Lipodeses and Lysosomal Storage Diseases

Question 1

AR

Deficiency of B galactosidase leading to accumulation of this lipid in CNS

Answer 1

GM1 gangliosides

Question 2

Deficient enzyme in GM1 gangliosidoses

Answer 2

B-galactosidase

Question 3

Diseases with cherry red macula

Answer 3

Tay Sachs
GM1 gangliosidoses
Neymann Pick’s disease
Sandhoff disease

Question 4

Hepatosplenomegaly
Hemolysis
Inclusions in WBCs
Rashes 
Edema 

Blind, deaf by 1 year of age

Die of heart failure or neurological defect with death in 3 years

GM1 ganglioside deposition in neurons leading to

Answer 4

GM1 Gangliosidoses Beta galactosidase

psychomotor retardation

Question 5

Deficiency of alpha subunit of hexosaminidase A

Accumulation of GM2 ganglioside in brain

Ashkenazi Jew

No organomegaly

Answer 5

Tay Sachs Disease GM2 gangliosidase

Alpha hexosaminidase A deficiency

Question 6

Inc level of GM2 gangliosides in the brain and PERIPHERAL ORGANS

Defect of beta subunit of hexosaminidase A and B

Answer 6

Sandhoff disease

Question 7

Six subtypes

Sphingomyelin deficiency

Answer 7

Neimann-Pick disease

Question 8

Gene erroneous in Neimann-Pick Sphingomyelinase deficiency

Answer 8

SMPD1 gene Neiman-Pick type A and B

Question 9

Most common of the lipid storage disorder

Answer 9

Gaucher disease

Question 10

Autosomal recessive

Deficiency of beta glucosidase (glucocerebrosidase)

Answer 10

Gaucher beta glucosidase deficency

Question 11

Beta glucosidase acts on

Answer 11

Fatty acid glucosylceramide accumulating in WBCs (mac)

Question 12

Mononuclear leukocytosis

Answer 12

Gaucher’s beta glucosidase deficiency

Question 13

X linked Recessive

Ceramide trihexosidase, globotriasylceramide or alpha galactosidase A deficiency

Answer 13

Fabry disease

Question 14

Autosomal Recessive

Deficiency of galactosylceramide B galactosidase or galactocerebrosidase deficiency

on gene GALC ch14(14q31)

Answer 14

Krabbe disease

Question 15

Autosomal recessive

Ceramidase deficiency

Inc of ceramide in peripheral organs, joints and lymphoid tissue

Answer 15

Farber disease
Farber’s lipogranulomatosis
Fibrocytic dysmucopolysaccharidosis

Question 16

Acid can form

Answer 16

Gamma aminobutyric acid GABA shutting patient’s brain and breathing

Question 17

Lactic acidosis -> GABA connection

Stroke like episode
Causes generalized tonic-clonic seizures often associated with hemiparesis and cortical blindness
Recurrent headache and vomiting (GABA)
Lesds to progressive neuro abnormality, coma and death

MRI show multiple strokes not in a vascular pattern

Inc lactic acidosis in blood and urine

Muscle biopsy: diagnostic ragged red fibers

Answer 17

MELAS

Mitochondrial encephalopathy

Question 18

Rare neurometabolic disorder affecting CNS
Crucial cells in brain stem and basal gang are effected with mutations in mitochondrial DNA

Cells have no energy and inhibits motor function

Movement disorder

Episodes of lactic acidosis

No tx or high carb diet

Answer 18

Leigh Subacute Necrotizing Encephalomyelopathy (SNEM)

Question 19

Inherited deficiency of lysosomal enzyme for degradation of glycosaminoglycan (GAGs) resulting in widespread lysosomal storage of dermatan and heparan sulfate

Answer 19

Mucopolysaccharidoses

Question 20

Gargoyle cells containing lysosomes engorged with mucopolysaccharide

Excessive urinary excretion of glycosaminoglycan, coarse features and stiff joint

Detection of enzyme deficiency in leukocyte or cultures fibroblast needed for diagnosis

Answer 20

Mucopolysaccharidoses

Question 21

AR
Milder form of Hurler
Normal intelligence and life span

Corneal clouding, stiff joint, aortic regurgitation (early diastolic decrescendo murmur) and wide pulse pressure because of decreased diastolic pressure (bounding pulses in radial artery)

Answer 21

Scheie syndrome

Question 22

Deficiency of alpha-L-iduronidase

Severe and progressive with clinical onset of 1 year of age and death by 10 years of age

MR, Heart disease, corneal clouding, organomegaly and coarse facies

Obstructive airway disease/Dystosis multiplex

Enlarged tongue, hearing loss, limited language

Answer 22

Hurler syndrome

Mucopolysaccharidosis Type I

Question 23

X linked Recessive
Deficiency of iduronate 2 sulfatase

Clear cornea but associated with retinitis and papilledema

Dystosis multiplex, mental retardation, organomegaly and coarse facies

Answer 23

Hunter Syndrome

Question 24

AR
Early in neonatal period with progressive encephalopathy
Death secondary to hyperammonia level (GABA), infection and cardiomyopathy or basal ganglia stroke

