DISEASE INFO
Leukodystrophy is a rare group of neurodegenerative diseases that affect the white matter of the brain. These diseases are genetic, progressive, and currently have no cure. The genetic abnormalities of leukodystrophy cause the irregular development of nerves' myelin sheath, which acts as a protective barrier to the nerves themselves. Without the healthy development of the myelin sheath, the nerve cells have difficulty sending and receiving electrical signals. Essentially, this abnormal development causes "exposed wiring" in the brain, significantly affecting the central nervous system's functionality.
Each form of leukodystrophy is directly linked to a specific genetic abnormality, which causes the degradation (or in some cases the overproduction) of the myelin sheath. While much is known about the genetic causes and clinical features of the multiple types of leukodystrophy, the rarity of the diseases has led to limited awareness and research efforts compared with more well known ailments.
The following information lists the affected gene(s), how often the disease occurs, how it is inherited, age of onset for symptoms, common symptoms, other known names, result of genetic mutation and prognosis for each leukodystrophy. For more information please see our sources located at the bottom of this page.
Adrenoleukodystrophy
Gene Affected- ABCD1
Disease Presence- 1:20,000 live births
Inheritance- x-linked recessive
Age of onset- ranges from 2 years to adulthood
Symptoms- emotional instability, hyperactivity, disruptive behavior; in adult forms it affects muscle stiffness, paraparesis and sexual dysfunction
Other names- x-linked ALD, ALD, x-ALD
Info- ALD is the most common peroxisomal disorder caused by a mutation of the ABCD1 gene. There are a number of different ways ALD can be expressed, and there is no reliable way to tell which form a person will develop. Left untreated, cerebral ALD is characterized by progressive demyelination leading to a vegetative state and death.
Adult-Onset Autosomal Dominant Leukodystrophy
Gene Affected- LMNB1
Disease Presence- unknown
Inheritance- autosomal recessive
Age of onset- adult (40-60 years old)
Symptoms- bladder retention, constipation, postural hypotension, erectile dysfunction, decreased sweating, cerebellar dysfunction (gait ataxia, loss of fine motor control, action tremors), spasticity, extremity weakness, cognitive impairment, personality changes
Other names- ADLD
Info- ADLD is caused by myelin disruption in the CNS, due to abnormalities in the LMNB1 gene. ADLD tends to progress slowly and shortens life expectancy slightly.
Aicardi-Goutieres Syndrome
Gene Affected- TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHDI1, ADAR1, IFIH1
Disease Presence- over 120 cases reported
Inheritance- autosomal recessive and autosomal dominant
Age of onset- neonatal, early infancy
Symptoms- microcephaly, neonatal seizures, poor feeding, jitteriness, cerebral calcifications, significant intellectual and physical problems, persistent crying, intermittent fever, dystonia, exaggerated startle response, glaucoma
Other names- AGS
Info- AGS is a result of the mutation of a number of different genes. Treatment is symptomatic with highly varying prognoses.
Alexander Disease
Gene Affected- GFAP
Disease Presence- fewer than 500 total reported cases
Inheritance- autosomal dominant, though most arise as spontaneous mutations
Age of onset- neonatal, infantile (0-2 years), juvenile (2-12 years), adult (over 12 years)
Symptoms- delays in physical/psychological/behavioral skills, macrocephaly, seizures, spasticity, hydrocephalus, idiopathic intracranial hypertension, dementia, gradual loss of bodily functions and ability to talk; in older onsent patients- bulbar symptoms and spasticity are common
Other names- fibrinoid leukodystrophy, AXD
Info- Alexander disease is caused by mutations in the GFAP gene, resulting in an excess of long chain fatty acids in the brain, which ruin the myelin. Treatment is symptomatic and may include shunt placement to relieve cranial pressure. There is no cure for Alexander disease and prognosis varies based on the age of onset. Usually, the earlier the onset, the worse the prognosis.
CADASIL
Gene Affected- Notch 3 (chromosome 19)
Disease Presence- unknown
Inheritance- autosomal dominant
Age of onset- age 30 to 70
Symptoms- migraine headaches, transient ischemic attacks, strokes, mood disorders, subcortical dementia, pseudobulbar palsy, urinary incontinence
Other names- Cerebral Autosomal Dominant Arteropathy with Subcortical Infarts and Leukoencephalopathy
Info- CADASIL is a common inherited stroke disorder caused by mutations in the Notch 3 gene. The disease is characterized by the progressive degeneration of smooth muscle cells in blood vessels. Treatment and prognosis are unknown.
