Autosomal dominant leukodystrophy with autonomous disease (Autosomal dominant leukodystrophy With autonomic disease) - Gen LMNB1
Autosomal dominant disease leukodystrophy with autonomous (ADLD), also known as autosomal dominant demyelinating leukodystrophy adult, is one of a group of genetic processes called leukodystrophies. Leukodystrophies are characterized by white matter abnormalities of the nervous system comprises nerve fibers covered by myelin. Myelin insulates and protects nerve fibers and promote rapid transmission of nerve impulses.
People with ADLD manifest signs and symptoms of the disease in adulthood, usually in the forties or fifties. Often, the first signs of the disease involve problems with the autonomic nervous system. These problems include difficulty with bowel and bladder function, orthostatic hypotension, and erectile dysfunction in men. Rarely, affected persons suffer from anhidrosis, which can cause dangerously high body temperature. Often, after the start of the autonomic nervous system problems, affected persons suffer from mobility problems. Affected individuals may have spasticity or weakness, involuntary rhythmic tremor, ataxia, limb loss and adiadochokinesia. These movement problems usually affect the legs first, but as the disease progresses, affects the arms and finally the face. In some people with ADLD, symptoms worsen during episodes of fever, infection or exposure to heat.
In general, intelligence is not affected; However, people who have had ADLD long may develop dementia. The ADLD progresses slowly, and affected individuals generally survive 10 to 20 years after the onset of symptoms.
This process is due to mutations in the gene LMNB1 (lamin B1), located on the long arm of chromosome 5 (5q23.2), encoding the protein lamin B1. Lamin B1 is a structural protein of intermediate filaments which provide stability and strength to the cells. Lamin B1 is a support component of the nuclear envelope. Specifically, this protein is found in the nuclear envelope. As part of the nuclear envelope, lamin B1 helps regulate movement of molecules between the inside and outside of the core. Protein also plays a role in DNA copying in preparation for cell division and expression of many genes to be involved in the organization of the chromosomes in the nucleus.
They have identified at least 30 LMNB1 gene mutations in people with autosomal dominant leukodystrophy with autonomous disease (ADLD). Almost all cases of ADLD are due to gene duplication LMNB1. As a result of this duplication, more lamin B1 normal is coded. In rare cases, a deletion of genetic material near the beginning of LMNB1 gene results in increased production of lamin B1. Although lamin B1 is found in cells throughout the body, it appears that cells in the brain are especially sensitive to changes in lamin B1. Oligodendrocytes seem to be particularly affected. Increased activity lamin B1 causes a decrease in the expression of genes that are important for the function of myelin. Furthermore, an increase in the amount of lamin B1 in the cells results in a hardening of the nuclear envelope, which may cause problems with cell function. Over time, these changes result in reduced production and maintenance of myelin.
In at least one family with ADLD, this process is due to a loss of genetic material near the beginning of the gene. It is believed that this deletion removes a DNA regulatory region that helps control gene expression LMNB1. As a result of the loss of this region, the gene is overexpressed LMNB1 and increases the synthesis of lamin B1, similar to the cases are due to a doubling of LMNB1.
In people with ADLD, demyelination occurs frequently in the central nervous system years before they develop movement problems. Demyelination of the spinal cord probably contributes to the problems of the autonomic nervous system by altering the transmission of nerve signals from the brain to the body. Movement problems are probably due to demyelination in the cerebellum and corticospinal tract nerve cells.
This process is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. In most cases, an affected person has an affected parent.
Tests in IVAMI: in IVAMI perform detection of mutations associated with autosomal dominant leukodystrophy with autonomous disease (ADLD), by complete PCR amplification of exons LMNB1 gene, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).