Congenital abnormalities Congenital abnormalities of metabolism of metabolism

Definition Definition

Abnormalities of specific enzymes of Abnormalities of specific enzymes of metabolism caused by genetic mutations metabolism caused by genetic mutations = = enzymopathiesenzymopathies

Decreased level of enzymes orDecreased level of enzymes or Changed enzyme functionsChanged enzyme functions

Clinical particularities Clinical particularities

1.1. Progressing course of the disease, Progressing course of the disease, often start later after birth (time for often start later after birth (time for accumulation of incorrect metabolites) accumulation of incorrect metabolites)

2.2. Multiple organ involvement Multiple organ involvement

3.3. Overwhelmed majority – autosomal- Overwhelmed majority – autosomal- recessive recessive

Suggestive Clinical Suggestive Clinical Presentations Presentations

Mental development deficitMental development deficit Athetosis, ataxiaAthetosis, ataxia Seizures Seizures Repeated comasRepeated comas Recurrent ketoacidosisRecurrent ketoacidosis Specific smell of urine/bodySpecific smell of urine/body MyopathiesMyopathies

Suggestive Clinical Suggestive Clinical Presentations – cont.Presentations – cont.

Skeleton abnormalitiesSkeleton abnormalities Changes of hair and skinChanges of hair and skin Cataract Cataract HepatosplenomegalyHepatosplenomegaly Malabsorption syndromeMalabsorption syndrome Unexplained deaths of sisters/brothers Unexplained deaths of sisters/brothers

Diagnosis Diagnosis

1.1. Biochemical methods Biochemical methods

2.2. Molecular-genetic methods Molecular-genetic methods

Screening systems are possible Screening systems are possible

Classification Classification

Abnormalities of metabolism of: Abnormalities of metabolism of: Amino acids Amino acids Carbohydrates Carbohydrates Lipids Lipids Vitamins Vitamins Hormones Hormones Purines and pyrimidinesPurines and pyrimidines Erythrocyte and hemoglobin enzymes …Erythrocyte and hemoglobin enzymes …

Amino Acids Metabolism Amino Acids Metabolism AbnormalitiesAbnormalities

1.1. ↑↑ concentration of amino acid in blood concentration of amino acid in blood and urine (and urine (phenylketonuriaphenylketonuria, histidinemia, , histidinemia, triptophanemia, hyperlisinemia) triptophanemia, hyperlisinemia)

2.2. ↑ ↑ excretion in urine → insufficient blood excretion in urine → insufficient blood level (homocystinuria, cystationuria) level (homocystinuria, cystationuria)

3.3. ↓ ↓ reabsorption in urine and gut reabsorption in urine and gut (cystinuria, hyperglicinuria)(cystinuria, hyperglicinuria)

4.4. Secondary hyperaminoacidurias, result Secondary hyperaminoacidurias, result of tubular pathies of tubular pathies

Phenylketonuria (PKU)Phenylketonuria (PKU)

Congenital abnormality of Congenital abnormality of phenylalaninephenylalanine metabolism with brain function metabolism with brain function predominantly impaired predominantly impaired

Frequency Frequency

1:10 000 in Russia1:10 000 in Russia 1:100 000 in Japan1:100 000 in Japan Almost never among Africans and Jews Almost never among Africans and Jews

Autosomal-recessive Autosomal-recessive

Types of PKU Types of PKU

1 type – deficit of p1 type – deficit of phenylalanine henylalanine hydroxylase hydroxylase

2 type – deficit tetrahydrobiopterin (BH4)- 2 type – deficit tetrahydrobiopterin (BH4)- cofactor of pcofactor of phenylalanine hydroxylasehenylalanine hydroxylase

Mutations on short arm of 12-th Mutations on short arm of 12-th chromosome chromosome ((12q12q)). Over 100 known . Over 100 known mutations mutations

Pathogenesis – 1 type Pathogenesis – 1 type

Phenylalanine hydroxylase deficiencyPhenylalanine hydroxylase deficiency

↓↓

IImpaired ability to metabolize the essential mpaired ability to metabolize the essential amino acid phenylalanineamino acid phenylalanine

↓↓

storage of storage of phenylalaninephenylalanine, phenylethamine, , phenylethamine, phenyl pyruvic acid phenyl pyruvic acid

Clinics Clinics

Normal at birth Normal at birth 2-6 months: vomiting, irritability, 2-6 months: vomiting, irritability,

restlessness, increased reflexes, languor, restlessness, increased reflexes, languor, eczematous rash, seizures eczematous rash, seizures

After 6 month: profound mental After 6 month: profound mental retardation retardation

Mousy odor of urine and body (!) Mousy odor of urine and body (!)