Answer 24

Proprionic acidemia
Proprionyl coa carboxylase deficiency
Ketotic glycinemia

Converts proprionyl coa to methylmalonyl coa (prop coa carboxylase) in krebs

conversion of AA to sugar

Question 25

Body cannot breakdown lysine, hydroxylysine and tryptophan Excessive level of intermediate breakdown products accumulate and damage brain (basal ganglia) hence problem with movement regulation Causes CARNITINE DEFICIENCY bec glutaric acid is detoxified by carnitine MR can also occur

Answer 25

Glutaric Acidemia Type I

Question 26

AR Presents with progressive encephalopathy and secondary hyperammonemia Defect in metabolic pathway where methylmalonyl-coenzyme A (CoA) is converted into succinycl Coa by methylmalonyl coA mutase Required B12

Answer 26

Methylmalonic acidemia

Question 27

Biotin is needed in coversion of

Answer 27

Proprionyl CoA (3 Carbon) to Methylmalonyl CoA (4 Carbon) via Proprionyl CoA carboxylase (biotin)

Question 28

Methylmalonyl CoA (4Carbon) is convered to Succinyl Coa via

Answer 28

Methylmalonyl CoA mutase and VitB12

Question 29

mutation in HMGCL gene Plays essential role in break down of dietary proteins and fats for energy Rare disorder Body cannot properly process the AA leucine Body cannot make ketones -> no energy for fasting states Vomiting, dehydration, lethargy, convulsion, coma and metabolic acidosis Condition is mistaken for Reye syndrome CNS impairment

Answer 29

3 hydroxy 3methylglutaryl coa lyase deficiency HMG COA lyase deficiency Hydroxymethylglutaric aciduria

Question 30

AR Metabolic disorder which disrupts or prevents normal metabolism of branched chain AA leucine Deficiency of Isovaleric acid CoA dehydrogenase SWEATY FEAT odor causes by build up of isovaleric acid Half become apparent within few days after birth and other half during childhood Poor feeding, vomiting, seizure lack of energy leading to coma

Answer 30

Isovaleric acidemia

Question 31

Inc isovalerylglycine in urine | Inc isovalerylcarnitine in plasma

Answer 31

Isovaleric acidemia

Question 32

Inherited disorder of AA metabolism in which phenylalanine cannot be converted to tyrosine Deficiency of phenylalanine hydroxylase Screened for all newborns Patients are normal at birth but develop severe MR if not treated Hypopigmentation Eczema Mousy/musty odor and hypotonia Tx: limit dietary phenylalanine and inc dietary tyrosine Strict dietary restriction during pregnancy Stay away from artifical sweetener (aspartame)

Answer 32

Phenylketonuria

Question 33

Phenylalanine metabolism

Answer 33

Phenylalanine -> Tyrosine -> L Dopa -> NE -> Epi

Question 34

X linked Recessive Purine deposition in tissue Deficiency of Hypoxanthine-guanine phosphoribosyl transferase HGPRT ``` Delayed motor development Choreoathetosis (1 yr) Spastic CP SELF INJURIOUS BEHAVIOR Hyperuricemia (tophi, neuropathy, urinary tract caliculi) ``` Tx: allopurinol Death in 2nd or 3rd decade

Answer 34

Lesch Nyhan Syndrome

Question 35

Deficiency of fumarlacetoacetate Severe disease of liver, kidney and peripheral nerves organ damage from accumulation of metabolite of tyrosine degradation (succinylacetone)

Answer 35

Fumarylacetoacetate hydrolase FAH | Tyrosinemia

Question 36

AR FAH gene to ch15q Susceptible French Canadian from Saguenay-Lac Saint Jean region of Quebec Untreated, affected appears normal at birth and typically presents between 2 and 6 months of age Acute hepatic crisis Odor: BOILED CABBAGE due to inc methionine metabolite

Answer 36

Tyrosinemi Type I

Question 37

Acute Hepatic crisis with catabolic state Episodes of acute peripheral neuropathy (40%) resembling acute porphyria Renal involvement as Fanconi-like syndrome with normal anion gap metab acidosis, hyperphosphaturia, hypophosphatemia, vit D resistant ricket Increased levels of succinylacetone in urine is diagnostic Tx: low phenylalanine and tyrosine diet but does not slow progression Liver transplant alleviates HCC risk

Answer 37

Tyrosinemia Type I

Question 38

Drug of choice for tyrosinemia

Answer 38

Nitisinone | inhibits tyrosine degradation at 4-HPPD

Question 39

Catabolism of AA -> production of free ammonia (GABA) In mammals, ammonia is detox to urea water soluble via urea cycle Urea cycle never shuts off

