| Tyrosinemia type I | |
|---|---|
| Other names | Hereditary Tyrosinemia type I, HT1 |
 | |
| Mutation of enzyme fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway | |
| Specialty | Hepatology, nephrology, neurology |
| Symptoms | Failure to thrive, enlarged liver, fever, vomiting, diarrhea |
| Usual onset | Variable, usually with the first 2 years of life |
| Duration | Lifelong |
| Causes | Genetic (autosomal recessive) |
| Diagnostic method | Dried blood spot testing, urinalysis, genetic testing |
| Treatment | Dietary restrictions, Nitisinone, liver transplantation |
| Medication | Nitisinone |
| Prognosis | 93% survival rate at six years with treatment |
| Frequency | 1 in 1,850 (Saguenay-Lac Saint-Jean region, Quebec) |
Tyrosinemia type I is agenetic disorder that disrupts themetabolism of the amino acidtyrosine, resulting in damage primarily to theliver along with thekidneys andperipheral nerves.[1] The inability of cells toprocess tyrosine can lead tochronic liver damage ending inliver failure, as well asrenal disease andrickets. Symptoms such aspoor growth andenlarged liver are associated with the clinical presentation of the disease.[2] If not detected via newborn screening and management not begun before symptoms appear, clinical manifestation of disease occurs typically within the first two years of life. The severity of the disease is correlated with the timing of onset of symptoms, earlier being more severe.[1] If diagnosed throughnewborn screening prior to clinical manifestation, and well managed with diet and medication, normal growth and development is possible.
Tyrosinemia type I is anautosomal recessive disorder caused bymutations in both copies of thegene encoding theenzymefumarylacetoacetate hydrolase (FAH). FAH is a metabolic enzyme that catalyzes the conversion offumarylacetoacetate tofumarate andacetoacetate. It is expressed primarily in the liver and kidney. Loss of FAH activity results in the accumulation of certainmetabolic intermediates in the tyrosinecatabolic pathway.[2] These compounds are toxic to cells and lead todifferential gene expression andapoptosis in high concentrations.[2] HT1 is diagnosed when elevated levels ofsuccinylacetone (SA), one of the metabolites in this pathway, is detected inblood andurine samples.[1]
While there is no cure for tyrosinemia type I, management of the disease is possible utilizingdietary restrictions andmedications. A diet low in tyrosine andphenylalanine is utilized indefinitely once a diagnosis is suspected or confirmed. Additionally, the drugnitisinone (brand nameOrfadin) is prescribed and continued indefinitely in order to combat liver and kidney damage, promoting normal function of these organs.[1] Prior to the development of nitisinone, dietary restrictions and liver transplantation were the only forms of treatment for HT1.[2]
Tyrosinemia type I is especially prevalent in theSaguenay-Lac Saint-Jean region ofQuebec, where the prevalence is 1 in 1,850 births. It is most common among those withFrench-Canadian ancestry and this frequency of infliction has been attributed to thefounder effect.[3] There are five other known types of tyrosinemia, all of which derange the metabolism of tyrosine in the human body. They are distinguished by their symptoms and genetic cause.[2]
Type 1 tyrosinemia typically presents in infancy as failure to thrive andhepatomegaly. The primary effects are progressive liver and kidney dysfunction. The liver disease causes cirrhosis, conjugated hyperbilirubinemia, elevated AFP, hypoglycemia and coagulation abnormalities. This can lead tojaundice,ascites and hemorrhage. There is also an increased risk ofhepatocellular carcinoma.[citation needed]The kidney dysfunction presents asFanconi syndrome: Renal tubular acidosis, hypophosphatemia and aminoaciduria. Cardiomyopathy, neurologic and dermatologic manifestations are also possible. The urine has an odor of cabbage or rancid butter.[4]
The presentation of symptoms of tyrosinemia type 1 in terms of timing is broken into three categories: acute, sub-acute, and chronic.[citation needed]
The acute classification typically is presented clinically between birth and 6 months of age. The common presentation in an acute case issynthetic liver failure, marked by the lack of formation ofcoagulation factors inblood. Patients are prone to infections at this stage accompanied byfever,vomiting, increased tendency tobleed, anddiarrhea along withbloody feces as manifestations ofsepsis. Other symptoms includeenlarged liver,jaundice, andexcess abdominal fluid.[1][2]
Sub-acute cases present between 6 months and the first year of life and the severity ofliver disease is lessened to an extent. Again, synthetic function of the liver in terms of blood coagulation factors is impaired in addition toenlargement of the liver and spleen. The infant may also display afailure to thrive as their growth is limited by the disease. This growth impairment can manifest itself inrickets, which is the softening of bones.[1][2]
