Canavan's disease: what is it, symptoms, treatment, prognosis

What is Canavan disease?

Canavan's disease (also called spongy degeneration, Canavan disease - van Bogart - Bertrand) Is a rare genetic neurological disorder characterized by spongy white matter degeneration in the brain. Sick babies appear normal at birth, but usually the first symptoms begin to appear at the age of 3-6 months. Symptoms may include an abnormally large head (macrocephaly), lack of head control, decreased muscle tone leading to lethargy and delays in reaching milestones such as independent sitting and walking.

Most affected children develop life-threatening complications by age 10. Canavan disease occurs due to mutations in the aspartoacylase gene (gene ASPA), which affects the breakdown (metabolism) of N-acetyl-L-aspartic acid (NAA). It is inherited as an autosomal recessive condition.

Canavan's disease belongs to a group of diseases known as leukodystrophies. Leukodystrophies are a group of rare, progressive, metabolic, genetic disorders, affecting the brain, spinal cord, and often nerves outside the central nervous system (peripheral nerves).

Each type of leukodystrophy is caused by a defect affecting a specific gene, resulting in abnormal the development of one of at least 10 different chemicals that make up white matter brain. White matter is a tissue made up of nerve fibers. Many of these nerve fibers are coated with a set of fats (lipids) and proteins known as myelin. Myelin, collectively referred to as the myelin sheath, protects nerve fibers, acts as an insulator, and increases the rate at which nerve signals are transmitted.

Signs and symptoms

The symptoms and progression of Canavan disease varies from case to case. The disorder usually appears between 3 and 6 months of age, and the initial symptoms usually include:

• extremely poor head control;
• an abnormally large head (macrocephaly);
• decreased muscle tone (muscle hypotonia);
• weakness and lethargy.

Affected children may be apathetic (lethargic), lethargic, or irritable. Some people have trouble swallowing (dysphagia), which makes feeding difficult.

Affected children experience delays in reaching milestones (for example, children who are not can sit or stand unaided), and most of them never go. The progressive loss of abilities requiring coordination of mental and muscular activity (psychomotor regression) and mental retardation also become evident in infancy. Most affected children can learn to smile, laugh, look up, and socialize.

Additional symptoms affecting patients include:

• epilepsy;
• sleep disturbances / insomnia;
• Difficulty eating
• nasal regurgitation;
• Backflow of acid from the stomach into the esophagus (reflux), sometimes associated with vomiting
• deterioration of the nerves in the eyes (optic nerves) that transmit impulses from the nerve-rich membrane lining the eyes (retina) to the brain (optic atrophy).

Atrophy of the optic nerve can lead to decreased visual response. In most cases, hearing is not affected, but hearing loss is possible.

With age in sick children, hypotension can eventually develop into spasticity, a condition characterized by involuntary muscle spasms leading to slow, constrained movements legs. Sick children may have decerebral rigidity (increased tone of the extensor muscles and relative relaxation of the flexor muscles) or paralysis.

Canavan's disease ultimately leads to life-threatening complications; however, the severity and progression of the disease varies. In some patients, life-threatening complications develop in infancy, in others after adolescence.

Causes

Canavan disease is caused by abnormalities or changes (mutations) in the aspartoacylase (ASPA) gene. This mutation is inherited as an autosomal recessive trait. Genetic diseases are determined by a combination of genes for a specific trait found on chromosomes obtained from the father and mother.

Recessive genetic disorders occur when a person inherits the same abnormal gene for one trait from each parent. If a person receives one normal gene and one gene with the disease, the person will be a carrier of the disease, usually asymptomatic. The risk of two carrier parents passing on both defective genes and therefore having a sick child is 25% with each pregnancy. The risk of having a carrier child as a parent is 50% with each pregnancy. The risk of inheriting normal genes from both parents and being genetically healthy for this particular disease is 25%. The risk is the same for men and women.

The defective gene responsible for Canavan disease was matched to chromosome 17 (17pter-p13). Chromosomes are present in the nucleus of human cells and carry its genetic information. The cells of the human body usually have 46 chromosomes. Pairs of human chromosomes are numbered 1 through 22, and the sex chromosomes are labeled X and Y. Men have one X and one Y chromosome, while women have two X chromosomes. Each chromosome has a short arm, labeled "p", and a long arm, labeled "q". Chromosomes are further subdivided into multiple bands, which are numbered. For example, "chromosome 11p13" refers to lane 13 on the short arm of chromosome 11. The numbered stripes indicate the location of the thousands of genes present on each chromosome.

ASPA contains instructions for the development (coding) of aspartoacylase, an enzyme that breaks down (metabolizes) N-acetyl-L-aspartic acid (NAA). NAA is a compound that researchers believe plays a vital role in maintaining the white matter of the brain. Deficiency or inactive aspartoacylase leads to accumulation of NAA in brain tissue. The symptoms of Canavan disease are the result of damage to the white matter due to abnormally high levels of NAA.

