INHERITED METABOLIC DISORDERS

HATEM EL-SHANTI, MD

PEDIATRICS AND MEDICAL GENETICS

UNIVERSITY OF JORDAN

SCHOOL OF MEDICINE

HISTORY• Garrod’s (1857-1936) book “Inborn Errors of

Metabolism,” published 95 years ago, demonstrates the relationship between biochemistry, genetics and health

• By 1960, defects leading to accumulated metabolites in urine, blood or organs were studied and identified

• In the next 20 - 25 years, identification of a plethora of inherited metabolic diseases; the defects were identified by biochemistry of intermediates and enzymes

• The last decade of the 20th century witnessed a shift from biochemical to molecular methods with identification of mutations in genes responsible for the disorders

• 21st century saw the Human Genome ProjectEl-Shanti 23/28/2018

DEFINITIONS

• Metabolism comprises all biochemical processes occurring in the human body– Catabolism– Anabolism

• Biochemical reactions are grouped into pathways that are interrelated resulting in all physiologic activities

• Inherited Metabolic Diseases, inborn errors of metabolism, are disorders in the mechanism by which major foods are converted to energy or cellular and tissue building blocks and other products and the mechanisms by which all these products are degraded for excretion

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ENERGY PRODUCTION

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UREA CYCLE

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EPIDEMIOLOGY

• Individual inherited metabolic disease is rare, but collectively are common

• About 1,000 individual disorders are described so far• 1: 780 have an inherited metabolic disease and more

than 1: 500 are carriers • Most inherited metabolic disease are autosomal

recessive disorders, some are X-linked recessive, and very few show autosomal or X-linked dominant or mitochondrial inheritance

• Many of these disorders are treatable by diet and drugs• Quick, early and accurate diagnosis is advised to ensure

early treatment

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INHERITED METABOLIC DISEASES: TYPES• Disorders of toxic accumulation:

– Amino acid catabolism: PKU, MSUD, homocystinuria, tyrosinemia

– Organic acidurias: methylmalonic, propionic, iso-valeric, glutaric

– Sugar intolerance: galactosemia, hereditary fructose intolerance

– Metal intoxication: Wilson disease, hemochromatosis

– Porphyrias

• Disorders of energy production:– Mitochondrial: congenital lactic acidemia, fat oxidation disorders

– Cytoplasmic: disorders of glycolysis, gluconeogenesis, hyperinsulinism

• Disorders of large molecules: – Lysosomal storage diseases

– Peroxisomal disorders

– Disorders or cellular trafficking or processing: congenital disorders of glycosylation, errors of cholesterol synthesis

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IMD:CLINICAL PRESENTATION:HISTORY

• NEONATAL HISTORY:– Symptoms of intoxication: symptom-free period (few hours to 3 days);

lethargy; poor feeding; full decompensation. Urea cycle defects; organic acidemia, galactosemia (end of the week), tyrosinemia (late) [toxic accumulation type]. DD: sepsis and duct-dependent heart lesions.

– Lactic acidosis: metabolic acidosis; respiratory distress; tired. Mitochondrial disorders and disorders of pyruvate metabolism

– Dysmorphic features: blocks in making of complex molecules that are key to cell signaling and embryogenesis present with a pattern of dysmorphism. Zellweger syndrome and congenital disorders of glycosylation

– Seizures: hiccup followed by apnea or overt seizures. Glycine encephalopathy (non-ketotic hyperglycinemia), pyridoxine-dependent seizures. DD: hypoxic/ischemic events

– Vomiting and/or Diarrhea: hyperammonemia and CHO malabsorption

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CLASSIC GALACTOSEMIA• Disorder of galactose metabolism

• Galactose-1-phosphate uridyl transferase

• Mutation in GALT, autosomal recessive

• Presentation within a few days to one week

• Poor feeding, lethargy, vomiting

• Liver-cell damage, liver failure with jaundice and bleeding

• Overwhelming bacterial sepsis and shock (E. coli)

• Cataracts, speech difficulty, intellectual impairment, premature ovarian failure in females

• Stop breast or formula milk immediately; provide a lactose-free formula (sucrose)

• Emergency treatment may be necessary

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TYROSINEMIA• Disorder of tyrosine degradation

