NORD (National Organization for Rare Disorders)Symptoms of some types of leukodystrophy begin shortly after birth, but others develop later in childhood or even in adulthood. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems. Leukodystrophy can cause problems with movement, vision, hearing, balance, ability to eat, memory, behavior, and thought. Leukodystrophies are progressive diseases meaning that the symptoms of the disease tend to get worse over time. Some inherited leukoencephalopathies have stable white matter abnormalities. Magnetic resonance imaging (MRI) has markedly increased the awareness of hereditary white matter diseases associated with the formation of myelin and hypomyelination, in addition to the previously described classic leukodystrophies. New disease entities based on MRI and clinical patterns have been defined through the committed collaboration of neurologists in medical centers around the world. Microcephaly is a medical condition in which the brain does not develop properly resulting in a smaller than normal head. Microcephaly may be present at birth or it. Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, Charcot's disease and motor neurone disease (MND), is a specific disease that causes the. Symptoms of some types of leukodystrophy begin shortly after birth, but others develop later in childhood or even in adulthood. Each type of leukodystrophy affects a. The test menu below is a complete list of ARUP. A patient history form is requested for many of these genetic tests. Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motor neuron system. Although ALS is incurable and fatal, with median survival of 3. While the following list includes many disorders that have recently been described, it is not complete as there are new leukodystrophies identified each year. With the advances in whole genome sequencing, there will be many more new genetic disorders found including those that affect the white matter of the brain. For more information on the following disorders, search the Rare Disease Database. Adult- onset autosomal dominant leukodystrophy (ADLD)Adult- onset autosomal dominant leukodystrophy results from tandem duplication of the LMNB1 gene, which encodes the nuclear lamina protein lamin B1. At least six different genes have been described. Neuroimaging reveals leukoencephalopathy with calcifications and cerebral atrophy. Cerebrospinal fluid analysis reveals chronic lymphocytosis (elevated white blood cell count), elevated INF- a, and neopterin. Alexander disease. Alexander disease is a rare, progressive, leukodystrophy that usually becomes apparent during infancy or early childhood but juvenile and adult onset forms have also been reported. Alexander disease is characterized by degenerative changes of the white matter of the brain caused by a lack of normal amounts of myelin. The disorder is also associated with the formation of abnormal, fibrous deposits known as . The disease is caused by a dominant gain of function mutation in the glial fibrillary acidic protein (GFAP) (Chromosome 1. Treatment for Alexander. Strategies for future treatment include decreasing the expression of GFAP. CADASILCADASIL is a rare genetic disorder with dominant inheritance caused by a mutation in the NOTCH3 receptor gene. This condition presents with migraine headaches and multiple strokes in adults, even young adults, often without cardiovascular risk factors. CADASIL often progresses to cause cognitive impairment and dementia. The symptoms of CADASIL result from damage of various small blood vessels, especially those within the brain. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. CADASIL is an acronym that stands for: (C)erebral . Physical symptoms that appear in early infancy may include progressive mental decline accompanied by the loss of muscle tone, poor head control, an abnormally large head (macrocephaly), and/ or irritability. Physical symptoms appear in early infancy and usually progress rapidly. Canavan disease is caused by an abnormality in the ASPA gene (Chromosome 1. Canavan disease is inherited as an autosomal recessive genetic disorder. There are two common mutations among the Ashkenazi Jewish individuals that account for over 9. Jewish patients with Canavan disease. CARASILCARASIL is rare autosomal recessive disorder that is caused by mutations in cerebral small- vessel disease protein HTRA1 that controls the amount of TGF- B1 via cleavage of pro. TGF- B1b. Individuals with CARASIL are at risk of developing multiple strokes, even if they do not have cardiovascular risk factors. The symptoms of CARASIL result from damage to various small blood vessels, especially those within the