4 Disorders of Degradation Elisabeth Holme

4.1 Introduction

The aim of this chapter is to summarize treatment of disorders of tyrosine degradation. The tyrosine degradation pathway includes five enzymatic reac- tions, and inherited disorders have been identified in four of these enzymes. The character of the different disorders is quite different with respect to the pathogenic mechanisms and the organs affected. The pathogenesis of the disorders is either related to the high tyrosine level as such or to accumulation of toxic metabolites of tyrosine degradation. In type I, the hypertyrosinemia is a secondary phenomenon due to the liver damage caused by accumulation of fumarylacetoacetate and its derivatives. Dietary restriction of tyrosine and alone does not reduceproductionoftoxictyrosinemetabolitestoalowenoughleveltoprevent progressive liver and kidney disease, although it may alleviate acute symptoms. For a decade the primary treatment has been based on inhibition of tyrosine degradation at the level of 4-hydroxyphenylpyruvate dioxygenase by nitisinone (NTBC). The aim of the treatment is to block the production of fumarylacetoac- etate and its derivatives succinylacetone and succinylacetoacetate. The block of tyrosine degradation leads to an increase in the tyrosine level, which has to be controlled by a strict diet to prevent adverse effects of the high tyrosine level. The treatment of includes treatment of acute liver failure of infancy often in combination with sepsis, acute porphyria-like neurological crisis, hypophosphatemic rickets, and liver transplantation due to liver failure or to hepatocellular carcinoma. Management of these conditions is beyond the scope of this chapter, in which only the specific treatment of the metabolic disorder is covered. Treatment of tyrosinemia type II and III is confined to reduction of tyro- sine levels by dietary restriction. In tyrosinemia type II, the disorder with the highest tyrosine level, reduction of the tyrosine level is essential to heal and to avoid recurrent corneal and skin lesions, which are directly caused by the high tyrosine level. This requires a moderate reduction of tyrosine intake and might be achieved by protein restriction alone. In addition to these symptoms, tyrosinemia type II is often associated with neurological symptoms and vari- ous degrees of mental retardation and intellectual deficiency, as is tyrosinemia 50 Disorders of Tyrosine Degradation type III, in which there are no other symptoms. There is no evidence that these symptoms can be improved or prevented by a further reduction of the tyrosine level, but, when these cases are picked up by neonatal screening or diagnosed in infancy, it seems appropriate to use a more strict control of the tyrosine level during early childhood. Strict dietary control may also be indicated in pregnancy of women with these disorders, since the impact of high tyrosine levels on the developing brain is not known. is believed to be caused by an incomplete conversion of 4-hydroxyphenylpyruvatetohomogentisateby4-hydroxyphenylpyruvatedioxy- genase. The accumulated intermediary is detoxified by glutathione, which may bedepletedresultingin5-oxoprolinuria.Theenzymedefecthasnotbeenproven and the cause of this disorder is unknown. There is a reduced tolerance to pro- tein during infancy, but the condition requires no treatment after that age. is caused by accumulation of homogentisate, resulting in and destruction of connective tissue with progressive spinal, joint, and heart disease starting in adult life. Traditional treatment of alkaptonuria is based on protein restriction, to reduce homogentisate production, and ascor- bate treatment, to prevent oxidation and pigment formation from homogenti- sate. During childhood such treatment might be successful, but there are obvi- ouslong-termdifficultieswithcompliance.Thereisnoevidenceoflong-term beneficial effects. In a couple of adult cases, it has been shown in a short-term trial that a low dose of nitisinone is effective in reducing homogentisate pro- duction. Nitisinone treatment results in an increase in tyrosine concentration, some restriction of dietary protein would probably be required. The clinical effect of reducing homogentisate production has so far not been studied and a pertinent question is whether the start of treatment can be postponed until symptoms occur.

4.2 Nomenclature

No. Disorder Definitions/ Gene symbol OMIM No. comment

4.1 Tyrosinemia type I (fumarylacetoacetase, HTI FAH 276700 FAH) 4.2 Tyrosinemia type II (tyrosine aminotrans- HTII TAT 276600 ferase, TAT) 4.3 Tyrosinemia type III TIII HPD 276710 (4-hydroxyphenylpyruvate dioxygenase, HPD) 4.4 Hawkinsinuria (unknown) 140350 4.5 Alkaptonuria (homogentisate HGD 203500 dioxygenase, HGD) Treatment 51

4.3 Treatment

I 4.1 Tyrosinemia type I b To reducethe tyrosine the degradation loadpathway on To minimize the risk for possible adverse effects of high tyrosine concentration To block tyrosine degra- dation at the4-hydroxyphenylpyruvate level of dioxygenase to get no production of fumarylace- toacetate and its metabolites to get a normaltion liver and func- to minimizerisk the for HCC development. To heal the renal tubular defect and rickets. To cure and prevent neurological crisis Aim l day / / mol mol µ µ c in an otherwise normal amino acid profile 30–60 Plasma tyrosine 250–500 Target g kg and adults to normalize succinylacetone and 5-aminolevulinic acid excretion iod of rapid catch-up growth. During this period there is an increased liver transplantation, are no signs of improvement with respect to the Equivalent to 0.5–2 protein/ per day 0.4−1 kg / per day ≈ g kg / 30–100 mg per day kg / mg ProteinSee Phe +disorder Tyr 1.1.1 PAH- deficiency Natural Tyr +1–1.5 Phe- requirement tolerance protein free AAM per day divided into two doses e a Nitisinone Diet After initiation of therapy in acute cases there isIt might generally be a acceptable with per higherIn tyrosine a levels in few older cases children anSigns even of higher nitisinone treatment concentration is failure required in acute cases, whichNTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione) may require a tolerance/requirement for protein including tyrosine and phenylalanine coagulopathy within a week and increasing jaundice a b c d e 52 Disorders of Tyrosine Degradation

