Different types of Leukodystrophy

The term adrenoleukodystrophy encompasses two distinct genetic disorders; X-linked adrenoleukodystrophy and neonatal ALD. Both are characterized by varying degrees of adrenal involvement and demyelination.

Adrenoleukodystrophy (ALD) is a serious genetic disorder which progressively affects the adrenal gland, along with the white matter of the nervous system. In ALD, there is an abnormal accumulation of very long chain fatty acids, which causes tissue damage, however the exact nature of this relationship is not understood. This kind of illness is called a peroxisomal storage disease. ALD is an X-linked disorder which means it affects only males and is transmitted by a female carrier.

The first appearance of ALD varies. Usually it presents in boys of between 4 and 10 years of age, and the early signs include learning difficulties and perceptual problems, together with short- and long-term memory loss, various personality and behavioural changes, and symptoms of Attention Deficit Disorder.

It is common for boys with ALD to also have Addisons Disease, also known as adrenal insufficiency. This is a critical condition which may result in severe morbidity and mortality when undiagnosed or ineffectively treated. Once diagnosed, the treatment is relatively straightforward and usually requires lifelong hormone replacement.

ALD has an adult form, usually milder than the childhood condition. This illness is called adrenomyeloneuropathy (AMN).

Physical therapy, psychological support, special education, and visiting nurse services may be required to help the family cope with childhood ALD.

Treatment of ALD is still in the exploratory stage. The most promising treatments are:

1. a diet restricted in very long chain fatty acids, and
2. bone marrow transplant.

Find out more Adrenoleukodystrophy (ALD)

Associated very closely with adrenoleukodystrophy is the disorder adrenomyeloneuropathy (AMN), which is a milder “adult” form of ALD. It may affect older males in the same way as ALD, and also can occasionally affect women who are carriers of the defective gene responsible for ALD.

AMN is characterised by slowly progressive stiffness and weakness of the legs, and sphincter disturbances, and is often misdiagnosed as multiple sclerosis or familial spastic paraparesis. Early symptoms of AMN usually appear when patients are between 24 & 28 years of age. These patients have myelopathy, often with mild peripheral neuropathy, and half of them have moderate cerebral involvement, demonstrable by MRI scan.

While mental function may be entirely preserved, approximately half of AMN patients do develop cerebral changes at some time during the course of the illness, and then may show rapid neurological progression.

Adrenomyeloneuropathy is the condition suffered by Sister Julie Thomas, Founder of the Australian Leukodystrophy Support Group.

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Alexanders disease is the rarest of the identified leukodystrophies. The infantile form tends to appear between birth and two years, and most sufferers of this form do not survive past the age of 5 or 6. The destruction of the white matter in the brain is accompanied by the formation of fibrous, eosinophilic deposits. These are known as Rosenthal fibres.

Alexanders tends to be sporadic, appearing in families with no known history of the disorder. It is progressive, affects mostly males, and leads to both physical and mental retardation and dementia. The brain and head become progressively larger, leading the increased spasticity and sometimes seizures.

The myelin sheath of both the sensory and motor fibre tracts is affected in Alexander’s disease. The Rosenthal fibres are found distributed near the blood vessels of the brain and on the brain’s surface. The nerves affected by the disease’s demyelination do not correspond with the distribution of the Rosenthal fibres, and these two effects seem to be otherwise unrelated expressions of the disorder.

The exact metabolic error that causes Alexanders disease is unknown, but it is thought to be an autosomal recessive disorder, which may affect both males and females. The demyelination seems to be cause by the destruction of the astrocytic glial cells.

An exact diagnosis of Alexander’s disease may not be possible without study of post-mortem tissues or brain or nerve biopsy.

As well as the infantile form of the disease, Alexander’s disease is believed to have juvenile and adult onset forms. These occur less frequently and do not progress as rapidly as the infantile form. Older sufferers have widespread formation of Rosenthal fibres throughout their central nervous system, but have less white matter loss and therefore milder symptoms. Whether, however, the disorders described in older children and adults are all actually ‘Alexander’s disease’ or in fact some other similar disorder has not been determined.

Treatment of Alexanders disease is symptomatic and supportive.

Find out more Alexander Disease

Definition
Adult-onset autosomal dominant leukodystrophy (ADLD) is a very rare, slowly progressive, neurological disorder characterised by symmetrical widespread myelin loss in the CNS. Although different in some ways, it has often been confused with chronic progressive multiple sclerosis.

