b) Introduzione alle Leucodistrofie

INTRODUCTION

The leukodystrophies are genetically determined progressive disor- ders that affect the brain, spinal cord and peripheral nerves.
The term leukodystrophy derives from the Greek words "leuko" meaning white and referring to the white matter of the nervous system and "dystrophy" meaning imperfect growth or development.

White matter is white to the naked eye because it contains a complex chemical substance called the myelin sheath. Myelin contains a variety of fatty substances or lipids. Its function is to insulate the axon through which nerve impulses are conducted, much as does insulation around an electric wire; the axon being the biological equivalent of the wire. The myelin sheath is a very complex substance.
It is made up of at least ten, and probably more distinct chemicals. Each of the leuko- dystrophies affects one (and only one) of these substances that all affect the myelin sheath in some way, but otherwise, they are totally separate. Leukodystrophy of one type, does not in any way predispose to, or increase the risk of another type of leukodystrophy.

When the term dystrophy is used in medicine, it is meant to imply a condition which is genetically determined, and which is progressive; that is, the condition tends to get worse as the patient gets older. Muscular dystrophy is another example of this type of illness.
Sharply to be distinguished from the leukodystrophies are disorders due to inflammation, infections, or tumors. In respect to white matter dis- eases, an important distinction must be made from multiple sclerosis. Multiple sclerosis also affects the white matter of the nervous system, but it shows inflammation, it is not genetically determined, and it characteristically shows an "up and down" course, rather than slow progression.
While multiple sclerosis is fundamentally distinct from the leukodystrophies, occasionally the leukodystrophies are misdiagnosed as multiple sclerosis.
This is because diagnosis of neurological condi- tions is difficult. It has to rely on subtle and circumstantial evidence, and even the most experienced clinicians may have difficulty.

Genetic counseling is recommended for all leukodystrophies except Alexanders Disease where the specific biochemical defect is still unknown. Referrals to a regional genetics center can be obtained from the United Leukodystrophy Foundation.

PATTERNS OF INHERITANCE

The pattern of inheritance in leukodystrophy is either autosomal recessive or X-linked. In autosomal recessive disorders, boys and girls are affected equally, and both parents must be carriers (heterozygotes).
Carriers have no disability. When two carriers marry, on the average, one-half of their children will also be carriers, one-quarter will have the illness, and one-quarter will be entirely normal.

For X-linked (sex-linked) disorders only the mother is the carrier. If a woman is a carrier, then, on the average, one-half of her daughters will also be carriers, while the other half will be entirely normal.
One-half of her sons will have the illness and the other half will be en- tirely normal.

For a sex-linked disorder, if an affected man has children, then all of his sons will be entirely normal, but all of his daughters will be carriers.

From: Lubs, M-L., "Genetic Disorders" in Krajicek, M.J. and Tearney, A.I. Detection of Developmental Problems in Children, University Park Press, Baltimore, 1977.

ADRENOLEUKODYSTROPHY (ALD)

Adrenoleukodystrophy (ALD) is a serious progressive, genetic disorder which affects the adrenal gland and the white matter of the nervous system. ALD is a peroxisomal storage disease where an abnormal accumulation of very long chain fatty acids causes tissue damage, however the relationship is not understood.
ALD is an X-linked disorder which means it affects only males and is transmitted by a female carrier.

ALD can present in several forms. In the classic childhood form, boys are usually diagnosed between 4 and 10 years of age.
Early manifestations include learning disabilities, perceptual problems, atten- tion deficit disorder, short- and long-term memory loss, and various personality and behavioral changes.

Symptoms in the milder, male, adult form, adrenomyeloneu- ropathy, may include leg stiffness, progressive spastic paraparesis of the lower extremities and ataxia.
Although adult-onset ALD progresses more slowly than the childhood form, it, too, can ultimately result in deterioration of brain function. Onset of symptoms is usually between the ages of 21 and 35.

Occasionally, women who are carriers for ALD, develop mild symptoms which may include spastic paraparesis, ataxia, hypertonia, mild peripheral neurolopathy, and urinary problems.

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

Several therapeutic approaches have been attempted with ALD patients. The most promising, but which are still in the exploratory stages are, 1) a diet restricted in very long chain fatty acids, and 2) bone marrow transplant.

