Diseases Flashcards
Niemann-Pick
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)
Krabbe
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
Fabry
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)
Gaucher’s
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
Metachromic Leukodystrophy
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
Pompe’s
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
Hunter
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
Hurler
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
Glucose 6-Phosphate Dehydrogenase
Deficiency
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
MCAD Deficiency
- 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
CPT-I (Carnitine Palmitoyltransferase) Deficiency
Hypoketotic hypoglycemia
↑Carnitine in blood
LOW TO NO ACYLCARNITINES
↑FFA’s in blood
CPT-II (Carnitine Palmitoyltransferase) Deficiency
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
Carnitine Transporter Deficiency
Hypoketotic hypoglycemia
LOW CARNITINE (due to increased carnitine urinary loss)
LOW TO NO ACYLCARNITINES
↑FFA’s in blood
Tay-Sach’s
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)
Von Gierke’s Disease
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
Pompe’s Disease
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
Cori’s Disease
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
Anderson’s Disease
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
McArdle’s Disease
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
Hers’ Disease
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*
Tarui’s Disease
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
Essential Fructosuria
Deficiency: Fructokinase
Fructose accumulates in the urine
Benign, asymptomatic condition
Hereditary Fructose Intolerance
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
Non-Classical Galactosemia
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
Classical Galactosemia
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
Dihydropteridine Reductase Deficiency
- 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!!
Lesch-Nyhan Syndrome
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
SCID (1)
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
SCID (2)
PNP deficiency
- T-cell deficiency (selective immunodeficiency)
- Recurrent bacterial, viral, and opportunistic infections
- Bone marrow transplant
Orotic Aciduria
- 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
I-Cell Disease
○ 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
PKU (Phenylketonuria)
- 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
- Normal pathway: Phenylalanine –[Phenylalanine Hydroxylase]–> Tyrosine –> Fumarate + Acetoacetate
Blue Diaper Syndrome
- Transporter protein problem
- Blue Diaper Syndrome: failure to absorb Tryptophan in the Intestine
○ Tryptophan –> hydrolyzed by bacterial enzymes to form Indole (blue color)
- Blue Diaper Syndrome: failure to absorb Tryptophan in the Intestine
Cystinuria
○ 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
PCKD (Polycystic Kidney Disease)
- 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
Parkinson’s Disesae
- 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
Mitochondrial HMG CoA Synthase Deficiency
Mitochondrial HMG CoA Lyase Deficiency
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
