Inborn Errors of Metabolism

Inborn Errors of Metabolism (IEMs) constitute a diverse group of hereditary biochemical disorders, characterized by defects in specific enzymes. These enzymatic deficiencies lead to the accumulation of substrates and alternative metabolic products within the body:

• Heterogeneous Group: IEMs encompass a wide range of conditions, sharing the commonality of enzyme defects causing substrate buildup and altered metabolic pathways.
• Autosomal Recessive Inheritance: Most IEMs are inherited in an autosomal recessive manner, meaning both parents must carry the defective gene for the disorder to manifest in their offspring.
• The concept of IEMs was first introduced by Sir Archibald Garrod in 1902.
• While IEMs were historically referred to by this name, they are now often known as congenital metabolic diseases or inherited metabolic diseases.
• Genetic Basis: The majority of IEMs arise due to single gene defects. These genes code for enzymes essential in the conversion of various substances (substrates) into other compounds (products).

A typical chemical reaction in the body

But in the absence of the enzyme or cofactor Y,

Thus, when the factor Y is absent, a cascade of consequences unfolds:

• Accumulation of X: The deficiency of factor Y leads to an accumulation of substrate X.
• Deficiency of Z: Additionally, the inability to produce factor Y results in a deficiency of product Z, which would have been generated through its enzymatic action.

It's worth noting that the accumulated substance, substrate X, may or may not exert toxic effects within the body.

The clinical presentation of these disorders hinges on multiple factors:

• Toxicity of Precursor Products: The severity of clinical manifestations is influenced by the toxicity of accumulated precursor products.
• Alternative Synthetic Pathways: The presence or absence of alternative chemical reactions to synthesize the deficient product substance Z also impacts the clinical picture.

The epidemiological aspects of inborn errors of metabolism are multifaceted:

• Incidence in the USA: The incidence of IEMs in the United States is estimated to be around 1 in 1400 to 1 in 5000 live births. Similar incidence rates are observed globally.
• Approximately 20% of term neonates displaying features resembling sepsis lack the risk factors typically associated with sepsis. This subset may be indicative of underlying IEMs.
• Impact on Health: Individually rare, these disorders collectively contribute significantly to conditions such as failure to thrive, recurrent seizures, mental retardation, and sudden infant death syndrome (SIDS).
• Nigerian Context: In Nigeria, the incidence of individual IEMs is relatively low, estimated to range from 1 in 100,000 to 1 in 200,000 live births. However, when considered collectively, the prevalence increases to an estimated 1 in 1000 to 1 in 500 live births.
• No Gender Bias: Inborn errors of metabolism do not exhibit a significant predilection for either gender.
• Age of Onset Variability: The age of onset is influenced by various factors:
1. Type and Variant of IEM: Different IEMs may manifest at different ages due to variations in metabolic pathways and enzyme deficiencies.
2. Accumulation of Toxic Metabolites: Onset might be triggered by the accumulation of toxic metabolites or deficiency of essential substrates.
3. Environmental Factors: Factors such as diet and infections within the environment can also influence the timing of onset.

Morbidity and Mortality

The impact of inborn errors of metabolism extends to both morbidity and mortality:

• Morbidity Across Organ Systems: IEMs are known to potentially affect any organ system within the body. Furthermore, these disorders often involve the dysfunction of multiple organ systems, resulting in acute or chronic morbidity.
• Organ Dysfunction and Morbidity: The dysfunction of various organ systems contributes to morbidity, generating a range of clinical consequences.
• Neonatal Mortality: Certain IEMs, particularly those presenting in neonates, can lead to elevated mortality rates. The severity of these disorders and the critical developmental stages at which they manifest contribute to this increased risk of death.
• Impact in Adults: Even in adults, the initial presentation of certain IEMs can lead to life-threatening situations and mortality.

The pathophysiology underlying inborn errors of metabolism is intricate:

• Genetic Basis: These disorders originate from mutations in single genes.
• Enzyme and Transport Protein Defects: The majority of these mutations lead to defects in enzymes or transport proteins, affecting their structure or function.
• Impact on Biochemical Processes: These defects give rise to abnormalities in the synthesis or catabolism of carbohydrates, proteins, or fats.

Effects

The effects of inborn errors of metabolism encompass:

• Toxic Accumulation of Substrate: Accumulation of the substrate occurs prior to the enzymatic blockage.
• Accumulation of Intermediates: Metabolic intermediates stemming from alternative pathways can also accumulate.
• Defects in Energy Production: These disorders frequently result in defects in energy production.
• Deficiency of Products Beyond Blockage: The enzymatic deficiency often extends to the products generated beyond the blockage.

