Inborn Errors of Metabolism

Dr. Mohamed Haseen BashaAssistant professor ( Pediatrics)

Faculty of MedicineAl Maarefa College of Science and

Technology

Major categories of Inherited Metabolic Diseases

Disorders of carbohydrate metabolism

• Galactosemia

• Glycogen storage disease (types IA, IB, II, III, and IV)

• Hereditary fructose intolerance

Disorders of amino acid metabolism

• Phenylketonuria

• Maple syrup urine disease

• Nonketotic hyperglycinemia

• Hereditary tyrosinemia

Disorders of organic acid metabolism

• Methylmalonic acidemia

• Propionic acidemia

• Isovaleric acidemia

Disorders of pyruvate metabolism and the electron transport chain

• Pyruvate carboxylase deficiency

• Pyruvate dehydrogenase deficiency

• Electron transport chain defects

Disorders of the urea cycle

• Ornithine-transcarbamylase deficiency

• Carbamyl phosphate synthetase deficiency

• Transient hyperammonemia of the neonate

Lysosomal storage disorders

• GM1 gangliosidosis type I (b-galactosidase deficiency)

• Gaucher's disease (glucocerebrosidase deficiency)

• Niemann-Pick disease types A and B (sphingomyelinase deficiency)

Disorders of fatty acid oxidation

• Medium chain acyl dehydrogenase deficiency

Disorders of porphyrin metabolism

• Acute intermittent porphyria

Disorders of purine or pyrimidine metabolism

• Lesch - Nyhan syndrome

Disorders of steroid metabolism

• Congenital adrenal hyperplasia

Disorders of mitochondrial function

• Kearns-Sayre syndrome

Disorders of peroxisomal function

• Zellweger syndrome

Disorders of Carbohydrate Metabolism

Galactosemia

• Autosomal recessively inherited disorder results from deficiency of the

enzyme galactose-1-phosphate uridyl transferase, which is essential for

galactose or lactose metabolism

• Accumulation of galactose-1-phosphate results in damage to the Brain,

Liver and Kidney.

• When lactose-containing milk feeds such as breast or infant formula are

introduced, affected infants develop vomiting, hypoglycemia, feeding

difficulties, seizures, irritability, jaundice, hepatomegaly, splenomegaly

and hepatic failure.

• Sepsis due to E coli is typical.

• Even if treated early, there are usually moderate learning difficulties (adult

IQ 60-80). Chronic liver disease, cataracts and developmental delay are

inevitable if the condition is untreated.

• Diagnosis is assisted by Non-glucose reducing substances in urine.

• Confirmation by Galactose-1-Phosphate uridyl transferase activity in

RBCs.

• Management is with a lactose- and galactose-free diet for life.

Hereditary Fructose Intolerance

• Occurs after ingestion of Fructose or sucrose (Glucose + Fructose)

• It results from deficiency of enzyme aldolase B results in inability to

metabolize Fructose or sucrose

• Severe and life threatening intoxication occurs with the accumulation of

Fructose-1-Phosphate in hepatocytes.

• Presents with emesis, abdominal pain, seizures and profound illness after

ingestion of fructose.

• May also present similar to Galactosemia.

• Diagnosis is by enzyme analysis.

• Life long avoidance of fructose.

Glycogen storage disease

Glycogen storage disease is the result of defects in the processing of glycogen

synthesis or breakdown within muscles, liver, and other cell types.

GSD Type I( Von Gierke’s Disease)

Enzyme deficiency: glucose-6-phosphatase

Symptoms: Hypoglycemia, Hyperlipidemia, Hepatomegaly, Lactic acidosis, and

Hyperuricemia.

Progression: Growth failure

This deficiency impairs the ability of the liver to produce free glucose from glycogen

and from gluconeogenesis. Since these are the two principal metabolic mechanisms

by which the liver supplies glucose to the rest of the body during periods of fasting,

it causes severe hypoglycemia.

Treatment:

• The essential treatment goal is prevention of hypoglycemia and the

secondary metabolic derangements by frequent feedings of foods high in

glucose or starch.

• Two methods have been used to achieve this goal in young children:

(1) Continuous nocturnal gastric infusion of glucose or starch; and

(2) Night-time feedings of uncooked corn starch.

GSD Type II- Pompe’s disease

• Accumulation of glycogen in the lysosome due to deficiency of the

lysosomal acid alpha-glucosidase enzyme that transforms glycogen in to

glucose in lysosomes.