Canavan Disease
Gene Affected- ASPA
Disease Presence- unknown
Inheritance- autosomal recessive
Age of onset- neonatal, infancy and childhood
Symptoms- mild form includes developmental delay, problems with speech or achievement at school, urine NAA is slightly elevated; severe form includes hypotonia, developmental delay and other neurological impairments, very high NAA concentraion in urine, blood and cerebrospinal fluid
Other names- ACY2 deficiency, aminoacylase 2 deficiency, aspartoacylase deficiency, spongy degeneration of the brain, CD
Info- CD is caused by lack of or low levels of the aspartoacylase enzyme activity, resulting from mutations in the ASPA gene. An onset of symptoms during neonatal or infancy align with the severe form of CD and average survival is 10 years, sometimes longer. Symptoms that begin in childhood align with the mild form of CD and prognosis is good with a typically normal life expectancy.
CARASIL
Gene Affected- HTRA1
Disease Presence- unknown
Inheritance- autosomal recessive
Age of onset- adolescent and adult
Symptoms- diffuse alopecia, gait disturbance, lower and mid back pain, disk herniations, nodular thickening, severe spondylitis deformans with osteoporosis, lumbago with no radiological anormalities, lacunar stroke, stepwise deterioration in brain function, psuedobulbar palsy, hyperreflexia, vestibular symptoms, opthalmoplegia, forgetfulness, emotional incontinence, personality changes, disorientation in time, apallic syndrome, abulia, akinetic mutism
Other names- cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, Maeda syndrome
Info- CARASIL is a cerebral small vessel disease caused by a mutation in the HTRA1 gene. The mutation leads to reduced or no amount of the gene which leads to increased signaling by the (TGF)-beta family, and the symptoms listed above. There is currently no cure and treatment is symptomatic. The prognosis is poor with the average duration of illness lasting 10 years.
Childhood Ataxia with Diffuse CNS Hypomyelination
Gene Affected- multiple EIF2B genes
Disease Presence- 148 total cases reported
Inheritance- autosomal recessive
Age of onset- childhood
Symptoms- extra-neurological affections, cognitive and behavioral dysfunction
Other names- CACH, vanishing white matter disease, myelinosis centralis diffusa
Info- CACH is caused by a mutation in the five EIF2B genes. These genes are involved in protein synthesis and regulation. Corticosteroids may be helpful in acute episodes. Prognosis may correlate with age of onset, with the earliest onset being the most severe.
CTX
Gene Affected- CYP27A1
Disease Presence- more than 300 total reported cases; estimated at 1:50,000 live births in Caucasians
Inheritance- autosomal recessive
Age of onset- neonatal and infancy
Symptoms- chronic diarrhea from infancy, cataracts, cholestasis, liver dysfunction, intellectual impairment; later into adulthood patients may acquire dementia, psychiatric disturbances, seizures, neuropathy
Other names- cerebrotendineous xanthomatosis, cerebrotendinous xanthomatosis, cerebral cholesterosis, Van Bogaert-Scherer-Epstein syndrome
Info- CTX is a form of xanthomatosis caused by a mutation of the CYP27A1 gene. It is associated with the deposition of cholestanol in the brain and other tissues, and higher levels of cholesterol in plasma. Early diagnosis and treatment are crucial to prevent progressive accumulation of cholestanol and cholesterol. Treated patients may have a normal lifespan. In untreated patients, life expectancy is 50 to 60 years. Some early deaths in infancy have also been reported.
Fabry Disease
Gene Affected- GLA
Disease Presence- 1:80,000 live births
Inheritance- x-linked recessive
Age of onset- childhood
Symptoms- proteinuria, kidney failure, cardiomyopathy, transient ischemic attacks, stroke, burning or tingling paresthesia, burning pain, anhidrosis, hypohidrosis, angiokeratoma, corneal changes, tinnitus, chronic fatigue, cardiac and cerebrovascular abnormalities, dyspnea, nephropathy
Other names- alpha-galactosidase A deficiency, Anderson-Fabry disease, Angiokeratoma corporis diffusum, diffuse angiokeratoma, FD
Info- Fabry disease is a progressive, multi systemic lysosomal storage disease. Enzyme enhancements with pharmacological chaperones and enzyme replacement therapy using in vitro engineered alpha-galactosidase A are under investigation. Current treatment may include pain management, anti arrhythmic agents, pacemakers or implantable cardioverter defibrillator, dialysis and kidney transplant. With time, the progression of the disease may cause organ failure.