brain. Individuals with CARASIL may develop a variety of symptoms relating to white matter involvement or leukoaraiosis (changes in deep white matter in the brain, which are observed on MRI). Such symptoms include an increasing muscle tone (spasticity), pyramidal signs, and pseudo bulbar palsy beginning between 2. Pseudo bulbar palsy is a group of neurologic symptoms including difficulties with chewing, swallowing and speech. Eventually, cognitive impairment and dementia may result. About half of cases have a stroke- like episode. The age of onset is 2. CARASIL is an acronym that stands for: (C)erebral . The lack of this enzyme prevents cholesterol from being converted into a bile acid called chenodexoycholic acid. Lipid rich deposits containing cholestanol and cholesterol accumulate in the nerve cells and membranes, and cause damage to the brain, spinal cord, tendons, lens of the eye and arteries. Affected individuals experience cataracts during childhood and benign, fatty tumors (xanthomas) of the tendons during adolescence. The disorder leads to progressive neurologic problems in adulthood such as paralysis, ataxia and dementia. Coronary heart disease is common. More than 3. 00 patients with CTX have been reported to date worldwide and about 5. CYP2. 7A1 gene. Almost all mutations lead to the absent or inactive form of the sterol 2. Dietary therapy with the bile acid, chenodeoxycholic acid, does correct many of the symptoms of CTX; however, early diagnosis of the disorder with early therapy leads to a better clinical outcome. The activity of cholesterol 7 alpha- hydroxylase, the rate limiting enzyme in bile acid synthesis, is normalized by this diet therapy and there is a reduction in the development of xanthomas. Childhood ataxia with cerebral hypomyelination. Childhood ataxia with cerebral hypomyelination (CACH), also known as vanishing white matter disease (VWMD), is an autosomal recessive leukodystrophy that is characterized by progressive deterioration in motor function and speech during the first five years of life. Clinical symptoms typically begin in the first few years of life, following a normal to mildly delayed early development. Common presenting symptoms include ataxia and seizures. The course is chronic and progressive with episodic decline following fever, head trauma, or periods of fright. Patients usually survive only a few years past the clinical onset, though the course is variable even among patients with mutations in the same e. IF2. B subunit. In the rare reports of adult- onset VWMD, the typical presentation consists of cognitive deterioration, pseudo bulbar palsy and progressive spastic paraparesis. An important association between VWMD and ovarian failure has been described, termed . VWMD may be one of the more common inherited leukoencephalopathies, though its exact incidence is not yet known. VWMD is caused by mutations in one of the 5 subunits of eukaryotic initiation factor 2. B (e. IF2. B). Despite the essential role of e. IF2. B in all cells, its defect curiously causes selective damage of white matter and in some cases damage to the ovaries alone. The ability of glia to regulate e. IF2 activity may represent a critical protective mechanism in response to stress conditions. Fabry disease. Fabry disease is a progressive X- linked lysosomal disorder due to a deficiency of the enzyme alpha- galactosidase A, leading to an accumulation of glycosphingolipids, mainly globotriaosylceramide GL- 3 in lysosomes. This accumulation triggers tissue ischemia and fibrosis. The classic form of the disease presenting in males with no detectable enzyme activity, is characterized by angiokeratomas, acroparesthesia, hyperhidrosis, corneal opacity in childhood or adolescence and progressive vascular disease of the heart, kidneys, and central nervous system. MRI findings include white matter abnormalities and vertebrobasilar stroke. In contrast, patients with mild forms of Fabry disease (female carriers and males with residual alpha- galactosidase activity) may remain asymptomatic until late adulthood. The incidence of Fabry disease is estimated to be 1/1. Recently enzyme replacement therapy and pharmacological chaperone therapy have been introduced to lower the GL- 3 accumulation in the lysosome. Fucosidosis. Fucosidosis is a rare autosomal recessive disorder characterized by deficiency of the lysosomal enzyme alpha- L- fucosidase, which is required to break down (metabolize) certain complex compounds (e. Fucose is a type of the sugar required by the body to perform certain functions (essential sugar). The inability to breakdown fucose- containing compounds results in their accumulation in various tissues in