Transcript Metabolic Disorders Case Histories

Case Histories
Case 1:
Positive Newborn Metabolic Screen
History:

NMS test result shows elevated Phenylalanine
(0.75 umole/l; normal <0.125)
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Term pregnancy
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Normal P/L/D
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BWt 3.1 kg,
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Normal neonatal course
Questions:
1.
Describe briefly what your initial counselling to parents
would be.
2.
What investigations would you under take to confirm
diagnosis?
Results of investigations
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Results
Plasma PHE=1.2umole/l;
tyrosine = 0.05 umole/l
Urine organic acids increased
PPA,PLA,PAA
1.
Questions
What other tests need
to be done to be sure
this baby needs diet
treatment?
2. What is the basis of
the diet treatment?
Metabolism of Phenylalanine
Dietary
Protein
Body
Protein
PHE
BH4
(PAH)
PPA
PLA
PAA
Tyrosine
qBH2
6-pyruvoylBH4
GTP
Phenylactetylglutamine
PHE levels in the Newborn with PKU
Screening Possible
P
H
E
NORMAL
RANGE
1
2
Days of Age
3
4
Untreated Phenylketonuria
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Signs / Symptoms
mental retardation
hypopigmentation
eczema-like rash
autistic-like behavior
autosomal recessive
high blood
phenylalanine levels
PKU: Diagnostic work-up
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Confirm that PHE level is elevated
Rule out biopterin deficiency disorders
Urine pterin levels
 Dihydrobiopterin reductase activity
 Biopterin load test (optional)
 If present start DOPA/carbiDOPA/5HTP
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If BH4 disorder not diagnsosed & PHE above
0.4 mM/l, start low PHE diet
Nutritional Treatment of PKU
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Diet has two components:
Medical Formula
Contains all nutrients
except those being
restricted
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+
Natural
Foods
Contains some
normal nutrients
and all those
being restricted
Must meet all nutritional needs + limit intake of
restricted nutrients to amts sufficient for growth
Case 2: Hepatomegaly with Abnormal
Liver Pathology
History:
 The pathologist in your hospital calls to discuss an
abnormal liver biopsy result
 8 month old boy with (R) abdominal mass extending
down into the iliac fossa
 Seen by Oncology re: ? Tumor; taken to OR for
open biopsy
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Question
 What do you see in the following
biopsy?
Case 2: patient & liver biopsy
Questions
1.
What types of disorders might cause this
appearance?
2.
What further historical information may be of
help?
3.
What further studies should you request from
the pathologist?
Questions
1.
What types of disorders might cause this appearance?
•
Glycogen storage disorders (types 1a & 1b, 3, 6 lysosmal
storage disorders (Gaucher, Niemann-Pick, MPS,
oligosaccharidoses, tyrosinemia, B-oxidation disorders
(MCAD, LCHAD, VLCAD)
2.
What further historical information may be of help?
•
Symptoms of hypoglycemia (relationship to fasting including
timing)
•
Mother indicates baby can only go about 2-4 hours without a
“bottle”
3.
What further studies should you request from the pathologist?
•
•
PAS staining +/- pretreatment with diastase
Electon microscopy
Diagnostic testing
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Fasting challenge +/- feeding challenges
Enzyme assays
Need fresh liver
 Need to choose specific enzymes to target based on
history
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Molecular testing
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Now have bank of mutations but expensive
GSD-II ( lysosomal)
GSD-IV
GSD-V,
GSD-VI,
GSD-IX
GSD-0
GSD-III
GSD-1a&b
GSD-VII
GSD-X,
GSD-XII,
GSD-XIII
GSD-XI
(LDH)
LIVER
MUSCLE
Glycogen Storage Disease IB
Controlled Fast
Time After Feed (min)
Glucose
(mM)
Lactate
(mM)
0
30
60
90
120
150
180
4.5
4.6
4.2 4.0
4.0
3.8
2.1
1.2
1.6
1.8 1.7
1.8
2.1
5.6
GSD IA &IB
Clinical features
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early onset hypoglycemia
lactic acidosis
hepatomegaly
Fanconi syndrome
hyperuricemia
hyperlipidemia
Diagnosis
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controlled fast (test BS &
LA)
enzyme (liver biopsy)
DNA testing
Therapy
provide 5 - 10 mg
glucose/kg/min
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continuous .nocturnal
infusion of CHO as polycose
or formula
frequent meals during days
corn starch days &/or nights
don’t over treat with CHO
Neutropenia in Type IB
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prophylactic antibiotics
GCSF
Emergency protocols for
illness, surgery etc.
Case 3:
18 month boy with hepatomegaly and obtundation
History:
 stuporous on admission
 found pale & sweaty and unarousable by parents
 Had been ill for about 18 hours with no significant intake
 Seizure in ambulance
Initial studies:
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Blood sugar = 0.2 mM/l, Na+=145, K+ =3.5, Cl- =104, TCO2 = 10
Urinalysis = Normal
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All other testing
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including lactate, NH4 & LFE’s normal
Key observations
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Severe hypoglycemia with hepatomegaly and no ketonuria
on setting of history of prolonged fasting
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Needs urgent treatment of hypoglycemia
 Route?
