T/F infant galactosemia is a contraindication to breast feeding
T
Alternative to breast milk if the infant has galactosemia
Soy protein based formula
Classic Galactosemia is due to absence of
Galactose-1-phosphate uridyltransferase
Others: Galactokinase, uridine diphosphate galactose-4-epimerase
Jaundice, hepatomegaly, and positive urinary-reducing substance; infant
Galactosemia
Mode of inheritance of Galactosemia
Autosomal recessive
Galactosemia, SIGNS AND SYMPTOMS
Cataracts, hepatosplenomegaly, mental retardation
Galactosemia, TREATMENT
Exclude galactose and lactose from diet
Organs particularly damaged in galactosemia if not diagnosed at birth
Liver, brain, kidney
Neonates with galactosemia are at increased risk for ___ sepsis
Escherichia coli
T/F Elimination of galactose from diet in galactosemia does not ensure reversal of cataract formation.
T
In G6PD deficiency, symptoms develop ___ days after exposure to substance with oxidising properties
1-2
Heinz bodies
G6PD deficiency; thalassemia
Mode of inheritance of G6PD deficiency
X-LINKED RECESSIVE
Causes fulminant infection in glucose-6-phosphate dehydrogenase (G6PD) deficiency
Rocky Mountain spotted fever
RBC seen in G6PD
Schistocyte
Enzyme defect of hexose monophosophate (HMP) pathway resulting in hemolysis when exposed to stresses such as infection or certain drugs
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
Role of G6PD in RBCs
Normally maintains adequate level of glutathione in a reduced state
In G6PD deficiency, oxidized glutathione complexes with Hgb (denatured hgb, forming ___
Heinz bodies
G6PD makes RBCs ___ hence, easily undergoes lysis
Less deformable
Most common hemolytic enzymopathy
G6PD deficiency
Fava beans
G6PD deficiency
Bite cells on peripheral smear
G6PD deficiency
How to treat G6PD def in newborns
Reduce oxidative stress and specialized diets
T/F G6PD may cause jaundice even without anemia
T, via gene interaction with the promoter variant of the gene for UDPGT causing a deficiency similar to Gilbert’s disease
Basic defect in PKU
1) Phenylalanine hydroxylase OR2) Tetrahydrobiopterin (cofactor of phenylalanine hydroxylase)
Phenylalanine hydroxylase is responsible for what chemical reaction
Phenylalanine to tyrosine
Fate of excess phenylalanine in PKU
1) Transaminated to phenylpyruvate2) Decarboxylated to phenylethylamine
Best time to test for PKU
48-72 hours after birth (FIRST AID: after initiation of first protein feed); may be negative prior
T/F Patients with PKU appear normal at birth
T
Postnatal test for PKU
Guthrie test
Fair hair and skin, blue AR eyes, mousy odor
PKU
Prenatal testing for PKU
DNA probe
Ectopia lentis, marfanoid body habitus
Homocystinemia/ Homocystinuria
Homocystinemia/-uria: Accumulation of
Homocystine, methionine (because homocysteine is not remethylated to methionine)
Homocystinemia/-uria: Deficiency of
Cystathionine synthase
Maple syrup urine disease: Accumulation of
Branched-chain amino acids: leucine, isoleucine, valine (LIV) [Think MAPLE tree, tree of LIVe, has BRANCHes]
Maple syrup urine disease: Deficiency of
Branched-chain ketoacid dehydrogenase (decarboxylation of branched chain amino acids)
Maple syrup urine disease: Distinctive feature
Odor of maple syrup/caramel in urine, sweat, cerumen
Deficiency of neutral amino acids: tryptophan
Hartnup’s disease
Hartnup’s disease: Deficiency of
Sodium-dependent amino acid transport system in renal tubules and intestines
T/F Most patients with Hartnup disease are asymptomatic
T
Common inheritance of disorders of amino acid metabolism
AR
Food product that contains phenylalanine
Aspartame (Nutrasweet) contains phenylalanine
Treatment for PKU
Limit dietary phenylalanine (e.g., in artificial sweeteners) and increase tyrosine (in the first 16 years of life); oral administration of tetrahydrobiopterin
Decreased pigmentation in PKU is secondary to
Inhibition of tyrosinase by phenylalanine
Disorders of phenylalanine and tyrosine metabolism
PKU, Richner-Hanhart, Homogentisic acid, Albinism
Black diaper/urine
Alkaptonuria
Deficient in alkaptonuria
Homogentisic acid oxidase
Deficient in albinism
Tyrosinase/tyrosine hydroxylase
Subluxation of the lens, signaled by iridodonesis (quivering of iris) and myopia
