msud an autosmal recessive disease

1. Name:-Urvashi Mudgil
Roll no:-29
Biochemistry
seminar.
Maple Syrup Urine
Disease (MSUD)
Image: magazine.outlookindia.com.

2. INDEX
• What is MSUD?
• GENETIC INHERITANCE
• HISTORY
• What is BCKAD ?
• Function of BCKAD
• Types of MSUD
• Epidemiology
• Diagnosis
• Tests for MSUD & disadvantages
• Treatments & treatments to be manifest

3. WHAT IS MSUD ?
Maple Syrup Urine Disease(MSUD) is
an autosomal recessive disorder caused
by a deficiency of the branched chain
alpha keto acid dehydrogenase
complex(BCKDH).
The condition gets its name from the
distinctive sweet odor of affected
infants urine, particularly prior to
diagnosis & during time of acute
illness.
This Photo by
Unknown
Author is

4. Genetic inheritance of
MSUD
as an autosomal recessive disease.
Healthy baby
Healthy baby but carrier of
defective gene as recessive.
unhealthy baby with both chromosome carrying
defective gene.

5. History
•MSUDwasreportedin1954byJ.H.Menkes&hiscolleagues.
•Menkes—›family—>lost—>4infants—>attheageof3months.
↓
urinesmelledlikemaplesyruporburnt
sugar,hencegotitsnamed.
•previouslystatedasthedegenerativedisorderofneurosystem.
•1960→Dancisestablishedthatthemetabolicblockisduet0deficiency
ofenzymerequiredtometabolisetheBCAA.

6. What is BCKAD ?
. It is a multienzyme complex known as BRANCHED CHAIN
ALPHA KETO ACID DEHYDROGENASE
. 3 subunits comprise BCKAD multienzyme complex(contains
several copies of one or several enzyme packed into one
assembly.)
• E3→ Dihydrolipoamide dehydrogenase(DLD)
• E1→ BCKAD decarboxylase→E1 α
↓
E1 β
•E2 → Dihydrolipoamide Branched Chain
Transacylase (DBT)
↓regulatory subunit
*BCKAD Kinase *BCKAD phosphatase

7. BCKADC is located
within the matrix
This Photo by
Unknown Author is
licensed under CC BY
of
Cellular location !

8. cytogenetic & molecular
location
This Photo by Unknown Author is licensed under CC BY-
SA

9. Function of BCKAD
Branched chain amino acid
transaminase
α-ketoglutarate
Glutamate
Transamination
Branched chain α-
keto acid
dehydrogenase
NAD+ HS-CoA
NADH
+ CO2
Oxidative
carboxylation
Alpha-
ketoisocaproic acid
(KICA)
Alpha-
ketoisovalerate
(KIV)
Alpha –keto-beta-
mtehylvalerate
(KMV)
Keto acids
E2
Dihydrolipoyl
acyltransferase
E3
dihydrolipoamide
dehydrogenase
E1alpha &
E2 beta
Isovalyryl-
CoA
Isobutyrul-
CoA
Alpha –
Methylbutyryl
-CoA
Acetyl CoA

10. Leucine
H3C–C=CH-C-S-CoA
Acetyl- CoA
CH3-C-SCoA
||
O
ˉOOC-CH2-C-CH3
||
O
Acetoacetate
CH3
ˉOOC-CH2-C=CH-C-S-CoA
CH3
H2O
ˉOOC-CH2-C-CH2-C-SCoA
CH3
OH O
β- Methylcrotonyl -CoA β- Methylglutaconyl-CoA
β-Hydroxy-β-methylglutaryl-CoA
Isovalyryl -
CoA
Acyl-CoA
dehydrogenase
Dehydrogenation
ETF:FAD
ETF:FADH2
Q
QH2

11. Valine
CH2=C-C-S-CoA
|
CH3
||
O
H2O
CH2-CH-C-S-CoA
|
0H
|
CH3
||
O
H2O
CoASH
CH2-CH-C-Oˉ
|
OH
NAD+
NADH
HC-CH-COOˉ
Methylacryl-CoA
β-Hydrocybutyryl-CoA β-Hydroxyisobutyrate
Methylmalonate semialdehyde
NAD+ ,
CoASH
NADH, CO2
CH3-CH2-C-S-CoA
Propionyl-CoA
ˉOOC-CH2-CH2-C-S-CoA
Succinyl-CoA
Isobutyrul-CoA
Acyl-CoA
dehydrogenase