Diagnostic testing, carrier screening, and prenatal diagnosis are available through the laboratory of Dr. Hugo Moser at the Kennedy Krieger Institute in Baltimore, Maryland.
Specific information concerning the experimental treatments are also available through Dr. Moser or the United Leukodystrophy Foundation.

ALEXANDERS DISEASE

Alexanders disease belongs to a group of progressive neurological disorders in which the destruction of white matter in the brain is accompanied by the formation of fibrous, eosinophilic deposits known as Rosenthal fibers.
The majority of cases of Alexanders are sporadic; that is, without a known family history of the disorder. There are, however, a number of families with more than one affected child.
Alexanders disease begins in infancy, affects mostly males, and results in retarded development and dementia. It is quickly progressive and is the rarest of the identified leukodystrophies.

The onset of the infantile form of Alexanders disease is usually around six months, but may occur between 0 and 24 months of age.
Children who develop Alexanders in infancy generally do not survive past the age of 5 or 6 years. Physical and mental development is retarded, and there is progressive enlargement of the brain and head, increasing spasticity, and seizures in some cases.
Histologically, demyelination of both sensory and motor fiber tracts is found. In addition, the eosinophilic Rosenthal fibers are found evenly distributed throughout the brain near blood vessels, and on the surface of the brain. The demyelinated areas do not correspond to the distribution of the Rosenthal fibers.

Alexanders disease is thought to be an autosomal recessive disorder which can affect both males and females. The metabolic error is unknown, and the demyelination and fiber formation seem to be otherwise unrelated parallel expressions of the disorder.
It is the degeneration of the astrocytic glial cells which seems to lead to demyelination. An exact diagnosis may not be possible without study of postmortem tissues or brain or nerve biopsy.

In addition to the infantile form of the disease, juvenile and adult onset forms are recognized, occuring less frequently and with a longer course of progression.
These individuals have in common the widespread formation of Rosenthal fibers throughout the central nervous system. Older patients have less white matter loss and have correspondingly milder symptoms.
It is not clear, however, that the disorders described in older children and adults are all the same disorder and should be called Alexanders disease.

Treatment of Alexanders disease is symptomatic and supportive.

CANAVAN DISEASE (SPONGY DEGENERATION)

Canavan disease is a form of leukodystrophy which causes the white matter of the brain to be replaced by microscopic fluid filled spaces.
A hereditary disease in children, this disorder is characterized by structural abnormalities and deterioration of motor, sensory, and intellectual functions.
It seems to affect persons of Eastern European Jewish ancestry most frequently.

Onset of Canavan disease is in early infancy, with the loss of previous acquired skills and death usually occuring before the age of four years.
The first symptoms include feeding difficulties, progressive mental retardation, apathy, muscular flaccidity (floppiness) and weakness, especially in the muscles supporting the head.
The head becomes progressively enlarged as the brain swells and the bones of the skull fail to fuse normally. Vision and sometimes hearing deteriorate due to nerve degeneration.
Spasticity and paralysis develop. Mental deterioration progresses with time.

Neurologic examination reveals decreased muscle tone (floppiness) and optic atrophy, or damage to the optic nerve (optic atrophy). The brain itself is enlarged.
Cyst-like spaces pervade the white matter, and the myelin sheath "insulating" the neurons' axons is destroyed in most parts of the brain. Large quantities of fluid accumulate in the membranes covering the brain.
Computerized axial tomography (CAT scan) demonstrates severe white matter changes, and helps to rule out hydrocephalus. Pneumonia may develop due to depressed chest movement while breathing.

Canavan disease is inherited through an autosomal recessive mechanism and affects both male and female infants alike. Biochemical markers are excessive amounts of N-acetylaspartic acid in body fluids and 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 Research Institute of Miami Children's Hospital in Miami, Florida.

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

CEREBROTENDINOUS XANTHOMATOSIS (CTX)

Cerebrotendinous Xanthomatosis presents with cataract, tendon xanthomas (yellowish deposits on some tendons), mental retardation, and a progressive neurological disease.
The biochemical basis is complex but beginning to be understood. Most encouraging is the observation that oral administration of certain bile acids can prevent further progression of the illness, and also may bring about improvement.

CTX has an autosomal recessive pattern of inheritance. Patients with CTX may present first with cataracts or with mold mental retardation.
A specific finding, which is missed unless it is looked for, is the presence of fatty tumors (called Xanthomas) in the tendons, most often in the Achilles tendon or heel cord.
Later on, patients may develop seizures, emotional or psychiatric disturbances, and motor deficits.

