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METABOLIC DISEASES

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mona magdi

on 19 June 2014

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Transcript of METABOLIC DISEASES

BASIC METABOLISM
* Fat Oxidation Disorders:
- FA:
1. NOT metabolized by brain (depends on live B-oxidation --> ketones)
2. best source of energy for the heart

- FAO disorders:
Muscle / heart /liver

Approach to a metabolic case
Disorders of AA metabolism
*Organic Acidemias
* Urea Cycle Defects:
METABOLIC DISEASES
Thank you!
1. CHO metabolism
- Glucose:
1. Energy
2. Glycogen
3. AA and TG

- oxidation --> ATP

- Fructose/Galactose/Lactose -->
Glucose --> metabolism
Introduction
Glycolysis
- 1 Glucose --> 2 pyruvate

- Aerobic:
TCA cycle & oxidative phosphorylation

- Anerobic:
Lactate

- Glycosis in:
RBCs & Muscles during exercise

- provide intermediates

- The THREE enzymes
steps --> irreversible
Pyruvate metabolism
Pyruvate:
+ Pyruvate carboxylase
--> oxaloacetate
--> enter the TCA cycle
+ pyruvate
dehydrogenase
--> acetyl-CoA
--> 1. TCA cycle
2. FA synthesis
3. Ketone bodies synthesis
4. steroid synthesis
TCA cycle
- in cells WITH mitochondria (not RBCs)

- gives the final common pathway of metabolism of AA, glucose and FA

- Function:
provides reduced cofactors (NADH, FADH2) --> donate electrons to the respiratory chain
Glycogen metabolism
- branched glucose

- in liver , muscles and kidneys

- liver --> all the body
muscles --> only muscles
Glycogen synthesis
- ++ by insulin
Glycogenolysis
- ++ by adrenaline and glucagon
- N.B.:
* Elongation:
α-1,4 glycosidic bond

* Branch formation:
α-1,6 glycosidic bond
Protein Metabolism
- continuous protein turn-over (formed --> broke down --> reformed)

- Proteins are NOT stored-> Ptn intake is essential for good health

- AA :
1. amino group --> ammonia --> urea
2. carbon skeleton --> acetyl Coa / Pyruvate / ketone bodies
Gluconeogenesis
- ++ Glucagon, cortisol, ACTH

- occurs in liver (if prolonged starvation --> kidney)
Fat metabolism
- Fat has the highest caloric value

- TG = 3 FA + 1 Glycerol
--> Lipolysis (lipase) -->

1. Glycerol --in liver--> Glyceraldehyde-3-PO4 (glycolysis& gluconeogenesis)

2. FA -->


* N.B.:
- Essential FA --> NOT formed in body (no enzyme to form double bond if > 9 carbons) --> SO, they must be eaten

- They are:
1. Linolein (C 18:2)
2. α-linolenic (C 18:3)

- Walnut oil --> rich source
1. Inheritance
- RARE 1:800 births

- Commonly: AR
--> Except:
AD
1. Porphyrias (some are recessive)

2. Familial
hypercholesterolemia
XR
1. Lesch-Nyhan $

2. Hunter $

3. Ornithine Transcarbamylase (ORT) deficency

4. Fabry disease

5. Adrenoleukodystrophy
Matrilineal
- mitochondrial DNA point mutations
2. Presentation
- unspecific (mostly misdiagnosed as sepsis) --> look for clues in the history:
* Clues in the History:
1. Consanguinity
2. H/O of infant death (sp. >6mo)
3. Ethnicity
4. multiple miscarriages
5. maternal illness in pregnancy
6. Faddy eating
7. H/O of encephalopathies/ tachypnea (--> acidosis)
1. ++ fetal movements:
--> seizures

2.
Acute fatty liver of pregnancy (AFLP)

AND
Hemolysis, Elevated Liver enzymes, Low Platelets (HELLP) $
:
--> ++ Long chain fat oxidation defect
- at time of metabolic stress:
1. Neonatal period

2. Weaning

3. End of first year ( -- growth rate -> ++ ptn catabolism -> defects appear)

4. Intercurrent infections

5. Puberty
* Neonatal Presentations *
1. Failure to make/break complex molecules
- To make:
Dysmorphic - at birth (lack of molecules for embryogenesis)
- Ex.:

1. Smith-Lemli-Opitz $ --> cholesterol synthesis
2. Zellweger $ --> peroxisomal
3. congenital disorders of glycosilation --> glycosilation
- To break:
normal at birth - abnormal with accumulation
2. Intoxication
-
Key feature
:
Symptom-free period --> toxic material accumulate --> collapse
-
Typical
--> day 3 in life (no feeding by placenta)
-
DD:
duct dependent heart problems/ sepsis
- Aminoacidopathies:
1. tyrosinemia
2. Maple syrup urine disease (MSUD)
-
Urea cycle defects
(UCDs)
-
Organic acidemias
(OAs)
-
Sugar intolerances
: --> ex. galactosemia
3. Energy insufficency
- NO symptom-free period
- Immediate onset congenital lactic acidosis
- Respiratory chain defects
- Pyruvate metabolism defects:
1. pyruvate dehydrogenase
2. pyruvate carboxylase
- OR: diseases that present due to a delay in "fuel" provision
- can delay for months to present:
- Ex.:

1. Fat oxidation defects:
- medium-chain acyl-CoA dehydrogenase (MCAD)
- Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD)
- Very-long-chain hydroxyacyl-CoA dehydrogenase (VLCHAD)
2. Glycogen storage disease (GSD) types I and III
3. Defects in gluconeogenesis:
fructose biphosphatase deficiency
4. Neonatal Seizures
- SUSPECT IF:
In utero seizures

OR

early onset seizures (in absence of birth asphyxia
EFFECTIVE TTT
1. Pyridoxine-dependent seizures

2. Pyridoxal phosphate-dependent seizures

3. Biotinidase deficiency

4. GLUT1 (glucose transporter type 1) deficiency

5. Creatine disorders
No Effective TTT
- Molybdenum cofactor deficiency

- Non-ketotic hyperglycinaemia (NKH)

- Peroxisomal disorders
3. Examination
- Dysmorphic features
- odors --> unhelpful, except:
- Eyes -->
- Organomegaly -->
- MSUD:
--> SWEET odor of the napies

- isovaleric acidemia
:
--> SWEATY odor
- Corneal clouding:
1. mucopolysaccharidosis
2. cystinosis

- Cataracts:
1. Galactosemia
2. Peroxisomal
3. mitochondrial

- pigmentary retinopathy:
1. fat oxidation
2. mitochondrial

- Cherry-red spot:
1. Tay-Sachs disease
2. Niemann-Pick disease
3. Sandhoff disease
4. gangliosidosis Gm1
-
HSM:
storage disorder

-
Hepatomegaly ONLY:
Glycogen storage disease

-
Splenomegaly > hepatomegaly:
Gaucher's disease
4. Investigations
* at time of decompensation (to avoid stress tests)
* Key initial metabolic investigations:
-Ex.:
blood gas / ketones (urine dipstiks) / Organic acids (urine) / ..
* Perimortem investigations:
- Take samples from a patient at extremities --> protect reproductive future
- Blood:
1. RBCs --> refrigerate at 4*C
2. Plasma --> freeze -20*C
3. Acylcarnithine --> 4 spots on a Guthrie card
4. DNA --> EDTA sample

- Urine:
--> freeze -20*C

- Skin biopsy:
--> if NO culture media: do NOT freeze
put in 0.9% saline in 4*C in the fridge for 2 days

- Muscle/liver biopsy:
--> only if suspected related disease
freeze after < 1 h of death (no autolysis)
* Acid - Base status:
Anion Gap = Na + K - (Cl + HCO3)
Normally = 10-18 mmol/l
NORMAL anion gap + metabolic acidosis -->
HCO3 loss
> ++ acid

So, it's renal or gut
NORMAL pH + LOW pCO2
(<4.5 kPa) -->

significant acid - base disturbance
Marked KETOSIS in a NEWBORN

--> Mostly
metabolic disease
(uncommon in normal babies)
Urea Cycle defect

--> may present with MILD respiratory alkalosis
*
Ammonia
acts directly on the brain (respiratory stimulant) *
* Characters of metabolic and respiratory acidosis and alkalosis *
Metabolic Acidosis Metabolic Alkalosis Respiratory Acidosis Respiratory Alkalosis
low pH, low CO2

1. ++ acids load:
ex. Hypotension (lactate), DKA,..

2. -- acids excretion:
ex. DISTAL Renal
Tubular Acidosis

3. ++ HCO3 loss:
ex. PROXIMAL Renal
Tubular Acidosis
high pH, high CO2


1. ++ alkali load:
ex. Poisonning



2. -- unbuffered acids:
ex. pyloric stenosis, Cl losing diarrhea, diuretics


low pH, high CO2


HYPOVENTILATION

ex.:
encephalopathy, pneumonia, kyphoscoliosis
high pH, low CO2


HYPERVENTILATION

ex.:
++ ammonia, mechanical ventilation



* Metabolic Acidosis *
Key invs.:
1. Ketones
2. Glucose
3. Lactate
4. Ammonia


-


* Metabolic acidosis WITH ketosis:

- Diabetes
- Organic acidemias
- Ketolysis defects
- Mitochondrial disorders
- Gluconeogenesis defects
- Adrenal insufficency
* Metabolic acidosis WITHOUT ketosis:

- Fat oxidation defect
- Pyruvate dehydrogenase deficiency
- Ketone synthesis defect
- Renal tubular acidosis
Hypoglycemia
blood glucose < or = 2.6 mmol/l
Screen
- glucose/ insulin / C-peptide/ cortisol/ ketones/ ...
Key Additional Investigation
KETOSIS
-->Hypoketotic hypoglycemia:
1. Hyperinsulinism
2. Fat oxidation defects
3. LF
4. mitochondrial disorders
Hyperinsulinism
++ glucose demand > 10 mg/kg/min
glucose requirements (mg/kg/min) = (ml/h * %dextrose)/(6*weight in kg)
Clue by Fasting Tolerance:
- < 1 h --> hyperinsulinism

