Pediatric Emergencies Caused by Rare Inherited Metabolic Disorders.

Introduction:

Heredity refers to the process of carrying genes from one generation to the next generation. Children develop hereditary metabolic disorders when defective metabolic genes that control the metabolism are inherited. Usually, both parents possess a copy of the abnormal metabolic gene, and neither of the parents suffers from the disorder, as two copies of the abnormal gene are required to cause an inherited disorder. However, some hereditary metabolic disorders occur in boys as they are X-linked, and only one copy of the abnormal gene is sufficient enough to inherit the disease. Most inherited metabolic disorders are rare.

How Does Genetics Impact Metabolism?

• Most of the foods and drinks ingested are complex materials, which the body breaks down into simpler substances. The simpler substances are termed building blocks, which form materials the body needs to sustain life. The major building blocks are carbohydrates, proteins, and fats.

• Metabolism involves breaking down complex substances and their conversion after getting ingested.

• Enzymes are chemical substances that carry out metabolism.

• Metabolic disorders occur when the enzymatic function is affected or appears deficient or missing due to a genetic abnormality.

• Metabolic disorders occur either due to the inability to break down into a substance that is essential, which in turn leads to a build-up of toxic intermediate, or due to the inability to produce an essential substance.

• Metabolic disorders are classified according to the building block that is affected.

What Are the Pediatric Emergencies Encountered With Rare Inherited Metabolic Disorders?

Mitochondrial Disorders:

• Mitochondrial disorders belong to a group of hereditary metabolic disorders that occur due to improper functioning of the mitochondria.

• Mitochondria are known as the “powerhouse of the cell.” These are the tiny structures that provide energy to the cells.

• Except for red blood cells, all the cells of the body have mitochondria.

• In the case of mitochondrial disorders, impaired mitochondrial activity leads to the generation of less energy, causing cell injury and sometimes even cell death, ultimately interfering with the systematic functioning of the organ systems.

• Mitochondria supply energy to the brain, nerves, muscles, and retina, which require more energy than other organs.

• When disorders of mitochondria occur, these organs that require high energy are more prone to encounter complications. Some of the mitochondrial disorders encountered are as follows:

Leigh Syndrome:

1. Etiology: Leigh syndrome is a severe neurological disorder usually occurring in the first year of life. This condition presents as a gradual loss in mental and movement abilities and consequently results in death within two to three years of age because of respiratory failure.

2. Clinical Features: The first signs, like vomiting, diarrhea, and dysphagia, cause the inability to eat.

• Retarded growth.

• Weak muscle tone.

• Involuntary muscle contractions.

• Peripheral neuropathy (numbness in the feet and hands).

• Ataxia (altered balance).

• Ophthalmoparesis (disordered eye movements).

• Optic atrophy (refers to optic nerve damage).

• Hypertrophic cardiomyopathy (an abnormal condition characterized by thickening of the heart muscle).

• Respiratory failure.

• Lactic acidosis.

3. Diagnosis:

• Blood tests to check the lactic acid levels.

• MRI (magnetic resonance imaging) reveals the lesions of the brain tissue.

• Genetic tests detect the gene responsible for the disorder.

4. Management:

• Sodium citrate or sodium bicarbonate is given to treat lactic acidosis.

• Thiamine (vitamin B1) injection is administered to slow the disease progression.

• As such, there is no cure for the disease, and many cases turn fatal. However, symptomatic treatment is given to ease the discomfort.

• A high-fat, low-carbohydrate diet is beneficial for children suffering from the disorder.

• Tube feeding is indicated when the child is unable to eat orally.

Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS):

A. Etiology:

• Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a very rare genetic condition that occurs in childhood.

• The genetic disorder mainly affects the brain and nervous system (encephalo) and muscles (myopathy).

• MELAS is associated with elevated levels of lactic acid in the body and is accompanied by stroke-like symptoms, such as temporary muscle weakness.

• The change in the genetic makeup of the gene responsible for impaired mitochondrial function causes the disorder.

B. Clinical Features:

• Altered mental status.

• Hemiparesis. (paralysis of one side of the body).

• Seizures.

• Hallucinations.

• Difficulty speaking.

• Changes in behavior.

• Vomiting.

• Abdominal pain.

• Fatigue.

• Muscle weakness.

• Difficulty breathing.

• Partial loss of vision or hearing.

• Double vision.

• Dizziness and slurred speech.

• Inability to recognize parts of the body.

• Confusion.

C. Diagnosis:

• Diagnosis of MELAS includes a physical exam, and a detailed medical history is taken.

• Genetic testing remains the gold standard for detecting MELAS.

• Muscle biopsies and laboratory tests to detect lactic acid levels are the other investigations that aid in diagnosis.

• MRI (magnetic resonance imaging) serves as an important diagnostic tool in diagnosing MELAS.

• If the biopsied muscle tissue is turned into a ragged red fiber, then the patient is positive for having MELAS.

D. Management:

• Treatment for MELAS includes symptomatic treatment.

• Seizures are treated by administering anticonvulsant therapy.

• Patients suffering from hearing loss can benefit from cochlear implants to aid in hearing.

• Coenzyme q10 and L-carnitine are given to slow the progression of the disease by increasing the energy output of mitochondria.

• Physical activities play an important role as they help in lowering lactic acid levels in the body.

• Patients with genetic conditions should undergo genetic counseling for better treatment outcomes, which can also help in determining the families at risk.

Wolman Disease:

1. Etiology:

• The Wolman disease presents as a lysosomal acid lipase (LAL) deficiency disorder.

• It is a rare, hereditary metabolic disorder associated with the absence of an enzyme called lysosomal acid lipase (LAL), which is essential to break down fats.

• In the absence of lysosomal acid lipase, fats accumulate abnormally in various tissues and organs of the body.

• The Wolman disease manifests itself soon after birth, usually during the first weeks of life.

2. Clinical Features:

• Malabsorption of the food leads to persistent vomiting.

• Frequent foul-smelling diarrhea.

• Steatorrhea.

• Abdominal distention.

• Hepatosplenomegaly (enlarged spleen and liver).

• Liver fibrosis (excess accumulation of extracellular matrix like collagen protein in the liver).

• Ascites (excess accumulation of fluid in the abdomen).

• Retarted growth and development.

• Jaundice.

• Persistent low-grade fever.

• Hypotonia (decreased muscle tone).

• Poor development of motor skills.

3. Diagnosis:

• Physical examination reveals signs and symptoms characteristic of the disease.

• Laboratory tests to detect the reduced levels or absence of lysosomal acid lipase are advised.

• Mutations in the LAL gene can be identified by molecular genetic tests.

4. Management:

• Sebelipase alfa enzyme therapy is the treatment of choice for lysosomal acid lipase (LAL) deficiency.

• There is no definitive line of treatment as such. Symptomatic treatment is given to ease the discomfort.

• Medications are given as an adjunct to supplement the adrenal gland hormones due to impaired functioning of the adrenal gland caused by calcification.

• Proper nutrition can be maintained through an intravenous route.

Conclusion:

The clinical outcome of children with genetic metabolic disorders is multifactorial, which mainly depends on the type and severity of the underlying metabolic disorder, the ability to make a timely and apt diagnosis and the availability of adequate treatment protocols. Most of the children manage to sustain the disorder and live longer, but they remain at high risk for developing neurological defects and mental retardation. Hence, caregivers should address the problem carefully and should be swift in devising the diagnosis and treatment planning. Collaborative efforts should be made by referring to the metabolic specialist to manage the case effectively.