Later clinics Later clinics

Albinism (normally phenylalanine Albinism (normally phenylalanine → → tyrosine → melanin), light-colored hair tyrosine → melanin), light-colored hair and skin; skin burns and skin; skin burns from sun and skin from sun and skin eczema eczema

Seizures, muscle hypertony, Seizures, muscle hypertony, hyperkinesias hyperkinesias

2 type 2 type

Progressive course in spite of therapy Progressive course in spite of therapy → → death at 2-3 years of age death at 2-3 years of age

Diagnosis Diagnosis

Plasma phenylalanine level Plasma phenylalanine level > 270 > 270 mkmol/L (10 times higher than normal) mkmol/L (10 times higher than normal)

Normal serum tyrosine Normal serum tyrosine levellevel Norman BH4 level (type 1) Norman BH4 level (type 1) Increased level of phenylalanine Increased level of phenylalanine

metabolites in urine metabolites in urine

DDemyelination evidence on MRIemyelination evidence on MRI

Treatment Treatment

Diet!!!Diet!!! – strict restriction of phenylalanine – strict restriction of phenylalanine during first 6-10 years of life, again – at during first 6-10 years of life, again – at adolescence and during pregnancy:adolescence and during pregnancy:

Exclude high-protein food (meat, fish, Exclude high-protein food (meat, fish, milk and cheese, eggs, nuts, legumes, milk and cheese, eggs, nuts, legumes, white bread and cakes…)white bread and cakes…)

Special protein hydrolyzates without Special protein hydrolyzates without phenylalanine phenylalanine

Follow-upFollow-up

Strict control of blood phenylalanine level Strict control of blood phenylalanine level during the diet – every week or every during the diet – every week or every month.month.

! Phenylalanine is an essential amino ! Phenylalanine is an essential amino acid acid → not excluded completely→ not excluded completely

If during pregnancy level of If during pregnancy level of phenylalanine is high phenylalanine is high → risk of congenital → risk of congenital defects defects

Prognosis Prognosis

Type 1 – depends on time of diagnosis Type 1 – depends on time of diagnosis (screening for all newborns!)(screening for all newborns!)

Type 2 – unfavorable Type 2 – unfavorable

Carbohydrates Carbohydrates metabolism metabolism

abnormalities abnormalities Abnormalities of metabolism of:Abnormalities of metabolism of: Monosaccharides (glucose, fructose)Monosaccharides (glucose, fructose) Disaccharides (Disaccharides (lactoselactose, maltose, , maltose,

saccharose) saccharose) Polysaccharides (Polysaccharides (glycogenglycogen)) Mucopolysaccharidoses Mucopolysaccharidoses

Galactosemia Galactosemia

Inability (or severely decreased ability) to Inability (or severely decreased ability) to enzyme galactose (from lactose in milk)enzyme galactose (from lactose in milk)

1.1. Classical type – deficit of galactoso-1-Classical type – deficit of galactoso-1-phosphaturidiltransferaze phosphaturidiltransferaze

2.2. Deficit of galactokinaze Deficit of galactokinaze

Epidemiology Epidemiology

Autosomal-recessive Autosomal-recessive

Frequency 1:40 000 – 1:80 000 Frequency 1:40 000 – 1:80 000

Clinics Clinics

Start - first days and weeks of life:Start - first days and weeks of life: Refusal from breast feedingRefusal from breast feeding VomitingVomiting Signs of malnutritionSigns of malnutrition JaundiceJaundice Hepatosplenomegaly (cirrhosis) Hepatosplenomegaly (cirrhosis) Progressing cataract Progressing cataract Mental development deficit by 6 monthsMental development deficit by 6 months Risk of sepsis (cause of death) Risk of sepsis (cause of death)

Pathogenesis Pathogenesis

Accumulation of galactoso-1-phosphate Accumulation of galactoso-1-phosphate → toxic substance → toxic substance

