Inborn Errors of Metabolism in Critically Ill Newborns · 1. Paediatric and Neonatal Metabolic and...

PHOTO

Chief Scientific Research officer - NIRMAN, Navi Mumbai

MD, DCH, MCPS

RESEARCH AND AREA OF INTEREST –

1. Paediatric and Neonatal Metabolic and Genetic disorders, especially small molecule diseases. 2. More than 70 Publications and presentations. 3. 17 Chaptres in 6 medical text books 4. Publsihed 4 books on IEM. Dr. Anil B Jalan

MMC Speaker Code –MMC/MAS/03932/2015

Inborn Errors of Metabolism Approach to Acute Encephalopathy

Dr. Anil B. Jalan

MD, DCH, MCPS

NIRMAN

Dr. ABJ / C.I.N.B. 2

3

33

29

2423

2018

16 1614

11

8 87 7

5 54

3 3 3

20 Commonest Disorders in Critically ill Newborns

IEM in Critically ill Newborns

• 5 Important Steps in Management of IEM

1. Suspicion

2. Evaluation

3. Stabilization

4. Specific Treatment

5. Genetic Counseling



• 1. Suspicion:

a. Acute illness may be following a period of normalcy

b. Lethargy, Hypotonia, coma

c. Convulsions

d. Intractable hiccups

e. Apnea / respiratory distress



f. Sepsis - particularly E. Coli

g. Unusual odor

h. Jaundice

i. Dysmorphic Features

j. Organomegaly

k. + ve F/H/O parental consanguinity

l. SIDS



• 2. Evaluation :

a. Detailed history – Antenatal/Intra natal/Post natal & Family H/O

b. Physical examination

c. Initial screening tests

d. Advanced screening tests

f. Definitive diagnostic tests



• Physical Examinations :

a. Facial dysmorphism

b. Cataracts and Retinopathies

c. Skull abnormalities - (Structural brain anomalies)

d. Hypertrophic or dilated Cardiomyopathy

e. Hepatomegaly

f. Multicystic Dysplastic Kidneys



g. Myopathy

h. Typical brittle hair , sparse , light colored etc.

i. Genitalia - ambiguous etc.

j. Coarseness of facies

k. Specific odor of Urine or body - pleasant or unpleasant.



• Abnormal (Unpleasant odor)

1. M.S.U.D. , P.K.U.

2. Hereditary Tyrosinemia

3. Iso Valeric Acidemia

4. 3 - Methyl Crotonyl CoA Carboxylase def

5. MCD

6. Glutaric aciduria Type II



• Dysmorphic Features

1. Glutaric Aciduria Type II

2. Menke Kinky Hair Syndrome

3. Zellweger Syndrome

4. Neonatal Adreno - leuko - dystrophy

5. Smith Lemli Opitz Syndrome

6. Congenital Disorders of Glycosylation ( Lipodystrophy )


Lipodystrophy – CDG Ia

Dr. ABJ / NIRMAN 13

Inverted nipples

14


• Abnormal Hair :-

1. Lysinuric Protein Intolerance

2. Argininosuccinic Aciduria

3. Menke Kinky Hair Syndrome

4. PKU

5. Biotinidase def. (hair loss, alopecia)

6. Costello Syndrome

7. Griscelli Syndrome


Dr. ABJ / NIRMAN 17

Costello Syndrome Griscelli Syndrome

18


• Weaning Associated IEMs

1. Fructose Intolerance

2. Fructose 1,6 diphosphatase deficiency

3. Urea Cycle Defect

4. Lysinuric Protein Intolerance

5. HHH syndrome

6. MSUD / Organic acidurias



• 3. Stabilization :

a. Prevent Catabolism - Adequate Calories, Glucose Insulin Drip

b. Limit the intake of offending substance - e.g. Lactose, Leucine, Long chain fatty acids

c. Increase excretion of toxic substances - e.g. Sodium Benzoate / Carnitine

d. Increase the Residual enzyme activity by Co factor therapy -Biotin , Riboflavin etc.