Ectopia lentis
If homocystinuria is not diagnosed at birth, diagnosis is usually made after ___
3 years of age
Treatment for homocystinuria
High-dose vitamin B6
Most common inborn error of methionine metabolism
Homocystinuria
D/O of amino acid metabolism that looks like tetanus (muscular rigidity + opisthotonus)
MSUD
Which among the branched chain amino acids has a higher plasma level than the rest of the accumulating substances
Leucine
Poor feeding, vomiting in first week of life, proceeding to lethargy and coma
MSUD
Amino acid decreased in MSUD
Alanine
Urine precipitant test
MSUD
Aminoaciduria (neutral: alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, histidine) Normal plasma amino acid levels
Hartnup disease
Hartnup disease treatment
Nicotinic acid/nicotinamide and a high-protein diet in symptomatic patients
Deficiency of FAH
Tyrosinemia type I
Deficiency of TAT
Tyrosinemia type II
Deficiency of 4-HPPD
Tyrosinemia type III
Sweaty feet, acrid, ripe cheese odor
Isovaleric acidemia
Boiled cabbage, rancid butter odor
Tyrosinemia
Tomcat urine
Multiple carboxylase deficiency
Rotten fish odor
Trimethylaminuria
Glut-Val
Sickle cell anemia
Disorders of very long chain fatty acids
Peroxisomal disorders (Zellweger, infantile refsum disease, adrenoleukodystrophy)
Zellweger syndrome: Deficiency
Pipecolate oxidase
Infantile Refsum Disease: Deficiency
Phytanic acid
Smith-Lemli-Opitz Syndrome (SLOS): Deficiency
7-dehydrocholesterol reductase
Smith-Lemli-Opitz Syndrome (SLOS): Distinguishing feature
Syndactyly between 2nd and 3rd toes
Smith-Lemli-Opitz Syndrome (SLOS): Mutation in
Delta-7-reductase gene (DHCR7)
Lysosomal storage disease; results in accumulation of GM2ganglioside in brain; normal until 3-6 months old; cherry red spot on macula but NO hepatosplenomegaly; Hyperacusis; Froglike position
Tay-Sach disease
Tay-Sach disease, deficiency
Hexoaminidase A (tay-saX lacks heXosaminidase)
Lysosomal storage disease; Accumulation of GM2 ganglioside in brain and peripheral organs
Sandhoff
Sandhoff disease, defect
Hexosaminidases A + B
Distinguishes Tay-Sachs from Sandhoff
(+) heptaosplenomegaly in Sandhoff
Lysosomal storage disease; accumulation of glucocerebroside in reticuloendothelial system
Gaucher disease
Deficiency in Gaucher
β-glucosidase (a glucocerebrosidase)
Gaucher, characteristic cells
Gaucher cells: Histiocytes in bone marrow, liver, and spleen with crinkled/crumpled paper cytoplasm
Gaucher is more common in, infants vs adults
Adults
Lysosomal storage disease; accumulation of sphingomyelin and cholesterol in reticuloendothelial and parenchymal cells; 50% cherry red spot on macula, hepatosplenomegaly
Niemann–Pick
Niemann–Pick, deficiency
Sphingomyelinase [No man PICKs his nose with his SPHINGer]
Niemann–Pick: Diagnosis by 4 months, death by ___ of age
3 years
Characteristic cells of Niemann-Pick
Vacuolated histiocytes (foam cells) in bone marrow
The only X-linked recessive lysosomal storage disease; most are AR
Fabry disease
Lysosomal storage disease; normal at birth, diagnosis at 1 year; nodules (granulomas containing ceramide) on joints, subcutaneous tissue, and vocal cords (hoarseness, respiratory complications)
Farber disease/Lipogranulomatosis
Farber, deficiency
Ceramidase
Dark, red, punctate macules that do not blanch, occur in clusters, some become papules, distribution in bilateral and symmetric, naval and buttocks most common
Angiokeratomas
Lysosomal storage dse; angiokeratomas, progressive kidney failure, severe neuropathic limb pain, ocular opacities due to accumulation of glycosphingolipids in vascular endothelium, nerves, and organs
Fabry
Fabry, deficiency
Ceramide trihexosidase or α-galactosidase A
Progressive CNS degenration and death by 3 yo; globoid cells in areas of demyelination; accumulation of ceramide galactose within lysosomes of brain white matter; generalised rigidity, loss of head control, diminished alertness
Krabbe (globoid cell leukodystrophy)
Krabbe, deficiency
Galactosyl-ceramide β-galactosidase or galactocerebrosidase
Gangliosidoses
GM1, GM2 (Tay-Sachs, Sandhoff)
Differentiates Tay-Sachs from the rest of the GMs
No hepatosplenomegaly
Pili torti
Menkes disease
Menke disease, deficiency
