Breaking Down the Myelin Sheath
When our neural pathways communicate, they produce electrical impulses. Except, the transmission of these impulses aren’t all equal.
As we age, neurons in the brain begin to go through a process of myelination. Myelin is an insulating layer that forms over nerve cells in the brain and the spinal cord. Myelin’s made of up lipids and proteins that wrap around the axons of neurons.
Myelination begins in the peripheral nervous system where motor roots become myelinated. Myelination starts in the brain stem and cerebellum before birth, but isn’t completed in the frontal cortex until late in adolescence.
But why’s myelin important? The main function of myelin is to protect and insulate axons but also enhance transmission of electrical impulses, allowing for faster and more complex brain processes.
Myelin and Adrenoleukodystrophy
Today, 1 in 17,000 people are born with a genetic disease called adrenoleukodystrophy (ALD). ALD causes severe damage to your nervous system by breaking apart myelin structures that protect nerves in the brain and spinal cord. As a result, it makes it harder for nerves to send messages to your brain.
ALD has effects on the the Adrenoleukodystrophy protein (ALDP) which helps your body break down very long chain fatty acids (VLCFAs). If the protein doesn’t do its job, the acids build up inside your body, which result in a breakdown of myelin structures.
The adrenal glands which help control your immune system, blood pressure, and other functions are also harmed by ALD, affecting the ability for your body to produce hormones.
The symptoms, treatments, and prognosis of ALD vary depending on which type of ALD is present. Since ALD is not curable, doctors use medications to help slow down the progression of the disease.
ALD is an X-linked pattern, which means that the responsible gene mutation is on the X chromosome. ALD typically affects males at an earlier age than women who experience less severe symptoms.
Men only have one X chromosome, while women have two. Since women have two, they can have one normal gene and one copy of the mutation, which results in insignificant symptoms. Women can also be carriers of the gene without presenting symptoms.
ALD is known to cause various symptoms including muscle spasms, seizures, impaired vision, hyperactivity, difficulty remembering visual perceptions, paralysis, coma, or deterioration of motor control.
To gain a better understanding too if someone may have ALD, doctors use blood tests to look for abnormally high levels of VLCFAs, check on adrenal glands, or use sequencing to find the genetic mutation which causes ALD.
Types of ALD
ALD is divided into three types, affecting various age groups, showing very distinct symtpoms.
- Children cerebral ALD: This effects children between the age of 3 to 10 years old. It’s the most severe type of ALD which progresses rapidly and causes severe disability or even death.
- Adrenomyelopathy: AMN primarily affects adult men in their 20s. It’s milder than childhood cerebral ALD. It progresses slower in comparison and symptoms are less severe.
- Addison’s disease: Addison’s disease is a result of adrenal insufficiency. It occurs when the adrenal glands don’t secrete enough hormones, preventing healthy function of the body.
The Presence of Adrenomyelopathy
In half of the boys who inherit the mutated ALD gene, symptoms of the disease don’t develop until young adulthood which is a result of AMN.
Beginning in the mid 20s, patients with AMN exhibit neurological based motor lesions. These lesions progress over many years and inevitably results in moderate to severe handicap.
In approximately one third of AMN patients, the central nervous system can also become involved. These AMN patients undergo the same mental and physical deterioration as boys with the childhood form of the disease.
AMN can be broken down into two general clinical forms. AMN with cerebral involvement where the spinal cord and brain are both affected and AMN without cerebral involvement, where only the spinal cord is affected.
Of patients with AMN, approximately 54% have normal brain function, while 46% have brain involvement of varying degrees. Whether or not the brain is involved in AMN can be assessed by a Magnetic Resonance Image scan (MRI).
Symptoms of AMN
Symptoms are incredibly different for patients with AMN compared to childhood ALD as it’s less severe in comparison, but can ultimately result in death or vegetative state.
Initially, patients with AMN experience difficulty in walking or change their walking pattern. Spastic paraparesis is caused resulting in gradual, progressive weakness, and stiffness in the legs. AMN also causes ataxia, hypertonia, and dysarthria.
Many patients experience behavioural changes and seizures in sudden convulsions, attacks, or spasms. 70% of AMN experience adrenal insufficiency which are important in controlling blood pressure, hear rate, and reproduction. In adrenal insufficiency, these hormones are not produced at the appropriate levels and so these processes are not properly controlled.
How Do We Treat AMN?
Treatment of AMN varies based on the signs and symptoms in each person. For example, steroid replacement therapy may be prescribed in people with adrenal insufficiency. Physical therapy may also be recommended to help build and maintain muscle strength.
Many people use Lorenzo’s oil, which is a combination of glyceryl trierucate and glyceryl trioleate. It’s thought to aid in the normalization of VLCFA levels. However, there’s no evidence that Lorenzo can prevent AMN from occuring.
It’s also important to recognize that even if a man has a mild form of AMN without cerebral involvement, he could have relatives that develop severe X-ALD either in childhood or as adults, as the type of defect in the gene does not correlate directly to the clinical course of the disease.
Because of this, family members may want to be tested for the presence of the defective gene, so that they can make informed decisions regarding whether or not to have children or whether to have prenatal testing for the disease.
What The Future Looks Like for AMN Patients
There is currently no cure for ALD, but current advances in stem cell transplantation have improved the prognosis for affected individuals. Stem cell transplant a procedure where a patient receives healthy stem cells to replace damaged cells in the body.
Patients receive antibiotics and anti-rejection drugs to help their body accept the transplanted cells. Many also require red blood cells, platelets, and intravenous nutrition after the transplant.
Recent progress in understanding the molecular mechanisms responsible for X-ALD initiation and progression hold promise for the development of novel therapies.
Another potential approach is to find novel connectivity biomarkers for AMN. Through the use of myelin water imaging, demyelination of white matter structures can be detected. The use of MWI allows for connectivity measures between different brain regions to be detected of AMN patients.
These results can be compared to a healthy individuals in order to develop novel biomarkers which can detect the onset of AMN. This method allows for rapid visualization and earlier treatment for AMN patients experiencing progression of the disease. Want to get a better understanding of this idea? I’ll be posting a video on the potential approach we can take to develop biomakers for AMN soon!
- Myelin helps enhance transmission of electrical impulses in the nervous system
- ALD breaks apart myelin structures the protects nerves in the brain and spinal cord
- ALD is a gene-mutation on the X-chromosome which usually affects males
- There’s three types of ALD: Children cerebral ALD, Adrenomyelopathy, and Addison’s disease
- AMN affects patients in their mid 20s exhibiting neurological motor lesions
- There are two types of AMN: cerebral involvement and without cerebral involvement
- Currently there is no cure of AMN, however doctors can prescribe medication to slow down progression
- Current advances in stem cell transplantation have improved the prognosis for affected individuals