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Digestive Systems, Nutrition, & Metabolism > Diseases > Flashcards

Diseases Flashcards

1
Q

Niemann-Pick

A

Niemann-Pick

Autosomal recessive
Ashkenazi Jews

Sphingomyelinase

Sphingomyelin

Clinical presentation + DNA testing

Normal following birth then rapid regression of previously acquired motor/social skills

- Mental retardation
- CHERRY RED MACULA
- HEPATOSPLENOMEGALY
- FOAMY MACROPHAGES (histology)
- Xanthomas
- Pancytopenia: low platelet count

None

Supportive care until death (usually age 3)

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2
Q

Krabbe

A

Krabbe

Autosomal recessive

B-Galactocerebrosidase

Galactocerebroside

Clinical presentation
Brain imagining (MRI)
DNA testing

Varies based on age of onset
Gross neurological deficits
Hyperactive reflexes
Optic atrophy
DEMYELINATION of CNS and PNS
Developmental delay/regressions
	- Mental retardation
	- GLOBAL CEREBRAL/CEREBELLAR ATROPHY
	- VENTRICULAR DILATATION
	- GLOBOID MACROPHAGES (histology)
SIMILAR TO METACHROMIC LEUKODYSTROPHY

None
Stem cell transplant if dx is early age

Supportive care until death (usually age 2)
Adult-onset disease progresses slower and has longer lifespan

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3
Q

Fabry

A

Fabry

X-linked recessive
- Affects males more severely

a-Galactosidase A

Ceramide trihexoside

Clinical presentation
Alpha-galactosidase activity

Varies based on age of onset
Diagnosis MUCH OLDER AGE
	- Fatigue
	- Hypertension
	- Cardiomyopathy
	- ACROPARASTHESIA: PAIN/PARASTHESIA in extremities
	- CORNEAL CLOUDING
	- RENAL FAILURE: ↑creatine
	- PROTEINURIA
	- ANGIOKERATOMA: painless papular rash

Enzyme replacement therapy with alpha-galactosidase (Farazyme)

Life expectancy in males: 58
Life expectancy in females: 75
Cardiac disease and renal disease contribute to premature death
Less severe in females (X-linked)

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4
Q

Gaucher’s

A

Gaucher’s

Autosomal recessive
- Ashkenazi Jews

B-Glucosidase
(B-Glucocerebrosidase)

Glucosylceramide (Glucocerebroside)

Hepatosplenomegaly
Osteoporosis of long bones (aseptic necrosis of femur)
	- Bone pain and weakness
Mental retardation in infants
CRUMPLED TISSUE appearance in histology
	- Due to lipid accumulation
NOSEBLEEDS
ANEMIA
  • ERT
  • Onset is usually in adults but can be young
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5
Q

Metachromic Leukodystrophy

A

Metachromatic Leukodystrophy

Autosomal recessive

Arylsulfatase A

Cerebroside Sulfate

Cognitive deterioration
Mental Retardation
DEMYELINATION of CNS and PNS
Ataxia
Seizures
Hyporeflexia
Dementia
Yellow-brown and violet staining of nerves
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6
Q

Pompe’s

A

Pompe’s

Autosomal recessive

a-1,4-Glucosidase (Acid Maltase)

Glycogen (in lysosome vacuoles)

Glycogen: normal structure; accumulated in lysosomal vacuoles
Cardiomegaly
LVH
Hepatomegaly
Hypotonia (weakness)
  • ERT
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7
Q

Hunter

A

Hunter

X-linked recessive
- Affects males more severely

Iduronate Sulfatase

Dermatan Sulfate
Heparan Sulfate

Oligosaccharides in urine

Mental retardation: mild to severe
Physical deformities:
	- COARSE FACIAL FEATURES
	- SHORT STATURE
NO CORNEAL CLOUDING
  • BMT
  • ERT
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8
Q

Hurler

A

Hurler

Autosomal recessive

a-L-Idurodinase

Dermatan Sulfate
Heparan Sulfate

Oligosaccharides in urine

Dysmorphic facial features
Mental retardation
SKELETAL ABNORMALITIES / Dwarfing
Upper airway obstruction
Hearing loss
Deposition in coronary artery --> ISCHEMIA + EARLY DEATH
YES CORNEAL CLOUDING
  • BMT
  • ERT
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9
Q