- <4-6 h --> glycogen storage disease

- 10 - 20 h --> gluconeogenesis defects

- 15-24 h --> Fat oxidation defects/ ketone synthesis
and ketolysis defects
Lactate
* 1ry cause:

--> metabolic
(+ ketosis)


* 2ry causes:
(commoner)

shock / sepsis / hypoxia / LF
(+
ketosis ONLY in
:
1. Pyruvate dehydrogenase deficency
2. GSD type I
3. Fat oxidation defects

Lactate level
&
lactate:pyruvate ratio
--> NOT important
(low ratio < 10 maybe pyruvate dehydrogenase deficency)

*
Exacerbation in fasting
:
1. gluconeogenesis defect
2. GSD I > GSD III
3. respiratory chain disorders (++ lactate postprandially)
*CSF lactate:
++ in:

1. mitochondrial diseases
2. CNS sepsis
3. seizures
- in decompensated fructose biphosphatase deficency:
treat hypoglycemia --> RAPID resolving of the raised lactate level
Ammonia
hyperammonia may be delayed / squeezed sample
Transient Hyperammonia of the Newborn (THAN)
- Very early onset (in 1st 36 hours)

- + low glutamine

- Excellent prognosis if treated early ( hyperammonia is 2ry to bypassing the liver NOT a block in urea cycle)

Amino Acids
- in Blood and Urine


--> in blood:

1. MSUD --> ++ leucine, isoleucine and valine

2. UCDs --> ++ glutamine, -- arginine

3. Lactic acidosis --> ++ alanine

4. NKH / OAs --> ++ glycine

5. Phenylketonuria --> ++ Phenylalanine

6. Tyrosinemia --> ++ tyrosine
* urine AA:
- reflect renal threshold:
1. generalized AAuria --> proximal renal tubulopathy

2. specific transporter defect of cystinuria (
c
ystine,
o
rnithine,
a
rginine,
l
ysine)
* N.B.:
- an increase in serum single AA can be missed if you only check the urine AA, specially if the renal threshold has not yet been reached
Organic Acids
- measure only in urine

- specific diagnosis:
1. ++ Orotic A:
- UCDs
- mitochondrial
- benign hereditary orotic aciduria

2. ++ methylmalonate:
- Vit. B12 deficiency
- disorders methylmalonic aciduria

3. ++ succinylacetone:
- tyrosinemia type I

4. ++ dicarboxylic acids:
- fat oxidation defects
- medium chain TG3 feeds
- mitochondrial
Acylcarnitines
- in
Fat Oxidation defects
:
Carnitine + acyl-CoA
* length of acylcarnitine --> determines site of the block

- in
Organic Acidemias
:
Carnitine + AA
ex. propionylcarnitine

Total and free carnitine levels:
- Very Low: carnitine transporter defect

- low: fat oxidation AND organic acidemias

- High: carnitine palmitoyltransferase deficiency 1
(CPT1)
Urate
- end product of Purines metabolism

-
ALWAYS measure urine AND plasma levels:
* very efficient urate clearance --> high normal plasma urate and very high urine urate in
Lesch-Nyhan $

* opposite in
FJHN

- -- plasma urate in molybdenum cofactor deficency
- ++ because:

1. ++ production:
a. Lesch - Nyhan $
b. GSD type I
c. Rhabdomyolysis

2. -- excretion:
- Familial Juvenile Hyperuricaemic Nephropathy (FJHN)
Acute patient screening
Specific Metabolite Screen
* 2ry investigations:
- Neuroimaging (ex. leukodystrophies)

- Neurophysiology

- Echo (sp. Hypertrophic CMO/ Pompe’s disease)

- ECG

- EEG (ex. MSUD)

Enzymology
* Sample? which tissue has the enzyme:
1. Blood --> galactosemia
2. Liver --> OTC deficiency
3. Muscle -> Mitochondrial disease

* sometimes, genotype > invasive biopsy (ex. GSD type I)


* WBCs enzymes in patient with potential:
A. Neurodegenerative disease:
1. Tay-Sachs
2. Sandhoff
3. Sly mucopolysaccharidosis (MPS VII)
4. Mannosidosis in plasma
5. Gm1 gangliosidosis
6. Arylsulphatase A deficiency
7. Krabbe
8. Frucosidosis in white cells
B. Storage diseases

* Organomegaly Diseases:
1. Sly mucopolysaccharidosis (MPS VII)
2. Mannosidosis in plasma
3. Gm1 gangliosidosis
4. Niemann-Pick A and B
5. mannosidosis in white cells
6. fucosidosis in white cells
7. Wolman in white cells
Developmental delay
- done to little cases 1-3%
- important --> prevents further decompensation

Clues From History
1. Pregnancy: maternal health
2. F/H: consanguinity
3. Past Ho: unexplained hypoglycemia / self injuries / ..
4. TYPE of delay: Regression / Hypotonia / Speech
Metabolic Screen for Developmental Delay
- Ammonia
- Urate
- Lactate
- AA
- OAs (urine)
- GAGs and Oligosaccharides (urine


