OVERVIEW

What are inherited metabolic disorders?

Inherited metabolic disorders, also known as inborn errors of metabolism, are a broad category of diseases.

These disorders are caused by pathogenic genes inherited from one or both parents, leading to genetic defects in offspring. Patients exhibit reduced activity of specific enzymes or coenzymes, resulting in abnormalities in the synthesis, metabolism, transport, or storage of substances in the body, which trigger a range of symptoms.

Inherited metabolic disorders often manifest during the neonatal, infant, or childhood periods. Some may appear in adulthood but have underlying abnormalities during childhood. Clinical symptoms are typically nonspecific, including gastrointestinal, respiratory, or neurological issues, as well as metabolic acidosis. A family history of similar conditions is common.

These disorders can be triggered by factors such as diet and stress, with sudden onset and severe symptoms, particularly affecting the central nervous system. Without timely diagnosis and treatment, they can lead to developmental delays or even death, making them a significant cause of mortality in newborns and young children. Early detection, diagnosis, and treatment—especially during the asymptomatic (pre-symptomatic) stage—are crucial for managing inherited metabolic disorders.

Are inherited metabolic disorders common?

Inherited metabolic disorders encompass over 1,000 types of congenital metabolic abnormalities. While each individual disorder is rare or uncommon, the collective prevalence is not insignificant due to the large number of conditions.

What are the types of inherited metabolic disorders?

Inherited metabolic disorders are diverse and can be classified into the following categories based on the specific metabolic abnormality:

• Carbohydrate metabolism disorders: Galactosemia, fructose intolerance, glycogen storage diseases, sucrose and isomaltose intolerance, congenital lactic acidosis, pyruvate acidosis, etc.

• Amino acid and organic acid metabolism disorders: Phenylketonuria, tyrosinemia, alkaptonuria, albinism, maple syrup urine disease, isovaleric acidemia, homocystinuria, congenital hyperammonemia, hyperglycinemia, etc.

• Plasma protein and lipoprotein metabolism disorders: Hyperlipoproteinemia, abetalipoproteinemia, analbuminemia, transcobalamin II deficiency, etc.

• Lipid metabolism disorders: Gaucher disease, Niemann-Pick disease, etc.

• Purine metabolism disorders: Lesch-Nyhan syndrome.

• Pigment metabolism disorders: Methemoglobinemia, porphyria, etc.

• Renal tubular transport disorders: Nephrogenic diabetes insipidus, vitamin D-resistant rickets, Fanconi syndrome, renal tubular acidosis, etc.

• Other metabolic disorders: Wilson's disease, mucopolysaccharidosis, idiopathic hypercalcemia, hyperphosphatemia, etc.

SYMPTOMS

What are the common characteristics of inherited metabolic disorders?

Inherited metabolic disorders may present differently due to variations in enzyme activity deficiency, age of onset, clinical severity, and inheritance patterns. However, they also share some common features:

• Onset is often related to the consumption of specific types or quantities of food, and some patients may even instinctively avoid certain foods;

• The same symptoms recur repeatedly, often triggered by identifiable factors such as infections or excessive intake of certain foods, commonly seen in patients with mild enzyme deficiency;

• Some cases have a family history or a history of recurrent miscarriages or stillbirths;

• The condition tends to progressively worsen;

• Multiple organs are often affected;

• Symptoms are difficult to explain with common diseases;

• Laboratory tests often reveal metabolic acidosis, hypoglycemia, hyperammonemia, elevated free fatty acids, increased triglycerides, abnormal urinary ketones, decreased uric acid, and decreased creatinine.

What are the main features of inherited metabolic disorders during the acute phase?

The acute phase of inherited metabolic disorders is characterized by the following:

• Neurological damage: Manifestations may include lethargy, coma, or seizures.

• Digestive symptoms: Primarily refusal to eat, vomiting, and abnormal liver function (coagulation disorders, hepatomegaly, jaundice).

• Acute metabolic disturbances: Most commonly, acid-base imbalances, hypoglycemia, and hyperammonemia.

• Organ involvement and dysfunction: Mainly affecting the heart, liver, and other organs, leading to conditions such as cardiomyopathy, arrhythmias, or heart failure.

Most inherited metabolic disorders are life-threatening during acute episodes, with high mortality and disability rates, often causing irreversible neurological damage.

What are the unique signs of inherited metabolic disorders?