Glucose 6-Phosphate Dehydrogenase

Deficiency

A

G6PDH Deficiency:
- Most common genetic enzymopathy: 400 variants of G5PDH deficiency known
- X-linked recessive:
○ Males more affected than females
○ Homozygous mutation
- High hemolysis and anemia
○ Heterozygous mutation:
- Normally asymptomatic unless exposed to OXIDANT STRESS:
□ Primaquine: anti-malarial drug
□ Fava beans:
- HETEROZYGOUS ADVANTAGE:
○ Selected by Plasmodium faliparum malaria
○ Survivial benefit against malaria lethal infection

- NO NADPH produced
- Heinz Bodies:
	○ Met-Hb forms insoluble molecules within RBC
		§ Sulfhydryl groups within Hb will oxidize and crosslink with each other --> become very heavy --> precipitate in RBC --> small inclusions within the cell --> Heinz bodies
	○ 
- Hemolytic anemia
	○ Oxidant stress to RBC --> ↑H2O2 --> H2O2 accumulations --> membrane lyses
	○ Oxidant stresses:
		§ Infections
		§ Certain drugs
		§ Fava beans

Type II: Mediterranean type. more severe
Type III: African type. serious but not as severe

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10
Q

MCAD Deficiency

A
  • Autosomal Recessive
  • Presents in INFANCY
    Hypoketotic hypoglycemia
    Dicarboxylic acids (w-oxidation)
    Lactic Acidosis
    Hyperammonemia
    Muscle weakness
    ↑medium chain carboxylic acids
    ↑medium chain acyl carnitines
    LOW Carnitine in blood

Treatment:

  • Frequent feeding
  • Avoid fasting
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11
Q

CPT-I (Carnitine Palmitoyltransferase) Deficiency

A

Hypoketotic hypoglycemia
↑Carnitine in blood
LOW TO NO ACYLCARNITINES
↑FFA’s in blood

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12
Q

CPT-II (Carnitine Palmitoyltransferase) Deficiency

A

Hypoketotic hypoglycemia
Appears in older aged (not infant)
LOW Carnitine (low during attack in the muscle isozyme)
↑long chain acylcarnitines (C12-C16)
Rhabdomyolysis: b/c you don’t have B-oxidation to support muscle
Myoglobinuria

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13
Q

Carnitine Transporter Deficiency

A

Hypoketotic hypoglycemia
LOW CARNITINE (due to increased carnitine urinary loss)
LOW TO NO ACYLCARNITINES
↑FFA’s in blood

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14
Q

Tay-Sach’s

A

Tay-Sachs

Autosomal recessive
Jewish families of Eastern European descent

B-Hexosaminidase A

Gangliosides (GM2)

Assay: ↓B-hexosaminidase A in serum or leukocytes

Varies based on severity
Presents normal at birth --> progressive neurologic dysfunction
	- CHERRY RED MACULA
	- Seizures
	- Blindness / Loss of vision
	- Poor growth
	- Motor retardation
	- Muscular weakness
	- Ataxia
	- Mental retardation

None

Supportive care until death (usually age 3)

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15
Q

Von Gierke’s Disease

A

Type I GSD:
Deficient: Glucose-6-Phosphatase

Glycogen: Normal

Tissues Affected: Liver; Kidney

Severe hypoglycemia
Fasting lactic acidosis
Ketonemia
Hyperuricemia
Hyperlipidemia: ↑VLDL + skin xanthomas
Treatment: frequent feeding with slowly digested carbs
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16
Q

Pompe’s Disease

A

Type II GSD:
Deficiency: a-1,4-Glucosidase (Acid Maltase)

Glycogen: Glycogen accumulation in lysosome

Tissues Affected: HEART

Cardiomegaly
LVH
Hepatomegaly
Most patients die by age 2

17
Q

Cori’s Disease

A

Type III GSD:
Deficiency: a-1,6-Glucosidase (debranching)

Glycogen: Shorter branches (Impeded glycogenolysis)

Tissues Affected: Liver

Hepatomegaly
Hypoglycemia
Treatment: frequent feedings; high protein diet

18
Q

Anderson’s Disease

A

Type IV GSD
Deficiency: a-4,6-Glucosidase (branching)