Specific clues --> specific tests
5. Acute Management
1. STOP feeds

2. Promote anabolism:
- 10% dextrose + electrolytes--> if hyperglycemic: give insulin (don't -- % of dextrose)
- 5% dextrose if with 1ry lactic acidosis

3. Correct biochemical disturbance

4. Clear toxic metabolites:
dialysis / drugs

5. give enzyme cofactors
* if intermediary metabolism:

- STOP feeds in infections to -- metabolic load

- substitute with glucose polymer drinks to -- catabolism

- if failed --> admission for IV drugs
* Pitfalls in management:
1. Polonged cessation of feeds:
- ++ catabolism
- stop for max 48-72 h, then restart 0.5 g/kg/d

2. Hypotonic fluids:
- hyponatremic seizures
- add Na and K to dextrose

3. Post-acidosis correction hypokalemia:
- monitor K in correction
6. Long term management
* Genetic Counselling:

- Recurrence risk
- available prenatal testing and "preimplantation genetic diagnosis" PGD
- screen siblings
1. Phenylketonuria
- Commonest inborn error of metabolism
- 1 : 10000 , carrier rate 1:50
- 1-2% are because -- of Biopterin (essential cofactor for PAH)

- Clinical features:
1. Untreated (phenylalanine > 1000 umol/l):
- developmental delay in 1st year
- learning disability
- behavioural pbms
- -- pigmentations
- dry skin
2. Treated:
- Asymptomatic
- IQ < with 10 points than other sibling

* Diagnosis:
- ++ Phenylalanine (newborn screen)

- check for Biopterin defect
* Management:
1. Phenylalanine restriction:
--> monitor

2. AA supplement
--> NO phenylalanine

3. Special PKU products
--> minimsl or NO phenylalanine

4. Free foods

5. Neurotransmitter replacement in Biopterin defects
* Phenylalanine is an
ESSENTIAL AA
--> can't be totally excluded from diet

* Ppl with mild elevation of phenylalanine OR with hyperphenylalaninemia -->
ONLY monitor

* Phenylalanine is
TERATOGENIC
--> A girl with PKU MUST follow a STRICT diet preconception and during pregnancy
2. Tyrosinemia (type 1)
* Clinically:
- Early:
Liver disease + coagulopathy and proximal renal tubulopathy

- Late:
faltering growth + rickets (Due to Fanconi $)

- HCC late childhood
* Diagnosis
- ++ Tyrosine

- OAs:
++
succinylacetone
(PATHOGNOMONIC)

- ++ INR

- Liver enzymology (fumarylacetoacetase)

- Genotype
* Management
- Restricted Tyrosine

- AAs supplements (NO phenylalanine OR tyrosine)

-
Nitisinone
blocks catabolic pathway proximal to damaging metabolites

- Liver transplantation:
1. No response to Nitisinone
2. Tumour
(monitor with MRI & alpha fetoprotein)
3. MSUD
- Block of branched chain AA metabolism (Leucine / isoleucine / valine)

* Clinically:
- Encephalopathy
- seizures
-
SWEET ODOR
(mainly nappy)

* biochemical signs (Ex. ketosis) may be minimal --> we think it's sepsis

* Intermittent forms appear later, completely normal in between

* Cerebral edema --> complication in acute stage
* Diagnosis:
- ++ branched-chain AA
- ++ branched-chain oxo-Acids
( in urinary OAs)
- enzymology in fibroblasts
* Management:
- Low ptn diet

- branched-chain AA free supplements

- + Valine and isoleucine supplements (may -- to too low when controlling leucine)

- Trial of thiamine (Enzyme cofactor)
4. Homocystinuria
- commonest defect: cystathione-b-synthase deficiency
* Clinically:
- Marfan like

-
RESTRICTED JOINT MOVEMENTS

- Ectopia lentis (
DOWNWARDS
)

- Developmental delay/ retardation (
LOWER IQ
)

- Thrombosis (sp. DVT and Pulmonary embolism)

- Osteoporosis

-
MALAR FLUSH
* Diagnosis
- +++ homocysteine

- ++ methionine

- enzymology in fibroblasts
* Management
- -- plasma homocysteine --> prevent lens dislocation & thrombosis
- Ptn restriction

- Pyridoxine (cofactor) --> 50% respond

- Folate

- Betaine:
( -- homocysteine by remethylation)
--> specially in those who don't respond to Pyridoxine
5. Non Ketotic Hyperglycinemia
- defective glycine cleavage
- Glycine --> neurotransmitter: (centrally --> excitatory / peripherally --> inhibitory)
* Clinically:
- inutero seizures
- hiccups / hypotonia
- progressive apnea
- encephalopathy
- seizures
- marked developmental delay
* Diagnosis:
- ++ urine / plasma glycine

- CSF : Plasma glycine >0.09

- enzymology in liver / lymphocytes
* Management:
- Na benzoate:
-- plasma glycine (little neurological outcome effect)

- Dextromethorphan (NMDA receptor antagonist):
clock central action of glycine (-- fits)