Mechanisms of Inborn Errors of Metabolism

The mechanisms underlying inborn errors of metabolism are varied:

• Accumulation of Substrates: Some IEMs involve the accumulation of substrates to toxic concentrations within a blocked catabolic reaction. Examples include maple syrup urine disease, glucose-galactose malabsorption, and galactosaemia.
• Production of Toxic Byproducts: Certain disorders lead to the production of toxic byproducts through pathways that are normally minor. Notable examples are tyrosinemia type I and adenosine deaminase deficiency.
• Deficiency of End-Products: In other cases, there is a deficiency of end-products within an anabolic pathway. Albinism, orotic aciduria, and Zellweger's syndrome are illustrative examples.
• Loss of Regulation: Loss of regulation can result in the overproduction of intermediates, leading to toxic levels. Conditions like congenital adrenal hyperplasia, intermittent porphyria, and familial hypercholesterolemia exemplify this mechanism.

The clinical features of inborn errors of metabolism can exhibit varying patterns:

• Unrelenting Course: Some cases follow an unrelenting course, marked by rapid life-threatening deterioration that occurs over a matter of hours.
• Episodic Presentation: Others manifest episodically, with intermittent decompensation episodes followed by asymptomatic intervals.
• Insidious Onset: Certain conditions have an insidious onset, characterized by slow and gradual degeneration.

Several key points regarding the clinical presentation:

• Timing of Presentation: Disorders involving carbohydrates and proteins often present early and demonstrate a tendency for progressive deterioration.
• Delayed Onset for Fats and Glycogen Storage Disorders: Disorders associated with fats, glycogen storage diseases, and lysosomal storage diseases tend to manifest insidiously during childhood.

Neonatal Features

• Initial Normalcy: Neonates often appear normal at birth.
• The condition can be severe and lethal in the absence of proper treatment.
• Sudden Deterioration: Clinical deterioration may occur suddenly in a previously healthy neonate.
• Persistent Symptoms: Signs to watch for include persistent unexplained vomiting, poor feeding, diarrhea, dehydration, temperature instability, tachypnea, apnea, and bradycardia.
• Peculiar Odor: Some conditions might exhibit a peculiar odor in sweat or urine.
• Metabolic acidosis
• Hepatomegaly
• Poor weight gain
• Irritability
• Abnormal tone
• Lethargy
• Posturing
• Seizures
• Coma

Childhood Features

• Onset of symptoms with change in diet or preference for unusual diet
• Unusual odor, especially during an acute illness
• Failure to thrive
• Unexplained mental retardation, delay, or loss of developmental milestones
• Convulsions with or without fever
• Routine illness associated with severe symptoms and rapid progression
• Metabolic acidosis
• Hepatomegaly
• Dysmorphic or coarse features
• Skin, hair, or skeletal abnormalities
• Renal stones
• Microcephaly
• Teeth or enamel hypoplasia
• History of unexplained neonatal or sudden infant death in siblings or maternal male relatives
• History of consanguinity

Precipitants of Episodic Symptoms

• Diet
• Stress – from intercurrent illness, trauma, surgery, or immunization

The physical examination findings in patients with inborn errors of metabolism can vary:

• Nonspecific Findings: Physical examination findings may be nonspecific, and in many patients, they might appear normal.
• Importance of Findings: However, when present, physical findings become crucial indicators of the presence, category, and sometimes even the specific metabolic disease.

Examination findings frequently relate to major organ dysfunction or failure, with hepatic and/or neurologic manifestations being most common. Cardiac or pulmonary abnormalities are less common. These abnormalities include:

• Failure to Thrive: Notable weight and growth deficiency.
• Dysmorphic Features: Presence of abnormal physical features.
• Abnormalities of Hair, Skin, Skeleton: Aberrations in hair, skin, or skeletal structures, or a combination of these.
• Abnormal Odor: Unusual body odor.
• Organomegaly and Cardiac Changes: Organomegaly, dilated or hypertrophic cardiomyopathy, and hepatomegaly.
• Jaundice and Liver Dysfunction: Indications of jaundice and liver dysfunction.

Diagnostic investigations for inborn errors of metabolism include a range of tests:

• PCV (Packed Cell Volume)
• Random Blood Glucose
• FBC (Full Blood Count) with differential
• Electrolytes, Urea, and Creatinine (E, U + Cr)
• ABG (Arterial Blood Gas)
• LFT (Liver Function Tests)
• PT (Prothrombin Time), PTTK (Partial Thromboplastin Time)
• Serum NH3 (Ammonia)
• Urinalysis for pH and ketones
• Urine Reducing Substances
• Plasma Lactate and Pyruvate
• Plasma Amino Acids
• Screening Tests:

Commonly used neonatal screening tests include Mass Spectrometry and the Guthrie Test.