• 4. Specific Therapy :

A. Depends on particular disorders - special formulas- MSUD/ UCD diet etc.

B. Hormone replacement - e.g. in CAH

C. Enzyme replacement therapy

D. Gene therapy



• As Dr. Andrew Morris ( UK ) says :

• How to manage a critical baby :-

• 1. Stop all protein feeds

• 2. Start 10 % dextrose

• 3. Start lecturing



• 5. Genetic Counseling :-

• 1. Inheritance Pattern ( AR / AD / XL etc. )

• 2. General Population incidence

• 3. Course and prognosis of the disease

• 4. Screening possibilities for other babies and family members - MCAD deficiency

• 5. Prenatal Diagnostic feasibility



• Neonatal Types of IEM :-

• Short Symptom Free Interval < 24 - 48 hrs

• a. FAOD

• b. Mitochondrial Respiratory Chain Defects

• c. Disorders of Gluconeogenesis

• d. Disorders of Glycogenolysis

• e. Peroxisomal Disorders



• Long Symptom free Interval :- ( Feeding related )

• a. Amino-acidopathies

• b. Organic Acidemias

• c. Urea Cycle Defects

• d. Sugar Intolerance Syndromes - Galactosemia etc.



• Transient IEMs :-

• 1. Transient DM of NB

• 2. Transient Hyperammonemia of NB

• 3. Transient Tyrosinemia of NB ( Pre Term )

• 4. Some Varieties of Urea Cycle Defects

• 5. Transient N.K.H.G. of NB

• 6. Congenital Lactose Intolerance



• IEM associated with Severe Infection :-

• 1. Galactosemia

• 2. Methyl Malonic Acidemia / IVA

• 3. Multiple Carboxylase Deficiency

• 4. Glutaric Aciduria

• 5. NKHG

• 6. Purine Nucleoside Phosphorylase def.


Dr Andrew Morris , UK29


• 5 Major Points to be seen while evaluating NB with ? IEM

• 1. Metabolic Acidosis + / -

• 2. Hyperammonemia + / -

• 3. Lactate level elevated + / -

• 4. BSL - Hypo / hyper glycemia

• 5. Ketones / ketoacids + / -



• Specific Types - 1 :-

• Neurologic Distress with convulsions & / or myoclonic jerks :-

• a. Normal Ammonia and Lactate

• b. Normal BSL and blood counts

• c. No acidosis / no ketosis

• d. DNPH test negative



• 1. Non Ketotic Hyperglycinemia - NKHG

• 2. Sulfite Oxidase / Xanthine Oxidase def.

• 3. Pyridoxine dependency

• 4. Peroxisomal Disorders

• Imp. :- Glycine in CSF and blood

• :- EEG with Inj. Pyridoxine

• :- VLCFA analysis

• :- Urinary Sulfites



• Other D/Ds:-

• Serine Biosynthesis Disorders

• Creatine Biosynthesis Disorders

• Neurotransmitter Defects : including folinic acid responsive seizures

• GLUT 1 Transporter defect

• Menke’s Syndrome



• Neurologic Intoxication Type ( 2 ) :-

• Normal or mildly elevated Ammonia

• Normal Lactate

• No Acidosis

• Normal Blood Counts & Normal BSL

• Ketones + and DNPH +++



• MSUD

• Burnt Sugar like odor

• TLC - AA - Leucine / Isoleucine

• Valine / Methionine elevated

• OA 2-Oxo iso - Caproic Acid

• 2-Oxo 3 Methyl-valeric Acid

• 2-Oxo iso-valeric Acid



• Neurologic Intoxication with Dehydration ( 3 )

• Ammonia & Lactate + / ++

• Acidosis ++

• Ketones ++

• DNPH + / -

• Leucopenia / thrombocytopenia

• BSL - Normal / Elevated / Reduced



• Methyl Malonic Acidemia

• Propionic Acidemia

• Iso Valeric Acidemia

• Multiple Carboxylase Deficiency

• Biotinidase Def.

• Imp :- :- Sr. Biotinidase enzyme

• :- GC / MS for OA

• :- MS / MS for Acyl Carnitines



• Neurologic Distress with hepatic Signs (4 ) :-

• Ammonia ++ / +++ Mainly ammonia

• Lactate Normal / Mild elevation

• Acidosis No ( alkalosis + )

• BSL Normal

• Blood Counts Normal

• Ketones Absent

• DNPH Negative



• Urea Cycle Disorders , HHH

• FAOD - GA Type II

• CPT 2 / CACT , LCAD , LCHAD

• Imp :- Amino-acids - HPLC for Citrulline , Ornithine , Arginine , ASA , Orotic Acid

• MS / MS :- Acyl Carnitine Profile



• Neurologic distress with energy deficiency (5) mainly Lactic Acidosis

• Ammonia : Normal or mild +

• Lactate : +++

• BSL : Normal or Low

• Ketones : + / -

• Acidosis : ++

• DNPH : + / -



• Pyruvate Carboxylase Deficiency - PC

• Pyruvate Dehydrogenase Deficiency - PDH

• Kreb’s Cycle Defects

• Respiratory Chain Defects

• Multiple Carboxylase Defects

• Mitochondrial Defects

• Imp :- Lactate / Pyruvate Ratio

• :- Urine - GC / MS Qty.



