IEM - Heart DiseaseDr J P Soni

Professor

Dep Pediatrics

MCH, MDM Hospital

Inborn errors of metabolism (IEM) occur in approximately

1 in 4000 newborns.

It comprise more than 1000 distinct disorders in the

Online Mendelian Inheritance of Man database.

Why this talk?

• Metabolic disease is tough.

• Often thought of in last - as Differential Diagnosis and for that

tests are not easily available or they beyond the reach of parents because of

cost.

• most of the time these disorders have Catastrophic Outcomes.

• Heart disease in association with Metabolic disorders are even more tough to diagnose.

IEM are mostly transmitted as

Autosomal recessive

Very few disorders are either AD or X linked

Etiology of IEM - Heart diseases

Incidence of

CHD’s is 8-10/1000

IEM –Heart diseases are

Even more rare

Idiopathic

(Unknown etiology)Genetic defects

CHD’s

With

Genetic disorders

CHD’S

Without IEM

CHD’S

With IEM

Syndrome with CDH’s Genetic cause of CHD’s

Genomic Mutation ( Disorder of chromosome number or dosage)

Trisomy 21, 13, 18; Monosomy - OX Unknown

Chromosomal Mutation (deletion, insertion, inversion)

Di George Syndrome 22q11.2 deletion resulting in absent TBX1 Gene

Willams- Beuren Syndrome 7q11 Deletion, ELN gene

Genetic Mutation (Single gene disorders)

Noonan Syndrome Mutation in PTPN11,SOS1,RAF1,KRAS,BRAF, MEK1,MEK2 and HRAS

Holt –Oram Syn TBX 5 Mutation

Alagille Syn JAG1 or Notch mutation, Microdeletion or rearrangement at 20p12

resulting in absent JAG1 gene

Cardiofaciocutaneous Syn Mutation in KRAS,BARK,MEK1or MEK2; microdeletion at 22q11.2

Ellis –van Creveld Syn Mutation in EVC or EVC2

Marfan Syn Fibrillin-1 (MFS) TGFBR (MFS type II or Loeys-Dietz)

Char Syn Mutation in TTAP2B

CHARGE Syn Mutation in CHD7 and SEMA3E, microdeletion at 22q11.2

Costello Syn Mutation in HRAS(overlap with Noonan and

Cardiofaciocutaneous syn

Common Presentations of IEM• Encephalopathy with metabolic acidosis

• Encephalopathy without metabolic acidosis

• Neonatal hepatic syndrome

• Hypoglycemia

• Cardiac - Cardiomyopathy and heart failure - Non-immune hydrops fetalis

Hypertrophic cardiomyopathy

Dilated cardiomyopathy and

Mixed/other type of cardiomyopathy,

Arrhythmia, Conduction defect

Valvular Dysfunction- MR,AR,TR, Aortic Dilatation

They are of particular interest to clinicians because many have disease-specific treatments.

In Lysosome disorders

Bulk storage

Of substrate is responsible

cellular dysfunction

Mitochondrial Disorders - Impaired Energy production –ATP – cellular dysfunction

Mitochondrial Disorders

Micro Molecule

IEM Heart diseases

Micro Molecule

IEM Heart diseases

The micro molecular IEM like - Organic acidemia

Amino acidurias

Refsum disease and

Disorders of oxidative phosphorylation

Causes the production of toxic metabolites.

These TOXIC metabolites exert their deleterious effect by

Lowering the cellular pH (acids)

Inhibiting intermediary metabolism (acyl-CoA),

Oxidizing mitochondrial components such as DNA, lipids,

and proteins structures (free radicals).

