Imp

2.  Organic acidurias are an important class of
inherited metabolic disorders arising due to
defect in intermediary metabolic pathways of
carbohydrate, amino acids and fatty acid
oxidation with consequent accumulation of
abnormal (and usually toxic) organic acid
metabolites and increased excretion
of organic acids in urine.

3.  Neurological damage
 Developmental delay
 Symptoms ranging from poor feeding to
slow growth
 Lethargy
 Vomiting
 Dehydration
 Malnutrition
 Hypoglycemia

4.  Hypotonia
 Metabolic acidosis
 Ketoacidosis
 Hyperammonemia
 Hepatomegaly
 Respiratory distress
 Cardiac dysfunction
 If left untreated, death.

5.  structural disease e.g. brain tumors
 epilepsy.
 anoxic or hypoglycemic brain damage.
 degenerative changes e.g. Alzheimer's
dementia.
 brain trauma.

6.  In the normal degradation of many amino acids, the
intermediate metabolites are organic acids. Each
organic acid disorder is caused by a deficiency in a
specific enzyme necessary to this degradation
process. Mutations in the DNA sequences of the
enzymes in these pathways may lead to either
complete absence of a protein or reduced protein
activity, hence there is a wide spectrum of severity
for any given disorder.
 The organic acids accumulate in body fluids and
are excreted in the urine. Severe metabolic acidosis
can ensue.

7.  Most organic acidemias are inherited in
an Autosomal recessive fashion, though some
X-linked forms have been described.
 The affected neonate is usually normal at birth
and within the first days of life. The first clinical
findings result from the toxic encephalopathy
which usually arise as an acute attack within a
few weeks of life with symptoms such as poor
feeding, vomiting, Hypotonia and lethargy.

8.  In a milder form of the enzymatic deficiency,
the onset of acute episodic symptoms is
delayed and usually occurs within late
infancy or even later, with symptom free
intervals between attacks. Furthermore,
these disorders can present as a chronic
progressive form or even an asymptomatic
form. Patient prognosis can be much better
with early diagnosis and treatment.

9.  Numerous types of organic acidemias exist,
with Methylmalonic aciduria, Propionic acidemia
and Isovaleric acidemia among the most
prevalent forms. In aggregate, these diseases
are categorized into five groups:
 Branched chain organic acidemias
 Multiple carboxlase deficiencies
 Glutaric acidurias
 Fatty acid oxidation defects, and
 Disorders of energy metabolism.

10.  Methylmalonic acidemia is a disorder in which the
body cannot break down certain proteins and fats.
The result is a buildup of a substance called
Methylmalonic acid in the blood.
 Classic methylmalonic aciduria is caused
by mutations in the MCM gene (6p12–21.1) leading
to deficiency of the enzyme methylmalonyl-CoA
mutase (MCM, EC 5.4. 99.2), a defect in the
transport or synthesis of its cofactor, adenosyl-
cobalamin (cblA, cblB, cblC, cblF, cblD and cblX),
or a deficiency of the enzyme methylmalonyl-CoA
epimerase.

11.  whereas it can be alternatively caused by
defects in the biosynthesis of
adenosylcobalamin or by deficient cobalamin
transport.

12.  Propionic acidemia is caused by a defective
form of the enzyme propionyl-coenzyme A
(CoA) carboxylase, which results in the
accumulation of propionic acid. Propionyl-CoA
carboxyalse converts propionyl-CoA to
methylmalonyl-CoA.
 Metabolism of branched-chain amino acids,
odd-numbered fatty acids, cholesterol side
chains, thymine and uracil is impaired.

13.  Isovaleric acidemia (IVA) is a rare, but
potentially serious, inherited condition. It
means the body can't process the amino
acid leucine (amino acids are "building
blocks" of protein). This causes a harmful
build-up of the substance in the blood and
urine.

14.  Mutations in the IVD gene cause isovaleric
acidemia. The IVD gene provides
instructions for making an enzyme isovaleryl-
CoA dehydrogenase: that plays an essential
role in breaking down proteins from the diet.
Specifically, this enzyme helps process the
amino acid leucine, which is part of many
proteins.

15.  Maple syrup urine disease (MSUD) is a rare
genetic disorder characterized by deficiency of
an enzyme complex (branched-chain alpha-
keto acid dehydrogenase) that is required to
break down (metabolize) the three branched-
chain amino acids (BCAAs) leucine, isoleucine
and Valine, in the body. The result of this
metabolic failure is that all three BCAAs, along
with a number of their toxic byproducts,
(specifically their respective organic acids), all
accumulate abnormally.

16.  lactic acid.
 acetic acid.
 formic acid.
 citric acid.
 oxalic acid.
 uric acid.
 malic acid.
 tartaric acid.

