Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 2 - M-Z - I

Spastic cerebral palsy

Resources

BOOKS

Anderson, Rebecca Rae, and Bruce A. Buehler. Sotos Syndrome: A Handbook for Families. Omaha, NB: Meyer Rehabilitation Institute, 1992.

Cole, Trevor R.P. “Sotos Syndrome.” In Management of Genetic Syndromes, edited by Suzanne B. Cassidy and Judith E. Allanson. New York: Wiley-Liss, 2001, pp.389404.

PERIODICALS

Sotos Syndrome Support Association Quarterly Newsletter.

ORGANIZATIONS

Sotos Syndrome Support Group. Three Danda Square East #235, Wheaton, IL 60187. (888) 246-SSSA or (708) 6828815. http://www.well.com/user/sssa/ .

WEBSITES

Genetic and Rare Conditions Site.http://www.kumc.edu/gec/support/ .

The Family Village.http://www.familyvillage.wisc.edu/index.htmlx .

Cindy L Hunter, CGC

I Spastic cerebral palsy

Definition

Spastic cerebral palsy (CP) is a disorder in which brain damage results in a movement disability.

Description

Cerebral palsy is a nonprogressive disorder of movement and/or posture caused by a brain abnormality. It is evident before the age of two. There are several types of CP, but spastic CP is the most common—about 60%. The term “spasticity” refers to increased muscle tone (stiffness), leading to uncontrolled, awkward movements.

Genetic profile

Only about 2% of cases of CP are believed to result from genetic causes. Most cases of CP are associated with risk factors such as low birth weight, premature birth, and lack of oxygen at birth. Multiple births (such as twins or triplets) also have an increased risk. A genetic cause is more likely if these risk factors are not present. If the paralysis and spasticity are symmetrical—that is, if both sides of the body are similarly affected—then the condition is more likely to be genetic in nature. Mental retardation is usually, but not always, associated with

K E Y T E R M S

Cerebral palsy—Movement disability resulting from nonprogressive brain damage.

Spasticity—Increased muscle tone, or stiffness, which leads to uncontrolled, awkward movements.

genetic forms. Researchers have not yet found which gene is associated with the disease.

Demographics

CP has an overall incidence of one in 250 to 1,000 births. Most forms of CP that are genetic have an autosomal recessive pattern of inheritance. This means that in order for a child to have the disorder, they must inherit one altered copy of the causative gene from each parent. A person who has only one altered copy of the disease gene is called a carrier. Two carriers have a 25% chance of having a child with CP with each pregnancy. As studied in the British Pakistani population, a consanguineous marriage—marriage between relatives— appears to increase the prevalence of a genetic form of spastic CP.

Signs and symptoms

CP may not be noticed immediately after birth. Children with CP are slow to meet developmental motor milestones, which are expected ages at which certain mobility skills are achieved. These milestones include reaching for toys, sitting, and walking. People with CP also have abnormal muscle tone (increased in spastic CP), abnormal or uncontrolled movements, and abnormal reflexes. The spasticity may not be present at birth but usually develops during the first two years of life. Many children with spastic CP have normal intelligence, but mental retardation does occur, especially in inherited forms of the disease. Depending on the severity and extent of the paralysis, some affected individuals can walk (often late and with crutches or walkers), while others with more severe disability cannot walk at all. Seizures are not uncommon in individuals with CP.

Diagnosis

A diagnosis of spastic CP is based on delay in or lack of meeting developmental motor milestones, along with the presence of abnormal muscle tone, movements, and reflexes. Since the exact gene causing some cases of symmetric spastic CP has not yet been identified, molec-

ular testing is not available at this time. Since CP-like symptoms can be found in other genetic conditions, chromosome testing and molecular testing for other suspected conditions may help determine the cause of the CP-like symptoms. Testing may also enable other family members to be tested to see if they carry the condition, and to allow a fetus to be diagnosed prenatally. Prenatal diagnosis of known genetic conditions can be accomplished using procedures such as chorionic villi sampling, in which cells from the placenta are studied; and amniocentesis, in which skin cells from the fluid surrounding the fetus are studied.

Treatment and management

Treatment of spastic CP is focused on maximizing mobility through physical therapy, and/or providing necessary physical support using devices such as splints, walkers, and wheelchairs. Speech and occupational therapy are sometimes useful as well. Certain types of surgery of the bone, nerves, tendon, and brain tissue can correct abnormalities, improve mobility, and reduce spasticity. Orthodontic work on the teeth is often indicated in children with CP. Some level of special educational services is usually required.

Prognosis

Spastic CP is not a progressive condition, so living into old age is possible. However, complications such as reduced mobility, mental retardation, feeding difficulties, and respiratory infections can reduce the lifespan. More severe disabilities are associated with greater decreases in life expectancy, but at least half of people with CP live to at least age 35.

Resources

BOOKS

Geralis, Elaine, ed. Children with Cerebral Palsy: A Parents’ Guide. Bethesda, MD: Woodbine House, 1991.

Miller, Freeman, and Steven J. Bachrach. Cerebral Palsy: A Complete Guide for Caregiving. Baltimore: Johns Hopkins University Press, 1995.

PERIODICALS

McHale, D.P., et al. “A Gene for Autosomal Recessive Symmetrical Spastic Cerebral Palsy Maps to Chromosome 2q24-25.” American Journal of Human Genetics 64 (1999): 526-532.

ORGANIZATIONS

United Cerebral Palsy Association, Inc. (UCP). 1660 L St. NW, Suite 700, Washington, DC 20036-5602. (202)776-0406 or (800)872-5827. http://www.ucpa.org .