12. Isoleucine
CH3-CH=C-C-S-CoA
Tiglyl -CoA H2O
α-Methyl-β-hydroxybutyryl-
CoA
CH3-CH-CH-C-S-CoA
CH3-C-CH-C-S-CoA
α-Methylacetoacetyl-CoA
CoASH
Alpha –
Methylbutyryl -
CoA
Acyl-CoA
dehydrogenase

13. This Photo by
Unknown Author is
licensed under CC
BY-NC
1-Protein synthesis
2-Gluconeogenesis
3-Fatty acid synthesis
4-Cholesterol synthesis
5-Cellular signaling
Importance
of catabolism
of these
amino acids
IN BRAIN
BCKAD metabolise BCAA
to facilitate cerebral
GABA & glutamate
synthesis
In liver & kidney catabolism of
10% to 15% BCAA occur
Transamination & oxidation of
BCAA mostly occur in skeletal
muscles
This Photo by Unknown Author is
licensed under CC BY
This Photo by Unknown Author is
licensed under CC BY-NC-ND

14. Leucine Valine Isoleucine
Branched chain amino acid transaminase
Alpha-keto acids
Branched chain alpha-keto acid
dehydrogenase
Acetyl CoA
E1 APLHA
& E2 BETA
E3
E2

15. Absence of BCKAD effect…..
Leu
Leu
KICA
KICA
KICA
Blood osmolarity
effect
This Photo by Unknown Author is
licensed under CC BY
Myelin sheath
synthesis effects
Absence of other
amino acids occur
isoleu
isoleu
isoleu
This Photo by Unknown Author
is licensed under CC BY-NC-ND
Learning disability
and memory loss
This Photo by Unknown
Author is licensed under
CC BY-SA
Maple syrup odor in
urine
BAN
THIS!!!
Poor feeding
Leu
val
val
val

16. This Photo by Unknown Author is licensed under CC BY-NC
TYPES of MSUD

18. AGE OF
ONESET
GENES
BCKAD
SUBUNIT
BIOCHEMICAL
FEATURES
CLINICAL
FEATURES
VARIABLE VARIABLE
BCKDHA,
BCKDHB, DBT
E1 ALPHA, E1 BETA,
E2
Similar to classic but are
less severe
Normal BCAA when well, but
similar to classic when ill.
NEONATAL PERIOD: maple syrup odor
in urine and cerumen.
OLDER: feeding problem, poor growth,
developmental delay
Normal growth & neurological
development.
In stress situations, may present with
encephalopathy.
BCKDHA,
BCKDHB, DBT
E1 ALPHA, E1 BETA,
E2

19. AGE OF
ONESET
GENES
BCKAD
SUBUNIT
BIOCHEMICAL
FEATURES
CLINICAL
FEATURES
VARIABLE
DBT
E2
Improvement of leucine tolerance
& levels of BCAAs when on
thiamine supplementation
NEONATAL PERIOD: maple syrup odor in urine
and cerumen.
OLDER: feeding problem, poor growth,
developmental delay
VARIABLE
DLD
E3
Normal BCAA when well,
but similar to classic when
ill.
early-onset neurologic manifestations to adult-onset isolated liver
disease. The most frequent is the severe form characterized by
metabolic acidosis, encephalopathy, feeding difficulties, liver
failure, and early death. Besides the biochemical hallmarks of
MSUD, patients have increased levels of lactate, alanine, and α-
ketoglutarate, which are related to mitochondrial dysfunction.