Hypoglycemia → malnutrition Hypoglycemia → malnutrition Toxic damage of liver, brain, RBCs Toxic damage of liver, brain, RBCs

(anemia), lens (anemia), lens

Diagnosis Diagnosis

Decreased activity of galactokinase in Decreased activity of galactokinase in erythrocytes erythrocytes

Hypoglycemia Hypoglycemia

Possible prenatal diagnosis – Possible prenatal diagnosis – amniocentesis amniocentesis

Treatment Treatment

Diet – exclusion of milk, use of soy-milk Diet – exclusion of milk, use of soy-milk formulas – at least for 3 years formulas – at least for 3 years

Glycogenoses Glycogenoses

Glycogen metabolism disturbances Glycogen metabolism disturbances → → accumulation of glycogen in different accumulation of glycogen in different organs organs

Autosomal-recessiveAutosomal-recessive

Frequency 1:70 000 Frequency 1:70 000

12 types12 types

1.1. Glycogenic hepatonephromeagly (Glycogenic hepatonephromeagly (GirkeGirke))

2.2. Glycogenic cardiomegaly (Glycogenic cardiomegaly (PompePompe) )

3.3. Limitdextrinosis (Forbs-Kori) Limitdextrinosis (Forbs-Kori)

4.4. Amilopectinosis (Andersen)Amilopectinosis (Andersen)

5.5. Insufficiency of miophosphorylase Insufficiency of miophosphorylase (McArdl)(McArdl)

6.6. Insufficiency of hepatic phosphorilaze Insufficiency of hepatic phosphorilaze (Hers) (Hers)

Cont. Cont.

6. Deficit of phosphofructokinaze (Tarui) 6. Deficit of phosphofructokinaze (Tarui)

7. Tompson disease7. Tompson disease

8-12. Hage’s disease – subtypes A, B, C 8-12. Hage’s disease – subtypes A, B, C and D and D

Girke disease Girke disease

Deficit of glucose-6-phosphataze Deficit of glucose-6-phosphataze → → Accumulation of glycogen in liverAccumulation of glycogen in liver To lesser extend – in kidneysTo lesser extend – in kidneys Hypoglycemia Hypoglycemia Secondary hyperlipidemiaSecondary hyperlipidemia

ClinicsClinics

First signs are in infancy:First signs are in infancy: Vomiting, languor, adynamia, weight Vomiting, languor, adynamia, weight

deficit, seizures (hypoglycemia) deficit, seizures (hypoglycemia) Large hepatomegaly Large hepatomegaly Sometimes – palpable kidneys Sometimes – palpable kidneys Increased appetite Increased appetite

ClinicsClinics

Doll-like faceDoll-like face Short height Short height Short extremities and neckShort extremities and neck Large abdomenLarge abdomen Increased subcutaneous fatIncreased subcutaneous fat Decreased muscle strength Decreased muscle strength Almost normal mental development Almost normal mental development

Diagnosis Diagnosis

Hypoglycemia, acidosis, ketonuria Hypoglycemia, acidosis, ketonuria Test with adrenalin or glucagon: Test with adrenalin or glucagon:

unchanged or unchanged or ↓ blood glucose (insulin ↓ blood glucose (insulin stimulation). stimulation). Normally - ↑ glycogen break-Normally - ↑ glycogen break-up → ↑ blood glucoseup → ↑ blood glucose

Liver biopsy – increased glycogen and Liver biopsy – increased glycogen and decreased decreased glucose-6-phosphatazeglucose-6-phosphataze

Complications Complications

Diabetes mellitus Diabetes mellitus Intercurrent diseases Intercurrent diseases Possible malignant tumors – adenoma, Possible malignant tumors – adenoma,

carcinoma carcinoma

Pompe disease Pompe disease

Absence of acid lysosomal 1,4-Absence of acid lysosomal 1,4-glucosidaseglucosidase

Glycogen accumulates in:Glycogen accumulates in: LiverLiver KidneysKidneys HeartHeart Nervous systemNervous system Muscles Muscles

Clinics Clinics

Soon after birth: Soon after birth: Anorexia Anorexia Vomiting Vomiting Muscle weaknessMuscle weakness Cyanosis and shortness of breath Cyanosis and shortness of breath CardiomegalyCardiomegaly Respiratory insufficiency (intercostals Respiratory insufficiency (intercostals

and diaphragm weakness) and diaphragm weakness)