 How much glucose?
? Significance of no ketones in urine
?diagnostic testing
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VLCAD,MCAD, SCAD
Trifunctional
protein
Diagnostic Investigations
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Plasma acylcarnitnes suggest Medium Chain
Dehydrogenase deficiency (MCAD)
Plasma free carnitine levels low while
acylcarnitines high
14C- palmitic acid oxidation in leucocutes quite
reduced
Molecular diagnosis indicates homozygosity for
the common caucasian mutation.
MS/MS Analysis of plasma
acylcarnitines (?= MCAD)
100
INTERNAL STANDARDS
C8
% Intensity
C2
50
C10:1
C2
C16
C6
C8
C3
C3 C4
C10
C16
C18:1
C14:1
270
300
330
360
390
420
MS/MS PS 85
450
480
510
540
Phases of Glucose Homeostasis
1.Glucose absorptive phase: 3 - 4 hrs after glucose
ingestion (high insulin)
2.Post absorptive/early starvation: 3-12 hrs
glucose (from hepatic glycogen) to brain, RBC, renal
medulla
3. Early / Intermediate Starvation: 14+ hrs
gluconeogenesis & (later) lipolysis
Treatment
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Avoid fasting
L-carnitine if free carnitine low
Emergency protocol & letter
Sick day management
 Admission to ER/hospital to maintain blood
glucose with IV infusion to prevent excessive
lipolysis the would overload the B-oxidation
pathway
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Case 4: Neonatal Presentation
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5 d.o. male
Well for 72 hrs then became
lethargic, fed poorly, began
vomiting & developed alternating
flaccidity & opisthotonic posturing.
Became comatose
Developed hyperpnea and
respiratoy alkalosis progressing to
respiratory failure
O/E: hepatomegaly, hypothermia
Test Results
o
Normal: CBC, ‘lytes’, bld
glucose, lactic acid, urinalysis
o
o
o
o
not acidotic
not ketotic
not hypoglycemic
NH3 (350 umole/l)
? Differential Diagnosis
? Further testing
Case 4: Investigation Results
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5 d.o. male
Well for 72 hrs then became
lethargic, fed poorly, began
vomiting & developed alternating
flaccidity & opisthotonic posturing.
Became comatose
Developed hyperpnea and
respiratoy alkalosis progressing to
respiratory failure
O/E: hepatomegaly, hypothermia
Test Results
o
o
o
Normal: urine amino acids &
organic acids
Low: urea, arginine,
ornithine,
High: citrulline (1.21 mM)
glutamine (1.4 mM)
asparagine
? Probable Diagnosis
Detoxification of NH3 by Urea Cycle
Benzoate
Dietary Protein
Gut Bacteria
Endogenous Protein Catab
Buphenyl
NH4
PAA
NH4 + CO2
(CPS)
Carbamoyl Phosphate
GLN
GluA
PhAcGluNH2
(OTC)
Hippuric Acid
Ornithine
Citrulline
(Arginase)
MITOCHONDRION
Aspartate
(ASAS)
Urea
Arginine
Fumarate
(ASAL)
Argininosuccinic Acid
Approach To Differentiation of Urea Cycle
Disorders Causing Neonatal Hyperammonemia
Hyperammonemia
After 24 hrs
Before 24 hrs
Preterm
Fullterm
THAN
Metabolic acidosis
No
plasma citrulline
abs/tr
Yes
PDH PAA
GAII
>1000uM
MMA
100-300uM
etc.
uOA
etc.
low
Ur. Orotate
high
ASA
CPS
OTC
Citrullinemia
Approaches to Therapy of Urea Cycle Disorders
Acute Mgmt
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(based on NH3 level)
NPO
Dialysis ( prefer.
Hemodialysis)
IV: CHO (6–8 mg
Glc/kg/min)
Lipid (3 gm / kg)
Alternate Pathway
Therapy
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Oral (Phenylbutyrate + L-Arg)
IV (Phenylacetate + benzoate
+ L-arginine
Chronic Mgmt
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Low protein diet
–1.0 to 1.5 gm/kg/d
-Cyclinex (ess. AA’s)
(up to 50 % of
prot)
Phenylbutyrate (Buphenyl)
(450-650mg/kg/d)
Arg / ornith / citrulline
Regular monitoring
Case 5:
5 year old girl with hearing loss and macrocephaly
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Relatively normal global
development otherwise
Family history negative
& parents unrelated
S/S hepatomegaly, mild
contractures-hands,
knees & elbows
HM: Radiologicaal study
Case History: HM
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You were asked to see this girl for assessment
regarding macrocephaly and hearing loss
Initial investigations showed an abnormal urine
metabolic screen that positive for both CTAB &
Toluidine blue
All other initial metabolic studies normal
What would you do next?
“Coursened Features”
Laboratory Screening Paradigm
Yes
Course
facies
MPS
in urine
No
Uronic acid
MPS
Storage
Disease
MPS by TLC
Enzyme Assays
MLS II or III
Oligosaccharidoses
Total Hex
Oligo
screen
Enzyme Assays
How do you measure
mucopolysaccharide excretion?
