Inherited metabolic disorders

Last updated date: 08-Jun-2023

Originally Written in English

Inherited metabolic disorders


Heritable metabolic abnormalities, often known as inborn errors of metabolism, are hereditary illnesses. There are hundreds of known inborn metabolic abnormalities, such as albinism, cystinuria, and phenylketonuria (PKU).




The majority of meals and beverages consumed are complex compounds that the body must break down into simpler ones. This procedure may consist of numerous phases. The simpler compounds are then employed as building blocks to create the components required by the body to support life. Creating these materials may also need numerous processes. The fundamental basic components are

  • Carbohydrates
  • Proteins (amino acids)
  • Fats (lipids)

Metabolism refers to the complex process of breaking down and transforming the chemicals consumed. Metabolism is carried out by enzymes, which are chemical compounds produced by cells in the body. Various metabolic abnormalities can emerge if a genetic defect impairs the action of an enzyme or leads it to be deficient or absent entirely. 

These diseases are frequently caused by one or both of the following:

  • Inability to break down a substance that should be broken down, allowing a toxic intermediate substance to build up
  • Inability to produce some essential substance

Metabolic disorders are classified by the particular building block that is affected.


What is Inherited metabolic disorders? 

Inherited metabolic disorders

Inherited metabolic diseases (IMDs) are a diverse set of monogenic illnesses caused by a lack of activity in a particular pathway of intermediate metabolism. IMDs have serious clinical repercussions and are a major source of morbidity and mortality in clinical practice, particularly in pediatrics.

Although each illness is rare on its own, the overall frequency is significant; an incidence of 1 in 2500-5000 live births is sometimes reported. However, the majority of published research have concentrated on specific illnesses or sets of disorders, disorders that are checked for or diagnosed in specialised reference laboratories, or in certain populations at high risk for certain ailments.

The majority of inborn metabolic errors are inherited as autosomal recessive disorders. Some are caused by X-chromosome mutations and follow an X-linked recessive genetic pattern. Some mitochondrial diseases are caused by proteins that are delivered and operate in mitochondria but are not programmed for by conventional nuclear DNA. These have an autosomal recessive inheritance pattern. Many mitochondrial illnesses are inherited in a unique way, with solely maternal transmission. The mitochondrial DNA (which is circular, like that of a bacterium) is derived entirely from the egg and hence the mother. The mitochondria in the sperm are not passed on to the zygote.

Although the findings of these research have been consistent, a lack of good epidemiological data makes it challenging for those wanting to plan and offer appropriate therapeutic treatments for these individuals. This is growing increasingly important as new laboratory methods for diagnosis and screening emerge, as do new (sometimes expensive) therapy alternatives. As a result, more patients are surviving into adulthood, with significant implications for their health and health-care systems. There are hundreds of hereditary metabolic illnesses that are caused by various genetic flaws. Here are several examples:

  • Familial hypercholesterolemia
  • Gaucher disease
  • Hunter syndrome
  • Krabbe disease
  • Maple syrup urine disease
  • Metachromatic leukodystrophy
  • Mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS)
  • Niemann-Pick
  • Phenylketonuria (PKU)
  • Porphyria
  • Tay-Sachs disease
  • Wilson's disease


Phenylketonuria (PKU)

Phenylketonuria (PKU)

The most prevalent inborn mistake in amino acid metabolism is phenylketonuria (PKU), also known as phenylalanine hydroxylase deficiency. For clarity, the words PKU and phenylketonuria will be used throughout the paper. A phenylalanine hydroxylase (PAH) deficiency inhibits the body's capacity to metabolize the necessary amino acid phenylalanine. This causes phenylalanine to accumulate in bodily fluids.

Individuals with classic PKU nearly invariably have intellectual handicap unless their phenylalanine levels are regulated with dietary or pharmacologic therapy.


