TYROSINEMIA TYPE 1

INTRODUCTION

Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive

condition (OMIM 276700) resulting in hepatic failure with comorbidities involving
the renal and neurologic systems (for a comprehensive review, see Mitchell et al.1).
Clinical symptoms typically begin before 2 years of age, with the majority of
children presenting before the age of 6 months with evidence of acute liver failure
and renal dysfunction. Neurologic crises, manifesting as painful episodes affecting
extremity and/or abdominal function, accompanied by hypertension and
hyponatremia, may present at any time and may result in respiratory failure and
death.2 A few affected children may present over the age of 2 years with isolated
coagulopathy or other signs of liver dysfunction, renal tubular disease,
hypophosphatemic rickets, and failure to thrive. All children with HT-1 are at high
risk for hepatocellular carcinoma (HCC) and this also may be the first recognized
clinical event.3 Survivors of these devastating complications in the past developed
hepatomas that often transitioned to HCC, with lifetime frequencies as high as
37%.4–7 An effective medical treatment with 2-[2-nitro- 4-trifluoromethylbenzoyl]-
1,3-cyclohexanedione (NTBC, nitisinone) exists but requires early identification of
affected children for optimal long-term results. Initial efforts at newborn screening
(NBS) to detect presymptomatic infants with HT-1 by measuring tyrosine levels
identified some, but not all, affected children. Recently introduced, the use of blood
succinylacetone (SA) as the NBS marker is predicted to identify all infants affected
with HT-1.8 If correctly identified and appropriately medically managed, the
majority, if not all, of these infants with HT-1 can anticipate a life free of hepatic or
renal disease.

CAUSES
Tyrosinemia is caused by mutations in the fumarylacetoacetate hydrolase (FAH)
gene that is responsible for the production of the FAH enzyme. Deficiency of this
enzyme leads to an accumulation of fumarylacetoacetate and accumulation of
tyrosine and its metabolites in the liver, kidney, and central nervous system
eventually causing tyrosinemia type I.Tyrosinemia type I is inherited as an
autosomal recessive genetic condition. Recessive genetic disorders occur when an
individual inherits two copies of an abnormal gene for the same trait, one from each

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parent. If an individual receives one normal gene and one gene for the disease, the
person will be a carrier for the disease but usually will not show symptoms. The risk
for two carrier parents to both pass the defective gene and have an affected child is
25% with each pregnancy. The risk to have a child who is a carrier like the parents
is 50% with each pregnancy. The chance for a child to receive normal genes from
both parents and be genetically normal for that particular trait is 25%. The risk is
the same for males and females. Parents who are close relatives (consanguineous) have a
higher chance than unrelated parents to both carry the same abnormal gene, which increases the
risk to have children with a recessive genetic disorder.

SYMPTOMS
Symptoms associated with tyrosinemia type I often vary greatly from person to
person. Infants with tyrosinemia type I typically present with either the acute or
chronic form of the disorder.

The acute form of tyrosinemia type I is present at birth (congenital) or during the
first months of life. This form of the disorder is more common and severe than the
chronic form. Infants with the acute form exhibit rapid onset of symptoms usually
beginning with failure to gain weight and grow at the expected rate (failure to
thrive). Additional early symptoms include fever, diarrhea, bloody stools (melena),
and vomiting. Affected infants may also exhibit an abnormally enlarged liver
(hepatomegaly), a tendency to bruise easily, jaundice, lethargy, and/or irritability.
Some affected infants may develop a distinctive, cabbage-like odor.
Eventually infants with the acute form of tyrosinemia type I experience
developmental delays, an abnormally enlarged spleen (splenomegaly), and
accumulation of fluid (edema) in the abdomen (ascites). The disorder may rapidly
progresses to acute life-threatening liver failure and blood clotting abnormalities
(coagulopathy).
The chronic form of tyrosinemia type I occurs less frequently than the acute form
and is characterized by a more gradual onset and less severe expression of the
symptoms. Symptoms of tyrosinemia type I may not become apparent in infants
with the chronic form of the disorder until after six months of age. Failure to thrive
is often the first symptom. Additional symptoms include developmental delays and
progressive scarring and impaired function (cirrhosis) of the liver resulting in
chronic liver failure. Many infants with tyrosinemia type I develop kidney (renal)
abnormalities such as renal Fanconi syndrome, a rare disorder characterized by
kidney dysfunction that often leads to progressive softening and weakening of the

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bone structure (rickets). Fanconi syndrome is also associated with episodes of
vomiting, dehydration, weakness, and fever.