* N.B.:
- Available prenatal testing

- Poor development prognosis
- Defect in AA catabolism --> ++ OAs

- Examples:
1. branched-chain AA degradation:
- Propionic acidemia
- methylmalonic acidemia

2. leucine catabolism:
- isovaleric acidemia

3. lysine and tryptophan metabolism:
- Glutaric Aciduria type 1
* Propionic, methylmalonic and isovaleric acidemias:
* OAemias Clinically:
- Acute neonatal encephalopathy (intoxication) / chronic intermittent
- dehydration
- MARKED acidosis (++ anion gap) , ketosis
- Neutropenia +/- thrombocytopenia
- progressive extrapyramidal $
- renal insufficency
- pancreatitis
- acute onset CMO
* Diagnosis:
- marked metabolic acidosis
- ketosis
- ++ lactate
- ++ ammonia
- Glucose (variable)
- neutropenia
- urinary OAs
- enzymology
* N.B.:
Proprionate is partially made by intestinal organisms --> so, the decompensation can be caused by CONSTIPATION
* Management:
- Protein restriction

- Carnitine:
(glycine in IVA)
--> -- OAs by conjugation and release by kidney

-
Metronidazole (MMA / PA):
kill gut flora

- Vit. B12 (some MMA)

- Liver transplantation (MMA / PA)
1. Glutaric aciduria type I
* Clinically:
- Before decompensation:
1. asymptomatic
2. macrocephaly

- After decompensation
(after 1st year --> infections):
1. encephalopathy
2. dystonia
3. feeding pbms
4. irritability
* Diagnosis:
- ++ 3 OHglutarate

- ++ glutarylcarnitine

-
MRI brain:
frontal atrophy/ subdural hematoma/ -- signal to basal ganglia

- Enzymology on fibroblasts

- genotyping
* N.B.:
- large head at birth + no other reason --> CHECK for GA-1

- GA-1 can mimic NAI ( encephalopathy + bilateral subdurals)
* Management:
- Carnitine

- Ptn restriction

- Agressive ttt of infections

- Hyperalimenation
- Nitrogen --UC--> urea
- all are AR , EXCEPT OTC deficiency (XR)
* Clinically:
- Vomiting

- Encephalopathy (after symptom free period)

-Tachypnea (ammonia ++ RC)

- Progressive spastic diplegia AND development delay (in -- arginase)

* N.B.:
Arginase deficiency --> rarely hyperammonemia
* Diagnosis:
- Respiratory alkalosis + encephalopathy

- Orotic aciduria --> the block is at OTC or beyond

- confirm by enzymology
* management:
- Ptn restriction

-
Na benzoate
+ glycine
&
Na phenylbutyrate
+ glutamine :
--> H2O metabolites --> excrete by kidneys

- Arginine supplements (essential AA)
--> except in arginase deficency

- Liver transplantation
* Medium Chain Acyl-CoA dehydrogenase deficiency:
- commonest 1:10000 (as PKU)
- Peak presentation: in Winter and Autumn (--> infections)
- 25% present by mortality
- 13% of survivors --> neurological pbms
* Clinically:
-
HYPOKETOTIC HYPOGLYCEMIA

- encephalopathy

- Reye $ like $:

- presentation at 15 mo (--> after diarrhea)

- Sudden infant death $ (>6 mo)

- common G985 mutation
* Diagnosis:

* There's a newborn screening


- hypoglycemia + low/absent ketones

- ++ octanoylcarnitine (C8 carnitine)

- ++ hexanoleglicine (C6 glycine)

- Genotyping
* Management:
- NO fasting

- if unwell --> glucose polymer
not tolerated --> IV 10% dextrose + electrolytes
* N.B.:
- If a previous child with MCADD, feed the new child every 3 hours 'till results appear.

- neonatal deaths were reported.
* Long chain defects:
- More severe:
1. earlier onset
2. meticulous diet watching

* Clinically:
- hypoketotic hypoglycemia

- Myopathy

- Hypertrophic CMO

- Pigmentary retinopathy (LCHAD)

- Peripheral neuropathy

- maternal hepatic $ in pregnancy
* Diagnosis:
- Hypoketotic hypoglycemia

- characteristic long-chain acylcarnitines

- characteristic dicarboxylic aciduria in urinary OAs

- ++ creatine kinase

- fat oxidation studies on fibroblasts

- genotyping

* N.B.:

Mother had AFLP or HELLP $ --> screen for acylcarnitines
* management:
- long chain FA restriction
- Walnut oil
- avoid fasting
- uncoocked corn-starch (at 2 y) --> prolong glycemic control)


- if unwell --> glucose polymer
not tolerated --> IV 10% dextrose + electrolytes
* Mitochondrial disorders:
* mitochondrial genetics:
- double stranded circular DNA

- matrilineal inheritence BUT both are affected

- 10% of nuclear genes code for healthy mitochondria ( ex. all complex II subunit)

- mostly AR

- cells can contain many copies of mitochondria (heteroplasmy) --> disease IF mutant mtDNA > wild type mtDNA

- wild type cells > reproductive powers than > mutant cell, SO, reproductive cells with heteroplasmy can improve but NOT brain & muscle.