Fucosidosis
Gene Affected- FUCA1
Disease Presence- 1:2,000,000 (fewer than 100 total cases reported)
Inheritance- autosomal recessive
Age of onset- type 1 is 0-18 months; type 2 is around 18 months; type 3 is approximately 1-2 years
Symptoms- progressive neurological deterioration, skin abnormalities, growth retardation, skeletal disease, coarsening of facial features, recurrent sinopulmonary infections, seizures, visceromegaly, angiokeratoma and dysostosis
Other names- n/a
Info- Fucosidosis is a rare lysosomal storage disorder where mutations in the FUCA1 gene drastically reduce or prohibit the alpha-L-fucosidase enzyme. There are three types of the disease, with type 1 being the earliest age of onset and most severe. Currently, treatment is symptomatic. A bone marrow transplant may spur the production of normal amounts of fucosidase, however, more research is needed to prove the effectiveness of this treatment. Prognosis ranges from less than six years with type 1, to 30-40 for other types.
GM1 Gangliosidosis
Gene Affected- GLB1
Disease Presence- 1:100,000 - 200,000 live births
Inheritance- autosomal recessive
Age of onset- type 1 is 0-6 months; type 2 is 7-36 months; type 3 is 3-30 years
Symptoms- delayed motor and cognitive development, generalized dystonia, facial coarsening, hypertrophic gums, cherry-red macula, visceromegaly, dysostosis, psychomotor delay
Other names- beta-galactosidase-1 deficiency, GLB1 deficiency, Landing disease
Info- GM1 gangliosidosis is a lysosomal storage disorder. The mutation of gene GLB1 leads to toxic accumulation of gangliosides in body tissues and especially in the central nervous system. There are three types of the disease based on the age of onset, with the most severe being type 1. Currently there is no cure and treatment is symptomatic, but substrate reduction therapy is a potential approach for clinical trials in late-onset forms.
Krabbe Disease
Gene Affected- GALC (and rarely in infant form- PSAP)
Disease Presence- 1:100,000 - 250,000 live births
Inheritance- autosomal recessive
Age of onset- infantile (2-6 months); late infantile/juvenile (1-8 years); adult (8+ years)
Symptoms- infantile form symptoms include irritability, stiffness, poor head control, feeding difficulties, intermittent thumb clasp, episodes of increased temperature, developmental delay, hypertonic episodes with opisthotonus, myoclonic seizures, developmental regression, vision deficits, hypotonia, blindness, deafness; adult symptoms include weakness, gait disturbances, burning paresthesias, hemiplegia, vision loss, peripheral neuropathy, and potential cognitive regression
Other names- GALC deficiency, galactocerebrosidase deficiency, galactosylceramidase deficiency, globoid cell leukodystrophy
Info- Globoid cell leukodystrophy (Krabbe) is a lysosomal disorder that is caused by mutations in the GALC gene and affects the white matter of the central and peripheral nervous systems. Current treatment is typically stem cell transplantation in pre-symptomatic infantile patients and mildly affected late-onset patients, and has been shown to slow disease progression. Other treatment options are currently under research. Prognosis is poor in infantile form (under 3 years). The disease is normally fatal within 2-7 years of symptom onset in juvenile form. Adult onset patient survival is much greater.
L-2-Hydroxyglutaric Aciduria
Gene Affected- L2HGDH
Disease Presence- fewer than 1:1,000,000
Inheritance- autosomal recessive
Age of onset- childhood
Symptoms- motor retardation, epilepsy, mental deterioration, speech difficulties, loss of independent walking, macrocephaly, hypotonia, spasticity, extrapyramidal symptoms, behavioral disorders, brain tumors
Other names- L-2-HGA; L-2-hydroxyglutaric acidemia
Info- L-2-hydroxyglutaric aciduria is the result of the mutation of the L2HGDH gene. There is currently no cure and treatment is symptomatic. Prognosis is poor but most patients reach adulthood.