ClinicsClinics

Recurrent pneumonias Recurrent pneumonias Round face, large tongueRound face, large tongue Muscle hypotoniaMuscle hypotonia Failure to thrive Failure to thrive

Diagnosis Diagnosis

Blood, urine tests and test with Blood, urine tests and test with adrenalin/glucagon are normaladrenalin/glucagon are normal

Muscle or liver biopsy are decisive Muscle or liver biopsy are decisive

Prognosis Prognosis

High mortality during first year of life High mortality during first year of life

Lipids metabolism Lipids metabolism abnormalitiesabnormalities

Glycolipidoses:Glycolipidoses:

1.1. Cerebrosidoses (e.g., Cerebrosidoses (e.g., Gaucher’sGaucher’s disease)disease)

2.2. Gangliosidoses (e.g., Gangliosidoses (e.g., Tay-Sachs Tay-Sachs disease) disease)

Gaucher’s diseaseGaucher’s disease

Decreased activity of glucocerebrosidaze Decreased activity of glucocerebrosidaze → glucocerebrosid accumulation in → glucocerebrosid accumulation in reticulo-endothelial system reticulo-endothelial system

Pathology Pathology

Overloaded with glucocerebrozide Overloaded with glucocerebrozide histiocytes (Gausher’s cells) spleen red histiocytes (Gausher’s cells) spleen red pulp, lymph nodes, liver sinusoids and pulp, lymph nodes, liver sinusoids and bone marrow bone marrow

Decreased activity of enzyme in liver and Decreased activity of enzyme in liver and kidneys kidneys

Clinics Clinics

Nasal bleedingNasal bleeding Skin hemorrhagic rashesSkin hemorrhagic rashes Profound metrorrhagias Profound metrorrhagias Developmental and growth delayDevelopmental and growth delay Late menarche Late menarche Bone pains Bone pains

Physical exam Physical exam

Huge hepatosplenomegalias Huge hepatosplenomegalias Brownish coloring of hands and face Brownish coloring of hands and face

(patchy or diffuse) (patchy or diffuse) Hypersplenism (anemia, leucopenia, Hypersplenism (anemia, leucopenia,

thrombocytopenia) thrombocytopenia)

Types Types

Chronic (= adult), mild neurological Chronic (= adult), mild neurological changes, if any – older childrenchanges, if any – older children

Infantile – severe neurologival changes Infantile – severe neurologival changes (seizures, muscle hypertonus, (seizures, muscle hypertonus, opistotonus) – at 6 month of age opistotonus) – at 6 month of age

Juvenive – intermediate Juvenive – intermediate

Treatment Treatment

If clinics not sever – no treatment If clinics not sever – no treatment Severe – splenectomy, prednisone, Severe – splenectomy, prednisone,

stimulators of leucopoesis and stimulators of leucopoesis and thrombopoesis thrombopoesis

Prognosis is quite favorable Prognosis is quite favorable

Tay-Sachs DiseaseTay-Sachs Disease

Deficit of hexosaminidaze A (lysosomal Deficit of hexosaminidaze A (lysosomal enzyme) enzyme) → accumulation of gangliosides → accumulation of gangliosides in gray matter of brain (100-300 times in gray matter of brain (100-300 times higher than normal) and in liver and higher than normal) and in liver and spleen. spleen.

Epidemiology Epidemiology

Frequency – 1:250 000Frequency – 1:250 000 Among Jews-Ashkenazi – 1:4 000Among Jews-Ashkenazi – 1:4 000

Autosomal - recessiveAutosomal - recessive

Clinics Clinics

First 3-4 months – no clinics First 3-4 months – no clinics Later: less active, crying, looses acquired Later: less active, crying, looses acquired

skillsskills Vision abnormalities (impaired fixation) Vision abnormalities (impaired fixation) Soon – blindness and deafness Soon – blindness and deafness Severe mental degradation Severe mental degradation Hypotonia, paralysis of extremities Hypotonia, paralysis of extremities Seizures with opistotonus Seizures with opistotonus

Prognosis Prognosis

Mortality at age 1-1,5 yearsMortality at age 1-1,5 years

No specific treatmentNo specific treatment

Important – prenatal diagnosis Important – prenatal diagnosis

All the lectures are done! All the lectures are done!