- If no nuclear defect -->
can't diagnose prenatally


* Clinically:
- any tissue can be affected, specially brain / heart / muscles / kidney / liver; NOT RBCS (no mitochondria)

- 33% --> neonatal
80% --> 1st 2 years

- most $ are due to mtDNA mutations and are uncommon in children:
1. Mitochondria Encephalomyopathy with Lactic Acidosis and Stroke like episodes (MELAS)
2. Kearns - Sayre $

- Incomplete $:
ex.: CNS: Leigh $
muscle: myopathy ...etc
* investigations:
- multiple organ of unrelated organs involvement "illegitimate associations" --> suspect mitochondrial pbm --> examine Muscle / bladder cell

- peripheral lactate can be persistently ++

- Histochemistry:
* stainning of complex II and IV
- Respiratory chain enzymology:
* complexes I-IV + V

- Invs:
ex.: MRI brain / echo / ..
* Management:
- SUPPORTIVE

- antioxidant replacement: successful in v little cases (ubiquinone, riboflavin)

- Dichloroacetate -->
-- the elevated lactate but no better outcome
* disorders of CHO metabolism
1. Glycogen storage disease:


- Glycogen can't be broken down

- Liver forms --> Hepatomegaly and
Hypoglycemia

BUT, Muscle forms --> Weakness and Fatigue
1. GSD Ia "von Gierke disease":
* Clinically:
- Hepatomegaly + NO splenomegaly

- Doll like face + thin limbs

- failure to thrive

- bruising ( low platelet function)

- nephromegaly
* Complications
- renal insufficency / liver adenoma / HCC / gout / osteopenia / PCO
* Investigations
- Hypoglycemia

- ++ lactate (-- when glucose is given)

- Hyperlipidemia

- Hyperuricemia

- Genotype --> -- liver enzymology
* TTT:
- Frequent feeds:
when 2 yrs old --> give uncoocked cornstarch --> slow release SO ++ gap between feeds

- Allopurinol

- Liver transplantation
- Glucose 6 phosphatase deficiency

- can't form glucose (blocked gluconeogenesis& glycogenolysis) --> LIMITED FASTING TIME 1-4 h

- present at 3 mo
2. GSD IB
- Glucose 6 phosphate translocase deficency

- same phenotype as von Gierke disease, +:
neutrophil dysfunction
1. recurrent skin sepsis
2. large mouth ulcers
3. IBD

- TTT:
as von Gierke disease, +:
1. prophylactic
Septrin
(cotrimoxazole) for severe mouth ulcers
2. Granulocyte colony stimulating factors
GCSF
in resistant cases

3. GSD II (Pompe's disease)
- acid maltase deficiency ( in lysosomes) --> lysosomal storage disease

- infantile form:
hypotonia / weakness/ hyporeflexia/ large tongue

- ECG: giant QRS

- Blood film: vacuolated lymphocytes

- confirm: enzymology fibroblasts

- death within the 1st year

4. GSD III
- debrancher enzyme

- III a --> muscles and liver
III b --> ONLY liver




- LACTATE ++ when glucose is given

- confirm --> WBCs enzymology

- TTT: not severe as I / high ptn
diet for IIIa
- clinically:

JUST like type I, but:
1. longer fasting time
2. NO nephromegaly
3. CLEAR myopathy (progressive in IIIa)
4. CMO is a complication NOT a feature
5. adenomas / liver fibrosis / cirrhosis --> RARE
5. GSD IV:
- Branching enzyme

- Very rare

- Hepatomegaly and progressive liver disease

- confirm: liver histology and enzymology

- TTT: liver transplantation
6. GSD VI (Liver phosphorylase deficiency) and GSD IX (Phosphorylase-b-kinase deficiency):
- inheritence: X linked or Recessive

- hypoglycemia is rarely a problem

- GSD IX --> confirm in RBC enzymology: liver can be normal

- TTT: uncooked cornstarch once
or 2 times a day
* MUSCLE GSDs*
* GSD V (muscle phosphorylase deficiency), McArdle disease and GSD VII (phosphofructokinase deficiency):
- weakness and fatigue + post exercise stiffness
- ++ serum creatin kinase

- On exercise:
lactate CAN'T ++ / there's ++ Uric acid& ammonia
--> after rest: exercise can be restarted "2nd wind" as FA become available

- Ptn is beneficial
- McArdle: benefit from glucose
- avoid extreme exercise
2. Galactosemia
* Clinically:
- Neonatal onset:
at the end of 1st week
jaundice / hepatomegaly/ coagulopathy /
oil-drop cataract

-
Later:
at a few months
rickets / proximal tubulopathy / faltering growth

-
associations:
Eschirechia Coli sepsis
* Diagnosis
-
reducing substances in urine:
disappear as feeding stops

-
changed liver functions:
like ++ INR

-
Gal-1-PUT (Galactose 1 PO4 uridyltransferase) assay:
if the child had a transfusion --> screen parents for carriers in stead
* management:
- Lactose / galactose free diet

