3CLASSICAL GALACTOSEMIA Defective enzyme: Galactose-1-phosphate uridyltransferase (incidence 1:40,000)Mechanism: Accumulation of galactose-1-phosphate causes intracellular ATP depletion and very toxic for liver, kidney and brain.
5Clinical findings: Progressive symptoms after start of milk feeds Clinical findings: Progressive symptoms after start of milk feeds. Usually starting on the 3rd and 4th day.Vomiting, diarrhea, jaundice, disturbances of liver function tests, death from severe liver and renal failure, sepsis (especially by E. Coli), bilateral cataracts (due to galactitol accumulation)
6DiagnosisLow galactose-1-phosphate uridyltransferase activity (Beutler test)High galactose and galactose-1-phosphate levels (N: mg/dL) in serum or erythrocytes.Renal tubular damage: Generalized aminoaciduria, albuminuria,Reducing substances in urine (Fehling or Benedict test) due to glucosuria and galactosuria.
7Therapy: Lactose-free and galactose restricted diet throughout life Therapy: Lactose-free and galactose restricted diet throughout life. Keep galactose-1-phosphate levels under 5mg/dL.Complications: Mild mental retardation, ataxia, tremor; gonodal dysfunction, disturbed pubertal development (especially in girls)
8EPIMERASE DEFICIENCY Galactose Galactose-1P Glucose Galactitol galaktokinaseGalactose-1PGalactose-1-phosphate uridyltransferaseepimeraseGlucoseMost of the cases are asymptomatic.Symptomatic cases like classical galactosemia.
12HEREDITARY FRUCTOSE INTOLERANCE Defective enzyme: Aldolase B (incidence 1:20,000)Mechanism: Accumulation of fructose-1-phosphate causes intracellular ATP depletion and very toxic for liver, kidney and brain.
13Clinical findings: Symptoms after weaning or supplementary feeds. Vomiting, apathy liver dysfunction with hepatomegaly, hypoglycemia (inhibition of glycogenolysis) renal tubular dysfunction, distribution of liver function tests, failure to thrive, aversion to fructose containing foods/sweets, no caries.
14Diagnosis: Clinical symptoms with fructose loading (dangerous Diagnosis: Clinical symptoms with fructose loading (dangerous!); positive effect of withdrawing fructose; enzyme studies.Renal tubular damage: Generalized aminoaciduria, albuminuria, Reducing substances in urine (Fehling or Benedict test) due to glucosuria and galactosuria.Therapy: Strict fructose restricted diet throughout life.
21Type I a (von Gierke)/ Clinic/Laboratory Neonatal hypoglycemiaLactic acidosis, ketosisHepatomegalyHyperuricemia goutHyperlipidemiaLipid accumulation in the cheeks (doll facies).
22Type I a (von Gierke)/Diagnosis Hypoglycemia inresponsive to glucagonGlucose challange test: Glucose (increase), Lactate (decrease)Diagnosis: Low liver glucose-6-phosphatase levels.
23GSD Type I a (von Gierke)/Therapy Avoid hypoglycemia by means of continous carbohydrate intake.Frequent meals (every 2-3 hours in infants, 4-6 hours in school age)Slowly resorbed carbohydrates (raw –uncooked- starch)Limited fructose, lactose, no sucrose,Nights: Continous intake of glucose polymers (starch) via nasogastric tube
24GSD Type IbEnzyme: Glucose-6-phosphate transporter (edoplasmic reticulum)Clinical: looks like GSD type IaPlus: neutropenia, leucocyte dysfunction, frequent infections, Crohn like inflammatory bowel disease.Treatment of neutropenia: G-CSF and GM-CSF
25GSD type Ic and Id Clinical: Similar GSD type Ia Ic: Inorganic phospate transport defect (T2 protein disorder)Id: GLUT 7 microsomal transport defect
26GSD type VI Hers disease Enzyme: Liver phosphorylase defectClinical: Failure to thrive, hepatomegaly, mild hypoglycemiaDiagnosis: Elevated lactate and transaminases, enzyme studies: Liver, erythrocytes, leucocytesPrognosis: Fairly good, often asymptomatic
28GSD type VII Tarui disease Enzyme: phosphofruktokinase (muscle, erythrocyte, platelets)Severe myopathyPostprandial exercize intolerance (does not respond to glucose infusion)Mild hemolytic anemiaHyperuricemia (post exercize)PAS positive, abnormal amilopectin accumulation
29GSD type IX Enzyme: Phosphorylase kinase X related liver form (most frequent)AR liver and muscle formAR liver formMuscle formCardiac form
30GSD type II (Pompe disease) Enzyme: alpha-1,4-glucosidase (asid maltase); lysosomal enzyme; minimal role in glucose metabolism.Storage of cholesterol esters and triglycerides.İnfantile form : Severe cardiomyopathy and myopathy, hypotonia, hepatomegaly, failure to thrive, untreated fatal in the first yearJuvenile-adult form: Slowly progressing skeletal muscle weakness, no cardiomyopathyDiagnosis; Vacuolated lymphocytes, EKG: PR-shortness and massive QRS waves, enzyme studiesEnzyme replacement therapy
32GSDType III (Cori / Forbes disease) Defective Enzyme: Debrancher enzyme= amylo-1, 6-glucosidase accumulation of limit dextrin in liver and muscle.Type IIIa: (Liver+muscle involvement): In infancy same as in GSD Type I; but normal lactate/uric acid, mild hypoglycemia, improvement in childhood, hepatomegaly, normal kidney size, failure to thrive; Progressive myopathy, cardiomyopathy, neuropathyType IIIb: (Only liver involvement)Diagnosis: decreased alanine, leucine, isoleucine, elevated valine; increased transaminases and cholesterol. Enzyme studies: Liver, muscle, erythrocytes, fibroblastsTherapy: Frequent feeding, maintain normoglycemia
33GSD Type IV (Andersen disease) Defective Enzyme: Branching enzyme = amylo-1,4->1,6 transglucosidase; accumulation of amylopectin like glycogen moleculeClassic form: failure to thrive, hepatomegaly, progressive liver disease -> cirhossis, liver failure, often fatal by age of 4-5 yearsMild form; Non-progressiveNeuromuscular formsEnzyme studies: Liver, muscle, erythrocytes, fibroblastsTherapy: Liver Transplantation ?
