FEDERAL UNIVERSITY DUTSINMA

FACULTY OF LIFE SCIENCE

DEPARTMENT OF BIOCHEMISTRY AND MOLECULAR BIOLOGY

ASSIGNMENT

COURSE CODE: BCH 321

NAME: LAWAL MUHAMMAD

MATRIC NUMBER: SCI/2018/5026

DEPARTMENT: BIOCHEMISTRY AND MOLECULAR BIOLOGY

QUESTION

WRITE ON:

CAUSES,CLINICAL SYMPTOMS,TREATMENT AND METABOLIC PATHWAY OF:

1. TYROSINEMIA TYPE 1.

2. MAPLE SYRUP URINE DISEASE(MSUD).

DATE:

MONDAY, March 2 2020

INTRODUCTION

Tyrosinemia type 1 (HTI) is an inborn error of tyrosine catabolism caused by defective activity of
fumarylacetoacetate hydrolase (FAH) and is characterized by progressive liver disease, renal tubular
dysfunction, porphyria-like crises and a dramatic improvement in prognosis following treatment with
nitisinone.

In other words Tyrosinemia type 1 is a genetic disorder characterized by elevated blood levels of the
amino acid tyrosine, a building block of most proteins . This condition is caused by a shortage of the
enzyme fumarylacetoacetate hydrolase, one of the enzymes required for the multi-step process that
breaks down tyrosine.

CAUSES OF TYROSINEMIA TYPE 1

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 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.

Tyrosinemia type I affects males and females in equal numbers. The prevalence has been estimated to
be 1 in 100,000 to 120,000 births worldwide. In Quebec, Canada, the birth prevalence is estimated to be
1/16,000. The estimated prevalence in the Saguenay-Lac Saint-Jean region of Quebec is one in 1,850
births. In Norway, the birth prevalence is estimated to be 1 in 60,000 births.

SYMPTOMS OF TYROSINEMIA TYPE 1

FAH deficiency

fumarylacetoacetase deficiency

fumarylacetoacetate hydrolase deficiency

hepatorenal tyrosinemia

hereditary tyrosinemia type 1

TREATMENT OF TYROSINEMIA TYPE 1

In 2017, Nityr (nitisinone tablets) was approved by the U.S. Food and Drug Administration (FDA) for the
treatment of hereditary tyrosinemia type 1. Nityr is manufactured by Cycle Pharmaceuticals.

The FDA approved the orphan drug Orfadin, a capsule and oral suspension formulation of nitisinone, to
treat tyrosinemia type I in 2002. Nitisinone was developed by Swedish Orphan International Biovitrum
AB and is marketed by Sobi, Inc.

These drugs should only be prescribed by physicians experienced in treating tyrosinemia type I since the
correct dose must be adjusted for each patient according to specific biochemical tests and to the weight.
Access to a nutritionist skilled in managing children with inborn errors of metabolism requiring a low
protein diet is an important part of therapy. Blood tests should be monitored regularly to maintain the
correct dose for the patient.

Nitisinone must be used in conjunction with a diet restricted in the amino acids tyrosine and
phenylalanine. Treatment with nitisinone and dietary management should begin as soon as possible
after the diagnosis is confirmed.

Infants with tyrosinemia type I are placed on a low protein diet that contains limited amounts of
phenylalanine and tyrosine. Some affected infants have exhibited an improvement of liver and kidney
abnormalities with dietary management alone. However, progression to cirrhosis, liver failure and
potential hepatocellular carcinoma is still possible. Physicians often recommend that affected individuals
observe a strict diet using special medical foods throughout their lifetime.

METABOLIC PATHWAY

2 MAPLE SYRUP URINE DISEASE (MSUD)

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.

CAUSES OF MSUD

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.

MSUD affects males and females in equal numbers. Estimated incidence is 1 in 185,000 live births. Due
to a founder effect, the disorder occurs with greater frequency among individuals in the Mennonite
populations in the United States, where the incidence is estimated to be as high as in 1 in 380. MSUD
occurs in the Ashkenazi Jewish population with an incidence estimated at 1:26,000 live births.

SYMPTOMS OF MSUD

BCKD Deficiency

branched-chain ketoacid dehydrogenase deficiency

branched-chain ketoaciduria

TREATMENTS OF MSUD
Individuals with MSUD must remain on a protein-restrictive diet that limits the amount of branched-
chain amino acids they take in. Protein-restriction must start as soon as possible after birth to promote
proper growth and development. Artificially-made (synthetic) formulas are available that provide all the
nutrients necessary for proper growth and development, but lack leucine, isoleucine and valine. It is
particularly important to limit the amount of leucine in the diet. The three amino acids are added to the
diet separately in small amounts so that affected individuals can grow and develop normally. The
amount of leucine, isoleucine and valine that can be tolerated by a child varies based upon residual
enzyme activity. Affected children must be regularly monitored to ensure that their amino acid levels
remain within acceptable normal ranges.

Other treatment is symptomatic and supportive. Early intervention is important in ensuring that children
with MSUD reach their highest potential.

Genetic counseling is recommended for affected individuals and their families

METABOLIC PATHWAY OF MSUD

REFERENCE

TEXTBOOKS

Mitchell GA, Grompe M, Lambert M, and Tanguay RM (2001) Hypertyrosinemia. In: Scriver CR, Beaudet
AL, Sly WS, Valle D (eds) The Metabolic and Molecular Basis of Inherited Disease. McGraw Hill, NY, pp
1776-806.

JOURNAL ARTICLES
Masurel-Paulet A, Poggi-Bach J, Rolland MO, et al. NTBC treatment in tyrosinaemia type 1: long-term
outcome in French patients. J Inherit Metab Dis. 2008; 31: 81-7.

McKiernan PKJ. Nitisinone in the treatment of hereditary tyrosinaemia type 1. Drugs. 2006; 66: 743-50.

Rashed MS, Al-Ahaidib LY, Al-Dirbashi OY, et al. Tandem mass spectrometric assay of succinylacetone in
urine for the diagnosis of hepatorenal tyrosinemia. Anal Biochem. 2005; 339: 310-7.

Pierik LJ, van Spronsen FJ, Bijleveld CM, van Dael CM. Renal function in tyrosinaemia type I after liver
transplantation: a long-term follow-up. J Inherit Metab Dis. 2005; 28: 871-6.

van Spronsen FJ, Bijleveld CM, van Maldegem BT, Wijburg FA. Hepatocellular carcinoma in hereditary
tyrosinemia type I despite 2-(2 nitro-4-3 trifl). J Pediatr Gastroenterol Nutr. 2005; 40: 90-3.