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WHEN TO SUSPECT INBORN ERROR OF METABOLISM IN NEONATE

Dr. Muhammad Arshad Alvi

MBBS, MRCP( Ireland), FRCPCH (UK)

FCPS Pediatrics, FCPS Pediatric Gastroenterology

Visiting consultant ped Gastroenterology, Hepatology & Nutrition

Department of Pediatrics Fatima Memorial hospital lahore

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What is IEM

What are clinical pointers towards IEM

Identifying specific disorder

How to investigate

How to manage metabolic crises

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Inborn errors of metabolism (IEM) are disorders in which there is a block at some point in the normal metabolic pathway
IEMs occur due to mutations in DNA.

DNA Enzyme

which code for a Receptor

Specific protein Transport vehicle

Membrane pump

Structural element

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Clinical Pointers Towards Diagnosis

Acute metabolic decompensation after a period of apparent well-being.

Severity of decompensation may seem out of proportion to the precipitating condition

Mild gastroenteritis resulting in severe dehydration

Unexplained deaths in family

The duration of the symptom-free period may range from hours to months and sometimes years.

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Poor weight gain

Irritability mimicking colic

Lethargy that can progress to coma

Seizures

Rapid, deep breathing that can progress to apnea

Unexpected infant death or a brief resolved unexplained event (BRUE)

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Feeding problems

Weak suck

Infrequent feeding due to lethargy

More frequent feeding due to hypoglycemia

Shorter feeding periods with lower intake due to hypotonia

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Recurrent vomiting (in some cases, the child may have been diagnosed with formula intolerance or pyloric stenosis during infancy

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Seizures

May occur in virtually all IEM
May be the only manifestation of pyridoxine-dependent seizures
Seizures are usually secondary to hypoglycemia
Accumulation of toxic metabolites in disorders of intermediary metabolism.
May respond poorly to standard anticonvulsant medications
Valproic acid is contraindicated in seizures due to metabolic disorder

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Respiratory abnormalities

Hyperpnea that then results in a respiratory alkalosis.
Tachypnea due to metabolic acidosis .

As the metabolic derangement progresses, there may be significant global neurologic depression leading to apnea

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Lethargy and/or dehydration with rapid response to infusion of intravenous (IV) fluid or glucose

Recurrent hypoglycemia

Metabolic decompensation out of proportion to duration or severity of acute illness

A personal or family history of thrombotic events (suggestive of homocystinuria)

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Photophobia, in cystinosis and tyrosinemia type II

Episodic abdominal pain, which may occur in Fabry disease and the hepatic porphyria

Anesthesia or surgery may trigger thromboembolic events in homocystinuria

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Triggering Factors

Acute infection, fasting, surgery, trauma, or even the birthing process

Increased consumption of a food component ( increased protein intake when switching from breast milk to cow's milk).

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Identifying Specific Metabolic Disorder

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INBORN ERRORS OF AMINO ACID METABOLISM ASSOCIATED WITH PECULIAR ODOUR:

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Encephalopathy

Urea cycle defect

Fatty acid oxidation defect

Encephalopathy with hepatic involvement

Fatty acid oxidation defect

Mitochondrial defect

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Severe metabolic acidosis

Organic acidemia

Gluconeogenic Defects

MSUD

Very high ammonia

Urea cycle defect

Very high lactate

Mitochondrial defect

Gluconeogenic defect

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Intractable seizures

Pyridoxine dependency

Non-ketotic hyperglycinemia

Molybdenum co-factor defect

Folinic-acid responsive seizures

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SIDS or BRUE

Fatty acid oxidation disorders
Amino acid disorders
Organic acidemias
Urea cycle disorders
Mitochondrial disorders

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Dysmorphic Features

Peroxisomal disorders

Pyruvate dehydrogenase deficiency
Congenital disorders of glycosylation
Lysosomal storage diseases.

Non immune hydrops Fetalis

Lysosomal storage disorder
congenital disorder of glycosylation

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Cardiomyopathy

Hypertrophic cardiomyopathy

GSD type II (Pompe disease)

Mucopolysaccharidoses

Dilated cardiomyopathy

Fatty acid oxidation disorders,

Organic acidemias, and

Mitochondrial disorders

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Diarrhea with hepatomegaly
GSD Type 1
Wolman’s disease
Hypercholesterolemia
Infantile Refsum disease
Respiratory chain disorders

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Hepatic Failure(Jaundice, Ascites, Hypoglycemia, Coagulopathy)

Tyrosinemia

Galactosemia

Neonatal hemochromatosis

Glycogen storage disease type IV.

