inborn error of metabolism

1. INBORN ERROR
OF
METABOLISM
BY TAIBA NAUSHAD

2. METABOLISM.
 It is the sum total of all the
chemical reactions takes place
inside an organism.
 It is of two types
• Catabolism
• Anabolism
 Catabolism- breakdown of
molecules into smaller units.
Energy is released.
 Anabolism- formation of
molecules from smaller units.
Energy is used in this process

3. INBORN ERROR OF METABOLISM.
 Inborn error of metabolism are the disorders caused due to the blockage
at certain point in normal metabolic pathway.
 As the name suggest in inborn error of metabolism there is an error in
metabolic pathways since from birth.
 Inborn error of metabolism are often referred as congenital metabolic
disorders or inherited metabolic disorders .
 Enzymes play an important role in facilitating the process by serving
as catalysts in the conversion of one chemical (metabolite) to another.

4. GARROD’S HYPOTHESIS
 In early 20th century Garrod studied the disease Alkaptonuria and
hypothesized that a defective enzyme cause an inborn error of
metabolism along a reaction pathway.
There are approximately 500 diseases due to inherited point defects
in metabolism.
 Diagnosis is important for treatment and genetic counselling.

5. ….

6. CATEGORIES OF METABOLIC
DISEASES.
1) Disorders of carbohydrate metabolism.
 examples:- Glycogen storage disease
 Galactosemia
 Diabetes Mellitus
2) Disorders of amino acid metabolism.
 examples:- Phenylketonuria
 Maple syrup urine disease
 Alkaptonuria
 Cystinosis
3) Disorders of lipids metabolism.
 Tay-Sachs disease

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4) Disorders of lysosomal storage disorders.
 examples:- Gaucher’s disease type 3
 Niemann-Pick’s disease
 Fabry’s disease
5) Mitochondrial Disorders.
 examples:- Kearns – Sayre Syndrome
6) Disorders of steroid metabolism.
 examples:- Congenital adrenal hyperplasia.
7) Disorders of Pigment metabolism.
 examples:- Albinism
 Gilbert disease

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9. DISORDERS OF CARBOHYDRATE
METABOLISM
◦It includes
Glycogen storage disease
Glycolytic pathway disorders

10. Glycogen storage disorders.

11. Glycolytic pathway disorders.

12. DISORDERS OF AMINO ACID
METABOLISM.
Amino acids are the building block of proteins and have many
functions in the body.
 Hereditary disorders of amino acids metabolism can be the result of
defects either in the breakdown of amino acids or in the body’s ability
to get the amino acids into cells.
 symptoms are produced in early life, newborns are screened for
several common ones.

13. Examples of amino acids metabolism disorder
1:- Phenylketonuria -
 Autosomal recessive .disorder
 caused by the deficiency of Phenylalanine hydroxylase.
 phenylalanine hydroxylase break Phenylalanine into Tyrosine.
 Deficiency of this enzyme result into accumulation of phenylalanine and sometimes deficiency of Tyrosine.
 Accumulation of phenylalanine led to seizures , brain damage and mental retardation.
 TREATMENT :- The Food and Drug Administration (FDA) has approved the drug Sapropterin (Kuvan) for
the treatment of PKU. It works by increasing your tolerance to phenylalanine. The drug is for use in
combination with a PKU diet.
 Special diet that limits foods containing phenylalanine. Infants with PKU may be fed breast milk. They
usually also need to consume a special formula known as Lofenalac. When your baby is old enough to eat
solid foods, you need to avoid letting them eat foods high in protein.