The final classification, chronic HT1, is detected with presentations occurring after one year of life. The course of the disease up to this point can lead to different ailments affecting the liver.Cirrhosis,liver failure, orcancer of the liver may present as a result of chronic liver disease. Additional symptoms common in this classification includecardiomyopathy,renal disease, andacute neurological crises.[1][2]
The liver is the organ affected most by Tyrosinemia Type I due to the high level of expression of the gene for fumarylacetoacetate hydrolase (FAH) in liver cells. The production of blood coagulation factors by the liver is disrupted, causinghemophiliac-like symptoms. Acute liver failure is common, especially in early life. Additionally, the synthesis ofalbumin in the liver may be defective, therefore leading tohypoalbuminemia. As the disease progresses,cirrhosis is common. This can lead to afatty liver and thedevelopment of tumors in areas affected by this scarring of liver tissue. These scars are known as nodules.[2] There is a 37% chance of developing ahepatocellular carcinoma (HCC) for untreated patients.[5]
Many patients display impaired kidney function and neurological symptoms. In addition to liver cells, kidney cell expression involves expression of the gene for FAH. Kidney failure is a potential result of impaired kidney function, but the most common symptom associated with renal dysfunction ishypophosphatemic rickets.[2] Neurological manifestations are characterized by acute neurological crises due to overaccumulation ofporphyrin. These crises are characterized byporphyria. They typically follow an infection. Patients can present with a variety of varied symptoms includingparesthesias,abdominal pain,pain-induced seizures, and can result inself-mutilation in response to this pain. Episodes can last for 1–7 days and can lead toneuropathy.[1][2]
Tyrosinemia type I is anautosomal recessive inherited condition. Mutantalleles in thegene are inherited from both parents. The genetic mutation occurs to the fumarylacetoacetate hydrolase (FAH) enzyme gene, located onchromosome 15. The most common mutation is IVS12+5(G->A) which is a mutation in thesplice site consensus sequence ofintron 12, therefore affectingexon 12. A second allele is the IVS6-1(G-T) mutation. This mutation results in a nonfunctional enzyme.[2]
Type 1 tyrosinemia is inherited in an autosomal recessive pattern.[6]
Fumarylacetoacetate hydrolase catalyzes the final step in the degradation oftyrosine - fumarylacetoacetate to fumarate, acetoacetate and succinate. Fumarylacetoacetate accumulates inhepatocytes and proximal renal tubal cells and causes oxidative damage and DNA damage leading to cell death and dysfunctional gene expression which alters metabolic processes like protein synthesis andgluconeogenesis. The increase in fumarylacetoacetate inhibits previous steps in tyrosine degradation leading to an accumulation of tyrosine in the body. Tyrosine is not directly toxic to the liver or kidneys but causes dermatologic and neurodevelopmental problems.[citation needed]
Fumarylacetoacetate hydrolase (FAH) is the final enzyme in the tyrosine metabolic pathway.[1] The mutation of FAH enzyme results in nonfunctional FAH in all cells expressing this gene and thus metabolizing tyrosine is impaired. FAH catalyzes the conversion offumarylacetoacetate tofumarate andacetoacetate. Loss of FAH results in the accumulation of upstream compounds in the catabolic pathway. These includemaleylacetoacetate (MAA) andfumarylacetoacetate (FAA). MAA and FAA are converted tosuccinylacetoacetate (SAA) which is then catabolized tosuccinylacetone (SA).[2]
The accumulation of MAA, FAA, and SA in cells inhibits the breakdown ofthiol derivatives, leading to post-translational modifications to theantioxidantglutathione. This inhibits the antioxidant activity of glutathione, leading toreactive oxygen species (ROS) damaging cell components. Over time, the combined effect of accumulation of toxic metabolic intermediates and elevated ROS levels in liver and kidney cells leads toapoptosis in these tissues which ultimately results in organ failure.[2] Accumulated SA in liver and kidney cells results in its release into the bloodstream, which leads to secondary effects. SA inhibits the enzyme5-ALA dehydratase which convertsaminolevulinic acid (5-ALA) intoporphobilinogen, a precursor toporphyrin. Consequently, porphyrin deposits form in the bloodstream and causeneuropathic pain, leading to the acute neurological crises experienced by some patients. Additionally. SA can function to inhibitrenal tubular function, thesynthesis of heme, and theimmune system.[2]