Signs & Symptoms of PKU

PKU infants often seem normal at birth. With early detection and treatment, afflicted individuals may never develop PKU symptoms. Untreated neonates who are not detected in the first few days of life, on the other hand, may be weak and feed poorly. Vomiting, irritation, and/or a red skin rash with tiny pimples may also occur. At many months of age, developmental delays may be seen.

Untreated children often have an IQ of less than 50. Intellectual dysfunction in PKU is caused by high amounts of phenylalanine in the brain, which destroys the fatty coating (myelin) of individual nerve fibers. It can also induce depression by lowering dopamine and serotonin levels in the brain (neurotransmitters).

Due to excessive phenylalanine levels interfering with the formation of melanin, a chemical that produces pigmentation, untreated newborns with PKU tend to have extremely pale eye, skin, and hair color. They may also have a musty or "mousy" body odor due to the presence of phenyl acetic acid in their urine or perspiration. Some untreated PKU patients experience neurological symptoms such as seizures, aberrant muscular movements, tight muscles, enhanced reflexes, involuntary movements, or tremor.

Untreated females with PKU who become pregnant are at significant risk of miscarriage or fetal development issues (intrauterine growth retardation). Untreated PKU can cause children to have an unusually tiny head (microcephaly), congenital heart problems, developmental defects, or facial deformities. The severity of these symptoms is strongly linked to high levels of phenylalanine in the mother. As a result, all women with PKU who have stopped therapy should begin it prior to conception and continue it during pregnancy, under the supervision of a metabolic geneticist and a nutritionist.


Diagnosis of PKU

Diagnosis of PKU

Screening for PKU involves the following:

  • Phenylalanine level determination: The traditional amino acid analysis is performed using ion exchange chromatography or tandem mass spectrometry.
  • As a bacterial inhibitory assay, the Guthrie test: Previously used, but now supplanted by tandem mass spectrometry
  • Molecular testing is normally not required for PKU diagnosis; nonetheless, a modest genotype-phenotype connection has been documented. Prenatal diagnosis also needs molecular testing.


Imaging studies

Cranial magnetic resonance imaging (MRI) examinations may be recommended in older people who have stopped taking the PKU diet and are suffering deficiencies in motor or cognitive function, or in situations where there are behavioral, cognitive, or psychiatric problems. Prolonged exposure to high phenylalanine levels has been shown to harm white matter integrity. The cerebrum, corpus callosum, hippocampus, and pons are the most seriously impacted brain regions in terms of volume reduction.


Standard Therapies

The objective of PKU therapy is to keep plasma phenylalanine levels between 2 and 6 mg/dL. This is usually accomplished with a well-planned and regulated diet. Because phenylalanine is an important amino acid, it must be limited in the child's diet with caution. A well-balanced diet can help to avoid intellectual impairment as well as neurological, behavioral, and dermatological issues. If treatment is not initiated at an early age, some degree of intellectual dysfunction might be predicted. However, some late-treated youngsters have performed admirably. Children with PKU who are treated with a reduced phenylalanine diet before the age of three months fare well, with an IQ in the normal range, according to studies.

When persons with PKU quit managing their phenylalanine intake, neurological abnormalities generally develop. IQ levels may fall. Difficulties in school, behavioral problems, mood swings, poor visual-motor coordination, poor memory, poor problem-solving abilities, weariness, tremors, poor focus, and depression are some of the other issues that may arise and become serious after nutritional management is discontinued.

After years of debate, specialists now almost unanimously agree that the diet should be followed continuously, and that individuals with PKU who interrupted the diet in childhood or later should resume it. Many young individuals have continued the diet and found that lower blood phenylalanine levels increase mental clarity.

Because phenylalanine is included in almost all natural proteins, it is hard to appropriately restrict the diet using only natural foods without jeopardizing health. As a result, phenylalanine-free dietary preparations are beneficial. Protein-rich foods such as meat, milk, fish, and cheese are often not permitted on the diet. Fruits, vegetables, and some cereals that are naturally low in protein are permitted in restricted quantities.