Answer 39

Urea cycle deficiency

Question 40

5 enzymes involved in synthesis of urea

Answer 40

``` Carbamyl phosphate synthetase Ornithine transcarbamylase Argininosuccinate synthetase Argininosuccinate lyase Arginase ```

Question 41

Most common genetic cause of hyperammonemia

Answer 41

Urea cycle deficiency

Question 42

AR 2 arginase in humans: A1 cytosolic expressed in liver and RBC A2 mitochondrial, expressed in renal and brain Inc arginine in plasma and CSF Inc urinary orotic acid Diagnosis confirmed by assaying arginase activity in RBC Tx: low protein diet devoid of arginine and administration of AA synthetic protein resulting in dec arginine and improved neurologic abnormality

Answer 42

Arginase deficiency

Question 43

Hyperammonemia Moderate elevation in LFT Nonspecific increase in plasma level of glutamine and alanine Moderate increase in plasma levels of citrulline (less in citrullinemia) and marked increase in plasma levels of arginosuccinic acid Dec in arginine Trichorrhexis nodosa (hair ab)

Answer 43

Argininiosuccinic acidemia

Question 44

90% of urea cycle takes place in

Answer 44

liver

Question 45

Death by 3-5 years of age Hyperacusis/exaggerated startle response Cherry red macula but clear cornea Frog like position Hepatosplenomegaly, normal WBC

Answer 45

Sandhoff GM2 gangliosidase beta hexosaminidase A and B deficiency

Question 46

Inc of sphingomyelin and cholesterol in reticuloendothelial and parenchymal cells, CNS (ataxia, dysarthria, BG dysfunction causing abnormal posturing eg dystonia) Widespread: cerebral cortex and subcortical structure leading to dementia and seizure Some have red macula but all have clear cornea, hepatosplenomegaly (thrombocytopenia), bleeding in skin and mucosa Dx by 4 months death by 3 years

Answer 46

Neimann-Pick sphingomyelinase deficiency

Question 47

Seen in bone marrow aspirates of Neimann-Pick Sphingomyelinase deficiency

Answer 47

Foam cells

Question 48

Splenomegaly in Neiman-Pick sphingomyelinase cause

Answer 48

Bleeding in skin and mucosal surfaces | Thrombocytopenia

Question 49

Inc levels of glucocerebroside in RES Bone fracture, bone pain and avascular necrosis Accumulation of glucoceramide in lungs, bone marrow hence pancytopenia

Answer 49

Gaucher beta glucosidase deficiency

Question 50

Gaucher cell in bone marrow have May also present with bruising, fatigue, anemia, thrombocytopenia, hepatosplenomegaly

Answer 50

crinkled paper in cytoplasm Gaucher beta glucosidase deficiency

Question 51

Beta glucosidase of Gaucher acts on

Answer 51

Fatty acid glucosyl ceramide

Question 52

Glucoceramide of Gaucher beta glucosidase deficiency accumulates in these types of cells

Answer 52

White blood cells | Macrophages

Question 53

Treatment for Gaucher Beta glucosidase deficiency

Answer 53

Enzyme replacement

Question 54

Inc glycosphingolipid in vascular endothelium, nerves, and organs Fatty compounds start to line blood vessels Inc risk of STROKE, heart attack and kidney damage in the YOUNG

Answer 54

Fabry ceramide trihexosidase alpha galactosidase A deficiency

Question 55

Angiokeratoma and telangiectasia Severe neuropathic limb pain Asymmetric corneal deposition (corneal clouding) Progressive renal failure, Hepatomegaly Cardiac involvement

Answer 55

Fabry ceramide trihexosidase alpha galactosidase A deficiency

Question 56

Lack of active saposin A Build up of glycosphingolypids called psychosine Inc of ceramide galactose within lysosomes of brain white matter

Answer 56

Krabbe galactosylceramide beta galactosidase deficiency

Question 57

Clear cornea Progressive CNS degeneration within first 6 months of life Optic atrophy, spasticity, early death and clear cornea

Answer 57

Krabbe galactosylceramide B galactosidase deficiency

Question 58

Krabbe galactosylceramide beta galactosidase deficiency shows these cells in areas of demyelination

Answer 58

Globoid cells

Question 59

Build up of this glycosphingolypid in Krabbe galactosylceramide B galactosidase deficiency causes axonal degeneration in CNS and PNS by disrupting lipid rafts

Answer 59

Psychosine

Question 60

Normal at birth Clinical onset at 4 months Nodules on joints and vocal cords (hoarseness) - swollen lymph nodes Xanthoma Severe MR and motor retardation Death by 2 years of age

Answer 60

Farber ceramidase deficiency Farber’s lipogranulomatosis Fibrocytic dysleukopolysaccharidoses

Question 61

50% have cherry red macula but clear cornea

Answer 61

GM1 gangliosidoses B galactosidase deficiency