Disorders of Amino Acid and Organic Acid

•Propionic acidemia – DCM

•Methylmalonic aciduria

•Malonic academia

•β-ketothiolase deficiency – DCM

•Mevalonic academia

•Tyrosinemia - HCM

•Oxalosis - HCM, RCM*

Micro Molecule Micro Molecule

IEM Disorders may be ofIEM Disorders may be of

Disorders of Glycogen Metabolism

•GSD II (Pompe disease, acid α-glucosidase/acid maltase) – HCM

•GSD III (Cori disease; debranching enzyme) – HCM

•GSD IV (Anderson disease; branching enzyme) – DCM

•GSD IX (cardiac phosphorylase kinase) – HCM

•PRKAG2 Deficiency – HCM with Wolff-Parkinson-White Syndrome

•Danon Disease (Pseudo-Pompe disease with normal acid maltase; LAMP2) – HCM

Disorder of Glycoprotein Metabolism

•Congenital disorders of Glycosylation – HCM

Micro Molecule

IEM Heart diseases

Micro Molecule

IEM Heart diseases

Now we will discuss few common Micro molecular disorders and heart diseases

The offspring of female suffering from PKU is at risk to develop several CHD’s if

maternal phenylalanine level is more than 900 microM %mg /dl (hyperphenylalaninemia).

Elevation of serum homocystine and methionine clinches the diagnosis of classical homocystinuria due

to CBS enzyme deficiency.

Prenatal diagnosis is by enzyme assay in amniocytes and

The neonatal screening is by high performance liquid chromatography is also possible.

The patients with Homocystinemia may have valvular heart defects –

Mitral regurgitation

Aortic regurgitation.

It has been seen that offspring's of women with MTHR gene mutation may have congenital heart

defects involving abnormalities of the great vessels (eg aorta; aortic valve; pulmonary artery; pulmonic valve).

Other cardiovascular manifestations include premature atherosclerosis and thromboembolic episodes.

It is hypothesized that homocystine results in altered expression of thrombomodulin in endothelial cells

result in platelet aggregation and thromboembolism involving major arteries and veins.

Alkaptonuria

•Alkaptonuria is a very rare congenital metabolic disorder that affects about 1 in 1 million births.

•This disease is transmitted by a single recessive autosomal gene, resulting in an irreversible, progressive, connective

tissue disease.

•Alkaptonuria is associated with homogentisic acid (HGA) oxydase enzyme deficiency .

•Homogentisic acid oxydase deficiency causes the excretion of large quantities of HGA in the urine, which turns dark

upon standing.

•Calcification of the heart’s Aortic, mitral and Tricuspid valve

•Calcification of the coronary arteries.

• Although the most common clinical feature is severe ochronotic spondyloarthropathy, a wide spectrum of clinical

manifestations—including ocular and cutaneous pigmentation, genitourinary obstruction by ochronotic calculi, and

cardiovascular system involvement

Adenosine monophosphate Protein kinase,

AMP activated, Gamma 2 non(PRKAG2)

The heterozygous mutations in the PRKAG2 gene is associated with the lethal congenital form

of no lysosomal Glycogen Storage Disease of the Heart - HCM and preexcitation –WPW

syndrome..

While the WPW and HCM-WPW causative mutations are inherited in an autosomal dominant

Mitochondrial disorders The main sources of energy in the

heart are fatty acids and secondarily

glycogen.

The Cardiac Muscle need high energy, because each

cell is packed with myofibrils that are specialized for

contraction.

Hydrolysis of ATP by the myosin heads provides the

force necessary to slide the myosin-containing thick

filaments over the actin-containing thin filaments

during sarcomere contraction.

1.Fatty acids that are not broken down

accumulate in cells, causing metabolic crisis,

cardiac arrhythmia, cardiomyopathy,

Mitochondria 2. When there is defects in oxidative phosphorylation

at mitochondria

There is inadequate production of ATP

The adaptive response of the heart muscle to inefficient

contraction is hypertrophy.

That why many IEM with mitochondrial disorders are

associated with Hypertrophic cardiomyopathy.

Fatty acid oxidation disorders and disorders of mitochondrial oxidative phosphorylation account for ≈15% of cardiomyopathies in infants.