Maple syrup urine disease (MSUD)

Maple syrup urine disease (MSUD)

Maple syrup urine disease (MSUD) is a rare genetic illness defined by a lack of an enzyme complex (branched-chain alpha-keto acid dehydrogenase) that is necessary in the body to break down (metabolize) the three branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. As a result of this metabolic failure, all three BCAAs accumulate abnormally, as do a number of their hazardous metabolites (particularly their respective organic acids). Plasma concentrations of BCAAs begin to rise within a few hours of delivery in the classic, severe type of MSUD. If left untreated, symptoms appear during the first 24-48 hours of life.

The presentation begins with non-specific indications indicating developing neurological dysfunction, such as tiredness, irritability, and poor eating, and is quickly followed by focal neurological signs such as aberrant movements, increased stiffness, and, eventually, seizures and deepening coma. If left untreated, further brain damage is unavoidable, and death typically happens within weeks or months.

The main distinguishing feature of MSUD is the formation of a distinct odor resembling maple syrup, which may be found in urine and earwax and can be noticed within a day or two of delivery. Toxic effects of leucine on the brain are followed by severe ketoacidosis induced by buildup of the three branched-chain ketoacids (BCKAs).

The disease can be successfully addressed with a customized diet that strictly controls the three BCAAs. Even with medication, people of any age with MSUD are at significant risk of having acute metabolic decompensation (metabolic crises), which are frequently precipitated by illness, injury, fasting, or even psychological stress. During these events, amino acid levels rise rapidly and unexpectedly, demanding quick medical attention.

MSUD is classified into three or maybe four types: classic, intermediate, intermittent, and potentially thiamine-responsive. The different subtypes of MSUD have varying degrees of residual enzyme activity, which accounts for the varying severity and age of onset. All kinds have an autosomal recessive inheritance pattern.


Signs & Symptoms of MSUD

MSUD symptoms and severity vary widely from patient to patient and are mostly determined by the amount of remaining enzyme activity.

The most prevalent and severe type of MSUD is classic maple syrup urine disease, which is characterized by little or no enzyme activity. Within 2-3 days, most newborns with typical MSUD have mild developing non-specific symptoms such as poor bottle or breast feeding and increased tiredness and irritability. As the infant's condition worsens, he or she begins to display more focal neurologic indications such as aberrant movements, hypertonia, and spasticity, eventually leading to seizures and coma.

There may be brief periods of severe hypotonia. Finally, central neurologic function ceases, resulting in breathing failure and death. By the time the first symptoms appear, a strong maple syrup odor may be identified in cerumen, perspiration, and urine.

Once the condition has been treated and stabilized, there is a life-long risk of abrupt or gradual recurrent metabolic decompensation, which results in the recurrence of all the symptoms seen in untreated individuals. The three branched-chain ketoacids (BCAAs) must be rigorously managed and monitored in the diet. Even if no dietary changes are made, metabolic crises can arise due to an imbalance between the enzyme's natural residual activity and increased BCAAs release of protein from tissues due to enhanced breakdown (catabolism).

Other consequences of typical MSUD include widespread loss of bone mass (osteoporosis), which may lead to fractures, and pancreatic inflammation (pancreatitis). Some people acquire elevated pressure in the skull (intracranial hypertension), resulting in intense headaches that are occasionally accompanied by nausea and vomiting.

Intermediate MSUD is distinguished by higher levels of residual enzyme activity than typical MSUD. Although the start and symptoms of intermediate MSUD can occur in infancy, the majority of children are diagnosed between the ages of five and seven. When symptoms do appear, they are comparable to those of the classical type and may include lethargy, feeding difficulties, poor development, ataxia, and acute metabolic crises that result in seizures, coma, brain damage, and, in rare cases, life-threatening neurological consequences.

It should be underlined that Intermediate MSUD patients are just as prone to neurologic sequelae and severe acidosis as classic MSUD patients. The odor of maple syrup is evident in the earwax, perspiration, and urine. Some afflicted youngsters may be asymptomatic for a long time. The basics of disease management are the same for both.