• Mainly hepatic Type ( 6)

• Hepatomegaly / Jaundice +++

• Liver cell Failure + / -

• Ammonia / Lactate + / -

• Ketones / DNPH + / -

• BSL Normal / +

• Acidosis + / -



• Galactosemia

• Tyrosinemia

• Fructose Aldolase deficiency

• Fructose 1 , 6 diphosphatase deficiency

• Neonatal haemochromatosis

• Respiratory Chain Defects

• Alfa - 1 - Antitrypsin deficiency



• Special Category :- Stroke Like Episodes

• 1. Urea Cycle Defect

• 2. MMA / PA / IVA

• 3. MELAS

• 4. Homocystinemia

• 5. Carbohydrate Deficient Glycoprotein Syn.

• 6. Thiamine responsive megalobastic anemia

• 7. Fabry’s Disease


Special Categories

• Lactic Acidosis without Ketonuria

• 1. PDH Def.

• 2. GSD

• 3. FAOD

• 4. Tissue Hypoxia ( never forget )


Special Categories

• Metabolic Acidosis with normal Anion Gap

• 1. Diarrhea ( GIT loss of Bicarb )

• 2. RTA -

• Hereditary fructose intolerance, HT1, Cystinosis,

• Fanconi Bickel Syndrome

• Lowe Syndrome, Vit DDR

• Wilson disease


IEM work up in a Suspected case

• Send samples for IEM for next step

1. Heparinized blood : 2 ml

2. EDTA Blood : 2 ml

3. Serum : 2 ml

4. CSF : 1 ml in each vial collected in 3 vials, serially numbered

5. Urine : 10- 15 ml

• All samples must be sent in Vacutainers only

• Coolant gel (1 or 2) in a thermocol box51

Urine Plasma / Blood CSF

Aminoacids Aminoacids Sugar, Lactate

Organic Acids Carnitine / Acyl Carn Aminoacids

Purine / Pyrimidines and Sulfites

VLCFA / Plasmalogen / Pipecolic Acid

Pipecolic Acid

MPS / Oligosaccharides Homocysteine and Sr. B12 Folates / MTHF

Ur / Pl - GAA, Creatine Plasma Sterols Pyridoxine Vitamers

Pterins Pterins / DHPR Pterins

Neurotransmitters Sr. Pyridoxine Vitamers, FMN, FAD, Riboflavin

Neurotransmitters

Urine / Pl Sulfocysteine Enzymes – Biotinidase, GALT GAA and Creatine

IEM work up in a Suspected case

• Additional studies that may be required :

1. MRI with MRS

2. EEG

3. BERA

4. Muscle Biopsy / Liver Biopsy ( LM / EM )

5. Genetic Studies ( CES / WES / WGS etc )

• Kindly discuss with metabolic physician before and after these studies.

53

Genetic Studies

• 1. Single Gene - PCR / MLPA / Meth-PCR

• 2. Trinucleotide repeats , FISH , Karyo etc. etc.

• 2. NGS Panel / Clinical / Whole Exome Sequencing

• 4. Mt. DNA Genome

• 5. CGH Array / Copy Number Variation

• 6. Whole Genome Sequencing

• 7. Transcriptomic studies ( RNA Sequencing ) with proteomics & Lipidomics

• 8. Genetic analysis in Muscle Bx or Fibroblasts ( Skin Bx ). 54

IEM in Critically ill Newborns Author and Editor : Dr. Anil B Jalan

• Pgs : 300 / Chapters : 21

• Tables : 80

• Flow charts : 7

• Fig / Photographs : 45

• GC-MS : Chromatograms and Mass Spectra : 27

• Original Cost Rs. 895/- 750/-

55

Thank You• Dr. Anil B. Jalan [ MD DCH MCPS ]

• C - 116, Om Rachana Society , Sector - 17

• Vashi , Navi Mumbai - 400 705

• email < [email protected] >

• Tel / Fax : 0091 22 6791 0236 / 37

• Mobile :- 98211 24578


Inborn Errors of Metabolism in Critically Ill Newborns · 1. Paediatric and Neonatal Metabolic and...

Documents

Transcript of Inborn Errors of Metabolism in Critically Ill Newborns · 1. Paediatric and Neonatal Metabolic and...