• Distinctive odors: Phenylketonuria produces a mouse-like or musty odor due to phenylacetic acid excretion; maple syrup urine disease emits a maple syrup-like smell from branched-chain α-keto acids; isovaleric acidemia causes a sweaty feet odor from isovaleric acid; type I tyrosinemia releases a rancid butter smell due to oxomethionine excretion; multiple carboxylase deficiency results in a cat urine odor from 3-hydroxyisovaleric acid.

• Abnormal facial features: Commonly seen in mucopolysaccharidosis, sphingolipidosis, and peroxisomal disorders.

• Skin and hair abnormalities: Hypopigmentation occurs in phenylketonuria, albinism, and homocystinuria; hyperpigmentation of skin and mucous membranes is seen in adrenoleukodystrophy; alopecia occurs in multiple carboxylase deficiency; brittle hair is observed in Menkes disease; angiokeratomas appear in Fabry disease; subcutaneous nodules develop in Farber disease; and ichthyosis is present in Refsum disease.

• Ocular abnormalities: Corneal clouding occurs in mucopolysaccharidosis, mucolipidosis, and Fabry disease; cataracts are seen in galactosemia, homocystinuria, and Lowe syndrome; glaucoma and lens dislocation appear in homocystinuria and Lowe syndrome; cherry-red spots in the macular region are observed in GM1 and GM2 gangliosidosis and Niemann-Pick disease.

• Hearing loss: Present in mucopolysaccharidosis, certain sphingolipidoses, Menkes disease, congenital hypothyroidism, and adrenoleukodystrophy.

What severe consequences can inherited metabolic disorders cause?

Inherited metabolic disorders often manifest suddenly due to dietary or stress factors, with severe symptoms and significant central nervous system damage. Without timely diagnosis and treatment, they can lead to developmental delays or even death, making them a major cause of mortality in newborns and young children.

Therefore, early detection, diagnosis, and treatment—especially during the asymptomatic (pre-symptomatic) stage—are crucial for managing inherited metabolic disorders.

CAUSES

What are the causes of inherited metabolic disorders?

Inherited metabolic disorders are genetic diseases caused by gene mutations, resulting from one or both parents carrying pathogenic genes that lead to hereditary defects in their offspring.

Who is more likely to develop inherited metabolic disorders?

Individuals with the following family history are more susceptible to inherited metabolic disorders:

• Consanguineous marriage of parents;
• Siblings with a history of unexplained encephalopathy, sepsis, sudden infant death syndrome, etc.;
• Family history of hereditary diseases, such as progressive neuropathy or unexplained nutritional disorders;
• Mother with a history of multiple spontaneous abortions;
• Severe vomiting or abnormal liver function during pregnancy.

Are inherited metabolic disorders contagious?

Inherited metabolic disorders are not contagious.

How are inherited metabolic disorders inherited?

Most inherited metabolic disorders are monogenic diseases, following autosomal recessive inheritance patterns. Simply put:

• If both parents show no symptoms but carry the pathogenic gene, their offspring have a 25% chance of inheriting the disease.
• If one parent has the disease and the other carries the pathogenic gene, their offspring have a 50% chance of inheriting the disease.

DIAGNOSIS

How are inherited metabolic disorders diagnosed?

The diagnosis of inherited metabolic disorders relies on laboratory tests, which can be divided into screening and confirmation. Screening primarily targets newborns to enable early diagnosis and treatment before symptoms appear. Confirmation requires biochemical tests, metabolite measurements, and enzyme activity assays.

What tests are needed for suspected inherited metabolic disorders?

Routine laboratory tests can provide diagnostic clues for these disorders. Based on test results combined with patient characteristics—such as age of onset, symptoms, and family history—a preliminary diagnosis can usually be made.

Routine laboratory tests include complete blood count, urinalysis, blood gas analysis, electrolytes, blood glucose, blood ammonia, blood lactate and pyruvate levels, and liver and kidney function tests. Among these, blood gas analysis, anion gap, blood ammonia, blood glucose, and blood lactate and pyruvate levels are particularly important for assessing the condition.

Specialized laboratory tests, such as liquid chromatography-tandem mass spectrometry (LC-MS/MS) for blood amino acids and acylcarnitine profiling, gas chromatography-mass spectrometry (GC-MS) for urine organic acid analysis, and high-performance liquid chromatography (HPLC), are the primary techniques used in China for screening and diagnosing inherited metabolic disorders.

