Diagnosis: Inborn errors of metabolism

Congenital metabolic disorders (more accurately inherited metabolic disorders, IMDs) represent a heterogeneous group of approximately 800–900 genetic diseases, whose common feature is the presence of biochemical or enzymatic abnormalities that can only be detected through specialized testing. IMDs are typical examples of rare diseases. They are mostly inherited in an autosomal recessive or X-linked recessive manner, but some are inherited dominantly, and a few have mitochondrial inheritance. Most inherited metabolic disorders are caused by mutations in genes encoding enzymes that facilitate the conversion of various substances (substrates) into other compounds (products).

Health problems in patients with these disorders arise either due to the accumulation of substances that are toxic or disrupt normal bodily functions, or due to a decreased ability to synthesize compounds essential for the body.

The beginnings of the discovery of inherited metabolic disorders are associated with Archibald Garrod, who was the first to point out the connection between human diseases and Mendel’s laws of inheritance and formulated the concept of inborn errors of metabolism. Garrod studied alkaptonuria and in 1902 published the book The Incidence of Alkaptonuria: A Study in Chemical Individuality, which was the first record of a case of recessive inheritance in humans. In 1923, he published another book titled Inborn Errors of Metabolism, in which he presented his studies on alkaptonuria, cystinuria, pentosuria, and albinism. The translation of the term “inborn errors of metabolism” led to the long-used but imprecise term “congenital metabolic disorders.”

The cause of inherited metabolic disorders (IMDs) is a genetically determined dysfunction of an enzyme or transport protein. The molecular basis of this dysfunction is usually homozygosity or compound heterozygosity for autosomal recessive disorders, hemizygosity for X-linked disorders, or the presence of mutations in a critical number of organelles for mitochondrial disorders. In some IMDs, mutations in the relevant genes are the sole factor required for the development of clinically apparent disease. In contrast, for other IMDs, clinical manifestation requires, in addition to the gene mutation, exposure of the patient to a substance they cannot properly metabolize.

At present, it is no longer appropriate to assume that inherited metabolic disorders are rare in the population and that a general practitioner will rarely encounter them. Diagnosis of metabolic disorders requires close collaboration between general physicians and specialized laboratories.

From the perspective of metabolites causing the clinical manifestations of the disease, inherited metabolic disorders can be divided into small-molecule disorders and large (complex)-molecule disorders. In the following text, classification will be based on the metabolic pathway or type of metabolite.

Clinical manifestations of metabolic disorders are highly variable and can appear both in childhood and later in life. The severity depends on the type of molecular defect, the degree of enzyme deficiency, and the role of the affected enzyme or other protein in metabolic pathways. In the neonatal and early infant period, severe deficiencies of key enzymes may present, and the course of these disorders is often life-threatening.

Some disorders present with specific symptoms characteristic of the disease, while others manifest nonspecifically, with signs common to many conditions.

Examples of specific symptoms include lens dislocation (ectopia lentis) and thromboembolic events in homocystinuria.

Nonspecific symptoms include psychomotor developmental delay, hypotonia, poor appetite, and failure to thrive. Gradually, dysfunction of individual tissues may develop, such as hypertrophic cardiomyopathy, CNS demyelination, hepatomegaly, liver disease, cataracts, or renal insufficiency.

A combination of nonspecific signs can sometimes create a characteristic clinical picture. For example, in a newborn with marked hypotonia (reduced muscle tone), a prominent forehead, broad nasal bridge, enlarged liver and spleen, liver damage, and polycystic kidneys, one might suspect peroxisomal disorders.

Suspicion of a metabolic disorder should be raised especially by the following signs:

Unexplained psychomotor retardation, muscle tone abnormalities, seizures
Unusual odor of sweat or urine
Recurrent episodes of unexplained vomiting, acidosis, behavioral changes, altered consciousness
Hepatomegaly (enlarged liver)
Kidney stones
Family history of consanguinity, recurrent spontaneous abortions, unexplained deaths resembling sepsis, occurrence of SIDS (sudden infant death syndrome), or Reye-like syndrome in the family—these should always prompt consideration of an inherited metabolic disorder.

According to the speed of onset of clinical symptoms, metabolic diseases are classified as acute, intermittent, or chronic.