The accumulation of unprocessedtyrosine itself in the blood stream as a consequence of deficient catabolism can also lead to disruption ofhormonal signaling andneurotransmission. Tyrosine is a precursor molecule required for synthesis of several neurotransmitters and hormones, mainlyDopamine,norepinephrine, andthryoxine. Excessive synthesis of these molecules due to elevated tyrosine levels can impair physical growth,motor function, and speech development.[7][8]
Beyond the identification of physical clinical symptoms outlined above, the definitive criterion for diagnostic assessment of Tyrosinemia Type I is elevated succinylacetone (SA) inblood andurine. Elevated SA levels are not associated with any other known medical condition, so there is minimal risk of misdiagnosis.[5] Quantitation of tyrosine levels is also used as a diagnostic but is less reliable due to high false positive and false negative rates.[9] Newborns are not generally screened for HT1 due to rarity of the condition and lack of apparent symptoms at time of birth.[1] However, prompt assessment upon the manifestation of physical symptoms such asfever,vomiting, increased tendency tobleed,diarrhea along withbloody feces, andjaundice is critical for improving long term prognosis.[1][2]
The primary treatment for type 1 tyrosinemia isnitisinone and restriction of tyrosine in the diet.[6] Nitisinone inhibits the conversion of 4-OH phenylpyruvate to homogentisic acid by4-Hydroxyphenylpyruvate dioxygenase, the second step in tyrosine degradation. By inhibiting this enzyme, the accumulation of the fumarylacetoacetate is prevented.[10] Previously, liver transplantation was the primary treatment option and is still used in patients in whom nitisinone fails.[citation needed]
Clinical treatment of HT1 relies on medications and strictregulation of diet. Nitisinone and dietary restrictions that decrease the amount oftyrosine andphenylalaine absorbed from theGI tract during proteindigestion are used in combination as therapeutic measures that control the disease state if they are continued indefinitely. If not, there is a lack of control over the disease, resulting in continued liver and kidney damage, contributing toorgan failure anddeath. In this case, a liver transplant may be required.[2] Levels of SA are monitored throughout treatment in order to assess treatment effectiveness.[9]
The prescribed diet for treatment of HT1 islow in protein. Patients received amino acid supplements lacking tyrosine and phenylalanine, most often by drinking a specially engineered formula, in order to acquire sufficient protein. It is recommended that tyrosine levels remain below 500 μmol/L.[5] Phenylalnine is the precursor to tyrosine. The ideology behind maintaining low tyrosine levels is two-fold. Firstly, it prevents the toxic metabolic intermediates from accumulating as a result of the dysfunctional tyrosine metabolic pathway. Prior to the introduction of nitisinone, this was the main treatment measure. Secondly, the mechanism of action of nitisinone is prevention of any tyrosine metabolism, thus it is important to prevent tyrosine from accumulating. Dietary protein consumption while taking nitisinone can also lead to side effects affecting the ocular system, which are easily reversed by removing protein from the diet.[9]
Nitisinone is prescribed ultimately to reduce the accumulation of toxic metabolic intermediates, such as succinylacetate, which are toxic to cells. It modifies the function of4-hydrooxyphenylpyruvate dioxygenase by acting as acompetitive inhibitor. 4-hydrooxyphenylpyruvate dioxygenase functions to convert4-hydroxyphenylpyruvate tohomogentisate as the second enzymatic reaction in the tyrosine catabolic pathway. This prevents the further catabolism of tyrosine.[5] It is recommended that nitisinone treatment begins immediately following a confirmed or suspected case of HT1.[1] It is supplied orally as acapsule orsuspension in dose increments of 2 mg, 5 mg, 10 mg, or 20 mg or 4 mg/mL respectively.[5] The starting dose is 1 mg/kg one time daily or 2 mg/kg one time daily for 48 hours if the patient is experiencing acute liver failure. Patient responsiveness to nitisinone is assessed by measuringblood coagulation activity and SA levels in blood and urine. Patients should display apositive response within 24–48 hours of first dose. Establishment of the long-term dosage will vary from patient to patient. It is recommended that nitisinone levels be maintained at 30-50 μM in the blood stream.[1]
Prior to the development of nitisinone, dietary restrictions and liver transplantation were the only forms of treatment for HT1.[2] A study regarding the efficacy of treatment with nitisinone and dietary restrictions found that 93% of people survived at two years, four years, and six years indicating the prognosis of stabilizing the HT1 disease state is positive.[5]