Clinical presentation
ADLD is a slowly progressive and fatal neurological disorder, characterised clinically by autonomic abnormalities, pyramidal and cerebellar dysfunction, and symmetrical demyelination of the CNS. The autonomic problems include bowel/bladder dysfunction, impotence (in males), orthostatic hypotension and decreased sweating. A survival rate of 20 years is common. Several symptoms distinguish ADLD from multiple sclerosis (MS). ADLD patients exhibit early autonomic dysfunction, and such extensive autonomic abnormalities have not been noted in MS patients. MS is an inflammatory disorder, while no pathological indication of brain inflammation has been found with ADLD, suggesting that ADLD is not an inflammatory disorder. Thus, ADLD is similar to, yet distinct from, chronic progressive MS.

Clinical course
Affected individuals usually begin to exhibit neurological symptoms, such as a loss of fine motor skills, in the fourth or fifth decade of life; however, autonomic abnormalities precede these symptoms by several years and are among the first to appear. The earliest symptoms usually involve abnormalities of the autonomic nervous system, such as bowel/bladder dysfunction, impotence, orthostatic hypotension and decreased sweating. These symptoms precede others by several years and are followed by loss of fine motor skills.

Diagnosis
Computed tomography (CT) scans and magnetic resonance imaging (MRI) studies indicate that the white matter abnormality begins in the frontal lobes of the brain and extends to the cerebellum. Upper motor neuron signs are also common phenotypic characteristics of this disorder. In addition to upper motor neuron dysfunction, ADLD patients also exhibit cerebellar signs. For instance, all patients experience ataxia.

Genetics
ADLD is inherited in an autosomal dominant manner. The gene has been localised to a 4cM region on chromosome 5q31. Genetic localisation will lead to cloning and characterisation of the ADLD gene, and may yield new insights into myelin biology and demyelinating diseases.

Treatment
No specific treatments are available.

Research
Extensive research is being conducted by Drs Ying-Hui Fu and Louis Ptacek at the University of California, San Francisco. For more information, or if you are interested in participating in the research, please visit the University of California, San Francisco page.

Canavans disease sets in during early infancy, and usually leads to death by the age of ten years. This form of leukodystrophy causes the white matter of the brain to be replaced by microscopic fluid filled spaces, and is characterised by structural abnormalities and the deterioration of motor, sensory, and intellectual functions. Curiously, this form seems to affect persons of Eastern European Jewish ancestry most frequently.

Feeding difficulties are often the first symptom, followed by progressive mental retardation and apathy. Physical symptoms include muscular flaccidity (floppiness) and weakness, especially in the muscles supporting the head. The brain swells, causing the head to progressively enlarge as the bones of the skull fail to fuse normally. Vision and sometimes hearing may deteriorate due to nerve degeneration, and spasticity and paralysis develop. Mental deterioration progresses with time.

Decreased muscle tone (floppiness) is revealed on neurologic examination, and damage to the optic nerve (optic atrophy). The brain itself is enlarged. Cyst-like spaces pervade the white matter, with large quantities of fluid accumulating in the membranes covering the brain.

The myelin sheath is destroyed in most parts of the brain, as demonstrated by computerized axial tomography (CAT scan), which shows severe white matter changes, and helps to rule out hydrocephalus. Pneumonia may develop due to depressed chest movement while breathing.

Canavans disease can affect both boys and girls, and is inherited through an autosomal recessive mechanism. Excessive amounts of N-acetylaspartic acid in body fluids appear in biochemical testing, as does deficiency of the enzyme aspartoacylase. Carrier detection and prenatal diagnosis are possible through the research efforts and from the laboratory of Dr. Reuben Matalon at the University of Texas in Galveston Texas.

Treatment of Canavans disease is symptomatic, and discomfort may be alleviated by means of supportive care.

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Xanthomas is a term describing the presence of yellowish fatty tumours on the tendons, which is a specific finding in the diagnosis of Cerebrotendinous Xanthomatosis. Most often found in the Achilles tendon, this revealing attribute tends to be missed unless specifically looked for. Patients with CTX may present first with cataracts or with mild mental retardation. Later on, patients may develop seizures, emotional or psychiatric disturbances, and motor deficits. CTX has an autosomal recessive pattern of inheritance.