Additionally, prenatal diagnosis can be performed by measuring enzyme activity in cultured amniotic fluid cells or chorionic villi, allowing detection of affected fetuses before birth.

Both nuclear DNA and mitochondrial DNA mutation analyses can be used for diagnosis. Mutation analysis also enables genetic counseling or prenatal diagnosis.

TREATMENT

Which department should I visit for inherited metabolic diseases?

For inherited metabolic diseases, you should visit the pediatrics and endocrinology departments.

Can inherited metabolic diseases heal on their own?

No.

How are inherited metabolic diseases treated?

The general treatment principle for inherited metabolic diseases involves adjusting for metabolic abnormalities caused by the disease, supplementing deficiencies, removing excess substances, and avoiding harmful elements.

Depending on the specific condition, treatment methods include dietary control, medication, enzyme replacement, organ transplantation, and gene therapy.

• Dietary control: For example, phenylketonuria can be effectively managed with a low-phenylalanine diet.

• Medication and enzyme replacement: Supplying missing metabolites, high-dose vitamins (coenzymes), enzymes, or using chelating agents to eliminate toxins.

• Organ transplantation: Bone marrow transplantation can correct adult-onset Gaucher disease. Other metabolic disorders such as adrenoleukodystrophy, mucopolysaccharidosis, and Lesch-Nyhan syndrome may also be corrected through bone marrow transplantation. Glycogen storage diseases, maple syrup urine disease, Wilson's disease, and certain congenital hyperammonemias may be treated with liver transplantation.

• Gene therapy: Still under further research.

Organ transplantation and gene therapy are curative approaches, but their widespread use is limited due to donor shortages, immune rejection, and incomplete gene therapy technology. Although the first three treatment methods cannot completely eliminate the disease, they can control symptoms, reduce attacks, and lower mortality and disability rates.

DIET & LIFESTYLE

What should patients with inherited metabolic disorders pay attention to in their diet?

The diet mainly involves restricting the intake of specific foods based on the characteristics of the disease to reduce the accumulation of toxic metabolites. However, while limiting the diet, it is essential to ensure adequate caloric and nutrient intake to support the child's normal growth and development.

• For phenylketonuria, it is necessary to restrict natural protein in food to control phenylalanine within physiological needs while supplementing with low- or no-phenylalanine formula to meet the child's protein requirements. Otherwise, long-term protein deficiency may lead to endogenous protein breakdown, increased blood phenylalanine levels, and malnutrition.

• For galactosemia, infants should immediately stop consuming dairy products after diagnosis and switch to soy milk, rice flour, etc., supplemented with essential nutrients like vitamins and fats. When introducing solid foods, dairy products and lactose-containing fruits and vegetables, such as watermelon and tomatoes, should be avoided.

What should patients with inherited metabolic disorders pay attention to in daily life?

Most inherited metabolic disorders require lifelong dietary and medical management, making daily life management crucial for patients and their families. For example:

• For glucose-6-phosphate dehydrogenase deficiency, the child's medical records or personal ID card should clearly list prohibited medications and foods like quinine and fava beans to prevent hemolytic jaundice.

• Patients with fatty acid oxidation disorders may experience non-ketotic or hypoketotic hypoglycemia under conditions such as fatigue, hunger, or high-fat intake, which can lead to sudden death in severe cases. Therefore, they should avoid fatigue and hunger and maintain a low-fat diet.

• Patients with organic acid, fatty acid, or urea cycle disorders may experience acute episodes triggered by fever, diarrhea, vomiting, hunger, fatigue, overeating, or vaccinations, leading to brain damage or even death. Thus, these conditions require immediate attention. During treatment for complications like epilepsy or infections, such patients should avoid medications like valproic acid and aspirin to prevent secondary hyperammonemia or Reye's syndrome.

PREVENTION

How to Prevent Inherited Metabolic Disorders?

The main preventive measures for inherited metabolic disorders include:

• Identifying carriers among the general population and family members of patients, providing genetic counseling, and avoiding consanguineous marriages to reduce the risk of disease in offspring;

• Encouraging contraception or sterilization for patients with severe dominant genetic disorders;

• Conducting prenatal diagnosis for high-risk pregnancies and opting for selective abortion if serious inherited metabolic disorders are detected to prevent the birth of affected infants.

How Can Patients with Inherited Metabolic Disorders Prevent Complications?

Early diagnosis and prompt treatment are key to preventing complications.