- Ca supplements (milk --> soya-based formula)
long term complications even with good care:
1. delayed development (specially speech)
2. feeding problems
3. infertility in girls

3. Hereditary fructose intolerance:
Key: symptoms appear with ingestion of fructose --> at weaning
* Clinically:
- Acute:
vomiting / symptomatic hypoglycemia

- Chronic exposure:
faltering growth/ HM / ascitis / jaundice / proximal renal tubulopathy

- Milder cases:
they LEARN to avoid sugary food

- Exacerbations AFTER ingestion of fructose-containning medicines
* Diagnosis
- H/O
- lactic acidosis
- hyperuricemia
- changed liver functions
-Aldolase B activity in liver
- genotyping ( if liver biopsy is contraindicated --> coagulopathy)
* TTT:
LIFELONG avoidance of Fructose
* Lipid disorders:
in circulation: cholesterol & TG + lipoproteins
* lipoproteins:
Chylomicrons VLDL LDL HDL
- dietary ptns mainly TG

- from gut to liver

- lipoprotein lipase
--> release FFA
in portal circulation
- Mainly TG + some
cholesterol from liver to extremities

- lipoprotein lipase
--> release FFA and leaving IDL (intermediate)
- Mainly cholesterol
+ some TG from
liver to extremities

- direct uptake by cells --> LDL receptors
- Cholesterol from extremities to liver

- Good cholesterol
1. HyperTGemia:
- Defective chylomicron removal:
lipoprotein lipase deficency / apolipoprotein C-II deficiency

OR

- ++ production of VLDL:
familial hyperTGemia
-
Rare
-
Clinically:
Colic / HSM / eruptive xanthomas / creamy plasma
- complications:
Rarely (TG >20 mmol/l)
Abdominal pain / pancreatitis
- TTT:
1. V low fat diet + essential FA supplements
2. fibric acid derivatives (-- TGs synthesis and ++ their clearance)
3. niacin
4. statin (mostly by -- VLDL synthesis)

* 2ry causes:

1. obesity
2. CRF
3. DM
4. liver disease
2. Hypercholesterolemia:
* Familial hypercholesterolemia
- defective LDL removal

- Commonest hyperlipedemia

- F/H is important in IHD
specially: Young / Girl

- homozygotes:
xanthemata in the 1st decade & angina before 20

- TTT:
MAINLY diet and exercise
- monogenic:
Heterozygote: 1:500
Homozygote: 1:1000 000

- mutations:
1. LDL receptor
2. Apo B
3. PCSK9 gene
* Management:
-
total Fat
intake < or = 30% total calories
-
saturated Fat
intake < or = 10% total calories
-
cholesterol intake
< 300 mg
-
Fruits and vegetable
= 5 a day
-
Fish
: TWICE a week

- NO smoking / alcohol
-
Statins:
1. > 10 y
2. teratogenic
3. competitive inhibition of 3-OH-2-methylglutaryl-CoA reductase
* Familial combined hyperlipidemia:
- hypercholesterolemia + hyperTGemia

- confirm by 1st degree relative with different biochemical phenotype

- Unknown genetics

- TTT:
healthy lifestyle + statins / firate / nicotinic acid
3. Abetalipoproteinemia:
- Rare
- AR
- undetectable apoenzyme B (Apo B)
- Fat and Fat soluble vit. malabsorption
* Clinical features:
- Poor weight gain
- steatorrhea
- CNS symptoms
- Retinitis pigmentosa
* Investigations:
- hypocholesterolemia

- Acanthocytes (blood film)

- --- vitamins (A, D, E, K)
* TTT:
- -- Fat intake (5-20 g/d)

- Walnut oil

- Fat soluble vits. supplements
* Peroxisomal Disorders:
- Peroxisomes have the enzymes for:
1. synthesis of:
a. Plasmalogens (cell wall)
b. cholesterol
c. bile acids
2. B-oxidation of VLCFA
3. breakdown of:
a. Phytanic acid (Vit. A)
b. glyoxylate

- AR except X-ALD

- screening --> plasmalogens

- 1st line invs --> VLCFA ( ++ in Z$ & X-ALD, but normal in RCDP
- Multiple enzymes affected (peroxisomal biogenesis defects):
1. Zellweger $ (Z$)
2. Neonatal adrenoleukodystrophy (NALD)
3. Infantile Refsum disease (IRD)

- several enzymes involved:
* rhizomelic chondrodysplasia punctata (RCDP)

- single enzyme block:
1. X linked Adrenoleukodystrophy
(X-ALD)
2. Refsum disease
3. Hyperoxaluria
1. Zellweger $:
- ++ VLCFA

- ++ phytanate

- ++ Bile acids intermediates

- --- plasmalogens

- confirm --> enzymology on fibroblasts

*Diagnosis:
* TTT:
-supportive

- death in 1st year

-Docosahexaenoic acid supplementation --> no clear benefit

* clinically:
- Dysmorphic

- severe neurological involvment

- sensorineural deafness

- occular abnormality

- HM

- calcific stippling (knees & shoulders)