Megalencephalic Leukoencephalopathy with Subcortical Cysts
Gene Affected- MCL1 (type 1), HEPACAM (type 2A and 2B), and 5% have unidentified mutations
Disease Presence- unknown
Inheritance- autosomal recessive or autosomal dominate
Age of onset- 0-12 months
Symptoms- megalencephaly, subcortical cysts, uncontrolled muscle tensing, involuntary writhing of limbs, difficulty swallowing, impaired speech, recurrent seizures, mild to moderate intellectual disability
Other names- MLC, megalencephalic leukodystrophy, megalencephaly-cystic leukodystrophy syndrome, vacuolating megalencephalic leukoencephalopathy with subcortical cysts, Van der Knaap syndrome
Info- There are three types of MLC that arise from either a mutation in the MCL1, HEPACAM or unidentified gene mutation. Patients with MLC have enlarged myelin sheaths that contain fluid filled pockets After time, the swelling goes down and the myelin sheath begins to deteriorate. Treatment and prognosis for MLC is unknown.
Metachromatic Leukodystrophy
Gene Affected- ARSA (most), PSAP (few)
Disease Presence- 1:40,000
Inheritance- autosomal recessive
Age of onset- late infantile, juvenile, adult
Symptoms- abnormally high muscle tone, abnormal muscle movements, behavior problems, decreased mental function, decreased muscle tone, difficulty walking, feeding difficulties, frequent falls, inability to perform normal tasks, incontinence, irritability, loss of muscle control, nerve function problems, personality changes, poor school performance, seizures, speech difficulties, swallowing difficulties
Other names- MLD, arylsulfatase A deficiency
Info- MLD is caused by a lack of the arylsulfatase A enzyme. Without this enzyme, an accumulation of sulfatides occur in a number of body tissues, ultimately leading to the destruction of myelin. Prognosis varies based on the onset of symptoms, ranging in a disease course of usually three to 20+ years.
Multiple Sulfatase Deficiency
Gene Affected- SMUF1
Disease Presence- fewer than 1:1,000,000 individuals (prevalence)
Inheritance- autosomal recessive
Age of onset- neonatal and infancy
Symptoms- mildly coarsened facial features, deafness, ichthyosis, enlarged liver and spleen, severe mental retardation, hypotonia, hydrocephalus
Other names- Austin disease, mucosulfatidosis
Info- Multiple sulfatase deficiency is a lysosomal storage disease caused by a deficiency in multiple sufatase enzymes, or in formylglycine-generating enzyme, which activates sulfatases.
Pelizaeus Merzbacher Disease
Gene Affected- PLP1
Disease Presence- 1:400,000 invididuals
Inheritance- x-linked recessive or x-linked dominant
Age of onset- all ages, but classic onset is within 0-2 months of birth
Symptoms- hypotonia, nystagmus, respiratory distress, stridor, motor and cognitive delay, spastic quadriparesis, ataxia, spastic paraplegia, peripheral neuropathy
Other names- diffuse familial brain sclerosis, PMD, Pelizaeus-Merzbacher brain sclerosis, sudanophilic leukodystrophy
Info- PMD is a disorder caused by mutations or dosage alterations in the PLP1 gene. These mutations cause CNS hypomyelination. Treatment may include gastrostomy, anti epileptic medications, physical therapy, antispasticity drugs, or corrective surgery for pulmonary compromise in the case of severe scoliosis. MPD is progressive, and prognosis varies on the disease form. In moderate forms, life expectancy is quite long with slow disease progression. In severe forms, death normally occurs within 20 years.
Pol III-Related Leukodystrophy
Gene Affected- POLR3A or POLR3B
Disease Presence- unknown
Inheritance- autosomal recessive
Age of onset- infancy, childhood and adolescent
Symptoms- hypomyelination, cerebellar atrophy, hypoplasia of the corpus callosum, intellectual disability (mild to severe), ataxia, delayed development of motor skills, unstable gait, tremor of arms and hands, abnormal teeth development, excessive salivation, dysphagia, speech impairment, abnormal eye movement, nearsightedness, cataracts, deterioration of the optic nerves, seizures, delayed signs of puberty
Other names- 4H, 4H syndrome, ADDH, dentoleukoencephalopathy, HCAHC, HLD7, HLD8, leukodystrophy with oligodontia, hypomyelination/hypodontia/hypogonadotropic/hypogonadism, LO, odontoleukodystrophy, Pol III disorder, TACH, tremor-ataxia with central hypomyelination
Info- Pol III leukodystrophy is caused by the mutation of either the POLR3A or POLR3B gene. These genes facilitate the creation of RNA polymerase III, which aids synthesis of several forms of RNA, including ribosomal RNA and transfer RNA (tRNA). These RNA molecules assemble protein building blocks into working proteins, and are essential to normal cell function.