Diagnosis of CTX is made 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 diagnosis of CTX is important, since it is by far the most treatable of the leukodystrophies. There is a very favorable response to chenodeoxycholic acid, a medication that can be taken by mouth.

GLOBOID CELL (KRABBES) LEUKODYSTROPHY
Krabbe's globoid cell leukodystrophy is a rare, degenerative, lysosomal enzyme disorder of the central and peripheral nervous systems that results from almost complete deficiency of galactosylceramide B-galactoside activity.
The onset of symptoms is usually between the ages of 3 and 6 months, after which infants rapidly lose previously attained developmental skills.
The children fail to thrive, have unexplained fevers, irritability, myoclonic seizures, blindness, spasticity, and paralysis and usually do not survive beyond the age of 2 years.

In addition to the severe infantile form, there are somewhat milder forms that occur 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 leukodystrophy follows an autosomal recessive pattern of inheritance and affects males and females equally. Diagnosis may be missed, particularly in older patients.
The enzyme that is tested for is galactocerebrosidase I (not galactosidase, which is a marker for a different disorder).

Samples for diagnostic, carrier, and pre-natal testing may be sent to the laboratory of Dr. David Wenger at Jefferson Medical College in Philadelphia, Pennsylvania.
Testing protocol may be obtained from Dr. Wenger or the United Leukodystrophy Foundation.

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

METACHROMATIC LEUKODYSTROPHY (MLD)

Metachromatic Leukodystrophy, along with Adrenoleukodystrophy, is probably the most frequently observed leukodystrophy. MLD is caused by a build up of sulfatides, a component of myelin in the nervous system and a build up of sulfatides in various organs of the body including, kidney, liver, and gall bladder.
This accumulation of sulfatides is due to a missing enzyme, arylsulfatase A. The sulfatides are not properly broken down when this enzyme is missing.
Why this increase in sulfatide levels causes demyelination is unclear at this time.

MLD is transmitted by the autosomal recessive type of inheritance and manifest 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.

In the infantile form the child will develop normally until approximately one year of age or later. He/she then begins a time variable, downhill course of continuous, progressive nervous system involvement.
The child will first be floppy due to low muscle tone and may have speech abnormalities and halting of mental development.
Later, he/she will lose the ability to make many voluntary movements and will be unable to speak or to see and will lose mental abilities.
Ultimately, the child will be bedridden, functioning at the level of a newborn. Due to the loss of swallowing ability, the child is usually tube fed. Death usually occurs within three to six years.

In addition to clinical studies, blood and urine tests are done to diagnose MLD. The level of arylsulfatase A can be measured in the blood; in MLD, the levels are very low.
The urine can be analyzed for the presence of sulfatides; these are increased in the urine of patients with MLD. Carrier detection and prenatal diagnosis are available; genetic counseling is advised.

Samples for diagnostic screening may be sent to the laboratory of Dr. David Wenger at Jefferson Medical College in Philadelphia, Pennsylvania.
Testing protocol may be obtained from the United Leukodystrophy Foundation.

Bone marrow transplant has been used experimentally for children with the mild form of MLD. A few hospitals throughout the U.S. have experience with bone marrow transplants in MLD.
The most experienced center is the University of Minnesota Hospital where transplants are done under the direction of Dr. William Krivit.

NEONATAL ALD

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.
Neonatal ALD has an autosomal recessive pattern of inheritance, affecting both males and females.
Biochemical advances have provided accurate and convenient diagnostic methods, namely the demonstration of abnormally high levels of very long chain fatty acids in tissues and body fluids.

Neonatal ALD closely resembles the Zellweger cerebro-hepatorenal syndrome, and may, in fact, represent a somewhat milder variant of that disorder. Neonatal ALD may itself be heterogeneous.
While there is no doubt that it is distinct from X-linked ALD, the classification of neonatal ALD is still in a state of flux.

Neonatal ALD is characterized by severe or profound mental retardation, impaired psychomotor development, possible impaired liver function, and retarded growth.

The range of phenotypic variation in neonatal ALD is still not fully defined. It may vary from an extremely severe illness with intractable seizures during the first day of life, to a milder form compatible with survival to the mid-teens or possibly longer.

Treatment of neonatal ALD is symptomatic and supportive.

PELIZAEUS-MERZBACHER DISEASE

Pelizaeus-Merzbacher Disease is a progressive, degenerative central nervous system disease in which coordination, motor abilities, and intellectual function deteriorate.
It often progresses rapidly, although some patients have lived to old age.

