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Full-text available
  • Dec 2020
Hereditary tyrosinemia type 1 (HT1) is an inherited condition in which the body is unable to break down the amino acid tyrosine due to mutations in the fumarylacetoacetate hydrolase (FAH) gene, coding for the final enzyme of the tyrosine degradation pathway. As a consequence, HT1 patients accumulate toxic tyrosine derivatives causing severe liver damage. Since its introduction, the drug nitisinone (NTBC) has offered a life-saving treatment that inhibits the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD), thereby preventing production of downstream toxic metabolites. However, HT1 patients under NTBC therapy remain unable to degrade tyrosine. To control the disease and side-effects of the drug, HT1 patients need to take NTBC as an adjunct to a lifelong tyrosine and phenylalanine restricted diet. As a consequence of this strict therapeutic regime, drug compliance issues can arise with significant influence on patient health. In this study, we investigated the molecular impact of short-term NTBC therapy discontinuation on liver tissue of Fah-deficient mice. We found that after seven days of NTBC withdrawal, molecular pathways related to oxidative stress, glutathione metabolism, and liver regeneration were mostly affected. More specifically, NRF2-mediated oxidative stress response and several toxicological gene classes related to reactive oxygen species metabolism were significantly modulated. We observed that the expression of several key glutathione metabolism related genes including Slc7a11 and Ggt1 was highly increased after short-term NTBC therapy deprivation. This stress response was associated with the transcriptional activation of several markers of liver progenitor cells including Atf3, Cyr61, Ddr1, Epcam, Elovl7, and Glis3, indicating a concreted activation of liver regeneration early after NTBC withdrawal.
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... Noteworthy changes are also present in the ratio of several amino acids suggesting that the availability of amino acids for neurotransmitter biosynthesis and liver function may be altered [22]. Due to the aforementioned effects of NTBC therapy, concerns exist for patients to develop ocular, cutaneous and possible neurological complications including mood changes, lower IQ and depression as observed in hereditary tyrosinemia type 2 (HT2,OMIM #276600) and type 3 (HT3, OMIM #276710) patients as a consequence of hypertyrosinemia [24][25][26]. Corneal keratopathy, with the risk of developing blindness, has been detected even with low dose NTBC in TIMD patients [27]. NTBC therapy, due to the concomitant hypertyrosinemia, requires therefore lifelong dietary adjustment by a tyrosine-and phenylalanine-restricted diet in order to reduce the debilitating side-effects of the drug. ...
View
... Early signs include photophobia, pain, tearing, and redness, while corneal epithelial central and paracentral opacities, superficial or deep dendritic ulcerations, corneal neovascu- larization, and corneal scars appear later.22Pseudodendritic corneal lesions are frequently misdiagnosed as herpetic keratitis and treated unsuccessfully with antiviral agents which, in the long term, may result in ocular surface toxicity due to antiviral medication and also postpone an appropriate diagnosis.6,24,26,39,46,56In agreement with ...
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Nitisinone-Induced Keratopathy in Alkaptonuria Disease: A Case Report and Literature Review
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  • Jun 2018
We report a case of nitisinone-induced keratopathy in a 52-year-old male patient with Alkaptonuria (AKU) disease in Jordan. The patient presented with slight drop of left eye vision for the last four weeks, associated with a foreign body sensation in his left eye. On examination, it was found that his left eye vision was reduced to 6/12 and there was left dendrite-like corneal opacities in the left eye. He was given 10 mg of nitisinone per day, two years before his visual complaint. Three months following discontinuation of nitisinone, his visual acuity and corneal opacities disappeared completely. This is the fifth reported case of nitisinone-induced keratopathy, due to secondary tyrosinaemia in alkaptonuria. © 2018, Journal of Clinical and Diagnostic Research. All rights reserved.