Hypothetic mechanism for cardiac arrhythmias in fatty acid oxidation disorders

Damien Bonnet et al. Circulation. 1999;100:2248-2253

In Carnitine phosphate transferase- I defect -

The accumulation of acylcarnitine

May have toxic effects on the phospholipids of the sarcolemma and may interact with different ionic channels

Lead to arrhythmia

Glutaric acidaemias (GAs)

Glutaric acidemia type I - Glutaryl-CoA dehydrogenase plays a key role in the metabolism of lysine,

hydryoxylysine and tryphtophan. It deficiency leads to GAstype I

.

Glutaric acidemia type II is caused by a deficiency in two enzymes-

Electron transfer flavoprotein and

Electron transfer flavoprotein dehydrogenase .

These enzymes in mitochondria break down proteins and fats to provide energy for the body.

When one of the enzymes is defective or missing, partially broken down nutrients accumulate in

the cell and damage them.

Glutaric aciduria type III - A defect is caused by peroxisomal glutaryl-CoA oxidase deficiency.

Peroxisomes play an important role in the metabolism of long-chain and very long-chain fatty acids, the

biosynthesis of plasmalogens, cholesterol synthesis, bile acid synthesis, amino acid metabolism and purine metabolism

Glutaric aciduria type II.

1-day-old child was referred for neonatal cardiac control because fetal echocardiography diagnosed atrial bigeminy during routine follow-up.

Neonatal Echocardiography was normal and 12-lead ECG showed premature atrial and ventricular beats.

During his first month of life, the patient experienced many episodes of atrial tachycardia. The diagnosis of fatty acid oxidation disorder was suspected because of neonatal recurrent hypoglycemia. At 4 months of age, hypertrophic hypokinetic cardiomyopathy was diagnosed; the child died at 7 months of age during cardiogenic shock.

1-day-old boy was referred to the neonatal intensive care unit for tachycardia. A 12-lead ECG showed polymorphic ventricular tachycardia.

Echocardiography was normal, as was liver function, renal function, and neuromuscular examination. Sinus rhythm was restored by amiodarone. At 9 months of age, he had Reye syndrome, which led to the diagnosis of VLCAD deficiency.

Conduction disorders and atrial tachycardias were observed in patients with defects of long-chain fatty acid transport across the inner mitochondrial membrane –

Carnitine palmitoyl transferase type II deficiency Carnitine acyl carnitine translocase deficiency and The patients with trifunctional protein deficiency.

Ventricular tachycardias were observed in patients with any type of fatty acid oxidation deficiency.

Inborn errors of fatty acid oxidation should be considered in unexplained sudden death or near-miss in infants and in infants with conduction defects or ventricular tachycardia.

Conclusion - The accumulation of Arrhythmogenic intermediary metabolites of fatty acids, such as long-chain acyl carnitines, may be responsible for arrhythmias.

Refsum disease

Cardiac involvement is characterized by with conduction abnormalities and cardiomyopathy.

Refsum disease is characterized by anosmia and early-onset retinitis pigmentosa, which are both universal findings

with variable combinations of neuropathy, deafness, ataxia, and ichthyosis. Onset of symptoms ranges from age

seven months to over age 50 years.

Phytanic acid is almost only of dietary origin: Restriction of the diet reduces plasma and tissue levels.

The average daily intake of phytanic acid is 50-100 mg/day and this should ideally be reduced to 10-20 mg/day

Fish, beef, lamb and dairy products should be avoided.

Poultry, pork, fruit and other vegetables are allowed.