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Persistent and severe hypoglycemia

Galactosemia

Fatty acid oxidation defects

Glycogen Storage Disorders & disorders of gluconeogenesis.

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Low maternal serum estriol

Smith-Lemli-Opitz syndrome

Decreased fetal movement

GSD type IV

Lysosomal storage diseases

Peroxisomal disorders( Zellweger syndrome)

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The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), Acute fatty liver of pregnancy (AFLP), and hyperemesis are associated with long-chain 3-hydroxyacly-CoA dehydrogenase deficiency

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Laboratory Test

Complete blood count:

Liver function tests

Urine reducing substances

Serum uric acid, Triglycerides

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Arterial blood gases

Blood glucose

Plasma ammonia

Urine ketones

Serum lactate

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Normal Plasma Ammonia

No Acidosis

PKU, Non Ketotic Hyperglycinemia,

Galacosemia, Peroxisomal disorders

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High Plasma Ammonia

No Acidosis

No Ketosis

UREA CYCLE DEFECT

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Normal or High Plasma Ammonia

Acidosis

Ketosis

Organic acidemias, Mitochondrial disorders

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Normal or High Plasma Ammonia

Acidosis

No Ketosis

Fatty acid oxidation defects

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Quantitative plasma amino acids

Acylcarnitine profile�

�

Qualitative urine organic acids

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Neuroimaging

Zellweger syndrome has diffuse cortical migration &sulcation abnormalities
Menke’s disease, pyruvate decarboxylase deficiency & nonketotic hyperglycinemia: Agenesis of corpus callosum has been reported in
Maple syrup urine disease (MSUD): brainstem & cerebellar edema.
Propionic & methylmalonic acidemia: basal ganglia signal change.
Glutaric aciduria: frontotemporal atrophy, subdural hematomas.

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Metabolomic profiling

An emerging clinical diagnostic test that can screen for hundreds of small molecules in a single test.
Attractive feature of metabolic profiling is small number of human metabolites (approximately 7000) relative to the estimated numbers of genes (25,000), transcripts (100,000) and proteins (1,000,000).
Provides most integrated measure of phenotype and medical condition.

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Molecular genetic testing

Congenital disorders of protein glycosylation and mitochondrial/energy disorders
Significant role in assessing eligibility for novel therapies as they are developed

Genetic variants are not always identifiable

Variants of uncertain pathogenicity are identified that require some functional (biochemical or enzymatic) confirmation

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IMMEDIATE MANAGEMENT �

Aggressive treatment before confirmation of the diagnosis may be lifesaving

Pending confirmation of the diagnosis, supportive interventions are undertaken.

Fluid resuscitation, removal of accumulating metabolites, and prevention of catabolism (by promoting anabolism).

Selected cofactors may be administered, before confirmation of the diagnosis and in some cases to support the diagnosis

infants and children with critical metabolic illness require immediate management to prevent further acute deterioration and long-term sequelae. Appropriate and aggressive treatment before confirmation of the diagnosis may be lifesaving or prevent or reduce the long-term neurologic sequelae of some of these conditions [10,18,21].

Pending confirmation of the diagnosis, supportive interventions are undertaken. These include provision of ventilatory support and fluid resuscitation, removal of accumulating metabolites, and prevention of catabolism (by promoting anabolism). In addition, selected cofactors may be administered, if indicated, before confirmation of the diagnosis and in some cases to support the diagnosis (eg, pyridoxine) [2,27].

Specific therapy is usually initiated after confirmation of the diagnosis. Treatment should be planned in consultation with a geneticist or specialist in metabolic disease

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Stabilize circulation, airway, and breathing �

Fluid resuscitation with usually normal saline, Lactate (ie, lactated Ringer's solution) should be avoided because of the potential to exacerbate lactic acidosis

The administration of hypotonic fluids may cause cerebral edema .

Ventilatory support should be provided as necessary when direct toxic effects of metabolites cause respiratory depression or cerebral edema.

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Treat hypoglycemia to prevent catabolism �

An infusion rate of 8 to 10 mg of dextrose per kilogram body weight per minute should be adequate to suppress catabolism

Insulin as a continuous IV infusion (0.05 units per kilogram body weight per hour) may be administered to maintain serum glucose between 100 and 120 mg/dL

Treatment of hypoglycemia should be initiated as soon as possible. Administration of intravenous (IV) dextrose (with electrolytes) provides energy and prevents catabolism. An infusion rate of 8 to 10 mg of dextrose per kilogram body weight per minute should be adequate to suppress catabolism. Dextrose solutions containing up to 10 percent dextrose can be infused through a peripheral IV catheter. Central IV access may be necessary to administer higher concentrations of dextrose if initiation of oral intake will be delayed for more than 24 hours. Critical blood samples for evaluation of metabolic causes of hypoglycemia should be obtained before treatment, if possible (see 'Hypoglycemia' above). The treatment of hypoglycemia is discussed in detail separately. (See "Management and outcome of neonatal hypoglycemia" and "Approach to hypoglycemia in infants and children", section on 'Immediate management'.)

