About canavan's leukodystrophy
What is canavan's leukodystrophy?
Canavan disease is rare genetic neurological disorder characterized by the spongy degeneration of the white matter in the brain. Affected infants may appear normal at birth, but usually develop symptoms between 3-6 months of age. Symptoms may include an abnormally large head (macrocephaly), lack of head control, severely diminished muscle tone resulting in "floppiness," and delays in reaching developmental milestones such as independent sitting and walking. Most affected children develop life-threatening complications by 10 years of age. Canavan disease occurs because of mutations in the aspartoacylase (ASPA) gene that affects the breakdown (metabolism) of the N-acetylaspartic acid (NNA). It is inherited as an autosomal recessive condition.
Canavan disease belongs to a group of disorders known as the leukodystrophies. The leukodystrophies are a group of rare, progressive, metabolic, genetic disorders that can affect the brain, spinal cord and often the nerves outside the central nervous system (peripheral nerves). Each type of leukodystrophy is caused by an abnormality affecting a specific gene that results in abnormal development of one of at least 10 different chemicals that make up the white matter of the brain. The white matter is tissue composed of nerve fibers. Many of these nerve fibers are covered by a collection of fats (lipids) and proteins known as myelin. Myelin, which collectively may be referred to as the myelin sheath, protects the nerve fibers, acts as an insulator and increases the speed of transmission of nerve signals. Each type of leukodystrophy affects a different part of the myelin sheath, leading a range of different neurological problems.
What are the symptoms for canavan's leukodystrophy?
The symptoms and progression of Canavan disease varies from case to case. The disorder usually becomes apparent between 3 and 6 months of age and the initial symptoms usually include extremely poor head control, an abnormally Large head (macrocepahly), and severely Diminished muscle tone (hypotonia) resulting in “floppiness.” Affected infants may be generally unresponsive (apathetic), lethargic or irritable. Some infants may experience difficulty swallowing (dysphagia), which contributes to feeding difficulties.
Affected infants also show delays in reaching developmental milestones (e.g., sitting or standing unassisted) and most never walk independently. The progressive loss of abilities requiring the coordination of mental and muscular activity (psychomotor regression) and Mental retardation also become apparent during infancy. Most affected infants do learn to smile, laugh, raise their heads and interact socially.
Additional symptoms that affect children with Canavan disease include seizures, sleep disorders, feeding difficulties, nasal regurgitation, backflow of acid from the stomach to the esophagus (reflux) sometimes associated with vomiting, and deterioration of the nerves of the eyes (optic nerves) that transmit impulses from the nerve-rich membrane lining the eyes (retina) to the brain (optic atrophy). Optic Atrophy may cause reduced visual responsiveness. In most case, hearing is unaffected, but Hearing loss can occur.
As affected infants age, Hypotonia may eventually develop into spasticity, a condition characterized by Involuntary Muscle Spasms that result in slow, stiff movements of the legs. Affected individuals may eventually exhibit uncontrolled rigid extensions and rotations of the arms, legs, fingers, and toes (decerebrate rigidity) or paralysis. Canavan disease eventually progresses to cause life-threatening complications; however, the severity and progression of the disease varies. Some individuals develop life-threatening complications in infancy; others live beyond their teen-age years.
In the last few years, a mild form of Canavan disease has been recognized, with characteristic mutations of the ASPA gene and only slightly increased NAA in the urine. These children may be only slightly delayed, can learn and go to school. The head may be somewhat enlarged, but the typical white matter changes associated with Canavan may be absent. The prognosis is certainly much better.
What are the causes for canavan's leukodystrophy?
Canavan disease is caused by disruptions or changes (mutations) to the aspartoacylase (ASPA) gene. This mutation is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
The defective gene responsible for Canavan disease has been mapped to chromosome 17 (17pter-p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The ASPA contains instructions for developing (encoding) aspartoacylase, an enzyme that breaks down (metabolizes) N-acetylaspartic acid (NAA). NAA is a compound that researchers believe plays a vital role in maintaining the brain’s white matter. Deficient or inactive aspartoacylase results in the accumulation of NAA in brain tissue. The symptoms of Canavan disease result from damage to the white matter from the abnormally high levels of NAA.
What are the treatments for canavan's leukodystrophy?
The treatment of Canavan disease is directed toward the specific symptoms that are apparent in each individual. Supportive care may alleviate some discomfort. Physical therapy and early intervention may help to improve posture and communication skills, respectively. If swallowing difficulties occur, feeding tubes may be useful to ensure proper nutrition and hydration.
Genetic counseling and carrier testing will benefit families in which this disease occurs.
What are the risk factors for canavan's leukodystrophy?
Canavan disease affects males and females in equal numbers. It affects all ethnic groups, but occurs with greater frequency in individuals of Ashkenazi Jewish descent. In this population, the carrier frequency is estimated to be as high as one in 40-58 people. The risk for an affected child born to Ashkenazi Jewish parents is between 1 and 6,400 and 1 in 13,456. The carrier frequency in other populations is not known, but most likely far lower. The overall incidence of Canavan disease in the general population is unknown.
Is there a cure/medications for canavan's leukodystrophy?
Seizures may be treated with anti-seizure (anti-convulsant) medications.