I 4.2 Tyrosinemia type II

Protein Phe + Tyr Natural Tyr + Phe free Targeta Aim requirement tolerance protein AAM Diet See 1.1.1 30–150 ≈ 0.4−1.5 Equivalent Plasma tyrosine To resolve and prevent PAH defi- mg/kg per g/kg per to 0.5–2 g 250–800 µmol/l occurrence of corneal ciency day day protein/kg in an otherwise and skin lesions. per day normal amino acid profile a Eye symptoms rarely occur at tyrosine concentration below 800 µmol/l, but because of the uncertainty of possible adverse effects on the developing brain it seems reasonable to aim at a concentration at least below 500 µmol/l during infancy and early childhood

I 4.3 Tyrosinemia type III

Protein Phe + Tyr Natural Tyr + Phe-free Targeta Aima requirement tolerance protein AAM Diet See 1.1.1 30–100 ≈ 0.4−1.5 Equivalent Plasma tyrosine To avoid possible PAH mg/kg per g/kg per to 0.5–2 g 250–800 µmol/l adverse effects of deficiency day day protein/kg per in an otherwise tyrosine day normal amino acid profile a Eye and skin lesions have not been described in patients with HTIII, although tyrosine up to 1300 µmol/l has been observed. The only reason for dietary treatment is because of the uncertainty of possible adverse effects on the developing brain, and it seems reasonable to aim at a concentration below at least 500 µmol/l during infancy and early childhood

I 4.4 Hawkinsinuria Symptoms have occurred after weaning and return to breastfeeding, or a diet restricted in phenylalanine and tyrosine may be required during infancy. No treatment is required after infancy.

I 4.5 Alkaptonuria Thereisnoevidenceforlong-termeffectsofascorbateand/orproteinrestriction treatment, but improvement of symptoms has been reported with treatment with ascorbate 0.5–1 g/day and protein restricted to the minimum requirement for age (see disorder 1.1.1, PAH deficiency). Experimental treatment with ni- tisinone 0.05–0.1 mg/kg BW per day has been tried. Follow-up/Monitoring 53

4.4 Follow-up/Monitoring

I 4.1 Tyrosinemia type I . l / mol µ Higher con- centration as indicated by incomplete biochemical response Nitisinone Minimum concentration of 30 acids/renal succtubular markers Signs of tubular disease disap- pear within the 1st month in short-standing disease, but may not heal completely in long-standing cases +1 week +1 month +2 months +4 months +6 months +9 months +12 months -Fetoprotein Urinary amino α There might be an initial increase due to rapid regener- ation of liver tissue. After that there should be a steady decline resulting in normaliza- tion during the 2nd year of treatment +1 week +1 month +2 months +4 months +6 months +9 months +12 months RBC porpho- bilinogen synthase 5-amino- levulinate (urine) Normalization within 1–2 months +1 week +1 month +2 months +4 months +6 months +9 months +12 months mol / 0.3−0.1 < Urine and plasma succinyl- acetone Precipitous disappearance of urinary suc- cinylacetone ( mmol creatinine). Continuous decline of plasma succiny- lacetone until normalization at 2–4 months depending on the initial concentration +1 week +1 month +2 months +4 months +6 months +9 months +12 months l / mol µ Amino acid profile in an otherwise normal profile centration of 250–500 1–2 times weekly until stabilization, then gradual increasing intervals to match the other metabolic controls Specific biochemi- cal markers Target Tyrosine con- 54 References

In stable older patients, it may be adequate with biochemical monitoring twice a year. However, I consider it important with continuous, frequent monitor- ing of serum α-fetoprotein for early detection of HCC in addition to regular monitoring by ultrascan and other imaging techniques as required. Gradual normalization of liver function is expected to occur during the first 6monthsoftreatment. Growth and development should be followed and are expected to be normal. Eye symptoms should be checked with a slit-lamp investigation by an oph- thalmologist to reveal tyrosine-induced corneal lesions.

I 4.2 Tyrosinemia type II Amino acid profile as for tyrosinemia type I. The corneal lesions are expected to be alleviated within a week after initiation of therapy. Skin lesion are expected heal within a few months. Regular follow-up of growth and development.

I 4.3 Tyrosinemia type III Amino acid profile as for tyrosinemia type I. Regular follow-up of growth and development.

I 4.4 Hawkinsinuria If a tyrosine and phenylalanine restricted diet is introduced should the amino acid profile be checked monthly. The 5-oxoprolinuria should normalize rapidly and remain normal after protein restriction. There should be a normal growth and development.

I 4.5 Alkaptonuria If protein restriction is introduced there should be regular follow-up of the amino acid profile and growth.

References

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