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TYROSINEMIA TYPE II: Mutation update, eleven novel mutations and description of five independent subjects with a novel founder mutation
Article
Background: Tyrosinemia type II, also known as Richner-Hanhart Syndrome, is an extremely rare autosomal recessive disorder, caused by mutations in the gene encoding hepatic cytosolic tyrosine aminotransferase, leading to the accumulation of tyrosine and its metabolites which cause ocular and skin lesions, that may be accompanied by neurological manifestations, mostly intellectual disability. Aims: To update disease-causing mutations and current clinical knowledge of the disease. Materials and methods: Genetic and clinical information were obtained from a collection of both unreported and previously reported cases. Results: We report 106 families, represented by 143 individuals, carrying a total of 36 genetic variants, 11 of them not previously known to be associated with the disease. Variants include 3 large deletions, 21 non-synonymous and 5 nonsense amino-acid changes, 5 frameshifts and 2 splice variants. We also report 5 patients from Gran Canaria, representing the largest known group of unrelated families sharing the same P406L mutation. Conclusions: Data analysis did not reveal a genotype-phenotype correlation, but stressed the need of early diagnosis: All patients improved the oculocutaneous lesions after dietary treatment but neurological symptoms prevailed. The discovery of founder mutations in isolated populations, and the benefits of early intervention, should increase diagnostic awareness in newborns.
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Transforming Growth Factor: β3 Regulates Cell Metabolism in Corneal Keratocytes and Fibroblasts
Chapter
  • Nov 2015
Corneal keratocytes (HCKs) are specialized cells that reside in the corneal stroma, the largest layer of the human cornea. HCKs play a major role in corneal transparency and orchestrate corneal wound healing upon injury. Following an injury to the cornea HCKs adjacent to the wound undergo apoptosis and HCKs outside the wound area are activated, and they assume the role of remodeling the damaged stroma. Once activated the cells are termed fibroblasts (HCF). One of the key factors of this activation is thought to be transforming growth factor-beta (TGF-β). Five TGF-β (-β1,-β2,-β3,-β4, and -β5) have been identified and three (-β1,-β2, and -β3) are found in humans. We have recently identified TGF-β3 as a growth factor that can reduce or rescue corneal fibrosis in vitro. In this chapter, we present evidence that TGF-β3 plays a major role in regulating the metabolism of both HCKs and HCFs in vitro. We investigated both a conventional monolayer 2D system and a 3D self-assembled extracellular matrix (ECM) model. We targeted a total of 256 endogenous water-soluble metabolites by LC-MS/MS of which more than 60 were significantly regulated between different groups. These findings are expected to help achieve a better understanding of the specific and redundant functions of these metabolites.
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Role of leucocytes in ocular inflammation of Tyrosin mia II
Article
Full-text available
  • Jul 1986
  • INVEST OPHTH VIS SCI
In the animal model of tyrosinemia II only corneas from tyrosine(tyr)-fed rats produce chemoattractants in organ culture. To study the role of neutrophils (PMNs) in production of these chemoattractants, leukocytes (WBCs) were depleted using i.p. cyclophosphamide (CP). Saline (SAL)-treated rats maintained 18,375 +/- 894 WBC/mm3 (mean +/- SEM) with 4168 +/- 424 PMNs. Rats receiving CP (150 mg/kg day 0, 75 mg/kg day 4) has 1565 +/- 170 WBC (565 +/- 129 PMN) on day 3, and 398 +/- 68 WBC (19 +/- 5 PMN) on day 8. Rats ate a low-protein +/- 5% tyr diet on days 4-8. Only SAL-treated tyr-fed rats developed plaque-like gray epithelial lesions; histopathology showed corneal epithelial necrosis, stromal edema, and epithelial and stromal PMN infiltration. Control and CP-treated tyr-fed rat corneas showed no inflammation. On day 8 corneas were cultured in RPMI 1640 + 5% heat-inactivated fetal bovine serum. After 3 days, supernatants were assayed for chemotactic activity (leading front method); data were expressed as the percentage of peritoneal PMN migration relative to 5% zymosan-activated rat serum. The mean total migration toward 75% supernatant from SAL-treated, tyr-fed rat corneas was 79%, whereas migration toward corneal supernatants from controls and CP-treated tyr-fed rats ranged from 42-48%. Corneal extracts were assayed for proteolytic activity. WBC depletion prevented the increase in cathepsin B- and D-like activities present in tyr-fed corneas, suggesting that PMNs were a major source of these enzymes. The data suggest that WBC depletion reduces both corneal inflammation in vivo and the production of chemotactic activity by tyr-fed corneas in culture.