37GLUT 1 deficiencyClinical: Epileptic encephalopathy, microcephaly, psyhomotor retardationDiagnosis: Fasting CSF: CSF glucose/ Blood glucose<0.45; lactate: N, or decreasedTherapy: Ketogenic diet.Avoid these drugs: barbiturates, ethanol, methylxantinesPrognosis: Satisfactory with early treatment
38GSD tip XI (Fanconi-Bickel syndrome) GLUT 2 defectClinically resembles GSD type IaDwarfism, Fanconi syndrome, ricketsFasting hypoglycemia (no response to glucagon), postprandial hyperglycemia, aminoaciduria, phosphaturia, glucosuriaGlycogen accumulation in liver and kidneys
39Congenital glucose-galactose malabsorption SGLT1 deficiencySevere intestinal glucose and galactose transport defects, mild renal transport defect.Clinical: Severe neonatal diarrhoea, dehydrationDiagnosis: Mild glucosuria, reducing substance in stools, normal fructose toleranceTherapy: Dietary replacement of gucose/galactose with fructose
40Renal glucosuria SGLT2 deficiency Renal transport defect of glucose and galactoseNo intestinal defectBenign glucosuria with normal blood glucose and absence of generalized tubular dysfunction.Therapy: None
44Cystic fibrosis-Genetics Cystic fibrosis gene is localized in the long arm of 7th chromosome (7q31.2).Cystic fibrosis gene codes cystic fibrosis transmembrane regulator (CFTR).There are more than 600 mutations. The most frequent mutation is delta-F508, 70-80% in USA and 30% in Turkey)Incidence: 1:2500 in Caucasians, less frequent in Orientals where cholera is endemic. Incidence in Turkey is not known, but presumed to be high.
45PATHOGENESISCTFR is inserted in the cell membranes and has the properties of ion channels.In cystic fibrosis cAMP-dependent chloride channels that regulate the water secretion and sodium channels regulate the water reabsorption are defective.
46Apical membranes of epithelial cells of exocrine glands are impermeable to chloride, and secondarily sodium and water.Additionally epithelial cells reabsorb excessive amount amounts of sodium and secondarily water.Decreased water secretion and increased water reabsorption (dehydrated secretions) lead obstruction, cysts and fibrosis in the exocrine glands (bronchial tree, pancreatic duct, gastrointestinal glands etc) with the exception of sweat gland.
47In sweat glands, chloride secretion and thereby the water secretion is normal in the secretory coil. On the other hand sodium and secondarily chloride reabsorption by the ductus is decreased.Therefore excessive amounts of salt are lost in the sweat (chloride levels are more than 60 mEq/L).
49CLINICAL MANIFESTATIONS The most life threatening clinical features of CF, are pulmonary obstruction and infections.Thick mucous secretions are associated with chronic obstructive lung disease predominantly involving the small airways.Recurrent and persistent infections with Pseudomonas aeroginosa and cepecia (virtually diagnostic) and Staphylococcous lead to bronchiectasis and respiratory failure, often accompanied by cor pulmonale and death
50CLINICAL MANIFESTATIONS In 80-90% of the patients exocrine pancreatic deficiency causes steatorhea and failure to thrive.In 10-20% of the patients, meconium ileus occurs in the neonatal period. Failure to pass meconium in the first hours of life.Abdominal roentgenograms show dilated loops of bowel with a collection of granular ground-glass material in the lower central abdomen.
52CLINICAL MANIFESTATIONS Excessive lost of salt in the sweat leads hyponatremic dehydration in young children especially during high environmental temperature.Secondary hyperaldosteronism causes hypopotasemia and metabolic alkalosis (Pseudo-Bartter syndrome).10% of patients diabetes mellitus develops, especially after the age of ten.
53CRITERIA FOR DIAGNOSIS OF CYSTIC FIBROSIS Typical pulmonary manifestations and/orTypical gastrointestinal manifestations and/orA history of cystic fibrosis in the family plus* Sweat chloride concentration >60mEq/L and/or* Pathologic CTFR mutation on both chromosomes.
54NEONATAL SCREENINGMost of the patients with CF can be identified by determination of immunoreactive tripsinogen in blood spots (Guthrie card).This test is neither sufficiently sensitive nor spesific for CF.This test is not valid after the age of three months (Serum tripsinogen levels decrease during progressive pancreatic damage).
55Pulmonary therapyThe objective of pulmonary therapy is to clear secretions from airways and to control infectionsChest percussion + postural drainageBronchodilators: ß-sympathomimetic agents, teophyllineExpectorants: Are not effective, curcumin may be helpful (stimulation of Cl channel)%3-7 NaCl inhalation
56Antibiotic therapyAerosol and/or intravenous: (Pseudomonas is more difficult to treat and rarely is eradicated)Pseudomonas aeroginosa: amikasin, gentamycin, tobramycin, netilmycin, imipenemStaphylococcous aereus: voncomycin, oxacillin
57Nutritional therapyHigh caloric diet (150% of normal calorie) without fat restrictionPancreatic enzyme replacementFat-soluble vitamins (A,D,E,K) supplementation