• Damages muscle and nerve cells throughout the body.

• The build-up of glycogen causes progressive muscle weakness (myopathy)

throughout the body and affects various body tissues, particularly in the

heart, skeletal muscles, and weakness facial and oral muscles.

• Pompe's disease is one of the infiltrative causes of restrictive

cardiomyopathy, Skeletal myopathy , Macroglossia and hepatomegaly.

• Progression: Death by age - 2years.

Treatment:

European Medicines Agency (EMEA) and the U.S. Food and Drug

Administration (FDA) both granted marketing approval for the drug Myozyme

(al glucosidase alfa) for treatment of Pompe's disease.

Myozyme replaces the missing enzyme in the disease, which helps to break

down the glucose.

•Early diagnosis and early treatment leads to much better out comes.

Disorders of Amino acid Metabolism

Phenylketonuria

• PKU is a metabolic disorder caused by a deficiency of the liver enzyme

phenylalanine hydroxylase.

• The inability to metabolize PKU exists from the time the infant is in the

womb.

• Neurologic signs include seizures, spasticity, hyperreflexia, and tremors,

Mental Retardation, severe developmental delay.

• Fair Skin and blue eyes, “Mousy Odor” & Eczema.

• It is recommended that the blood for screening be obtained in the first 24-

48 hr of life after feeding protein.

• For neonatal Screening, The method of choice is Tandem mass

spectrometry , which identifies all forms of hyperphenyalaninemia with a

low false-positive rate, and excellent accuracy and precision.

• The addition of the phenylalanine/tyrosine molar ratio has further

reduced the number of false- positive results.

• Diagnosis must be confirmed by measurement of plasma phenylalanine

concentration.

Meat, fish, eggs, cheese, milk products, legumes, and bread are all foods that

have high levels of phenylalanine, should be avoided.

The only treatment available for PKU is a low phenylalanine diet for life.

 It is recommended that women with PKU who are of child bearing age, closely

adhere to the low-phenylalanine levels before conception and throughout

pregnancy. The risk of miscarriage, mental retardation, microcephaly, and

congenital heart disease in the child is high if the mother’s blood

phenylalanine is poorly controlled.

Maple syrup urine Disease(MSUD)• Valine, Ieucine & Isoleucine are the branched chain & essential amino

acids. These amino acids serve as an alternate source of fuel for the brain

especially under conditions of starvation.

• Maple Syrup Urine Disease is a genetic disease in which the amino acids

leucine, isoleucine and valine cannot be broken down by branched-chain

alpha-keto acid dehydrogenase.

Clinical ManifestationsTime Symptom/Sign12-24 hours Maple syrup odor(Burnt sugar) to cerumen, Elevated BCAA 2-3 days Irritability, poor feeding , Ketonuria 4-5 days Encephalopathy (lethargy, apnea, atypical movements)

7-10 days Coma and respiratory failure

Diagnosis

• Peculiar odor of maple syrup found in urine, sweat, and cerumen.

• confirmed by amino acid analysis showing marked elevations in plasma levels of

leucine, isoleucine, valine, and alloisoleucine (a stereoisomer of isoleucine not

normally found in blood)

• Urine contains high levels of leucine, isoleucine, and valine and their respective

ketoacids. These ketoacids may be detected qualitatively by adding a few drops of

2,4-dinitrophenylhydrazine reagent (0.1% in 0.1N HCl) to the urine; a yellow

precipitate of 2,4-dinitrophenylhydrazone, is formed in a positive test.

• Neuroimaging during the acute state may show cerebral edema, with advancing age,

hypo myelination and cerebral atrophy.

• The enzyme activity can be measured in leukocytes and cultured fibroblasts.

• Newborn screening is by Tandem mass spectrometry -based amino acid profiling

of dried blood spots between 24 and 48 hours of life

Treatment

• Acute state is aimed at hydration and rapid removal of the branched-chain

amino acids and their metabolites from the tissues and body fluids by

Peritoneal dialysis or, preferably, hemodialysis is the most effective mode

of therapy in critically ill infants.

• Sufficient calories and nutrients should be provided IV or orally.

• Cerebral edema, if present, may need to be treated with mannitol, diuretics

(e.g. Furosemide), or hypertonic saline.