Affected populations

The disease affects men and women in equal numbers. Affects all ethnic groups, but occurs more frequently in Ashkenazi Jews. In this population group, it is estimated that the frequency of carriers of the disease is 1 in 40-58 people. The risk of having a sick child among Ashkenazi Jewish parents ranges from 1 in 6400 to 1 in 13456 people. The frequency of gene carriers in other populations is unknown, but most likely much lower. The overall incidence of Canavan disease in the general population is unknown.

Diagnostics

The diagnosis of Canavan disease can be suspected in children with characteristic signs of the disorder (for example, poor head control, macrocephaly, etc.) signs). The diagnosis can be confirmed by careful clinical evaluation, a detailed history of the patient, and various specialized examinations. Such tests may include gas chromatography-mass spectrometry, a device that detects elevated levels of NAA in urine. Elevated levels of NAA can also be found in blood and cerebrospinal fluid (CSF).

Examination of certain cells of the skin's connective tissue (cultured fibroblasts) can also reveal a deficiency of the enzyme aspartic acid. Aspartic acid activity is also absent in leukocytes.

Prenatal diagnosis of the disease is available through amniocentesis by measuring the level of NAA in the fluid surrounding the developing fetus (amniotic fluid) at 16-18 weeks of gestation. If both parents have known mutations in the ASPA gene, then prenatal diagnosis by sampling is available chorionic villi, in which samples of placental cells are removed at 10-12 weeks of gestation for detection mutations.

Symptomatic Disorders

Symptoms of the following disorders may be similar to those of Canavan disease. Comparisons can be useful for differential diagnosis.

• Leukodystrophies are a group of very rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord and peripheral nerves. Each type of leukodystrophy results from a specific gene defect resulting in abnormal development one of at least 10 different chemicals that make up the white matter (myelin sheath) brain. The myelin sheath is the protective covering of the nerve, and the nerves cannot function normally without it. Each type of leukodystrophy affects different parts of the myelin sheath, resulting in a number of neurological problems.
• Metachromatic leukodystrophy, the most common form of leukodystrophy, is a rare inherited neurometabolic disorder that affects the white matter of the brain (leukoencephalopathy). It is characterized by the accumulation of a fatty substance known as sulfatide (sphingolipid) in the brain and other parts of the body (i.e. liver, gallbladder, kidneys and / or spleen). The protective fatty coating on nerve fibers (myelin) is lost from areas of the central nervous system (CNS) due to sulfatide build-up. Symptoms of metachromatic leukodystrophy may include epilepsy, personality changes, spasticity, progressive dementia, movement disorders progressing to paralysis, and / or visual impairment leading to blindness. Metachromatic leukodystrophy is inherited as an autosomal recessive trait.
• Tay-Sachs disease - a rare neurodegenerative disease in which a lack of an enzyme (hexosaminidase A) leads to excessive accumulation of certain fats (lipids), known as gangliosides, in the brain and nerves cells. This abnormal accumulation of gangliosides leads to progressive dysfunction of the central nervous system. The disorder refers to lysosomal storage diseases. Lysosomes are the main digestive units in cells. Enzymes in lysosomes break down or "digest" nutrients, including some complex carbohydrates and fats. Symptoms associated with Tay-Sachs disease may include exaggerated startle responses to sudden noises, lethargy, loss of previously acquired skills (i.e. psychomotor regression) and severely reduced muscle tone (muscle hypotension). As the disease progresses, affected infants and children may develop cherry red spots in the middle layer of the eyes, gradual loss of vision and deafness, and an increase in muscle stiffness and limitation of movement (spasticity), possible paralysis, uncontrolled electrical disturbances in the brain (epilepsy), and cognitive impairment (dementia). Tay-Sachs disease is inherited as an autosomal recessive trait.
• Certain mitochondrial disorders, such as Lee disease (Lei)may be associated with spongiform degeneration of the central nervous system. Mitochondrial disorders are characterized by mutations that affect the energy-producing parts of the cell (mitochondria). Mitochondrial diseases often limit the ability of affected cells to break down food and oxygen and produce energy. In most mitochondrial disorders, an abnormally large number of defective mitochondria are present in the cells of the body. Mitochondrial diseases often affect more than one organ system in the body.

Canavan's disease treatment

Treatment for Canavan disease focuses on the specific symptoms that each patient experiences. Supportive therapy can relieve some of the discomfort. Physical therapy and early intervention will help improve posture and communication skills, respectively. If you are having trouble swallowing, feeding tubes will help to ensure proper nutrition and hydration. Epilepsy is treated with antiepileptic (anticonvulsant) drugs.

Forecast

The prognosis for Canavan disease is poor. Life expectancy is variable. Some children die in the first few years of life, while others can live to be 10 years old, although some people who are sick live to 20 years. The prognosis often depends on the clinical course of the disease, as well as on the level of medical care provided.