Acute metabolic diseases usually begin to manifest in the neonatal or early infant period, although late-onset forms of these disorders also exist. Often, a triggering mechanism that provokes the development of clinical symptoms can be identified. In amino acid metabolism disorders or urea cycle disorders, manifestations of the metabolic disease occur after the introduction of oral feeding, when transitioning to a diet higher in protein, or during catabolic states caused by infections. In fatty acid β-oxidation disorders, triggers include fasting or insufficient coverage of increased energy demands during stressors such as intercurrent infections, stress, physical exertion, or vaccination.

In any full-term, otherwise healthy newborn or infant who experiences a sudden deterioration in clinical condition after a symptom-free period—such as refusing to feed, vomiting, altered consciousness, seizures, or respiratory failure—an inherited metabolic disorder should always be considered in the differential diagnosis. Many of these disorders are amenable to treatment if therapeutic interventions are initiated early. Such interventions may include elimination of toxic metabolites from the body through hemodiafiltration, dietary measures (low-protein diet, exclusion of certain dietary components), or management strategies (anti-hypoglycemic regimen).

Metabolic diseases with an intermittent course manifest in attacks triggered by changes in diet or increased energy demands of the body during acute catabolic states. Between attacks, patients are usually free of any clinical symptoms, and diagnosis is often dependent on periods of disease decompensation (for example, transient forms of leucinosis, recurrent Reye-like syndrome attacks in certain fatty acid β-oxidation disorders, late-onset forms of ornithine transcarbamylase deficiency—urea cycle disorder, or fructose-1,6-bisphosphatase deficiency from gluconeogenesis disorders).

The most common manifestation of chronically progressive metabolic diseases is the gradual slowing, stagnation, or even regression of previously normal psychomotor development, occurring after a variable symptom-free period. This is how lysosomal diseases from the group of mucopolysaccharidoses and glycoproteinoses begin to present, with the development of facial dysmorphism characterized by coarse facial features and organ storage manifestations (hepatosplenomegaly, corneal clouding, dysostosis multiplex, valvular defects, development of hypertrophic cardiomyopathy). Neurodegenerative metabolic diseases, in addition to deterioration of psychomotor development, present with progressive neurological symptoms (Krabbe disease, metachromatic leukodystrophy, X-linked adrenoleukodystrophy, gangliosidoses, neuronal ceroid lipofuscinoses, Lesch–Nyhan syndrome). Mitochondrial energy metabolism disorders primarily affect energy-demanding tissues (CNS, heart, muscles, liver) and cause general symptoms such as poor growth and failure to thrive.

Diagnostics:
In the case of an inherited metabolic disorder caused by an enzyme or transport protein deficiency, specific metabolites accumulate at the site of the metabolic block. Suspicion of a particular inherited metabolic disorder can then be raised either by detecting an increased concentration of metabolites accumulating upstream of the block or by detecting a decreased (or absent) concentration of metabolites downstream of the block. A suspected diagnosis of an inherited metabolic disorder must then be confirmed, which can be done at the enzyme or gene level.

Treatment:
Modern treatment of patients with inherited metabolic disorders (IMDs) is based on understanding the pathogenesis of the diseases and depends on the type of disorder and its clinical severity. Currently, effective treatment is known for approximately one-third of patients with IMDs.

In the acute phase of the disease, hemodialysis or hemodiafiltration is used to remove toxic metabolites from the body. To maintain long-term metabolic compensation in amino acid metabolism disorders, a low-protein diet supplemented with essential amino acids through specialized dietary preparations is used. In fatty acid β-oxidation disorders, frequent meals with restricted fat content are recommended. Treatment of certain IMDs may involve high-dose administration of selected vitamins. For some patients with lysosomal diseases, injectable recombinant enzyme therapy is effective, while others may benefit from hematopoietic stem cell transplantation or organ transplantation (liver, kidney, heart).

Primary prevention of IMDs is not possible due to their genetic origin. However, secondary prevention is highly important and relies on early diagnosis of specific IMDs. A classic example of successful secondary prevention is neonatal screening programs, which allow early initiation of appropriate treatment when the disorder is treatable. Except for mitochondrial inheritance disorders, the vast majority of IMDs can be diagnosed prenatally in at-risk families.

Inborn errors of metabolism

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