Alexander disease is a very rare
autosomal dominant leukodystrophy
Leukodystrophies are a group of usually inherited disorders characterized by degeneration of the white matter in the brain. The word ''leukodystrophy'' comes from the Greek roots ''leuko'', "white", ''dys'', "abnormal" and ''troph'', "growth". Th ...
, which are neurological conditions caused by anomalies in the
myelin
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...
which protects nerve fibers in the brain. The most common type is the infantile form that usually begins during the first 2 years of life. Symptoms include mental and physical developmental delays, followed by the loss of developmental milestones, an abnormal
increase in head size and seizures. The juvenile form of Alexander disease has an onset between the ages of 2 and 13 years. These children may have excessive vomiting, difficulty swallowing and speaking, poor coordination, and loss of motor control. Adult-onset forms of Alexander disease are less common. The symptoms sometimes mimic those of
Parkinson’s disease
Parkinson's disease (PD), or simply Parkinson's, is a chronic condition, long-term neurodegeneration, degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disea ...
or
multiple sclerosis, or may present primarily as a
psychiatric disorder
A mental disorder, also referred to as a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitt ...
.
According to the
National Institute of Neurological Disorders and Stroke, the destruction of white matter is accompanied by the formation of
Rosenthal fiber
A Rosenthal fiber is a thick, elongated, worm-like or "corkscrew" eosinophilic (pink) bundle that is found on staining of brain tissue in the presence of long-standing gliosis, occasional tumors, and some metabolic disorders.
Associated conditi ...
s—abnormal clumps of protein that accumulate in
astrocyte
Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...
s in the brain.
The disease occurs in both males and females, and no ethnic, racial, geographic or cultural/economic differences are seen in its distribution. Alexander disease is a progressive and often fatal disease.
Presentation
Delays in development of some physical, psychological and behavioral skills; progressive enlargement of the head (
macrocephaly
Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to ...
),
seizures
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...
,
spasticity
Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles ...
, and in some cases also
hydrocephalus
Hydrocephalus is a condition in which an accumulation of cerebrospinal fluid (CSF) occurs within the brain. This typically causes increased pressure inside the skull. Older people may have headaches, double vision, poor balance, urinary inc ...
,
idiopathic intracranial hypertension, and
dementia
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
.
Cause
Alexander disease is a genetic disorder affecting the
midbrain
The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...
and
cerebellum of the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
. It is caused by
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
s in the
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
for
glial fibrillary acidic protein
Glial fibrillary acidic protein (GFAP) is a protein that is encoded by the ''GFAP'' gene in humans. It is a type III intermediate filament (IF) protein that is expressed by numerous cell types of the central nervous system (CNS), including astro ...
(GFAP)
that maps to
chromosome 17
Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 83 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total D ...
q21. It is inherited in an
autosomal dominant manner, such that the child of a parent with the disease has a 50% chance of inheriting the condition, if the parent is
heterozygotic. However, most cases arise ''de novo'' as the result of sporadic mutations.
Alexander disease belongs to
leukodystrophies
Leukodystrophies are a group of usually inherited disorders characterized by degeneration of the white matter in the brain. The word ''leukodystrophy'' comes from the Greek roots ''leuko'', "white", ''dys'', "abnormal" and ''troph'', "growth". Th ...
, a group of diseases that affect the growth or development of the
myelin sheath
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...
. The destruction of
white matter
White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distributi ...
in the brain is accompanied by the formation of fibrous,
eosinophilic
Eosinophilic (Greek suffix -phil-, meaning ''loves eosin'') is the staining of tissues, cells, or organelles after they have been washed with eosin, a dye.
Eosin is an acidic dye for staining cell cytoplasm, collagen, and muscle fibers. ''E ...
deposits known as
Rosenthal fiber
A Rosenthal fiber is a thick, elongated, worm-like or "corkscrew" eosinophilic (pink) bundle that is found on staining of brain tissue in the presence of long-standing gliosis, occasional tumors, and some metabolic disorders.
Associated conditi ...
s.
Rosenthal fibers appear not to be present in healthy people,
but occur in specific diseases, like some forms of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
, Alzheimer’s, Parkinson’s, Huntington’s, and ALS.
The Rosenthal fibers found in Alexander disease do not share the distribution or concentration of other diseases and disorders.