19.  Here are some health problems that can
happen if metabolic acidosis is not
treated:
 Your kidney disease can get worsen.
 Bone loss (osteoporosis), which can lead to
a higher chance of fractures in important
bones like your hips or backbone.
 Muscle loss because of less protein in your
body.

20.  Blood acidity increases when people ingest substances
that contain or produce acid or when the lungs do not
expel enough carbon dioxide. People with metabolic
acidosis often have nausea, vomiting, and fatigue and may
breathe faster and deeper than normal.
 Extreme acidemia can also lead to neurological and
cardiac complications: Neurological: lethargy, stupor,
coma, seizures. Cardiac: Abnormal heart rhythms (e.g.,
ventricular tachycardia) and decreased response to
epinephrine, both leading to low blood pressure.

22.  Organic acidurias generally present with
hyperammonemia and high anion gap
metabolic acidosis.
 A diagnosis in the first 24–48 h is vital and
can prevent chronic sequel including
physical/mental retardation.

23. An acceptable normal range of ABG values of
ABG components are the following noting
that the range of normal values may vary
among laboratories and in different age
groups from neonates to geriatrics:
 pH (7.35-7.45)
 PaO2 (75-100 mmHg)
 PaCO2 (35-45 mmHg).

24.  Analysis of organic acids in urine is of
paramount importance for the diagnosis of
organic acidurias.
 More than 100 different organic acids are
excreted in urine in these conditions.
 Confirmatory diagnosis of organic acidurias
require expensive instruments like HPLC,
GC/MS or tandem mass spectrometry and
enzyme assays/DNA analysis.

25.  High-field proton NMR is a promising
technique for the diagnosis of OAD.
 Screening tests like DNPH test (Di nitro
phenyl hydrazine test) and thin layer
chromatography are also employed but they
do not confirm the diagnosis.

27. Metabolic acidosis from the OAs can be controlled by using
calories in the form of
 10% dextrose containing fluids
 Precursor-free amino acid mixtures
 Hemodialysis
 Hemofiltration
 ECMO (Extracorporeal membrane oxygenation) is a form
of life support used for babies, children and adults with life-
threatening heart and / or lung problems. ECMO provides
time for the body to rest and recover by doing the work of
the heart and lungs.

28.  Most of the common organic acidurias can
be effectively treated;
 Amino acid based formulas provide energy,
nitrogen, vitamins and minerals which can
promote anabolism and growth. Goal of
nutritional therapy is to provide all essential
nutrients to promote physical and mental
development.

29.  Synthetic amino acid based formulas should
provide approximately 50% of daily protein
requirement. At the same time, the offending
dietary precursor amino acid has to be
restricted.
 Fasting also has to be avoided.
 Secondary carnitine deficiency is common and
hence L-Carnitine (as well as biotin) is also
given.
 Metronidazole is given to reduce endogenous
gut propionate.

30.  Treatment of the acute case includes
 dialysis,
 correction of fluid and electrolyte imbalances
 correction of acidosis
 Maintenance of cerebral function with adequate
perfusion, oxygen and glucose as the case
demands.
 Selective detoxificants like glycine and carnitine
are given in some cases.

31.  Sometimes, patients with OAD present in a
critical condition, with eventual death. Even
when the treatment is not available, the
identification of OAD is important for the
genetic counseling and for making the pre-
natal diagnosis possible in a future gestation.

32.  https://pubmed.ncbi.nlm.nih.gov/?term=Vaidyanath
an%20K%5BAuthor%5D
 https://www.uptodate.com/contents/organic-
acidemias-an-overview-and-specific-
defects/contributors
 Shennar HK, Al-Asmar D, Kaddoura A, Al-Fahoum
S. Diagnosis and clinical features of organic
acidemias: A hospital-based study in a single center
in Damascus, Syria. Qatar Med J. 2015 Jul
4;2015(1):9. doi: 10.5339/qmj.2015.9. PMID:
26535177; PMCID: PMC4614323.

33.  https://www.ncbi.nlm.nih.gov/books/NBK1231/
 https://www.ncbi.nlm.nih.gov/books/NBK92946/
 https://rdcu.be/dc5ul
 Vockley J, Ensenauer R. Isovaleric acidemia: new aspects
of genetic and phenotypic heterogeneity. Am J Med Genet
C Semin Med Genet. 2006 May 15;142C(2):95-103. doi:
10.1002/ajmg.c.30089. PMID: 16602101; PMCID:
PMC2652706.

34.  Blackburn PR, Gass JM, Vairo FPE,
Farnham KM, Atwal HK, Macklin S, Klee
EW, Atwal PS. Maple syrup urine disease:
mechanisms and management. Appl Clin
Genet. 2017 Sep 6;10:57-66. doi:
10.2147/TACG.S125962. PMID: 28919799;
PMCID: PMC5593394.

35. THANK YOU
DEAR MADAM
MADIHA & CLASS
FELLOWS