Consideration of other conditions is vital to the diagnostic process:

• Sepsis
• Meningitis
• Reye Syndrome
• Electrolyte Derangement
• Viral Hepatitis

Various inborn errors of metabolism can be classified into distinct groups:

• Protein Metabolism - Amino Acidopathies: This group encompasses conditions such as phenylketonuria, tyrosinaemia, homocystinuria, and maple syrup urine disorder.
• Organic Acidopathies and Urea Cycle Defects: Disorders in this group include organic acidopathies and urea cycle defects related to glutamic aciduria.
• Lysosomal Storage Disorders: Diseases such as Hurler syndrome fall under this category.
• Peroxisomal Disorders: Zellweger's syndrome is an example of a peroxisomal disorder.
• Carbohydrate Metabolism - This group includes conditions like Glycogen Storage Disease, Galactosemia, fructose intolerance and primary lactic acidemia.

Inborn Errors of Amino Acid Metabolism Associated with Abnormal Odour

Inborn Error of Metabolism	Associated Abnormal Odor
Glutaric acidemia (type II)	Sweaty feet
Hawkinsinuria	Swimming pool
Isovaleric acidemia	Sweaty feet
Maple syrup urine disease	Maple syrup
Hypermethioninemia	Boiled cabbage
Multiple carboxylase deficiency	Tomcat urine
Oasthouse urine disease	Hops-like
Phenylketonuria	Mousy or musty
Trimethylaminuria	Rotting fish
Tyrosinemia	Boiled cabbage

• A defect in galactose metabolism
• Results from deficiency of enzyme Galactose-1-phosphate uridyl transferase
• Galactosemia denotes the elevated level of galactose in the blood
• Autosomal recessive disorder

Genetics

• The gene for uridyl transferase is located on chromosome 9p13.
• The most common mutation in galactosemia affects a specific part of the genetic code, changing the amino acid glutamine to arginine at position 188 in exon 6.
• Another common variation of the uridyl transferase enzyme, known as the Duarte variant (D), is caused by a change from adenine (A) to guanine (G) in exon 10. This alteration modifies the amino acid asparagine 314 to aspartic acid.

Pathogenesis

• The root cause of many acute symptoms in classic galactosemia is the accumulation of galactose 1-phosphate in body tissues.
• Cataracts, which are clouding of the lens in the eye, are thought to develop due to the buildup of galactitol. Galactitol causes swelling, protein clumping, and disruption of the lens fibers.
• The same galactitol-driven swelling process is believed to cause sudden swelling in the brain, termed acute cerebral edema.
• Galactose or its metabolites might affect the functioning of white blood cells (granulocytes), making them less effective in fighting infections, possibly leading to sepsis.

Types

There are two primary types of galactosemia:

• Classical Galactosemia involves the deficiency of the enzyme GALT, causing issues with galactose breakdown.
• Galactose Kinase Deficiency is another form resulting from an issue with the galactose kinase enzyme.

Classical Galactosemia

• A more severe disorder than galactose kinase deficiency.
• Caused by the deficiency of the GALT enzyme.
• The GALT enzyme, also known as Galactose-1-phosphate uridylyltransferase, plays a crucial role in the galactose metabolism pathway.
• Its main task is to convert galactose-1-phosphate into glucose-1-phosphate.
• A deficiency in this enzyme results in the accumulation of galactose-1-phosphate leading to toxicity in the liver, kidney, brain, and lens, affecting cell metabolism.
• Hypoglycemia is a characteristic feature as galactose-1-phosphate cannot be converted to glucose-1-phosphate for glycolysis.
• Symptoms include lethargy, refusal to suck, and convulsions.
• Onset of symptoms usually occurs during the second half of the first week of life.
• The incidence is approximately 1 in 60,000.
• This injury might start before birth.

Galactose Kinase Deficiency

• Caused by the deficiency of galactose kinase.
• The galactose kinase enzyme is responsible for phosphorylating galactose to form galactose-1-phosphate, which is an essential step in the metabolism of galactose.
• Galactose Kinase Deficiency is characterized by the accumulation of galactose and galactosuria.
• The hallmark feature is cataract formation, caused by the production of galactitol in an alternative pathway.

Features of Galactosemia

• Baby appears normal at birth.
• Vomiting when fed with milk diet.
• Diarrhea.
• Gradual/progressive weight loss and wasting.
• Jaundice usually emerges in the first or second week of life.
• Noticeable and progressive enlargement of the liver (hepatomegaly).

Consequences; Untreated cases may lead to:

• Death.
• Infantile cataracts in survivors.
• Mental retardation due to impaired growth.
• Proteinuria and general amino aciduria, indicating renal tubular damage.
• Presence of galactose in urine (galactosuria).
• Symptoms may improve by temporarily replacing milk with intravenous or lactose-free nutrition.
• Patients with galactosemia have a higher susceptibility to Escherichia coli neonatal sepsis.
• Death can occur rapidly due to liver and kidney failure, as well as sepsis.
• If not diagnosed early, ongoing damage to the liver (cirrhosis) and brain (mental retardation) becomes severe and irreversible.