Insulin as a continuous IV infusion may be administered if necessary to promote anabolism and maintain serum glucose between 100 and 120 mg/dL (5.56 mmol/L to 6.67 mmol/L). A typical dose for insulin in these situations is 0.05 units per kilogram body weight per hour as a continuous IV infusion. The rate should be adjusted based upon blood sugar levels [2].

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Correct metabolic acidosis �

Bicarbonate may be necessary to correct metabolic acidosis

Overcorrection of acidosis may have adverse effects on the central nervous system

Administration of bicarbonate to hyperammonemic patients should be avoided since it may cause cerebral edema and decrease the urinary excretion of ammonia

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Management of hyperammonemia�

Sodium benzoate (IV/oral)- loading dose 250 mg/kg then 250400mg/kg/day in 4 divided doses. (IV preparation not available in PAK)

Sodium phenylbutyrate (not available in Pak)-loading dose 250 mg/kg followed by 250-500 mg/kg/day.

L-arginine (oral or IV)- 300 mg/kg/day (IV preparation not available in PAK) L-carnitine (oral or IV)- 200 mg/kg/day

Dialysis is the only means for rapid removal of ammonia and hemodialysis is more effective and faster than peritoneal dialysis

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Indication Of PD

Intractable Metabolic acidosis

Ammonia level greater 500

Severe electrolyte imbalance (serum sodium 160meq)

Coma

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Discontinue all feeds. Provide adequate calories by intravenous glucose and lipids.

Start intravenous lipid 0.5 g/kg/day (up to 3 g/kg/day).

After stabilization gradually add protein 0.25 g/kg till 1.5 g/kg/day.

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Rememebr

Long exclusion of protein intake can result in breakdown of endogenous protein

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COFACTOR REPLACEMENT THERAPY

The catalytic properties of many enzymes depend on the participation of non protein prosthetic groups, such as vitamins & minerals as obligatory cofactors. �

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L-carnitine: 100-200 mg/kg /day in three divided doses

Biotin 10 mg/day

Vitamin B12 1-2 mg/day

Thiamine: up to 300 mg/day in 4 divided doses

Riboflavin: 100 mg/day in 4 divided doses.

Co-enzyme Q10: 5-30 mg/kg/day in three divided doses

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��

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��Treatment of newborn with refractory seizures (suspected metabolic etiology)��

If patient persists to have seizures despite 2 or 3 antiepileptic drugs in adequate doses, consider trial of pyridoxine 100 mg intravenously. If IV prep not available, oral pyridoxine can be given (15 mg/kg/day).

If seizures persist despite pyridoxine, give trial of biotin 10 mg/day and folinic acid 15 mg/day (folinic acid responsive seizures).

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�Management of asymptomatic newborn with a history of sibling death with suspected IEM�

After baseline test start oral glucose polymer or dextrose feeds

After 24 hours start breast feeds.

Monitor sugar, blood gases and urine ketones, blood ammonia Q6 hourly.

Some recommend starting (MCT oil) before starting breast feeds.

After 48 hours, repeat metabolic screen. Obtain samples for urine organic acids

Need careful observation and follow-up for the first few months, as IEM may present in different age groups in members of the same family.

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Emergency Management at Home�

Administration of emergency Solution

The solution is given orally if able at a minimum of 3 hourly intervals and

during night as well .�If the patient has a tube feeding the feeds be given through it for better

toleration .

Normal diet should be discontinued:�Prevent toxins accumulation .�Encourage appetite & promote tolerance to Emergency Protocol .

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Take Home Message

IEM must be suspected in all critically ill newborns

Seizures ,Hypoglycemia
Coarse facies/dysmorphic features
Parenchymal liver disease
Cardiomyopathy
Organomegaly
Unexplained acidosis
Corneal opacity, cataract or dislocation of lens
Hyperammonemia

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Aggressive management with 1.5 times maintenance IV fluid (D10 with half normal saline) should be started immediately

Protein should be restricted for 24 to 48 hours

Metabolic acidosis must be corrected along with cofactor replacement therapy
If no improvement in 48 hours ,PD should be planned

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Thank you