• Fumarylacetoacetate hydrolase

• Mutation in FAH, autosomal recessive

• Screening with succinylacetone

• Presentation within a few months

• Failure to thrive, vomiting, diarrhea

• Liver failure with jaundice and bleeding

• Renal tubular failure with rickets

• Neurologic crisis: mental status change, neuropathy, abdominal pain and respiratory failure (1-7 days)

• Risk of hepatic cancer

• Nitisinone (NTBC), with low phenylalanine and tyrosine diet

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ZELLWEGER SYNDROME

• Peroxisomal disorder

• Very long chain fatty acids

• Myelin breakdown

• 12 genes: peroxins [PEX1-12]

• Presents in newborn period– Hypotonia; poor feeding

– Dysmorphic features

– Hearing & vision loss

– Seizures

– Liver problems

– Kidney problems

– Neuronal migration defects

– Chondrodysplasia punctata

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GLYCINE ENEPHALOPATHY• Non-ketotic hyperglycinemia

• Heterogeneous, autosomal recessive

• Glycine is non-essential amino acid as it is made from serine

• Glycine is a neuro-inhibitor in the brain and is excitatory at the spinal cord

• Due to errors in glycine cleavage system (enzyme complex), leading to accumulation of glycine

• Presentation is shortly after birth

• Lethargy, poor feeding, hypotonia, myoclonic jerks, apnea

• Those who survive have intractable seizures and severe intellectual disability

• Diagnosis is by measuring CSF and plasma glycine with the ratio being more than 0.09

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ORNITHINE TRANSCARBAMYLASE DEFICIENCY• Urea cycle defect

• X-linked, severe in males, females may have a milder disease

• Presentation at birth or later with symptoms of hyperammonemia

• Lethargy, poor feeding, hypotonia, vomiting, respiratory distress, seizures, coma

• Developmental delay, intellectual disability, progressive liver damage

• Decompensation episodes

• Treatment with scavenger drugs, citrulline, low protein diet, avoidance of valproate and systemic steroids

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IMD:CLINICAL PRESENTATION:HISTORY

• OBSTETRIC HISTORY:– Excessive movement may indicate in utero seizures

– Previous multiple spontaneous abortions

– Maternal complication: Hyperemesis gravidarum; acute fatty liver of pregnancy and HELLP syndrome (hemolysis; elevated liver enzymes; low platelets) associated with fat oxidation disorders particularly the long chain and very long chain acyl-coA dehydrogenase deficiency (LCAD & VLCAD)

• FAMILY HISTORY: – Obtain a three generation pedigree

– Recessive: consanguinity, healthy parents, recurrence

– X-linked: affected males, although some disorders may be present in a milder form in females, such as ornithine transcarbamylase (OTC) deficiency

– Mitochondrial DNA disorders: matrilineal with heteroplasmy

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IMD:CLINICAL PRESENTATION:HISTORY• PAST MEDICAL HISTORY:

– Hospital admission: pneumonia (lactic acidosis)

– Cardiac presentation: cardiomyopathy

– Liver disease: jaundice

– Eye symptoms: retinopathy or cataract (galactokinase deficiency, galactosemia type 2)

– Cyclic vomiting and/or Diarrhea

• DIETARY HISTORY:– Avoidance of food: avoidance of proteins in urea cycle or sugars in

hereditary fructose intolerance

• GROWTH AND DEVELOPMENTAL HISTORY: – Most inherited metabolic disorders have some impact on development with

a few exceptions like MCAD deficiency El-Shanti 173/28/2018

HEREDITARY FRUCTOSE INTOLERANCE

• Inability to metabolize fructose

• Autosomal recessive disorder

• Mutations in Aldolase B [ALDOB]

• Introduction of fruits & juices

• Failure to thrive

• Ingestion will cause nausea and vomiting, abdominal pain and bloating, and hypoglycemia

• Repeated ingestions may lead to liver cirrhosis and failure, chronic renal disease and failure

• Avoidance of sweet foods

• Treatment is by dietary restriction of fructose, sucrose and sorbitol

• Treatment of liver and kidney disease3/28/2018 El-Shanti 18

THANK YOU

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