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2:- Maple syrup urine disease –
 Caused by the partial or complete deficiency in Branched- chain alpha keto acid dehydrogenase.
 Rare, Autosomal recessive Disorder.
 The enzyme complex that decarboxylate Leucine , Isoleucine and Valine.
 Children with this disease unable to metabolize branched chain amino acids , so amino acids and their by products
accumulates in blood.
 Seizures ,mental retardation , neurological changes , urine and sweat smells like maple syrup.
 TREATMENT :- The two main approaches to the treatment of maple syrup urine disease
(MSUD) are
 (1) long-term daily dietary management .
 (2) treatment of episodes of acute metabolic decompensation.
 The mainstay in the treatment of maple syrup urine disease is dietary restriction of branched-
chain amino acids (BCAAs).

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PHENYLKETONURIA MAPLE SYRUP URINE DISEASE

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3) Alkaptonuria :-
 Rare, Autosomal recessive disorder.
 Caused by the loss of Homogentisic acid oxidase activity.
 Affected individual accumulates large quantities of homogentisic acid , an intermediary product of the catabolism of
Tyrosine and Phenylalanine.
 Which darkens the urine and deposits in connective tissues causing a debilitating arthritis.
 Alkaptonuria was not only the first characterized inborn error of metabolism but the first ever disease identified as
being inherited.
 TREATMENT :-Alkaptonuria is a lifelong condition .
 there's currently no specific treatment or cure. However, a medicine called nitisinone is given to the
patients, and painkillers and lifestyle changes may help you cope with the symptoms.
 management of joint pain, physical and occupational therapy, joint replacements and surgery when
needed

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18. DISORDERS OF LIPID METABOLISM.
1) Tay- Sachs disease :-
 Rare , Autosomal recessive disorder.
 caused due to the deficiency of an enzyme hexosaminidase A.
 Result in excessive accumulation of certain fats ( lipids) known as gangliosides in brain and nerve cells.
 Neurodegenerative disorder.
 Affected infants loose motor skills such as turning over, sitting and crawling , seizers vision and hearing loss ,
paralysis, startle reactions to loud sounds.
 TREATMENT :- There is no cure for Tay-Sachs.
 Treatment typically consists of keeping the child comfortable. This is called “palliative care.”
 Palliative care may include medication for pain, anti-epileptics to control seizures, physical
therapy, feeding tubes, and respiratory care to reduce mucus buildup in the lungs.

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20. LYSOSOMAL STORAGE DISORDER.
1) Gaucher’s disease type 3 :-
 Autosomal recessive disorder.
 Caused due to the mutation in GBA gene that codes for the lysosomal enzyme glucocerebrosidase.
 Symptoms are Avascular necrosis , Bone pain , Encephalopathy , Fatigue , Hepatomegaly, Brain is
affected.
 TREATMENT :- Gaucher disease has no cure.
 Patients with Gaucher disease type 3 can receive enzyme replacement therapy (ERT) to
address symptoms not involving the brain, like organ enlargement and bone issues.
 ERT works well to control complications that most commonly occur in patients with Gaucher
disease type 1.
 There is no good treatment for the brain damage of types 2 and 3.

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2) Niemann Pick Disease :-
 Autosomal recessive disorder
 caused by mutations in the SMPD1 gene.
 This gene provide instructions for producing an enzyme called acid sphingomyelinase found in lysosome.
 Symptoms are walking problems, enlarged spleen and liver , seizures, jaundice after birth, loss of muscle
tone, irregular speech.
TREATMENT :- No cure exists.
 No effective treatment is available to people with type A or B.
 For people with mild to moderate type C, a drug called miglustat (Zavesca) may be
an option.
 Physical therapy is an important part of treatment to help maintain mobility as long as
possible.

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3) Fabry’s disease:-
Rare, Autosomal recessive disorder.
Caused due to the deficiency of an enzyme called alpha galactosidase -A.
Affect many parts of the body that is skin , eyes , gastrointestinal system , kidneys , heart
, brain and nervous system.
Symptoms include episodes of pain and burning sensation.
TREATMENT :-There is no cure for Fabry disease.
 Recombinant alpha-galactosidase A (alpha-Gal A), the enzyme that is
deficient in patients with Fabry disease, and migalastat hydrochloride, an oral
pharmacologic chaperone that facilitates trafficking of alpha-Gal A to
lysosomes, are therapeutic options for eligible individuals.