Copper-dependent enzymes
Deficiency of copper-dependent enzymes is also seen in
Wilson disease
(+) urine sulfatide test with front-occipital demyelination
Metachromatic leukodystrophy (MLD)
Defect in metachromatic leukodystrophy (MLD)
Arylsulfatase A deficiency
Amino acid deficiency that resembles pellagra
Hartnup disease (niacin is from tryptophan)
Attacks of Hartnup disease are triggered by
Sunlight, emotional stress, sulfonamides
Chromosome involved in Refsum disease
6
Mucopolysaccharidoses
Hurler, Scheie, Hurler-Scheie, Hunter
Mucopolysaccharidoses: More severe form
Hurler
Mucopolysaccharidoses: Milder form
Hunter
Mucopolysaccharidoses: X-linked
Hunter
Mucopolysaccharidoses: Milder form of Hurler
Scheie
Enzyme deficiency in Hurler, Scheie, and Hurler-Scheie disease
α-L-iduronidase
Enzyme deficiency in Hunter disease
Iduronate sulfatase
Inherited deficiencies of lysosomal enzymes needed for the degradation of glycosaminoglycans (GAGs) resulting in widespread lysosomal storage of dermatan and heparan sulfates
Mucopolysaccharidoses
GAGs accumulated in mucupolysaccharidoses
Dermatan sulfate and Heparan sulfate (both also stored in Sly)
Corneal clouding, mental retardation, gargoylism
Hurler
Corneal clouding, normal intelligence
Scheie
Mild mental retardation, no corneal clouding
Hunter
Characteristic cells of mucopolysaccharidoses
“Gargoyle”cells containing lysosomes engorged with mucopolysaccharide
Stored GAG in Sanfilippo A-D
Heparan sulfate
Mucopolysaccharidoses with stored keratin sulfate
Morquio A and V
Mucopolysaccharidoseswith only derma tan sulfate as stored GAG
Maroteaux-Lamy
Glycogen storage diseases
Very Poor CArbohydrate Metabolism I- Von Gierke II- Pompei III- Cori IV- Andersen V- McArdle
Glycogen Accumulation: Liver, kidney, and intestine
Von Gierke [Ist boyfriend is a GIERKE, who flattered (MASSIVE HEPATOMEGALY) the girl with DOLL-LIKE FACIES AND FAT CHEEKS by giving her FAVA beans]
Glycogen Accumulation: Skeletal muscle
McArdle
Glycogen Accumulation: Cardiac and skeletal muscle
Pompe
Von Gierke, deficiency
Glucose-6-phosphatase
McArdle, deficiency
Skeletal muscle glycogen phosphorylase
Pompe’s, deficiency
α-1,4-glucosidase (acid maltase)
Von Gierke, glycogen-to-glucose metabolism stops at ___
Glucose-6-phosphate
Von Gierke, distinguishing characteristics
Hypoglycemia, lactic acidosis, hepatomegaly
Hyperglycemia + lactic acidosis
DKA
Glucose > glucose 6 phosphate
Hexokinase
Glucose 6 phosphate > 6 phosphogluconate
G6PD
Glucose 6 phosphate > 6 phosphogluconate provides energy to produce
GSH from GSSG via glutathione reductase
Function of glutathione
Protects cells from hemolysis due to free radicals
Doll-like facies with fat cheeks
Von Gierke
Definitive diagnosis of G6PD deficiency
Liver biopsy
Meds known to exacerbate illness in G6Pd deficiency
Sulfonamides, antimalarials, fava beans
Sulfonamides and antimalarials are also contraindicated in patients with
Porphyria
Diagnosis of galactosemia
Reducing substance in urine
X-linked disorder of purine metabolism resulting in deposition of purines in tissues and subsequent clinical abnormalities
Lesch–Nyhan Syndrome
Lesch–Nyhan Syndrome, deficiency
Hypoxanthine–guanine phosphoribosyl transferase (HGPRT)
Retardation of motor development, spastic cerebral palsy, self-injurious behavior, extrapyramidal symptoms, tophi, gouty arthritis
Lesch–Nyhan Syndrome
Lesch–Nyhan Syndrome, diagnosis
Elevated serum uric acid levels; Definitiv - HGPRT analysis
Lesch–Nyhan Syndrome, treatment
Supportive therapy; Allopurinol to reduce serum uric acid levels; Prevention of self-injury
Highest concentration of HGPRT is found in
Basal ganglia
Rate limiting step in uric acid synthesis
Xanthine oxidase
Seen in gout when hyperuricemia affects big to joint
Podagra
Progressive external ophthalmoplegia involving all extra ocular muscles (frozen eye); and pigmentary degeneration of the retina (retinitis pigmentosa)
Kearns-Sayre Syndrome
Most frequent mitochondrial disease of the perinatal period and early infancy
Leigh Encephalopathy/Subacute Periventricular Necrotizing Encephalopathy (SPNE)
Idiopathic basal ganglia calcification in the young
Fahr syndrome
Treatment of Fahr syndrome
Steroids