Pathology
Alexander disease causes the gradual loss of bodily functions and the ability to talk. It also causes an overload of long-chain
fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
s in the brain, which destroy the myelin sheath. The cause of Alexander disease is a mutation in the gene encoding GFAP.
A
CT scan shows:
* Decreased density of white matter
*
Frontal lobe
The frontal lobe is the largest of the four major lobes of the brain in mammals, and is located at the front of each cerebral hemisphere (in front of the parietal lobe and the temporal lobe). It is parted from the parietal lobe by a groove be ...
predominance
* Dilated
lateral ventricles
The lateral ventricles are the two largest ventricles of the brain and contain cerebrospinal fluid (CSF). Each cerebral hemisphere contains a lateral ventricle, known as the left or right ventricle, respectively.
Each lateral ventricle resemble ...
may present
Diagnosis
Detecting the signs of Alexander disease is possible with
magnetic resonance imaging (MRI), which looks for specific changes in the brain that may be tell-tale signs for the disease.
It is even possible to detect adult-onset Alexander disease with MRI.
Alexander disease may also be revealed by
genetic testing for its known cause.
A rough diagnosis may also be made through revealing of
clinical symptom
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...
s, including enlarged head size, along with
radiological studies
Radiology ( ) is the medical discipline that uses medical imaging to diagnose diseases and guide their treatment, within the bodies of humans and other animals. It began with radiography (which is why its name has a root referring to radiat ...
, and negative tests for other leukodystrophies.
Treatment
No cure or standard procedure for treatment is known, although a
University of Wisconsin
A university () is an institution of higher (or tertiary) education and research which awards academic degrees in several academic disciplines. Universities typically offer both undergraduate and postgraduate programs. In the United States, ...
study shows promise with gene editing of the astrocytes.
A phase III clinical trial of an
antisense therapy
Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre- ...
, sponsored by
Ionis Pharmaceuticals
Ionis Pharmaceuticals, Inc. is a biotechnology company based in Carlsbad, California, that specializes in discovering and developing RNA-targeted therapeutics. The company has 3 commercially approved medicines: Spinraza (Nusinersen), Tegsedi (I ...
, began in 2021. A
bone marrow transplant
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...
has been attempted on a child, but it made no improvement.
Hydrocephalus may be seen in younger patients and can be relieved with surgery or by implanting a shunt to relieve pressure.
Prognosis
The prognosis is generally poor. With early onset, death usually occurs within 10 years from the onset of symptoms. Individuals with the infantile form usually die before the age of seven.
Usually, the later the disease occurs, the slower its course.
Prevalence
Its occurrence is very rare. The infantile form occurs from birth to 2 years of age.
The average duration of the infantile form is usually about 3 years. Onset of the juvenile form presents between 2 and 12 years of age.
Duration of this form is in most cases about 6 years. The adult form occurs after 12 years.
In younger patients,
seizures
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...
,
megalencephaly
Megalencephaly (or macrencephaly; abbreviated MEG) is a growth development disorder in which the brain is abnormally large. It is characterized by a brain with an average weight that is 2.5 standard deviations above the mean of the general populati ...
,
developmental delay
Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive and physical development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech ...
, and
spasticity
Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles ...
are usually present. Neonatal onset is also reported.
Onset in adults is least frequent. In older patients,
bulbar
The medulla oblongata or simply medulla is a long stem-like structure which makes up the lower part of the brainstem. It is anterior and partially inferior to the cerebellum. It is a cone-shaped neuronal mass responsible for autonomic (invol ...
or
pseudobulbar symptoms and
spasticity
Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles ...
predominate. Symptoms of the adult form may also resemble
multiple sclerosis.
No more than 500 cases have been reported.
See also
*
The Myelin Project
*
The Stennis Foundation The Stennis Foundation is a registered nonprofit organization based in the U.S. The foundation is primarily a fundraising organization, sending money to various research projects. Currently, the Stennis Foundation supports research at Duke, Kennedy ...
References
External links
OMIM entries on Alexander diseaseInfantile-onset Alexander disease in a child with long-term follow-up by serial magnetic resonance imaging: a case reportAlexander Disease: New Insights From Genetics
{{Cytoskeletal defects
Disorders causing seizures
Leukodystrophies
Rare diseases
Demyelinating diseases of CNS
Neurological disorders in children
Cytoskeletal defects