the body. Fucosidosis results in progressive neurological deterioration, skin abnormalities, delayed growth, skeletal disease and coarsening of facial features. The symptoms and severity of fucosidosis are highly variable and the disorder represents a disease spectrum in which individuals with mild cases have been known to live into the third or fourth decades. Individuals with severe cases of fucosidosis can develop life- threatening complications early in childhood. Hypomyelination is present on the MRI scans. The disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain fats and carbohydrates. Low levels or inactivity of the alpha- L- fucosidase enzyme leads to the abnormal accumulation of fucose- containing compounds in the tissues of individuals with fucosidosis. GM1 gangliosidosis. GM1 gangliosidosis is an autosomal recessive disorder due to deficiency of the lysosomal enzyme . More than 1. 00 mutations have been described. Three types of GM1 gangliosidosis have been described. Microcephaly - Wikipedia. Microcephaly is a medical condition in which the brain does not develop properly resulting in a smaller than normal head. A homozygousmutation in one of the microcephalin genes causes primary microcephaly. It is usually defined as a head circumference (HC) more than two standard deviations below the mean for age and sex. Occasionally, some will grow normally and develop normal intelligence. Severely impaired intellectual development is common, but disturbances in motor functions may not appear until later in life. Subsequently, the head fails to grow, while the face continues to develop at a normal rate, producing a child with a small head and a receding forehead, and a loose, often wrinkled scalp. As the child grows older, the smallness of the skull becomes more obvious, although the entire body also is often underweight and dwarfed. Development of motor functions and speech may be delayed. Hyperactivity and intellectual disability are common occurrences, although the degree of each varies. Convulsions may also occur. Motor ability varies, ranging from clumsiness in some to spasticquadriplegia in others. It has been classified in two types based on the onset. Relationships have been found between autism, duplications of chromosomes, and macrocephaly on one side. On the other side, a relationship has been found between schizophrenia, deletions of chromosomes, and microcephaly. This can result in other severe brain malformations and birth defects. Because the size of the brain is mostly determined by the size of the head, microencephaly is implied when discussing microcephaly. Due to their proximity to the bomb, the pregnant women's in utero children received a biologically significant radiation dose that was relatively high due to the massive neutron output of the lower explosive- yielding Little Boy. For example the Notch pathway genes regulate the balance between stem cell proliferation and neurogenesis in the stem cell layer known as the ventricular zone, and experimental mutations of many genes can cause microcephaly in mice. Many of them were presented as different species (e. Both these individuals were cited as influences on the development of the long- running comic strip character Zippy the Pinhead, created by Bill Griffith. Retrieved 1. 1 March 2. The American Journal of Human Genetics. The American Journal of Human Genetics. J Craniofac Genet Dev Biol. Nelson's Textbook of Pediatrics (1. Philadelphia: WB Saunders. Petersen; Erin Staples; Dana Meaney- Delman; Marc Fischer; Sascha R. Jamieson (January 2. MMWR Early Release on the MMWR website. Bibcode: 2. 01. 0PNAS. C. R.; Corvin, Aiden; Craddock, Nick J.; Gill, Michael; Hultman, Christina M.; Lichtenstein, Paul; Mc. Quillin, Andrew; Pato, Carlos N.; Ruderfer, Douglas M.; Owen, Michael J.; St Clair, David; Sullivan, Patrick F.; Sklar, Pamela; Purcell (Leader), Shaun M.; Stone, Jennifer L.; Ruderfer, Douglas M.; Korn, Joshua; Kirov, George K.; Mac. Gregor, Stuart; Mc. Quillin, Andrew; Morris, Derek W.; O. Bibcode: 2. 00. 8Natur. S. Cooper; Kahler, Anna K.; Mattingsdal, Morten; Athanasiu, Lavinia; et al. Proceedings of the National Academy of Sciences. Bibcode: 2. 01. 0PNAS. R. International Society for Infectious Diseases. New England Journal of Medicine. Retrieved 1 June 2. Retrieved 1 June 2. Centers for Disease Control and Prevention. New England Journal of Medicine. Catalog of prenatally diagnosed conditions. ISBN 9. 78- 0- 8. Retrieved 2. 5 March 2. Pediatric clinics of North America. The Journal of neuroscience : the official journal of the Society for Neuroscience. American Journal of Human Genetics.
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