• After recovery from the acute state requires a diet low in branched-chain

amino acids. Synthetic formulas devoid of leucine, isoleucine, and valine are

available commercially. Because these amino acids cannot be synthesized

endogenously, small amounts of them should be added to the diet;

Tyrosinemia (Type 1) Hepatorenal Tyrosinemia

• Tyrosinemia type 1 is a Severe disease of the liver, kidney, and peripheral nerves is

caused by a deficiency of the enzyme fumaryl acetoacetate hydrolase.

• Organ damage result from accumulation of metabolites of tyrosine degradation,

especially fumaryl acetoacetate and succinyl acetone.

• In the common form, symptoms develop within the first few months of life and may

include diarrhea, bloody stools, failure to thrive, vomiting, lethargy, irritability, and a

“cabbage-like” odor to the skin or urine.

• If untreated, liver problems such as hepatomegaly, jaundice, easy bleeding/bruising,

and swelling of the legs/abdomen are common.

• Kidney problems can cause rickets and delays in walking. Without treatment, liver

and kidney problems usually lead to death.

• Periodic episodes of pain/weakness (particularly in the legs), tachycardia, breathing

problems, seizures, and coma may occur.

Diagnosis

• Reduced fumarylacetoacetase enzyme in cultured fibroblasts,

• Increased tyrosine levels in blood ,

• Increased urinary succinylacetone and tyrosine metabolites,

• Increased serum alpha feto protein,

• Liver biopsy shows features of cirrhosis.

Management

• Diet low in tyrosine and phenylalanine formula

• The treatment of choice is nitisinone(NTBC), which inhibits tyrosine degradation

and prevents acute hepatic and neurologic crises. In early-treated patients, nitisinone

has greatly reduced the need for liver transplantation.

Disorders of Organic acid Metabolism

( Organic Acidaemias)

Organic Acidaemias

These presents with the elevation of one or more organic acids and often patient

presents in the first few days of life severely unwell neonate with acidosis,

vomiting and neurological features.

Patient may have intermittent acute attacks triggered by stress.

Clinical features

Vomiting, lethargy, seizures, coma, hypertonia, opisthotonus, hypoglycemia and

metabolic acidosis.Disease Enzyme defect Specific treatmentMethylmalonic acidemia Cobalamin defect B12Propionic acidemia Propionyl Co A Carboxylase Metronidazole

Isovaleric acidemia Isovaleryl CoA dehydrogenase Glycine

Investigations

Metabolic acidosis, Hypoglycemia, ketosis, Hyperammonemia(more than

200)

Management

• Acute attacks are treated with rehydration and calories, Correction of

acidosis and hemofiltration if necessary.

• Benzoate helpful to remove ammonia.

• Carnitine may be beneficial.

Long term features due to organic acidemia are mental retardation, seizures

and movement disorders. Failure to thrive, anorexia, osteoporosis and renal

impairment may occur.

Lysosomal storage disorders

Gaucher's disease

• It is one of the most common lysosomal storage diseases and the most

prevalent genetic defect among Ashkenazi Jews.

• Gaucher disease results from the deficient activity of the lysosomal hydrolase,

acid β-glucosidase.

• The enzymatic defect results in the accumulation of glucosylceramide, in

cells of the reticuloendothelial system. This progressive deposition results in

infiltration of the bone marrow, progressive hepatosplenomegaly, and

skeletal complications.

• Patient presents with epistaxis or bruising from thrombocytopenia, chronic fatigue

secondary to anemia, hepatomegaly with or without elevated liver function test

results, splenomegaly, and bone pain.

• Patients presenting in the 1st decade frequently have growth retardation and a more

malignant course.

• In symptomatic patients, splenomegaly is progressive and can become massive.

• Most patients develop radiologic evidence of skeletal involvement, including an

Erlenmeyer flask deformity of the distal femur. Clinically apparent bony

involvement, which occurs in most patients, can present as bone pain, a

pseudoosteomyelitis pattern or pathologic fractures.

• The pathologic hallmark of Gaucher disease is the Gaucher cell in the

reticuloendothelial system, particularly in the bone marrow

Treatment

• Enzyme replacement therapy. Most symptoms (organomegaly, hematologic

indices, bone pain) are reversed by enzyme replacement therapy.

• Enzyme preparations are approved by the FDA for the treatment of type 1

Gaucher disease, including vela glucerase alfa and Tali glucerase alfa.

• Alternative treatment includes, the use of oral substrate reduction agents

designed to decrease the synthesis of glucosylceramide by chemical inhibition

of glucosylceramide synthase (e.g., miglustat).

• Bone marrow transplantation (BMT), which is curative.