Management

General management principles include:

• Resuscitation.
• Elimination of toxic metabolites.
• Enhancement of deficient enzyme activity, for example, through administration of co-factors.
• Dietary supplementation of deficient end-products.
• Reducing flux through deficient pathways.

Diagnosis and Treatment

• A high index of suspicion is crucial, particularly for a child with recurrent hypoglycemia.
• Urinary reducing sugar can be assessed using the Clinitest test.
• Clinistix is utilized to detect glucose.
• Diagnosis involves identifying the enzyme defect in cord blood.
• Treatment involves excluding foods containing lactose and galactose, with an absolute contraindication to breastfeeding.

Long-Term Effects:

Patients may experience:

• Ovarian failure with primary or secondary amenorrhea.
• Decreased bone mineral density.
• Developmental delay and learning disabilities that worsen with age.
• Speech disorders are common, and some may suffer from poor growth and impaired motor function and balance.
• The extent of galactose-1-phosphate level control does not always correlate with long-term outcomes.

• PKU is an example of aminoacidopathy.
• It is an autosomal recessive disorder resulting from either a deficiency of or sub-optimal activity of Phenylalanine hydroxylase or BH4 (Tetrahydrobiopterin).
• This leads to an accumulation of Phenylalanine with the formation of Phenylketones excreted in the urine.

Epidemiology

• PKU is rare in blacks and Asians.
• It is more common in native Americans.
• The worldwide prevalence is about 1:10,000, while in the UK, it's about 1:20,000.

Types

There are 2 types:

• Classical: This type involves a deficiency of the enzyme phenylalanine hydroxylase.
• Hyperphenylalaninaemia: This type is caused by a deficiency of the cofactor.

The symptomatology of both types is similar; however, deficiency of the cofactor is more severe and difficult to treat.

• Phenylpyruvic acid and Phenylethylamine are neurotoxic substances.
• They disrupt normal neural metabolism and can lead to brain damage.

Clinical Features

• PKU is usually associated with very high levels of phenylalanine, often >20mg/dl.
• The child is usually normal at birth, and manifestations often develop over the first year of life.
• Severe mental retardation is the hallmark of PKU.
• Characteristic features include:
  • Blue eyes
  • Blond hair
  • Eczema
  • Mousy odor
  • Vomiting
  • Seizures
  • Hypertonia
  • Delayed milestones
  • Microcephaly

BH4 Deficiency

• This condition is unique in that neurological deterioration persists despite good serum phenylalanine control.
• Features of BH4 Deficiency include:
  • Normal at birth
  • Regression of milestones
  • Trunkal hypotonia
  • Seizures
  • Feeding difficulties before the 1st birthday

On Examination

• Exanthematous rash
• Mousy odor
• Hyperactive deep tendon reflex
• Microcephaly with growth retardation as they grow
• Prominent maxilla
• Widely spaced teeth
• Enamel hypoplasia

Investigations

• Plasma Phenylalanine
• BH4 loading test
• Enzyme assay
• Serum Prolactin
• Screening for urinary Phenylketones
• Neonatal screening tests: Guthrie, mass spectrometry

Management

• Can be challenging
• Dietary restriction (for life) with regular plasma Phenylalanine monitoring
• Supplements: BH4, Tyrosine (an essential amino acid in this condition)
• Optimal Prenatal care
• For females, be strict when considering conception – plan it and comply with food while pregnant.

Prognosis

• Good, especially for the classic type in the developed world, if detected early (within 1st 10 days of life) and appropriate regimen instituted
• Prognosis for PKU due to BH4 deficiency appears guarded

• General health protection
• Specific health protection
  • Genetic counseling to discuss mode of inheritance recurrence risks
  • Family planning
    • Prenatal diagnosis/pre-implantation fertilization
• Early diagnosis and treatment
• Neonatal screening and screening of other family members
• Definitive tests (Enzyme assay, DNA analysis, Histological evaluation of tissue)

Prevention of Limitation and Disability

• Strict adherence to dietary and pharmacologic regimen is recommended for patients diagnosed with an inborn error of metabolism.
• Early treatment of symptoms and recognition that physiologic stressors, including intercurrent illness, trauma, surgery, and changes in diet may precipitate symptoms, is important in avoiding metabolic decompensation.

Rehabilitation

• Educational services
• Employment services
• Treatment of behavioral problems
• Provision of audiovisual aids
• Support groups

• Prognosis varies based on individual types of IEM and the different forms.
• Early diagnosis and prompt treatment improve the prognosis.
• Strict adherence to dietary and pharmacologic regimen is very important.
• Early treatment of intercurrent illnesses and infections.
• Long-term follow-up is required.
• Genetic counseling plays an important role in the prevention of IEM.