Dr. A.Radha Rama Devi, M.D

Consultant, Sr Paediatrician & Clinical Geneticist & President of Indian Society of Inborn Errors

Rainbow Children Hospital & Dr Reddys Institute of Life Sciences, University of Hyderbad

Sandor Speciality Diagnostics Pvt Ltd, Hyderabad

Area of special interest: Inborn Errors of Metabolism & Newborn Screening

Awards and honours : President Medal In MBBS; Gold medal in Medicine

British council Travel fellowship, UK.

Life time Achievement award in Inborn errors of Metabolism by the

Hyderabad branch of Indian academy of Paediatrics.

Senior Women Bio-scientist: Department of Biotechnology (2005)

Top 10 women in Medicine (2007)

Dr. I. C.Verma Outstanding Researcher Award- 2018

Sandor Oration Award- ISIEM,Pune,2019

Achievements: Started the first large scale New-born Screening in India.

How do I manage Suspected Inborn error of metabolism?

Dr.A.Radha Rama Devi

Rainbow children Hospital

Hyderabad

Inborn errors of metabolism – Points to remember

• With appropriate therapy, patients may completely recover without sequelae

• Early diagnosis is a prerequisite for effective treatment,

• Neonatal screening plays an important role in early diagnosis,

• Tandem mass spectrometry has increased the number of diseases that can bedetected.

Management of IEM-From diagnosis to prevention

• Includes

• Clinical presentation

• Biochemical diagnosis

• Molecular confirmation

• Treatment including Novel therapies.

• Family screening

• & Prevention

•

• PND

Management of IEM

Is a combination of 3 aspects – Nutritional Supplements, Dietary

Modifications and Medical Care.

Diet is the sole form of therapy or

used in combination with other

treatments

Cell therapy

Transplant

• Remember 75% of IEMs are treatable!

Principles of Management

• Treatment of patients with a known IEM should be disease and patientspecific.

• Management includes critical care and follow up care and prevention

• Strict adherence to dietary and pharmacologic treatment life long

• Avoid precipitating factors and stresses to prevent acute

decompensation

Follow treatment protocols developed by an IEM specialist.

Provide Instructions for resuscitation measures in an acute crisis.

Medical Care

Emergent treatment

• Critical management is similar to any other disease

• Establish airway, breathing, circulation

• Discontinue oral intake in patients with encephalopathy and

vomiting for the first 24-48hours

• Address associated complications – hypoglycaemia, MA,

Hyperammonemia.

Metabolic acidosis

• Correct electrolyte abnormalities.

• Add electrolytes at maintenance concentrations,

• Sodium bicarbonate or, if the patient is hypokalemic, potassium acetateshould be administered.

• Rapid correction or overcorrection may have paradoxical effects on theCNS.

• For intractable acidosis, consider haemodialysis // peritoneal dialysis.

Metabolic complications-Hypoglycemia

• IV dextrose bolus, as D10 for neonates and D10 or D25

beyond the neonatal period, followed by continuous IV

administration of dextrose.

• Prevent catabolism, and promote urinary excretion of

toxic metabolites

• High-volume maintenance fluid will also promote urinary

excretion of some toxic metabolites.

• Add insulin, 0.2-0.3 IU/kg, as needed to maintain glucose

level in the desired range.

Hyperammonemia

• Significant hyperammonemia is life-threatening and must

be treated immediately.

• To reduce ammonia, sodium benzoate 250mg/kg

• Ammonia level >500-600 mg/dL, hemodialysis

• If hemodialysis is not available, peritoneal dialysis (< 10% as effective as hemodialysis)

• or double volume exchange transfusion (even less effective)

Inpatient care :

• Once toxic metabolites have been normalized & able to tolerate enteral feeding, protein is reintroduced as an essential amino acid solution,

• initially at 0.5-0.75 g/kg/day and gradually increased.

• Include natural protein 0.8gm/kg/day in the form of breast milk or regular milk(never stop natural protein totally). Will cause symptoms of malnutrition

• Required calories/day is met with protein free formula foods.

Pharmacologic therapy

• To increase activity of abnormal cofactor-dependent

enzymes (e.g., thiamine [B-1] 5-20 mg/day PO up to 500

mg/day,

• biotin 5-20 mg/day PO,

• riboflavin [B-2] 200-300 mg PO tid,

• cobalamin [B-12] 1-2 mg/day IM) may be given.

Follow up

• Regular follow up is essential

• Evaluate growth & development

• Periodically monitor the levels of the metabolites either in urine or blood based on the type of the disorder.

• Adjust dietary requirement as per the weight and age.

• Medical therapy to be continued life long

Extended treatment

• Transplantation (organ or bone marrow)

• Enzyme replacement therapy

• Prevention & Counselling

OTC def

Liver Transplant

4yr girl

Rec Hyperammonemia >600Umol.

Rpted hospitalistion

Growth failure

Behavioral changes

Molecularly confirmed OTC gene mutation

Underwent pediatric cadaver transplant

2yrs post transplant, normal ammonia

On regular diet

Attending school

ERT IN GAUCHER TYPE I

• Management of a Known IEM

A case of organic aciduria

• As a representative for all IEMs management

• From Diagnosis- NBs

• Management

• Prevention

• 3months baby

• Irritability, refusal to feed

• Encephalopathy

• Hypoglycemia, hyperammonemia, met acidosis

• Managed in the ICU

• Follow-up with MMA diet, had two decompensation events and managed.

• Doing well, aged now 11yrs

• Family counselling, specific gene identified

• Provided PND in the next pregnancy.

A case of MMA- Sequence of management

MRI

Batwing appearance

Sylvian fissure

Child with Glutaric Aciduria Type I

35days old female infant born to 1st cousin couple.

Macrocephaly, (intrauterine)arachnoid cyst, Subdural

hematoma

NBS detected elevated C5DC in TMS(2.0/<0.7)

Neurosonogram Small cyst near the ventricles, minimal

internal hydrocephalous. AF wide patent bulging

Urine organic acids & mutation study confirm GAI

Diet replacement since 3rd week of life Normal

development Presently aged 12 yrs.

PND done in next pregnancy. Normal fetus

Late diagnosis

Severe Movement disorder

Dystonia

Wheel chair bound

ID with high GA levels

Second child affected ,diagnosed at 11

months

No follow-up

Caution:

Watch for tryptophan deficiency

symptoms during diet management.

Citrllinemia

IVA

IVA

MMAMMA

MMA

PKU

GA1

Take Home message

• DO NEW-BORN SCREENING TO ALL NEONATES

• DO METABOLIC SCREENING TO ALL HIGH RISK BABIES

• DO METABOLIC SCREENING TO ALL BABIE BORN TO RELATED PARENTS & PARENTS WITH BAD OBSTETRIC HISTORY

Give the required treatment for the specific disorder

Positive counselling and PND in subsequent pregnancies and

to their immediate families.