20. Epidemiology
This Photo by Unknown Author is licensed
under CC BY-SA
Portuguese gypsies population
1 case in 71 births
This Photo by Unknown Author is licensed under
CC BY-SA Mennonites population
1 case in 380 births
This Photo by Unknown Author is licensed under CC
BY-SA
Ashkenazia Jewishpopulation
1 case in 26000 births
World wide cases are 1
in 1,85,000

21. This Photo by Unknown Author is licensed under CC BY-SA
cases are 59 out of 113 which is quite
high
Reasons: high birth rate
IN INDIA

22. New born screening test
NBS manifests for the test which identifies babies
at risk of having rare, but serious medical
conditions that can affect normal development.
Baby Shield Newborn Screening combines
biochemical testing of 100+ metabolic & genetic
conditions with confirmatory genetic testing
for screen-positive results.
Test time:
It is performed btw 24 hour to 48 hours after birth.
Because certain condition go undetectable if the blood sample is
drawn before 24hour of age.
AIM:
To manifest the metabolic disorders which may leads to
death of baby, and to allowing him to lead a healthy and
normal life.
Approach of test:
Few drop of bloods are collected on a special filter paper
by pricking the heel of the baby & is sent to laboratory

23. 1.Bacterial inhibition assay: for
leucine on dried blood spots
was introduced.
This Photo by Unknown Author is licensed under CC BY-SA
2. Quantitative plasma acid
profiling by MS
If elevation detected then additional studies
including urine organic acid analysis by gas
chromatography –MS will done
This Photo by Unknown Author is licensed under CC BY-SA

24. Disadvantage of NBS
The milder variant
forms are often
missed by NBS due
to the normal
leucine levels in the
new born period
Disadvantage of MS
Cannot distinguish
isobaric amino acids
including leucine,
isoleucine, alloleucine
& hydroxyproline
So, the positive cases require 2nd
tier testing as LC- MS

25. 1ST GOAL: to manage the diet by reducing BCAAs & provide
adequate macronutrients to prevent catabolism & help
maintain plasma BCAAs within the range of targeted
treatment ranges.
If the new born
is positive then
the dietary
management.
Leucine
(mg/kg)
Isoleucine
(mg/Kg)
Valine
(mg/Kg)
Protein
(g/kg body wt.)
0-6months
7-12 months
1-3yrs
4-8yrs
9-13yrs
14-18yrs
19above
40-100
40-75
40-70
35-65
30-60
15-50
15-50
15-50
30-90
30-70
20-70
20-30
20-30
10-30
10-30
40-95
30-80
30-70
30-50
25-40
15-30
15-30
2.5-3.0
1.5-2.5
1.3-2.0
1.2-1.8
1.2-1.8
1.1-1.7
1.1-1.7
age

26. Acute metabolic
management
1. Stop protein intake for 24 to 74 hours.
2. Provide hydration & calorific support.
3. Correct any metabolic abnormalities.
4. Eliminate toxic metabolites.
5. Address the underlying causes of the metabolic crises Acute
dietary treatment needs to be aggressive and include
sufficient energy (up to 150% of the normal energy
consumption), based on BCAA-free formula and fluid
administration (up to 150 mL/kg).In cases where
gastrointestinal delivery is not tolerated, BCAA-free
formulations exist (Coram Specialty Infusion Services)
This Photo by Unknown Author is licensed under CC BY-NC-ND

27. This Photo by Unknown Author is licensed under CC BY-SA
Pregnancy and
lactation

28. Treatment options to
manifest

29. •Frazier DM, Allgeier C, Homer C, Marriage BJ, Ogata B, Rohr F, Splett PL, Stembridge A, Singh RH.
Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach.
Available online. 2014. Accessed 4-14-20. [PubMed]
•Strauss KA, Carson VJ, Soltys K, Young ME, Bowser LE, Puffenberger EG, Brigatti KW, Williams KB,
Robinson DL, Hendrickson C, Beiler K, Taylor CM, Haas-Givler B, Chopko S, Hailey J, Muelly ER, Shellmer
DA, Radcliff Z, Rodrigues A, Loeven K, Heaps AD, Mazariegos GV, Morton DH. Branched-chain α-ketoacid
dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes. Available online.
2020. Accessed 4-14-20. [PubMed]
•Strauss KA, Wardley B, Robinson D, Hendrickson C, Rider NL, Puffenberger EG, Shellmer D, Moser AB,
Morton DH. Classical maple syrup urine disease and brain development: principles of management and formula
design. Mol Genet Metab. 99:333-45. Available online. 2010. Accessed 4-21-20. [PMC free article] [PubMed]
•Books –Voet & Voet , Moran, Horton
This Photo by Unknown Author is licensed under CC BY-NC