Tyrosinemia type I affects males and females in equal numbers. Its prevalence has been estimated to be 1 in 100,000 to 120,000 births worldwide. HT1 is especially prevalent in theSaguenay-Lac Saint-Jean region ofQuebec is one in 1,850 births. The elevated frequency of this disorder within individuals ofFrench-Canadian ancestry in Quebec is believed to be due to reduced genetic heterogeneity within the original founder population for the Saguenay-Lac Saint-Jean region.[11] The initial settlement of Saguenay Lac-Saint-Jean (SLSJ) occurred between 1838 and 1911. From a total of 28,656 settlers, 75 percent originated from the neighboringCharlevoix region. The settling of the Charlevoix region itself started in 1675 when 599 founders of mostly French descent moved to this region from the Quebec City area.[citation needed]
Worldwide, type I tyrosinemia affects about 1 person in 100,000. This type of tyrosinemia is much more common in Quebec, Canada. The overall incidence inQuebec is about 1 in 16,000 individuals. In theSaguenay-Lac-Saint-Jean region of Quebec, type 1 tyrosinemia affects 1 person in 1,846.[12] Thecarrier rate has been estimated to be between 1 in 20 and 1 in 31.[13]
Nitisinone was first used to clinically treat tyrosinemia type I in 1991. Nitisinone was approved by the European Medicine Agency (EMA) under exceptional circumstances in 2005. Originally, nitisinone was developed as a weed-killer by Zeneca Agrochemicals. It was epidemiologically observed that the growth of plants and weeds was inhibited under the bottlebrush plant (Callistemon citrinus). It became clear that neither the shade nor the litterfall of these plants was responsible for the suppression of plant and weed growth. Rather, a substance – which was identified as leptospermone – in the soil under the bottlebrush plant was shown to have bleaching activity on the emerging plants. The allelochemical leptospermone was extracted from the bottlebrush plant and chemically characterized. Leptospermone belongs to the triketone family and inhibits chloroplast development due to a lack of plastoquinone secondary to hepatic 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibition; thus, it served as a blueprint for the synthesis of nitisinone.[9]
In 1932,Grace Medes first described "a new disorder of tyrosine metabolism," She coined the condition "tyrosinosis" after observing 4-hydroxyphenylpyruvate in the urine of a 49-year-old man with myasthenia gravis. She proposed that the metabolic defect in this patient was a deficiency of 4-hydroxyphenylpyruvate dioxygenase, but her case remains puzzling and has since been assigned a separate OMIM number. The first typical patient with hepatorenal tyrosinemia was described in 1956 by Margaret D Baber at Edgware General Hospital in Middlesex, England. Starting the following year, Kiyoshi Sakai and colleagues, at the Jikei University School of Medicine in Tokyo, published 3 reports describing the clinical, biochemical, and pathological findings of a 2-year-old boy with hepatorenal tyrosinemia who was then thought to have an "atypical" case of tyrosinosis. Between 1963 and 1965, Swedish pediatrician Rolf Zetterström and colleagues at the Karolinska Institute in Sweden published the first detailed clinical account of hepatorenal tyrosinemia and its variants. Shortly thereafter, a Canadian group also described the clinical and laboratory findings of hepatorenal tyrosinemia. Both the Scandinavian and Canadian groups suggested that the Japanese patients described earlier by Sakai and colleagues had the same disorder, ie, hepatorenal tyrosinemia. In 1965, doubts emerged that the underlying biochemical cause of hepatorenal tyrosinemia was a defective form of the 4-hydroxyphenylpyruvate dioxygenase enzyme. In 1977, Bengt Lindblad and colleagues at the University of Gothenburg in Sweden demonstrated that the actual defect in causing hepatorenal tyrosinemia involved the fumarylacetoacetate hydrolase enzyme. This was subsequently confirmed using direct enzyme assays.[14]
In March 2014, a study successfully usedCRISPR gene editing to correct the FAH gene mutation inhepatocytes in amouse model of human type I tyrosinemia.[15] The study found that a singlehydrodynamic injection of aDNA plasmid, encodingCas9 and asgRNA, along with assDNA repair template cured enough hepatocytes of a FAH geneSNP to thewild-type gene to cure theweight-loss symptom of type 1 tyrosinemia in mice. Since human type 1 tyrosinemia is caused by a similar mutation in the same gene, this finding sets a precedent for further research intogene editing treatments for HT1.
As of April 2020, two new clinical trials, are underway in the USA for a Mass Spectrometry-based biomarker for the early and sensitive diagnosis of Tyrosinemia type 1 from blood plasma.[16]