Approximately 40 percent of affected infants also experience episodes of disease

affecting many nerves (polyneuropathy) often following a minor infection. These
episodes, which may be referred to as neurological crises, are associated with
severe pains in the legs and stomach, increased muscle tone (hypertonia), vomiting,
obstruction of the intestines (ileus), an irregular heartbeat (tachycardia), and high
blood pressure (hypertension). Some affected individuals may also exhibit self-
mutilating behavior (e.g., biting one’s tongue or grinding the teeth) during these
episodes. Neurological crises and respiratory failure may occur.

TREATMENT

A treatment of tyrosinemia type I is made based upon a thorough clinical evaluation,

a detailed patient history, and specialized tests. A treatment of tyrosinemia type I
may be suspected in infants who display failure to thrive and an enlarged liver
(hepatomegaly) during the first three months of life. The diagnosis is likely when
tyrosine metabolites and succinylacetone are detected in the urine. It is also
possible to make the diagnosis based on decreased activity of FAH in liver tissue or
cultured fibroblasts, but this test is not readily available. Molecular genetic testing
for FAH gene mutations is available to confirm the diagnosis.

Tyrosinemia type 1 may also be diagnosed through newborn screening programs.

Succinylacetone can be measured on the newborn blood spot by tandem mass
spectroscopy. Most states in the U.S. screen every newborn for tyrosinemia type 1.
Early detection is important because prompt identification and treatment may
prevent the development of serious problems during infancy.Carrier testing and
prenatal diagnosis by DNA analysis are available if the specific gene-causing
mutation has been identified in the family. Next Generation DNA sequencing
techniques, like exome sequencing, whole genome sequencing (WGS) can help in
identifying the mutations responsible for the disease. Prenatal diagnosis is also
possible by detection of succinylacetone and DNA analysis in amniotic fluid.

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 METABOLIC PATHWAY

The abnormalities in the pathway of tyrosine metabolism in tyrosinemia type I.

Tyrosine is provided both directly from dietary sources and by direct conversion of
dietary derived phenylalanine through the activity of phenylalanine hydroxylase
(PAH). The catabolic enzymatic activity deficient in tyrosinemia type I (HT-1) is
indicated (fumarylacetoacetate hydrolase (FAH)). The abnormally accumulated
products due to FAH deficiency are indicated along with their clinical effects.
Keratitis is not observed in untreated HT-1 patients but when NTBC therapy is used,
it produces elevations of blood tyrosine, which can produce ophthalmologic
complications, including keratitis. Succinylacetone is derived from accumulated
succinylacetate and is directly associated with renal and neurologic effects (Fanconi
renal tubular syndrome, porphyric type crises) and directly inhibits the pathway for
heme synthesis at the porphobilinogen synthase activity step. The accumulation of
increased levels of δ-aminolevulinic acid is associated with the neurologic
(porphyric-like) crises observed in untreated HT-1. Fumarylacetoacetate
accumulation is felt to be directly associated with the observed ongoing hepatic and
renal damage.

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 MAPLE SYRUP URINE DISEASE(MSUD)
INTRODUCTION

Maple syrup urine disease (MSUD) is a rare genetic disorder characterized by deficiency
of certain enzymes (branched-chain alpha-keto acid dehydrogenase complex) required
to break down (metabolize) the three branched-chain amino acids (BCAAs) [Leucine,
Isoleucine and Valine] in the body. The result of this metabolic failure is that all three
BCAAs, along with their various byproducts, accumulate abnormally throughout the
body. In the classic, severe form of MSUD, the plasma concentrations of the BCAAs
begin to rise within a few hours of birth. If untreated, symptoms begin to emerge, often
within the first 24-48 hours of life. The “non-specific” symptoms are those of increasing
neurological dysfunction and include lethargy, irritability and poor feeding, followed
soon by focal neurological signs such as abnormal movements and increasing spasticity,
and shortly thereafter, by convulsions and deepening coma. If untreated, progressive
brain damage is inevitable and death ensues usually within weeks or months. The
finding that is unique to MSUD is the emergence of a characteristic odor, reminiscent of
maple syrup that can most readily be detected in the urine and earwax and may be
smelled within a day or two of birth.

The disorder can be successfully managed through a specialized diet. However, even
with treatment, both affected children and adults patients with MSUD remain at high
risk for developing episodes of acute illness (metabolic crises) often triggered by
infection, injury, failure to eat (fasting) or even by psychological stress. During these
episodes there is a rapid, sudden spike in amino acid levels necessitating immediate
medical intervention.

There are three or possibly four types of MSUD: the classic type; intermediate type,
intermittent type, and possibly a thiamine-responsive type. The various subtypes of
MSUD have different levels of residual enzyme activity, severity, and age of onset. All
forms are inherited as autosomal recessive traits.