Evidence of Pelizaeus-Merzbacher Disease usually appears in early infancy, although onset is later in one form of the disease. The child grows slowly and fails to develop normal control of head movement.
The eyes wander aimlessly or in circular movements. Later symptoms include tremor, various involuntary movements, grimacing, weakness, unsteady gait, and muscle contractures.
In cases with later onset, speech usually deteriorates. As time progresses, legs and then the arms can become spastic, and mental functions deteriorate. Some patients experience convulsions.
Skeletal deformation may result from abnormal muscular stresses on bone.

Pathologic changes in the brain consist of destruction of the myelin sheath surrounding the axons of the nerve cells. These changes occur in subcortical parts of the cerebrum, the cerebellum, and the brain stem.
Breakdown products of myelin also accumulate in the brain. These stain characteristically.

One form of Pelizaeus-Merzbacher Disease affects male infants, while other forms may affect either sex. Infantile forms are either autosomal recessive or X-linked.
Hereditary traits are usually determined by two analogous genes. In a recessive disorder, both parents' genes are defective. X-linked recessive traits are expressed predominantly in males.
Females carry the gene on one of their two X chromosomes. Affected males cannot transmit the trait to their sons.

The form with adult onset is autosomal dominant. In autosomal dominant disorders, a single abnormal gene, contributed by either parent, "overrides" the normal gene contributed by the other parent causing disease.
Individuals with one affected parent have a 50% chance of inheriting the disorder. Males and females are in equal numbers.

Diagnosis and carrier detection are possible through DNA testing. Treatment of Pelizaeus-Merzbacher Disease is symptomatic and supportive.

REFSUM DISEASE

Refsum Disease has an autosomal recessive pattern of inheritance and is caused by accumulation of phytanic acid in blood and tissue 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 age of onset varies from early childhood to age 50, but signs are most often first seen by 20 years of age.
Males and females are affected alike. Diagnostic, carrier, and prenatal testing is available.

Refsum disease, along with Cerebrotendinous Xanthomatosis (CTX), is at this time, the most hopeful of the leukodystrophies.
Since phytanic acid is not made in the human body but comes exclusively from the diet, with restriction of such foods as dairy products, tunafish, 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.
Plasmapheresis as a supplement to the diet has been effective in providing a positive initial response.

ZELLWEGER SYNDROME

Zellweger Syndrome is a rare form of leukodystrophy affecting infants. It is characterized by reduction or absence of peroxisomes in the cells of the liver, kidneys, and brain.
Unusual problems in prenatal development, an enlarged liver, high levels of iron and copper in the blood, and vision disturbances are among the major manifestations of Zellweger Syndrome.

Zellweger Syndrome is present at birth and 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. Infants with Zellweger Syndrome often exhibit prenatal growth failure in spite of a normal period of gestation.
Other symptoms may include unusual facial characteristics, mental retardation, the inability to suck and/or swallow, and liver enlargement. Vision problems and congenital heart lesions occur less commonly.
Jaundice and/or gastrointestinal bleeding due to deficiency of a coagulation factor in the blood can also occur. Pneumonia or respiratory distress may develop if infections are not prevented or controlled.

Infections should be guarded against carefully to delay complications. There may also be abnormal bleeding that can be corrected by giving Vitamin K.

Zellweger Syndrome is inherited as an autosomal recessive trait. A deficiency or absence of 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 in the tissue of the brain, liver, and kidney is not yet known.

The study of very long chain fatty acids provides a convenient method for the early diagnosis and prental detection of Zellweger Syndrome.
Genetic counseling can be of benefit to families.

Treatment of Zellweger Syndrome is symptomatic and supportive.

c) Parametri clinici e storiografia terapeutica delle leucodistrofie

i) ADRENOLEUCODISTROFIA
ii) MORBO DI ALEXANDER
iii) MORBO DI CANAVAN
iv) XANTOMATOSI CEREBROTENDINEA
v) LEUCODISTROFIA A CELLULE GLOBOIDALI o MORBO DI KRABBE
vi) LEUCODISTROFIA METACROMATICA
vii) ADRENOLEUCODISTROFIA NEONATALE
viii) MORBO DI PELIZAEUS-MERZBACHER
ix) MORBO DI REFSUM
x) SINDROME DI ZELLWEGER