It is present in green vegetables but is tightly bound to chlorophyll

Disorders of Fatty Acid Metabolism

Carnitine Transport Defects

•Systemic primary carnitine deficiency – HCM, DCM

•Muscle carnitine deficiency – HCM, DCM

•Carnitine - palmitoyl transferase type II deficiency

•Carnitine acyl carnitine translocase deficiency

Fatty Acid Oxidation Defects

•Very long-chain acyl-CoA dehydrogenase deficiency – HCM

•Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency – HCM, DCM

•Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

•Multiple acyl-CoA dehydrogenase deficiency (glutaric academic type II) –

HCM

Mitochondrial Disorders

•Pyruvate dehydrogenase deficiency (Leigh disease) – HCM

•Complex I Deficiency – DCM

•Complex II Deficiency –

•Complex III Deficiency (Histiocytoid Cardiomyopathy) – HCM

•Complex IV Deficiency (muscle and Leigh disease forms) – HCM

•Complex V Deficiency – HCM

•MELAS (Mitochondrial transfer RNA mutation) – HCM

•MERFF (Mitochondrial transfer RNA mutation) – HCM, DCM

•Kearns-Sayre syndrome (mitochondrial DNA deletions/duplications) – HCM

•Barth syndrome (3-methylglutaconic aciduria type II) – HCM, DCM, Mixed

•Sengers syndrome – HCM

Peroxisomal Disorder

•Refsum disease (phytanic acid oxidase) – HCM, DCM

The Lysosomal Storage diseases is due bulk storage and infiltration of

substrate - Macro-molecules i.e. -

Triglycerides (fatty acid oxidation defects and

carnitine transport disorders)

Glycogen (hydrolysis) and

Mucopolysaccharides,

oligosaccharides,

glycolipids and

glycogen).

Eventually, they may occupy a large amount of the cytoplasm

& lysosomes become greatly increased in size and number.

This have a mechanical effect on cardiomyocyte

functioning by disrupting the alignment of myofibrils required for

efficient contraction.

Mucopolysaccharidosis are a group of metabolic disorders caused by the absence or malfunctioning

of lysosomal enzymes needed to break down molecules called glycosaminoglycans - long chains of sugar

carbohydrates in each of our cells that helps to

Build bone, cartilage, tendons, corneas, skin and connective tissue. Glycosaminoglycans are also found in the fluid that lubricates our joints.

The patients with mucopolysaccharidosis disease either do not produce enough of one of the 11 enzymes

required to break down these sugar chains into simpler molecules, or they produce enzymes that do not work

properly

Cardiac involvement has been reported in all MPS syndromes and is a

common with MPS I, II, and VI.

Cardiac valve thickening, dysfunction (more severe for left-sided than

for right-sided valves)

Hypertrophy of myocardium

Conduction abnormalities

Coronary artery and other vascular involvement may also occur.

Cardiac disease emerges silently

The mitral valve leaflets are markedly thickened like cartilage, particularly valve edges are thickened.

The subvalvular apparatus of the mitral valve develops shortened chordae tendineae and thick papillary muscles

resulting in dysmorphic and poorly mobile leaflets

Rx

ERT, supplying exogenous human

recombinant enzyme by regular intravenous

infusion, is approved for three types of

MPS;

laronidase for MPS I ,

Idursulfase for MPS II and

Galsulfase for MPS VI

Lysosomal Storage Disorders

Disorders of Mucopolysaccharide (Glycosaminoglycan) Metabolism

•MPS I (Hurler, Hurler-Scheie, and Scheie syndromes) – HCM, DCM

•MPS II (Hunter syndrome) – HCM

•MPS III (Sanfilippo syndrome) – HCM

•MPS IV (Morquio syndrome) – HCM

•MPS VI (Maroteaux-Lamy syndrome) – DCM

•MPS VII (Sly syndrome) – HCM

Disorder of Glycogen Metabolism

•GSD II (Pompe disease, acid α-glucosidase/acid maltase) – HCM

•Danon Disease (Pseudo-Pompe disease with normal acid maltase; LAMP2) – HCM

Disorders of Glycosphingolipid Metabolism

•Gaucher disease (glucocerebrosidase) - HCM*

•Fabry disease (α-galactosidase) – HCM

•*

Disorders of Combined Ganglioside, Mucopolysaccharide,

and Oligosaccharide Metabolism

•GM1 Gangliosidosis (HCM, DCM)