Glycogen: No branches on glycogen. Long insoluble chains

Tissues Affected: Liver

Hepatomegaly
Cirrhosis
Usually failure to thrive
Early death

19
Q

McArdle’s Disease

A

Type V GSD
Deficiency: Glycogen Phosphorylase (muscle)

Glycogen. Normal. Glycogen accumulates (muscle)

Tissues Affected: Muscle

↓exercise tolerance (first 30 minutes)
NO LACTIC ACIDOSIS
Muscle cramps
Myoglobinuria
RESPONSIVE to oral glucose b/c glycolysis is still functioning
20
Q

Hers’ Disease

A

Type VI GSD
Deficiency: Glycogen Phosphorylase (liver)

Glycogen: Normal. Glycogen accumulates (liver)

Tissues Affected: Liver

Hepatomegaly
Fasting hypoglycemia
- Only during fasting because GNG is still intact
- Much milder hypoglycemia than G-6-Pase deficiency*

21
Q

Tarui’s Disease

A

Type VII GSD:
Deficiency: Muscle Phosphofructokinase (PFK)

Glycogen: Normal

Tissues Affected: Muscle

↓exercise tolerance
Myoglobinuria
Hemolytic anemia: b/c RBC’s dependent on glycolysis
UNRESPONSIVE to oral glucose b/c glycolysis is nonfunctional

22
Q

Essential Fructosuria

A

Deficiency: Fructokinase

Fructose accumulates in the urine
Benign, asymptomatic condition

23
Q

Hereditary Fructose Intolerance

A 
Deficiency: Aldolase B
HFI: Hereditary Fructose Intolerance
	- Absence of aldolase B:
	- Intracellular trapping  inorganic phosphate as F1P
	- Signs:
		○ Severe hypoglycemia
		○ Lactic acidosis 
		○ Vomiting
		○ Jaundice
		○ Hemorrhage
		○ Hepatomegaly
		○ Hyperuricemia
	- Therapy:
		○ Rapid detection and removal of fructose and sucrose from the diet
- HFI leads to Hypoglycemia + Lactic acidosis
	○ Absence of aldolase B
	○ Intracellular trapping of inorganic phosphate as F1P
	○ Glycogen degradation IS INHIBITED DUE TO LACK OF PHOSPHATE --> hypoglycemia
	○ GNG is INHIBITED due to lack of Aldolase B --> hypoglycemia Lactic acidosis develops due to lack of Aldolase B
24
Q

Non-Classical Galactosemia

A

Galactokinase Deficiency

  • Rare autosomal recessive disorder
  • ↑Galactose in the blood (galactosemia) + urine (galactosuria)causes galactitol accumulation if galactose is in the diet
  • CATARACTS: due to ↑galactitol
  • Treatment: dietary restriction
25
Q

Classical Galactosemia

A

GALT Deficiency
- Autosomal recessive disorder (1:30,000 births)
- Galactosemia, galactosuria, vomiting, diarrhea, jaundice
- Hyperuricemia
- Accumulation of Gal-1-P and Galactitol in nerve, lens, liver, kidney tissue
• Liver damage
• Severe mental retardation
• Cataracts
- Treatment: rapid diagnosis + removal of galactose (lactose) from diet

26
Q

Dihydropteridine Reductase Deficiency

A
  • Dihydropteridine Reductase:
    ○ Normally catalyzes: Dihydrobiopterin –> THB (Tetrahydrobiopterin)
    ○ THB is required cofactor for 3 major reactions
    1. Phenylalanine –> Tyrosine (hydroxyphenylalanine)
    1) Catalyzed by: Phenylalanine Hydroxylase
    2. Tyrosin –> DOPA (dihydroxyphenylalanine)
    1) Catalyzed by: Tyrosine Hydroxylase
    3. Tryptophan –> Serotonin
    1) Catalyzed by: Tryptophan Hydroxylase
    • Defect in Dihydropteridine Reductase will IMPAIR ALL 3 REACTIONS!!
27
Q

Lesch-Nyhan Syndrome

A

HGPRT Deficiency
X-linked recessive

HGPRT Deficiency

- Inability to salvage hypoxanthine or guanine
- ↓IMP and ↓GMP lead to ↑de novo purine synthesis
Neurological deficits:
	• Spasticity
	• Mental retardation
	• Aggression
	• Self-mutilation
- ↑PRPP
- ↑hypoxanthine
- ↑guanine
- ↑de novo purine biosynthesis (PRPP feed-forward)
- ↑uric acid buildup --> GOUT
-  ↓dopaminergic neurons  ↓dopamine
28
Q