CTX is usually diagnosed by measuring the levels of bile alcohols in blood or urine, or of a substance called cholestanol in the blood. Cholestanol resembles cholesterol chemically, but can be distinguished from it by special chemical tests.

The biochemical basis of CTX is complex, but advances are beginning to be made toward understanding it. Diagnosis of the illness is important, since it is by far the most treatable of the leukodystrophies. Much encouragement has been gained through the observation that certain bile acids, administered orally, can prevent further progression of the illness, and may even bring about improvement.

There is a very favourable response to chenodeoxycholic acid, a medication that can be taken by mouth.

Find out more Cerebrotendinous Xanthomatosis (CTX)

Krabbe Disease, or Globoid Cell Leukodystrophy, is caused by an almost complete deficiency of galactosylceramide B-galactosidase activity. It is a rare degenerative disorder of the central and peripheral nervous systems.

The onset of symptoms is usually between the ages of 3 and 6 months, after which infants rapidly deteriorate, losing previously attained developmental skills. The children come down with unexplained fevers, irritability, myoclonic seizures, blindness, spasticity, and paralysis. Usually Krabbes is fatal before the age of 2 years.

Later onset Krabbe Disease exists and occurs in late infancy (6-18 months), the sub-teens, adolescence, or adulthood. There is involvement of the motor system, with spasticity, as well as changes in vision and the thinking processes.

Globoid Cell Leukodystrophy follows an autosomal recessive pattern of inheritance and affects males and females equally. The enzyme that must be investigated is B-galactocerebrosidase, rather than galactosidase, which is a marker for a different disorder. Diagnosis may be missed, particularly in older patients.

Bone marrow transplant has been performed in a limited number of patients with encouraging results in some of the more mildly involved, older patients.

Find out more Globoid Cell Leukodystrophy (Krabbe Disease)

Metachromatic Leukodystrophy is unusual among the leukodystrophies because, rather than being caused by too little of a myelin sheath component, it is caused by too much of one. A lack of the enzyme arylsulfatase A leads to a build up of sulfatides, a component of the myelin sheath, in the patient’s nervous system in various organs in the body such as the kidney, liver, and gall bladder. The sulfatides are not properly broken down when the enzyme is missing.

Although Metachromatic Leukodystrophy, along with Adrenoleukodystrophy, is probably the most frequently observed leukodystrophy, the reason why this increase in sulfatide levels causes demyelination is as yet unknown

MLD is an autosomal recessive type of disorder, and manifests in three types:

1. Late Infantile, with onset of symptoms between six months and two years of age;
2. Juvenile, with onset of symptoms after age four until age sixteen years;
3. Adult, with onset of symptoms after age sixteen and characterized by psychiatric disturbances evolving to dementia.

Only one form of MLD is seen within a family.

The infantile form strikes children after their first year. Until then the child will have been developing normally. Following onset, the disease follows a course of continuous, progressive nervous system involvement. This course is time variable, but is progressively downhill, with death usually occurring within three to six years.

The child will first become ‘floppy’ due to low muscle tone, and speech abnormalities may occur.

Soon after comes a halting of mental development, the loss of ability to make many voluntary movements. Mental abilities will be lost, and the child will be unable to speak or to see. Ultimately, the child will be bedridden. Swallowing ability is often lost, and the child will need to be tube fed.

MLD is usually diagnosed through blood and urine tests, together with clinical studies. In cases of MLD, the level of arylsulfatase A in the blood is very low, while sulfatide levels in the urine are increased. Carrier detection and prenatal diagnosis are available; genetic counselling is advised.

Bone marrow transplant has been used experimentally for children with the mild form of MLD.

Find out more Metachromatic Leukodystrophy (MLD)

Females with Leukodystrophy and ovarian dysgenesis in whom all other known causes of either Leukodystrophy or ovarian malfunction have been ruled out.

Usually present with difficulty walking (ataxia) or just mental retardation. So far all patients had progressive dementia and motor difficulties. They can become wheelchair bound.

Pelizaeus-Merzbacher disease takes its name from the two German neurologists who first described its main symptoms. The condition is caused by mutations which affect the gene controlling proteolipid protein (PLP). PMD appears to be X-linked, with mostly males being affected. Occasionally, though, females also develop the disease.