Refsum Disease
Gene Affected- PHYH (over 90% of cases), PEX7 (fewer than 10% of cases)
Disease Presence- roughly 60 total cases reported
Inheritance- autosomal recessive
Age of onset- infancy, childhood, adolescent or adulthood
Symptoms- anosmia, early-onset retinitis pigmentosa, neuropathy, cerebellar ataxia, deafness, ichthyosis, skeletal abnormalities, cardiac arrhythmia, near blindness, sensory neuropathy, muscular atrophy, weakness, peripheral sensory disturbances, autism-spectrum disorder, ADHD, short metacarpals and metatarsals at birth
Other names- adult refsum disease, classic refsum disease, HMSN 4, hereditary motor and sensory neuropathy type 4, heredopathia atactica polyneuritiformis, phytanic-CoA hydroxylase deficiency
Info- Refsum disease is a clinically variable, multi systemic metabolic disease. It is caused by mutations in either the PHYH or PEX7 gene, which are involved in lipid metabolism and protein transport. Specific diet and supportive treatments are available to help manage symptoms. Cardiac monitoring is required, as the main cause of death is arrhythmia and heart failure. Prognosis in cases without treatment is generally poor.
Salla Disease
Gene Affected- SLC17A5
Disease Presence- fewer than 1:1,000,000 individuals (prevalence)
Inheritance- autosomal recessive
Age of onset- neonatal and infancy
Symptoms- nystagmus, hypotonia, reduced muscle tone and strength, cognitive impairment
Other names- sialic acid storage disease, Finnish type sialuria
Info- Salla disease is a lysosomal storage disease caused by a mutation in the SLC17A5 gene.
Sjogren-Larssen Syndrome
Gene Affected- ALDH3A2
Disease Presence- 1:250,000 in Sweden (unknown outside of Sweden)
Inheritance- autosomal recessive
Age of onset- early childhood
Symptoms- dry/scaly skin, red skin, itchiness, intellectual disability, speech difficulties, delayed speech, seizures, delayed motor skills, muscle stiffness, nearsightedness, sensitivity to light
Other names- FALDH deficiency, ichthyosis oligophrenia syndrome, SLS, congenital icthyosis mental retardation spasticity syndrome
Info- Sjogren Larssen Syndrome is caused by a mutation in the ALDH3A2 gene. These mutations affect the normal process of fatty acid oxidation, which results in fat buildup in cells that can't be broken down. The excess fat accumulations cause the symptoms listed above. It is not clear what the consequences of excess fat accumulation is in the brain, but it is likely that it disrupts the formation of myelin. These symptoms are apparent by early childhood and usually do not worsen with age.
Zellweger Syndrome
Gene Affected- one of the 13 PEX genes
Disease Presence- 1:50,000 live births in North America, 1:500,000 in Japan
Inheritance- autosomal recessive
Age of onset- neonatal
Symptoms- dysmorphic craniofacial features, profound hypotonia, seizures, macro and microcephaly, high arched palate, micrognathia, redundant neck skin folds, skeletal abnormalities, subcortical renal cysts, multiple eye findings, visual changes and loss, sensorineural hearing loss, psychomotor delay
Other names- ZS, cerebrohepatorenal syndrome
Info- Zellweger syndrome is the most severe variant of the peroxisome biogenesis disorders. Mutations in the effected PEX gene lead to abnormal peroxisome biogenesis. There is currently no cure for ZS. Regardless of intervention, infants usually die within the first year of life.
References:
Below are the list of references for much of the above information.
https://ghr.nlm.nih.gov/condition/metachromatic-leukodystrophy
http://medical-dictionary.thefreedictionary.com/mucosulfatidosis
https://en.wikipedia.org/wiki/Online_Mendelian_Inheritance_in_Man
http://ghr.nlm.nih.gov/condition=fucosidosis
http://www.ismrd.org/glycoprotein_diseases/fucosidosis
http://children.webmd.com/fucosidosis
http://rarediseases.about.com/od/rarediseasesf/a/fucosidosis.htm
http://www.omim.org/entry/300100?search=x-ald&highlight=xald
http://www.ncbi.nlm.nih.gov/books/NBK1172/
http://www.ninds.nih.gov/disorders/alexander_disease
http://ulf.org/alexander-disease
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