Uronic acid
How is this testing
done?
GAG electrophoresis
What are the useful
GAGS in diagnosing
a particular MPS
disorder?
How do you measure
mucopolysaccharide excretion?
Uronic acid
A
B
Acid Hydrolysis to free
monosaccharide subunits
+
Colorimetric detection
of the uronic acid (A or B)
GAG electrophoresis
Additional testing
Urine MPS excretion
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Uronic acid by acid
hydrolysis /carbazole
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Uronic acid is 52 ug/ml
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(Normal < 16.7)
Other methods
GAG electrophoresis
( HM spec)
Diagnosis & Management
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Mucopolysaccharidosis Type III
 San Filippo syndrome
 Four different enzyme deficiencies all leading to
inadequate breakdown of heparin sulfate
 She had deficiency of heparin-N-sulfatase (MPS-IIIA)
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No definitive treatment at present
extensive social/psychological/educational support
 appropriate for child with neurodegenerative disorder
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Case 6:
Recurrent Abdominal Pain in 6 yo Male
History
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The mother of a six year old boy tells you that her son
has had three episodes of abdominal pain without any
flu-like symptoms or other systemic problems.
During the last episode, blood but no bacteria or “pus”
cells were seen in his urine. The urine did not smell,
look cloudy or have an unusual color.
Her husbands had had similar episodes as a child but
these had stopped once he followed the advice of a
pediatrician to ”drink lots of water” at nights.
Your initial investigations showed that this boy had a normal
physical exam, normal CBC. ‘lytes, urea & creatinine and
aside from microscopic hematuria, a normal microscopic &
chemical urinalysis
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What do you think is causing his abdominal pain &
microscopic hematuria?
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What genetic / metabolic disorders should you
consider in your differential diagnosis list?
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What specific testing would you suggest to investigate
these possibilities?
Differential Diagnostic List
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Cystinuria (basic aminoaciduria)
Partial HGPRTase deficiency (uricosuria)
GSD I (uricosuria)
Primary hyperoxaluria (oxalic aciduria +/- glycolic or
glyceric acid)
Idiop. Hypercalciuria (calcium oxalate or urate)
Hyperparathyroidism (calcium oxalate / urate)
Adenosine phosporibosyl transferase deficiency
(dihydroxyadenosinuria)
Results of Special Testing
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Unable to isolate characteristic stones in random urine
specimen
Urine oxalic acid, calcium, uric acid / creatinine ratio all
normal
urine oxypurine profile normal
cystine, lysine, ornithine & arginine but no other amino
acids elevated in urine
Plasma amino acid profile normal
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What is your Diagnosis?
Cystinuria
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disorder of basic amino acid
transport involving renal
tubule & GI mucosa
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Types I, II & III (newer
classification refers to type I
as classical & others as nonclassical)
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urolithiasis:poor solubility of
cystine when:
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Heterozygotes (type II) may
excrete Cyst. Lys & Orn +/arg but in reduced amts
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Renal immaturity (< 1 yr)
may cause “apparent”
cystinuria in Type III carrier
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urine concentrated (cystine>
1200 uM/l)
urine acidic
autosomal recessive
1: 7000
Dibasic Amino Aciduria
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Normal: Cystine filtered at glomerulus but over 98 %
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Common renal tubular reuptake mechanism for dibasic amino
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Nephrolithiasis: onset by 10 yrs (25-30 %) to 20 yrs (50-60 %)
reabsorbed in proximal renal tubule
acids (cystine,lysine, ornithine, arginine). All increased in urine but not blood
if transporter is deficient
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Cystine precipitates out in urine / renal filtrate at concentrations above
1200 uM/l
stones: hexagonal, golden-brown, grain size to staghorn size
 account for 1-3 % of all stones in adults (kids ?)
 Subtypes based on amt excretion of cys/lys/orn but not arg in
heterozygotes. Type III has similar defect in mucosal uptake
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Molecular Genetics
Locus 2: 19q13.1
Locus 1: 2p16.3-p21
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Type I cystinuria
rBAT protein
SLC3A1 gene
40+ mutations
Transmembrane protein
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Non-Type 1 cystinuria
Bo, +AT protein
SLC7A9 gene
30 + mutations
Complexes with rBAT
protein to form dibasic
amino acid transporter
Phenotype/Genotype Correlation
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Cystinuria I/I:
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Cystinuria III/III
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two fully recessive SLC3A1 mutations
no gut absorption
kidney - high risk for nephrolithiasis
two incompletely recessive SLC7A9 mutations
stones in adults
some gut absorption
Mixed types: I/III(A), I/III(B), II/II,
Treatment of Cystinuria
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dilution of urine:
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drink up to 4.0 liters fluid / day (1.75 - 2.0 l/m2/24 hr)
important to drink during the night time (water at bedside)
monitor urine cystine concentrations morning & evening
“alkalinization” of urine: NaHCO 3 ( 1.5 - 2.0 mEq/kg/24
hr)
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Medication: D-penicillamine, Thiola R (tiopronin)
Surgical: lithotripsy etc.