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Familial tyrosinaemia with eye and skin lesions. Presentation of two cases
Article
  • Feb 1977
Two cases of tyrosinaemia with eye and skin lesions typical of the Richner-Hanhart syndrome are described. The patients are a 29- and 26-year-old brother and sister. They do not show neurological abnormalities or mental retardation. Parents are not consanguineous and family history is negative for similar conditions. The diagnosis of type II tyrosinaemia was based upon an increase of blood tyrosine (14-16mg/100 ml), tyrosinuria and absence of liver and kidney abnormalities. The treatment with a low tyrosine phenylalanine diet has resulted in a disappearence of the ocular manifestations while the cutaneous lesions are much improved.
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Inherited and de novo deletion of the tyrosine aminotransferase gene locus at 16q22.1----q22.3 in a patient with tyrosinemia type II
Article
  • Jan 1988
Tyrosinemia II is an autosomal-recessively inherited condition caused by deficiency in the liver-specific enzyme tyrosine aminotransferase (TAT; EC 2.6.1.5). We have restudied a patient with typical symptoms of tyrosinemia II who in addition suffers from multiple congenital anomalies including severe mental retardation. Southern blot analysis using a human TAT cDNA probe revealed a complete deletion of both TAT alleles in the patient. Molecular and cytogenetic analysis of the patient and his family showed one deletion to be maternally inherited, extending over at least 27 kb and including the complete TAT structural gene, whereas loss of the second TAT allele results from a small de novo interstitial deletion, del 16 (pter----q22.1::q22.3----qter), in the paternally inherited chromosome 16. Three additional loci previously assigned to 16q22 were studied in our patient: haptoglobin (HP), lecithin: cholesterol acyltransferase (LCAT), and the metallothionein gene cluster MT1,MT2. Of these three markers, only the HP locus was found to be codeleted with the TAT locus on the del(16) chromosome.
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Clinical Picture and Problems of Keratoplasty in Richner-Hanhart Syndrome (Tyrosinemia Type II)
Article
  • Feb 1988
The Richner-Hanhart syndrome seen in a middle-aged woman is described. The patient had the typical clinical manifestations of tyrosinemia II with a bilateral keratopathy, palmar and plantar hyperkeratosis. The patient was subjected to a specific diet and to perforating keratoplasty. Postoperative systemic therapy with steroids had a negative influence on the clinical manifestations; dendritic lesions which developed on the corneal graft disappeared after interruption of the systemic steroid therapy. This suggests that cortisone treatment after keratoplasty should be avoided in this special metabolic disorder.
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Painful keratoderma and photophobia: Hallmarks of tyrosinemia type II
Article
  • Mar 1995
  • J Pediatr
Tyrosinemia type II (Richner-Hanhart syndrome), which is caused by a deficiency of hepatic tyrosine aminotransferase, results in elevated plasma and urinary tyrosine concentrations. We describe a young boy who was seen at 6 months of age with red eyes, photophobia, and eye pain that were not suspected to be caused by tyrosinemia II until painful plantar keratoderma developed at 2 1/2 years of age. Treatment with a diet low in tyrosine and phenylalanine reversed the manifestations of the disease.
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Tyrosinemia Type II: Nine cases of ocular signs and symptoms
Article
  • Nov 2001
  • AM J OPHTHALMOL
To report nine cases of tyrosinemia type II, with ocular signs and symptoms. Participants included nine patients (18 eyes) who were followed for a mean follow-up period of 6.5 years (range, 2 to 8 years). Intervention included dietary restriction of tyrosine and phenylalanine, which led to resolution of ocular and cutaneous lesions, improved behavior in one patient, and may have prevented developmental delay in others. The main outcome measures were visual acuity and serum tyrosine levels to determine the response to dietary therapy. Intelligence testing and developmental screening were performed when appropriate. All patients presented with ocular signs and symptoms as the primary manifestation of disease and serve to illustrate the typical ocular findings of this syndrome. Three patients presented with cutaneous manifestations, and one patient had mild mental impairment at the time of diagnosis. Recalcitrant pseudodendritic keratitis may be the presenting sign in tyrosinemia type II. Awareness of the presenting signs and symptoms may accelerate the diagnosis and dietary intervention. Initiation of a tyrosine-restricted and phenylalanine-restricted diet in infancy is most effective in preventing cognitive impairment.
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