- Faltering growth
2. X-ALD:
- cerebral pediatric form:

start from 5 - 10 y with severe neurological degeneration

--> complete vegetative state

--> death within few years
* Clinically:
- school failure
- visual impairement
- quadriplegia
- seizures (late sign)
- adrenal insufficency

* All boys with adrenal failure --> VLCFA measurement

*neurological symptoms may begin
in adults (adrenomyeloneuropathy)
as cord $

* Female carriers --> MS as adults
* Diagnosis
- ++ VLCFA
- blunted Synacthen test
- hypoglycemia
- Neuroimaging:
bilateral / posterior / white-matter involvement

- DD:
- subacute sclerosing panencephalitis

- Batten disease

- Wilson disease

- Niemann-Pick C disease
* Management:
- lorenzo oil (oleic & eruci acid) -->
-- VLCFA but still progresses

- BM transplantation before progression
( serial neuroimaging)


- ttt of adrenal insufficency
* Mucopolysaccharidosis:
- accumunlation of GAGs
- normal at birth
* Classification:
- Hurler $ : Body & CNS
- Sanfillipo $ : CNS
- Morquio & Maroteaux-Lamy $ : body (have atlantoaxial instability --> prophylactic cervical spine fusion in the first 2-3 days)

- Hurler has:
scapular nodules & corneal clouding; NOT Hunter
* Hurler $:
- alpha-iduronidase deficiency (as Scheie disease --> milder)


* clinically:
- coarse features
- airway problems
- dysostosis multiplex
- CMO/ valvular disease
- HSM
- Hernias
- Stiff joints
- developmental delay
* Diagnosis:
- ++ urine GAGs:
heparan/dermatansulfate

- confirm:
enzymology in WBCs
* TTT:
- Early recognition --> early BM transplantation

- Enzyme replacement therapy --> face looks better but neurological defects (doesn't cross BBB)

- Supportive
* Sphingolipidosis:
* sphingolipids:
- membrane lipids
- 3 groups:
1. sphingomyelin
2. cerebrosides
3. gangliosides
- lysosomal hydrolases --> breaks them down, SO, if defficient --> accumulate causing:
1. psychomotor retardation
2. neurological degeneration
3. +/- HSM
1. Tay-Sachs disease:
* Clinically:
*Diagnosis:

-vacuolated lymphocytes in blood film

-Hexoaminidase deficiency --> in
WBCs enzymology


*TTT:
supportive
2. Gaucher disease
-- Glucocerebrosidase --> ++ cerebrosides:
1. in viscera
2. +/- brain
* Clinically:
Type 1 Type 2 Type 3
- non neuropathic (80-90%)

- splenomegaly > HM

- anemia

- bleeding tendency

- skeletal pain

- deformities

- osteopenia

- abdominal pain (splenic infarcts)
- ACUTE neuropathic

- SEVERE CNS involvment

- convergent squint

- horizontal gaze palsy

- HSM
- subacute neuropathic

- convergent squint

- horizontal gaze palsy (early sign)

- splenomegaly > HM

- slow neurological deterioration
- Diagnosis:
- Markers:
1. ++ ACE
2. ++ Acid phosphatase

- BM aspiration --> Gaucher's cells
(crumpled tissue paper cytoplasm)

- WBCs enzymology for glucocerebrosidase --> definitive diagnosis

- ++ enzyme chitotriosidase (follow activity)
- management:
- ERT --> visceral diseases type 1 and 3

- BM transplantation:
1. in the past
2. role in neuro aspect to type 3

- splenectomy

- no ttt for type 2
3. Niemann - Pick disease:
- = sphingomyelinoses

- A and B -differ from- C
* sphingomyelinase deficency:
* clinically:
Type A (infantile) Type B (visceral)
- feeding difficulties

- HM > SM

- cherry-red spot

- lung infiltrate

- Neurological decline (deaf/blind/spasticity)

- DEATH within 3 years
- Milder course

- NO neurological factor

- HSM

- lung infiltrates

- Ataxia

- Hypercholesterolemia
* Diagnosis
- BM aspirate --> Niemann- Pick cells

- WBCs enzymes

- genotyping (before onset of neurological signs)
* TTT
- SUPPORTIVE

- ERT for type B is under trial
2. Lysosomal cholesterol-export defect (secondary sphingomyelin accumulation):
- clinically:
Type C
- conjugated hyperbillirubinemia (earliest sign)

- HSM

- Neurological deterioration

- dystonia

- Cherry-red spot

- vertical ophthalmoplegia
- diagnosis
- Definitive:
cholesterol studies on fibroblasts and genotyping

- BM aspiration: Nieman-Pick cells

- WBCs enzymes: normal/slightly -- sphingomyelinase
- TTT:
- supportive

- miglustat

- substrate deprivation therapy

* prognosis is related to age of onset
4. Fabry Disease
- XR
- alpha-Galactosidase deficency (++ in BVs/ heart/ kidney/ autonomic spinal ganglia
- clinically:
- diagnosis:
- Malteses crosses in urine under microscopy

- WBCs enzymes
- management:
ERT reduces pain and stabilizes renal functions
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