SCID (1)

A

ADA Deficiency

  • ↑dATP (severe excess)
  • No cell division (neg feedback of dATP on RNR reductions)
  • Severe lack of B & T lymphocytes (combined immunodeficiency)
  • Predisposes patients to severe bacterial, viral, opportunistic infections early in life
  • Often fatal
  • Can be treated with BMT (bone marrow transplant) with or without gene therapy
  • Enzyme replacement Therapy
  • Prophylaxis: intravenous IgG
    • Used for the immunodeficiencies
29
Q

SCID (2)

A

PNP deficiency

  • T-cell deficiency (selective immunodeficiency)
  • Recurrent bacterial, viral, and opportunistic infections
  • Bone marrow transplant
30
Q

Orotic Aciduria

A
  • Orototate Phosphoribosyl Transferase deficiency or
  • Orotidylate Decarboxylase deficiency
  • Megaloblastic anemia
  • ↑Orotate in the urine
  • Supplement with CMP, UMP, URIDINE OR CYTIDINE
    • B9 or B12 supplementation will NOT be effective
31
Q

I-Cell Disease

A

○ Single gene defect in Phosphotransferase*
§ Affects ALL LYSOSOMES IN THE BODY*
○ Caused by deficiency of ability to phosphorylate mannose (marker for lysosomal residency)
○ Acid hydrolases are now instead secreted into extracellular media
○ Leads to substance build up in the lysosome and characteristic “inclusion cell” phenotype

- Skeletal abnormalities
- Restricted joint movement
- Coarse (dysmorphic) facial features
- Severe psychomotor impairment
- Death usually occurs by 6 years of age
- Diagnostic: Acide hydrolases in blood sample
	○ Acide hydrolases are normally only found in lysosomes
	○ In I-cell patients the enzymes are now instead found in high concentrations in the blood
32
Q

PKU (Phenylketonuria)

A
  • PKU can be due to mutation in Phenylalanine Hydroxylase
    • PKU can be due to mutation in Dihydrobiopterin Reductase
    • Phenylalanine (essential AA) is converted to Tyrosine
      • Normal pathway: Phenylalanine –[Phenylalanine Hydroxylase]–> Tyrosine –> Fumarate + Acetoacetate
        ○ THB (Tetrahydrobiopterin): COFACTOR for Phenylalanine Hydroxylase
33
Q

Blue Diaper Syndrome

A
  • Transporter protein problem
    • Blue Diaper Syndrome: failure to absorb Tryptophan in the Intestine
      ○ Tryptophan –> hydrolyzed by bacterial enzymes to form Indole (blue color)
34
Q

Cystinuria

A

○ Disorder of the kidney proximal tubules reabsorption of filtered cysteine and dibasic AA’s (Lysine, Ornithine, Arginine)
○ Inability to reabsorb cystine leads to accumulation and prcipitation of cystine STONES in urinary tract
○ KIDNEY STONES

35
Q

PCKD (Polycystic Kidney Disease)

A
  • Fluid filled sacs form in the kidney –> initiated in the neprhon then grow larger –> break off and continue to expand –> massive enlargement of the kidney
    • Leads to Kidney damage –> ↑urea in circulation –> ↑AMMONIA TOXICITY
    • ↑AMMONIA TOXICITY
    • Inability to reabsorb amino acids in the urine
36
Q

Parkinson’s Disesae

A
  • Degeneration of cells in the substantia nigra causes LOSS OF DOPAMINE
  • Patients are treated with L-DOPA to increase dopamine levels
  • Efficacy of L-DOPA treatment diminishes over time due to progressive loss of cells in the substantia nigra
37
Q

Mitochondrial HMG CoA Synthase Deficiency

Mitochondrial HMG CoA Lyase Deficiency

A 
Hypoketotic Hypoglycemia
NORMAL lactate
NORMAL ammonia
NORMAL carnitine
NORMAL ACYLCARNITINE
NORMAL FFA
These kids are normal; no developmental defect. But fasting or infection can initiate the disease

Digestive Systems, Nutrition, & Metabolism (3 decks)

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