While the majority of patients fit into one of the aforementioned groups, numerous families with several afflicted individuals have been discovered who do not fit into any of the above subtypes. These individuals are classed as having unclassified MSUD. It should be underlined that the lack of the maple syrup scent does not rule out MSUD in the context of such seemingly non-specific neurologic symptoms.


MSUD Diagnosis

Many MSUD infants are detected through neonatal screening programs. Tandem mass spectrometry, a sophisticated newborn screening tool that tests for more than 40 different illnesses using a single blood sample, has assisted in the identification of MSUD. Infants with moderate or intermittent versions of the condition may have completely normal blood metabolites after delivery, as with any inborn mistakes, and hence may be overlooked by newborn screening.

When patients appear later, the diagnosis is frequently made at a period of metabolic decompensation, when plasma amino acids and urine organic acids are normally analyzed and found to be grossly aberrant. The presence of the maple syrup odor is so distinctive that it, along with other symptoms, can be used to commence therapy until the patient is transported to an ICU. The testing of plasma BCAAs and urine organic acids provides preliminary confirmation. The BCAA complex activity may be tested in white blood cells or cultivated skin fibroblasts.


Standard Therapies

Standard Therapies

There are three major components to the therapy of classic, intermediate, intermittent, and thiamine-responsive MSUD: 

  1. Lifelong therapy to maintain an adequate diet;
  2. Lifetime maintenance of normal metabolic circumstances, including BCAA levels in the body; 
  3. Immediate medical intervention for metabolic crises.

Individuals with MSUD must follow a protein-restricted diet that limits their intake of branched-chain amino acids. To ensure appropriate growth and development, protein restriction should begin as soon as feasible after delivery. There are synthetic (artificial) formulations available that give all of the nutrients required for optimal growth and development but lack leucine, isoleucine, and valine. 

Diet management is a continual balancing act between providing adequate food, protein, and BCAAs to support normal growth and development on the one hand and attempting to keep the patient's condition and biochemistry within therapeutic ranges on the other. Limiting the quantity of leucine in the diet is very crucial. The three amino acids are all necessary nutrients. They are introduced to the diet in tiny doses based on their plasma levels.

The quantity of leucine, isoleucine, and valine that a kid can tolerate is determined by residual enzyme activity. Affected youngsters must be examined on a frequent basis to ensure that their food is appropriate and that their amino acid levels are within acceptable ranges.

Some doctors prescribe a thiamine treatment trial to see if an afflicted person is thiamine-responsive. However, no person with MSUD has ever been treated only with thiamine.

Even if afflicted individuals rigorously adhere to the specific diet, the danger of metabolic crisis persists. Metabolic crises necessitate rapid medical intervention to reduce blood levels of branched-chain amino acids, particularly leucine. Dialysis, a process in which blood is taken from the body and processed through a filter before being returned to the body, has been used to lower plasma leucine levels (hemofiltration).

The goal of severe metabolic crisis treatment is to diminish, and eventually reverse, the accelerated protein catabolism that is the core cause of such occurrences. 

It is critical to give all of the other amino acids in adequate quantities to allow for fresh protein synthesis. This is accomplished by the prudent use of intra GI drips or, more commonly, parenteral nourishment IV using leucine-free solutions. Many hospitals utilize whole parenteral nutrition solutions that are deficient in branched-chain amino acids. Furthermore, insulin can be utilized to increase anabolism, a metabolic process. Amino acids and other molecules are generated during anabolism to build new muscle and other proteins, as well as a wide range of other chemicals.


Homocystinuria (HCU)

Homocystinuria (HCU)

Homocystinuria is a hereditary condition that impairs the amino acid methionine metabolism. Amino acids are the fundamental building elements of life.