Niemann-Pick diseaseNiemann-pick is an autosomal recessive genetic disorder resulting in abnormal lipid

metabolism.

It can result from a deficiency of the acid sphingomyelinase enzyme,

Types of Niemann-pick diseases

Type A

Most severe form, occurs in early infancy. It is characterized by an enlarged liver and

spleen, swollen lymph nodes, and profound brain damage by six months of age.

Type B

involves an enlarged liver and spleen, which usually occurs in the pre-teen years. The

brain is not affected.

Type C

May appear early in life or develop in the teen or adult years. Individuals have only

moderate enlargement of the spleen and liver, and brain damage

Treatment

• Currently there is no specific treatment for NPD.

• Orthotopic liver transplantation in an infant with type A disease and cord

blood transplantation in several type B NPD patients.

• Bone Marrow Transplantation in a small number of type B NPD patients

has been successful in reducing the spleen and liver volumes, the

sphingomyelin content of the liver, the number of Niemann-Pick cells in the

marrow.

• A phase I trial of enzyme replacement therapy for type B NPD has been

completed.

• Clinical trials of miglustat have been performed and the drug has been

approved in Europe for the treatment of type C disease.

Disorders of Fatty acid oxidation

Fatty acid oxidation disorders

Fatty acids are oxidized CO2 and water in skeletal muscle and heart and to ketones in

the liver. Fats are the main source of energy during starvation.

All these disorders are AR.

Clinical features

Vomiting, hypoglycemia, lethargy, and coma induced by fasting. Cardiomyopathy,

Muscle weakness, Acute rhabdomyolysis, Reye like syndrome.

Disorders of fatty acid oxidation are

MCAD - Medium chain acyl dehydrogenase deficiency

VLCAD - Very long chain acyl dehydrogenase deficiency

LCHAD - Long chain L-3-hydroxyacyl-CoA dehydrogenase deficiency

CPT1 - Carnitine palmitoyl transferase1 deficiency

Investigations

During acute attack- hypoglycemia with low urinary ketones ie, hypo

ketotic hypoglycemia.

Urinary organic acids

Total and free carnitine levels may be low

Acyl carnitine profile of blood spot by TMS is usually diagnostic.

Confirmation by fibroblast FAOD studies, molecular genetics ex: MCAD

mutation.

Management

Prevention of fasting stress

Carnitine may be beneficial.

Disorders of Urea cycle

Urea cycle disorderThe urea cycle is the pathway by which waste nitrogen is converted to urea for

disposal.

UCDs are inherited as AR except OTC deficiency , which is X-linked recessive.

They often presents with neonatal illness with hyperammonemia( lethargy, poor

feeding, vomiting, convulsions, coma, respiratory failure) sometimes presents with

progressive spastic diplegia and developmental delay in arginase deficiency.

Diagnosis

Increased Serum ammonia

Raised plasma amino acid glutamine

Plasma AA and urine Orotic acid usually enables to make an initial diagnosis.

Enzyme assay is required to confirm the diagnosis

Urea cycle defect Enzyme deficiency Amino acid Orotic acid

N-Acetyl glutamate synthase deficiency

N-Acetyl glutamate synthase

Glu ↑, Arg ↓, Cit↓ Normal

Carbamoyl phosphatesynthase deficiency

Carbamoyl phosphate

synthase

Glu ↑, Arg ↓, Cit↓ Normal

Ornithine transcarbamylase deficiency

Ornithine transcarbamylase Glu ↑, Arg ↓, Cit↓ ↑↑↑

Citrullinemia Argininosuccinic synthase Glu ↑, Arg ↓, Cit↑↑↑ ↑

Argininosuccinic aciduria Argininosuccinic lyase Glu ↑, Arg ↓, Cit↑Argininosuccinate ↑

↑

Argininaemia Arginase Glu ↑, Arg ↑↑↑ ↑

Arg: Arginine, Cit: Citrulline, Glu: Glutamine

Treatment

Acute

Remove ammonia Increase waste nitrogen excretion using iv sodium

benzoate, sodium phenyl butyrate and arginine

or dialysis if above ineffective

Increase calories to prevent

protein breakdown

IV 10% glucose, lipids. Nil orally, No protein.

Low protein feed after 24-48 hrs

IV hydration and electrolyte

balance

Long term

Dietary protein restriction

Supplements of benzoate, Phenyl butyrate and arginine

Avoid catabolic state

Thank you