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 CAUSES

MSUD is caused by changes (mutations) in three different genes: BCKDHA, BCKDHB and
DBT. Mutations in these genes result in absent or decreased activity of human
branched-chain alpha-ketoacid dehydrogenase complex (BCKAD) enzymes. These
enzymes are responsible for breaking down the branched chain amino acids leucine,
isoleucine, and valine that are in protein-rich foods, [The BCAAs are the only amino
acids that have a split main carbon chain]. Accumulation of these amino acids and their
toxic byproducts (ketoacids) results in the serious health problems associated with
MSUD. The toxicity of these amino acids seems to be restricted to the leucine; indeed,
extra valine and isoleucine are often given during treatment. Accumulation of their
respective ketoacids results in metabolic acidosis.

MSUD is inherited as an autosomal recessive genetic condition. Recessive genetic

disorders occur when an individual inherits two copies of an altered gene for the same
trait, one from each parent. If an individual inherits one normal gene and one gene for
the disease, the person will be a carrier for the disease but usually will not show
symptoms. The risk for two carrier parents to both pass the altered gene and have an
affected child is 25% with each pregnancy. The risk to have a child who is a carrier like
the parents is 50% with each pregnancy. The chance for a child to receive normal genes
from both parents is 25%. The risk is the same for males and females.

Parents who are close relatives (consanguineous) have a higher chance than unrelated
parents to both carry the same abnormal gene, which increases the risk to have children
with a recessive genetic disorder.

SYMPTOMS

The symptoms and severity of MSUD at onset varies greatly from patient to patient and
largely relate to the amount of residual enzyme activity. Classic maple syrup urine
disease is the most common and most severe form of MSUD characterized by little to no
enzyme activity.

Most infants with classic MSUD show subtle emerging symptoms within 2-3 days; these
include poor feeding at bottle or breast and increasing lethargy and irritability. As the
decline continues, the infant further disengages and then starts to show increasing focal
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neurologic signs including athetoid [so called “fencing and “cycling”] movements
together with increasing hypertonia, spasticity and opisthotonus progressing to
convulsions and coma. There may be temporary episodes of extreme hypotonia. In the
end, central neurologic function fails with respiratory failure and death. By the time that
symptoms have emerged, a distinctive odor of maple syrup may be detected in
cerumen, sweat, and urine. This is derived from one of the organic acids that
accumulate along with the BCAAs as the disorder spirals out of control.

Once the disorder has been treated and stabilized, there remains a life long threat of
recurrent metabolic decompensation. Even without any change in dietary intake, these
episodes occur due to increased breakdown of protein resulting from a number of
metabolic stresses. Infection, psychological stress, fasting, trauma, fasting or indeed any
major change in dietary habits all cause a change in the metabolism of protein resulting
in more of the BCAAs requiring to be metabolized. These episodes are characterized by
emergence of the symptoms that are typical in an acute untreated case and due to
elevated BCAAs and metabolites

TREATMENT
Doctors can manage MSUD by controlling the level of the three amino acids (leucine,
isoleucine and valine) in the patient’s body. People with MSUD must always follow a
strict diet that provides essential nutrients but severely limits the amounts of the
three amino acids (people do need a small amount of the three amino acids for
normal growth and development). Thiamine-responsive MSUD can be managed
with high doses of vitamin B1 (thiamine) and a strict diet.

Doctors monitor people with MSUD throughout their lives to make sure the three
amino acids do not exceed a person’s tolerance level and begin to cause harm. When
patients with MSUD get sick, have fever, cannot keep food down due to vomiting or
diarrhea or when amino acids rise to dangerous levels, the patient must be
hospitalized immediately. In the hospital, doctors may:Give glucose and insulin
through a vein (using an IV) to adjust the level of amino acids in the body. Use an IV
or nasogastric feeding tube (through the nose) to deliver particular nutrients,
including the types of amino acids the person can tolerate.

Filter the person’s blood plasma and return it to their body (a procedure called
hemofiltration/dialysis) to lower the level of the three amino acids.

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Monitor the patient for signs of brain swelling or infection and acid buildup.

If your infant is diagnosed with MSUD, prompt medical treatment can avoid serious
medical problems and intellectual disability. Initial treatment involves reducing the
levels of BCAAs in your baby’s blood.Typically, this involves intravenous (IV)
administration of amino acids that don’t contain BCAAs, combined with glucose for
extra calories. The treatment will promote the utilization of existing leucine,
isoleucine, and valine in the body. At the same time it will reduce the BCAA level and
provide necessary protein.Your physician will create a long-term treatment plan for
your child with MSUD in conjunction with a metabolic specialist and a dietitian. The
goal of the treatment plan is to provide your child with all the protein and nutrients
needed for healthy growth and development. The plan will also avoid allowing too
many BCAAS to collect in their blood.

METABOLIC PATHWAY