Homocystinuria Causes

Homocystinuria is passed down through generations as an autosomal recessive characteristic. To be significantly impacted, the kid must inherit a non-working copy of the gene from each parent. Homocystinuria has some characteristics with Marfan syndrome, such as skeletal and ocular abnormalities.


Homocystinuria Symptoms

Homocystinuria Symptoms

Newborn babies look to be healthy. Early signs, if they exist, are not visible. Mildly delayed development or inability to thrive might be symptoms. Increasing visual issues may indicate the presence of this illness.

Other symptoms include:

  • Chest deformities (pectus carinatum, pectus excavatum)
  • Flush across the cheeks
  • High arches of the feet
  • Intellectual disability
  • Knock knees
  • Long limbs
  • Mental disorders
  • Nearsightedness
  • Spidery fingers (Arachnodactyly)
  • Tall, thin build


Exams and Tests

The child's height and weight may be noticed by the health care practitioner. Other indicators include:

  • Curved spine (scoliosis)
  • Deformity of the chest
  • Dislocated lens of the eye

If you have blurry or double vision, an ophthalmologist will do a dilated eye exam to check for lens displacement or nearsightedness. There might be a family history of blood clots. Mental illness or intellectual incapacity are other possibilities. Among the tests that can be ordered are the following:

  • Amino acid screen of blood and urine
  • Genetic testing
  • Homocysteine level
  • Liver biopsy and enzyme assay
  • Skeletal x-ray
  • Skin biopsy with a fibroblast culture
  • Standard ophthalmic exam


Homocystinuria Treatment

Homocystinuria has no known treatment. Approximately half of those suffering from the condition react to vitamin B6 (also known as pyridoxine(

Those who react will need to take vitamin supplements B6, B9 (folate), and B12 for the rest of their lives. Those who do not respond to supplements will need to consume a diet low in methionine. Most will require trimethylglycine treatment. A low-methionine diet or medication will not help pre-existing intellectual impairment. A doctor with experience with homocystinuria should regularly monitor medication and food.


Hunter syndrome

Hunter syndrome

Hunter syndrome (also known as mucopolysaccharidosis type 2 or MPS II) is a hereditary disorder in which the body produces insufficient iduronate 2-sulfatase enzyme (an enzyme that helps the body break down certain types of sugar). Hunter syndrome is more common among biological men (people assigned male at birth). There are two types of disease: those that advance quickly and those that progress slowly. The distinction between the two types is determined by when symptoms initially appear and how rapidly they advance.

  • What are the symptoms of Hunter syndrome?
  • Short stature (short height)
  • Hepatosplenomegaly (large liver and spleen)
  • Joint problems
  • Prominent (larger or more noticeable) facial features
  • Frequent ear infections
  • Hearing loss
  • Skeletal problems (conditions that affect the bones)
  • Umbilical hernia (when the intestines push through a weak spot in the abdomen, or belly area, near the belly button)
  • Developmental delay in some people


What causes Hunter syndrome?

Changes in the IDS gene cause Hunter syndrome. The instructions that guide our bodies how to develop and operate are encoded in our genes. The IDS gene is responsible for the production of the iduronate 2-sulfatase enzyme. Certain mutations (changes or misspellings) in the IDS gene cause people to produce too little or no iduronate 2-sulfatase enzyme.

The IDS gene is located on the X-chromosome (one of 2 sex chromosomes, or pieces of genetic material called DNA, in the body). It follows an x-linked inheritance pattern (genetic conditions or traits that are passed down from parent to child through the X chromosome).


Hunter syndrome Treatment

Idursulfase (Elaprase), a medication that substitutes the enzyme iduronate sulfatase, may be prescribed. It is administered through a vein (IV, intravenously). The early-onset variant has been treated with a bone marrow transplant, although the outcomes have been mixed. Each health issue brought on by this condition should be treated separately.



Inherited metabolic diseases are medical problems caused by genetic abnormalities that are most usually inherited from both parents and interfere with the body's metabolism. These diseases are sometimes known as inborn metabolic errors.