Symptoms usually appear in infancy, with the first sign usually being involuntary movements of the eyes, known as nystagmus. Sometimes laboured breathing accompanies this. Later, infants may show hypotonia or spasticity, with increased muscle tone. Intellectual and motor milestones such as sitting and crawling may be delayed. There may be wavering or tremor through the upper body due to impaired control of the head and trunk, and very occasionally the infant may have seizures. Some mutations of the PLP gene may result in a less severe disorder, involving spastic paraparesis, and gait disturbance due to spastic legs.

The prognosis of PMD is variable; Sometimes the mutations are more severe, leading the death of the sufferer at an early age, but other individuals survive into their thirties or fifties. The disorder tends to be progressive until death.

Currently there is no cure for PMD, and no standard course of treatment exists. Most care is symptomatic and supportive, and may include medication for movement disorders and seizures where these occur. There is a consortium of clinicians and researchers working on PMD in the United States, dedicated to research of the causes of the disorder and, hopefully, a cure.

Find out more Pelizaeus Merzbacher Disease (X-linked spastic paraplegia)

Females with Leukodystrophy and ovarian dysgenesis in whom all other known causes of either Leukodystrophy or ovarian malfunction have been ruled out.

Usually present with difficulty walking (ataxia) or just mental retardation. So far all patients had progressive dementia and motor difficulties. They can become wheelchair bound.

Pelizaeus-Merzbacher disease takes its name from the two German neurologists who first described its main symptoms. The condition is caused by mutations which affect the gene controlling proteolipid protein (PLP). PMD appears to be X-linked, with mostly males being affected. Occasionally, though, females also develop the disease.

Symptoms usually appear in infancy, with the first sign usually being involuntary movements of the eyes, known as nystagmus. Sometimes laboured breathing accompanies this. Later, infants may show hypotonia or spasticity, with increased muscle tone. Intellectual and motor milestones such as sitting and crawling may be delayed. There may be wavering or tremor through the upper body due to impaired control of the head and trunk, and very occasionally the infant may have seizures. Some mutations of the PLP gene may result in a less severe disorder, involving spastic paraparesis, and gait disturbance due to spastic legs.

The prognosis of PMD is variable; Sometimes the mutations are more severe, leading the death of the sufferer at an early age, but other individuals survive into their thirties or fifties. The disorder tends to be progressive until death.

Currently there is no cure for PMD, and no standard course of treatment exists. Most care is symptomatic and supportive, and may include medication for movement disorders and seizures where these occur. There is a consortium of clinicians and researchers working on PMD in the United States, dedicated to research of the causes of the disorder and, hopefully, a cure.

Find out more Pelizaeus Merzbacher Disease (X-linked spastic paraplegia)

Vacuolating leukoencephalopathy with subcortical cysts (VLE) is genetically determined leukoencephalopathy with widespread swelling and sponginess of the cerebral white matter and formation of subcortical cysts, always in the anterior-temporal area, often also in the frontal and parietal areas.

VLE is clinically a homogenous disease that does not have early and late-onset variance, although there is a variation in severity of the disease. All patients develop a macrocephaly during the first year of life and some patients already have it at birth. Typically, early development is normal or only mildly delayed. Independent walking is often delayed and unstable. Usually, a CT scan or MRI of the brain is obtained in this stage under the suspicion of slowly progressive hydrocephalus. The scans then show a diffuse abnormality of the cerebral white matter, which also is swollen. Because of that, the overlying cortex is stretched and gyri are weakened. MRI always shows subcortical cysts in the anterior-temporal area, often also in the frontoparietal area. This MRI picture should lead to the correct diagnosis.

During the first years of life, children with VLE usually have a normal or close to normal function. From the age of 4 to 5 years onwards, most children develop a slowly progressive cerebellar ataxia. Because of the ataxia speech becomes unclear too. From the age of late primary school onwards, mental slowing is noted and learning problems develop, although mental capacities remain relatively better intact than motor capacities. Most children have infrequent epileptic seizures, which can be easily controlled with anti-epileptic medication.

There are more severe variants. In some children, early development is already seriously delayed. Some children never achieve independent walking or lose it within a few years. Sometimes the epilepsy is more serious. However, there are also milder variants in which independent walking is maintained for several decades. In some patients, mental capacities remain intact for a long time.