•GM2 Gangliosidosis (Sandhoff disease) – HCM, DCM

Disorders of Glycosphingolipid Metabolism

•Gaucher disease (glucocerebrosidase) - HCM*

•Fabry disease (α-galactosidase) – HCM

•*

Disorders of Combined Ganglioside, Mucopolysaccharide, and

Oligosaccharide Metabolism

•GM1 Gangliosidosis (HCM, DCM)

•GM2 Gangliosidosis (Sandhoff disease) – HCM, DCM

Non-immune fetal hydrops

• Baby with Lysosomal storage diseases Gaucher type 2, Niemann –pick type C , GM1 Gangliosidosis, may be born with severe peripheral edema, which can have variable course -Excrete and improve; worsen and die

1. To reduce the formation of toxic metabolites by decreasing

availability of substrate.

2. To provide adequate calories.

3. To enhance excretion of toxic metabolites.

4. To institute co-factor therapy for specific disease and also

empirically if diagnosis is not established.

5. Supportive treatment- control seizures, maintain euglycemia,

body temperature, electrolyte and acid-base balance,

control infection and respiratory support, if needed.

Carnitine Deficiency L - Carnitine 100-400mg/kg/24hours or 25-100

mg/kg/day IV

Methyl malonic acidemia Vit B12 1 mg/Day, In addition to a protein mixture that

is devoid of methionine, threonine, valine, and isoleucine,

the patient should also receive L-carnitine treatment and

should be given antibiotics 10 days per month in order to

remove the intestinal propiogenic flora. The patient

should have diet protocols prepared for him with a “well

day diet” with low protein content, a “half emergency

diet” containing half of the protein requirements, and an

“emergency diet” with no protein content.

Glutraic aciduria type II Riboflavin 100-300mg/day Thiamine10-200mg/day

MSUD Thiamine10-200mg/day Riboflavin 100-300mg/day

Mevalonic acidemia Prednisone2mg/kg/day

Homocystinuria Pyridoxine 200-1000/day

Multiple carboxylase deficiency Biotin 10-60 mg/day oral

Biotinidase deficiency Biotin

Refsum disease

Phytanic acid is almost only of dietary origin:

The average daily intake of phytanic acid is 50-100 mg/day and this should ideally be reduced to 10-20

mg/day

Fish, beef, lamb and dairy products should be avoided.

Poultry, pork, fruit and other vegetables are allowed.

It is present in green vegetables but is tightly bound to chlorophyll

Neonatal ventricular arrhythmias are usually considered idiopathic when they are not associated with primary cardiac tumors, cardiac malformations, or a prolonged QT interval.

Idiopathic ventricular tachycardia is rare in neonates, is usually monomorphic, and has a good prognosis.

Regarding the conduction defects, the main cause of atrioventricular block in newborn infants is lupus or Gougerot - Sjögren disease in the mother.

The metabolic screening should be performed to exclude a fatty acid oxidation disorder in neonate with Atypical and severe cardiac arrhythmias, conduction defect, Acidosis and hypoglycemia.

Diagnosis can be easily ascertained by an Acylcarnitine profile from blood spots

on filter paper.

Inborn errors of metabolism (IEM) account for only 5% of all pediatric cardiomyopathy and 15% of those with

known causes, but they are of particular interest to clinicians because many have disease-specific treatments.

IEM – Heart disease should be suspected in neonate and infant if he is having

Cardiomyopathy

Conduction block without CHD and Neonatal SLE

Preexcitation syn with HCM & Hypoglycemia

Valvular lesion – MR,AR, Thickening

Dysmorphism with cardiomyopathy

Hyogylycemia with cardiomyopathy or arrhythmia

IEM – Heart disease can be treated with Vitamins, Enzyme replacement therapy

PKUA single mutant recessive allele of the Phenylalanine

Hydroxylase (PAH) gene Location : Long arm of Chromosome

12 -locus 22.

Missense mutations and deletions.

PAH only allow a tolerance of 20 mg/kg/day.

Dietary excess of plant proteins which results in the exhaustion of a protein cofactor Tetrahydrobiopterin BH4 needed by the enzyme.