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24. MITOCHONDRIAL DISORDERS.
1) Kearns – Sayre Syndrome:-
 Caused due to the mitochondrial DNA deletion.
 Mitochondrial DNA deletion result in the loss of gene important for mitochondrial protein formation
and oxidative phosphorylation.
 This result into weakness or paralysis of the eye muscles that impairs eye movement and cause drooping
eyelids (progressive external ophthalmoplegia) , pigmentary retinopathy which results from the
breakdown of light – sensing tissue.
 TREATMENT :-There is typically no treatment for limitation in eye movement.
 Endocrinology abnormalities can be treated with drugs.
 There is currently no effective way to treat mitochondria abnormalities in KSS.
 Treatment is generally symptomatic and supportive.

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26. DISORDERS OF STEROIDS
METABOLISM.
1) Congenital adrenal hyperplasia :-
 Autosomal recessive disorder
 It is caused by the deficiency of 21- hydroxylase.
 21-hydroxylase is an enzyme required to synthesize hormones ( Cortisol , Mineralocorticoids and androgens).
 This led to the impairment of cortisol synthesis which leads to excessive stimulation of the adrenal glands by
adrenocorticotrophic hormone , adrenal hyperplasia and excessive androgen synthesis.
 Symptoms include irregular or absent menstrual cycle , characteristics such as facial hair , excessive body hair ,
deepening of voice, severe acne.
 TREATMENT :- Classic CAH is treated with steroids that replace the low hormones.
 Infants and children usually take a form of cortisol called hydrocortisone.
 Adults take hydrocortisone, prednisone, or dexamethasone, which also replace cortisol.

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28. DISORDERS OF PIGMENT
METABOLISM.
1) Albinism:-
 Autosomal recessive disorder.
 Caused by the deficiency of tyrosinase enzyme.
 Characterized by little or no production of the pigment melanin.
 This enzyme help to change amino acid tyrosine into melanin pigment.
 White hair and very light skin colour.
◦ TREATMENT :- There’s no cure for albinism.
◦ Treatment can relieve symptoms and prevent sun damage , Treatment may include :
• sunglasses to protect the eyes from the sun’s ultraviolet (UV) rays.
• protective clothing and sunscreen to protect the skin from UV rays.
• prescription eyeglasses to correct vision problems.
• surgery on the muscles of the eyes to correct abnormal eye movements.

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30. GALACTOSEMIA.
 It is the inability of a body to utilize Galactose.
 Galactose accumulates in blood.
 It is caused due to deficiency of enzyme galactose-1-phosphate uridyl transferase.
 GALT breaks galactose to glucose
 Main source of galactose is milk products so galactose rich foods should be removed from the patient’s
diet.
 If not treated , infants develop cataract , liver disease , kidney problems , brain damage , and in some
cases lead to death.
TREATMENT:- The only treatment for galactosemia is avoiding foods that
contain lactose and galactose.

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32. HEREDITARY FRUCTOSE
INTOLERANCE.
 Caused due to the deficiency of Fructose-1-phosphate aldolase or
aldolase B.
 This result into Fructose-1-phosphate accumulation in the blood.
 Symptoms :- vomiting , hypoglycemia , failure to thrive cachexia ,
hepatomegaly , jaundice , coma.
TREATMENT :- eliminating fructose and sucrose from the diet.
 In the severe form, eliminating these sugars from the diet may
not prevent progressive liver disease.

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34. REFERENCES
◦BOOK REFERED – PEDIATRIC BOARD STUDY
GUIDE ( PAGE 143-165)
◦INBORN ERROR OF METABOLISM PPT-
www.slideshare.com
◦WEBSITE REFERED - raredisease.info.nih.gov ,
ghr.nim.nih.gov , medlineplus.gov
◦PICTURE SOURCE – google.

35. THANK YOU.