Find out more Van der Knaap Syndrome (Vacuolating Leukodystrophy with Subcortical Cysts or MLC)

Refsum’s Disease is caused by an accumulation of phytanic acid in the tissues and blood due to a genetically determined inability to degrade this substance. The accumulation of phytanic acid causes impaired vision and hearing and peripheral neuropathy, that is, impaired sensation and strength in the distal parts of all extremities.

The disorder has an autosomal recessive pattern of inheritance, and its age of onset varies from early childhood to age 50. Symptoms usually appear, however, 20 years of age. Males and females are affected alike. Diagnostic, carrier, and prenatal testing is available.

Together with Cerebrotendinous Xanthomatosis (CTX), Refsum’s disease is at this time, one of the most hopeful leukodystrophies. Phytanic acid is not made in the human body but comes exclusively from the diet, and thus restriction of certain foods such as dairy products, tuna fish, cod, haddock, lamb, stewed beef, white bread, white rice, boiled potatoes and egg yolk, further progress of the disease can be prevented and some of the symptoms improved. In addition, the supplement Plasmapheresis has been effective in providing a positive initial response.

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Zellweger Syndrome is a rare form of leukodystrophy affecting infants, of which a reduction or absence of peroxisomes in the cells of the liver, kidneys, and brain is characteristic. The major manifestations of Zellweger Syndrome include unusual problems in prenatal development, an enlarged liver, high levels of iron and copper in the blood, and vision disturbances.

Infants with Zellweger Syndrome have the disease from birth, and it is usually fatal within six months. It can often be recognized at birth due to profound lack of muscle tone; some infants may be unable to move. Prenatal growth failure, despite a normal period of gestation, are another manifestation of Zellweger, along with unusual facial characteristics, mental retardation, the inability to suck and/or swallow, and liver enlargement. Less commonly there may be vision problems and congenital heart lesions. Jaundice and/or gastrointestinal bleeding due to deficiency of a coagulation factor in the blood can also occur. This There may also be abnormal bleeding that can be corrected by giving Vitamin K. Infections should be guarded against carefully to delay complications, as pneumonia or respiratory distress may develop if infections are not prevented or controlled.

Zellweger Syndrome is inherited as an autosomal recessive trait. The deficiency or absence of the microbodies known as peroxisomes causes an accumulation of very long chain fatty acids the in body. The exact cause of the lack of these peroxisomes is not yet known. Early diagnosis and prenatal detection can be made through the study of the very long chain fatty acids which accumulate in the absence of peroxisomes.

Treatment of Zellweger Syndrome is symptomatic and supportive.

Neonatal ALD is autosomal recessive in its pattern of inheritance, so unlike the other form of ALD it affects both males and females. The disorder is now fairly easy to diagnose through biochemical tests, which demonstrate abnormally high levels in the tissues and body fluids of the very long chain fatty acids typical of ALD.

Neonatal ALD is similar to the Zellweger cerebrohepatorenal syndrome, and may actually represent a milder variant of Zellweger. While there is no doubt that it is distinct from X-linked ALD, the exact classification of this neonatal form of ALD is still indeterminate.

Individuals with Neonatal ALD suffer severe or profound mental retardation and impaired psychomotor development, together with possible impaired liver function and retarded growth.

The clinical presentation and course of neonatal ALD is still not fully defined. It may take the form of an extremely severe illness with intractable seizures during the earliest part of life, or manifest as a milder form where the sufferer may survive to their mid-teens or possibly longer.

Treatment of neonatal ALD is symptomatic and supportive.

Patients with the infantile form of this phytanic acid storage disorder show differences from the adult form. Early onset, associated with mental retardation, retinal pigmentation, hearing defects, enlargement of the liver, osteoporosis and failure to thrive.

Clinically, Infantile Refsum’s Disease shares some features with Adrenoleukodystrophy and Zellweger Syndrome, in that while IRD sufferers share the phytanic acid accumulation of adult Refsum’s, they also show the defective metabolism of bile acid as in Zellweger.

IRD is slowly progressive if left untreated, but as with adult Refsum’s Disease, a diet which limits the intake of phytanic acid presents a hopeful treatment.

Find out more Zellweger Spectrum (Zellweger Syndrome, Neonatal Adrenoleukodystrophy, and Infantile Refsum Disease