Toni I. Pollin, MS, CGC

I Spherocytosis, hereditary

Definition

Hereditary spherocytosis (HS) is a relatively common and highly variable inherited disorder of the red blood cells. In HS, red blood cells become sphereshaped, instead of the usual biconcave (hourglass) shape. The hourglass shape is vital for the blood cells to func- tion—it offers increased surface area so that oxygen and carbon dioxide can diffuse more easily through the cell’s tissue, and the shape lets the cells circulate more easily in tight places, like small capillaries. These spherocytes are broken down more quickly than normal red blood cells, resulting in anemia and related complications.

Description

Hereditary spherocytosis results from a molecular change in one of the proteins making up the cytoskeleton of the red blood cell. The cytoskeleton consists of the network of proteins that support and maintain the integrity of the red cell membrane. Genetic mutations in membrane proteins lead to loss of these and related membrane components. As the membrane becomes unstable and the surface area of the membrane decreases, spherocytes form. The spleen provides an environment that encourages spherocyte formation. Due to their increased rigidity, spherocytes tend to become trapped in the spleen and then broken down by macrophages, specialized white blood cells. This hemolytic process most often leads to mild, chronic anemia. Depending in part on the particular genetic mutation underlying HS in a given individual, anemia can also be severe and require chronic blood transfusions. Additional complications related to anemia can arise.

Demographics

HS has been seen in individuals of many ethnic backgrounds, but is particularly common among people of northern European background, affecting about one in 5,000 of such individuals.

Genetic profile

About 75% of all cases of HS are due to the presence of an autosomal dominant mutation, one in which the mutated gene is passed on from either parent. Most of these cases result from the inheritance of a mutation from one parent, but a fourth of these cases are sporadic and due to a new mutation that has occurred in the affected individual. A minority of cases of HS is recessively inherited. HS-causing mutations have been described in four genes, each of which codes for a protein involved in maintaining stability of the red blood cell

hereditary Spherocytosis,

Spherocytosis, hereditary

mutations in other cytoskeleton or red cell membrane proteins are rare but have been described.

Modifying genetic factors

Disease severity is not only affected by the nature of the primary genetic mutation; it is also impacted by other genetic variations. Individuals with HS who also have Gilbert syndrome have an increased risk of gallstones. Gilbert syndrome is caused by a change in the UGT 1A1 gene that results in increased levels of bilirubin. Researchers have also hypothesized that persons with other inherited or acquired forms of hemolytic anemia may also be at increased risk of gallstones if they also have a disease-causing HS mutation. The presence of hereditary hemochromatosis in addition to HS increases the propensity toward iron-overload. Hereditary hemochromatosis is a relatively common recessive condition that can lead to organ failure due to iron-overload, if untreated.

Signs and symptoms

Symptoms of HS can be extremely variable. Some individuals may experience onset as early as the neonatal period and require treatment. Others may have only mild anemia that does not require treatment and does not become evident until later in life. Some individuals with few and subtle signs may even go undiagnosed. Variability is largely influenced by the primary underlying genetic mutation, with the recessive forms of the disease tending to be most severe. This does not account for all the variability, however, given that multiple affected individuals within the same family carrying the same genetic mutation may have symptoms of varying severity. The effects of modifying genes or environmental factors may contribute to this additional variability.

Anemia

The red blood cell membrane has increased fragility in HS. Therefore, red cells are more easily broken down, a symptom called hemolytic anemia. This occurs primarily in the spleen. The spleen filters out old and abnormal red blood cells, as well as fights infection from bacteria, particularly the encapsulated type. Anemia can be unnoticeable or mild, or it can be rapid and severe. Rapid, acute breakdown of red blood cells can occur as a result of exposure to chemicals or medications that are known to further increase red cell membrane fragility. It can also occur as a result of infection that increases the hemolytic activity of the spleen or decreases red blood cell production. Acute aplastic anemia events, in which red blood cell production halts, can occur with deficient folate levels or following infection by a specific virus called parvovirus.

Jaundice

Jaundice occurs when the level of bilirubin, a breakdown product of hemoglobin, increases. As red blood cells breakdown rapidly, the liver may not be able to keep up with the increased need to metabolize bilirubin, which can deposit in the skin and eyes causing a yellowish discoloration.

Gallstones

Bilirubin levels can also be increased in the bile. Bile is the fluid secreted by the liver into the intestine. Bile reaches the intestine by passing through the gallbladder and bile duct. Excess bilirubin can form stones in the gallbladder early in life.

Hemochromatosis

Hemochromatosis, or high iron levels, is also characteristic of HS. Iron-overload can lead to dysfunction of organ systems, including the endocrine system, which directs hormone levels.

Other complications

Leg ulcers are also seen in HS, and acute kidney failure due to hemolytic anemia is a rare complication. Rarely, HS can be seen within a syndrome as one symptom in combination with other complications such as neurological problems and other congenital physical differences. Such syndromes may be caused by the deletion of a portion of a chromosome including a gene known to be associated with HS, among other genes.

Diagnosis

HS must be distinguished from other causes of hemolytic anemia that can resemble HS. These include immune hemolytic anemia, G6PD deficiency, unstable hemoglobin traits or diseases, Wilson disease, and spherocytosis due to burn injury or toxin exposure (i.e. clostridia—bee, spider, or snake venom). Routine blood tests are typically sufficient to diagnose HS, particularly if an individual is showing symptoms. A peripheral blood smear, which is a slide preparation of a blood sample, will show the presence of a number of spherocytes that are uniform in appearance. Bilirubin levels tend to be elevated. A complete blood count will show several abnormalities. Hemoglobin levels tend to be decreased. Reticulocytes, which are immature red blood cells, tend to be increased. Red blood cells tend to be smaller than normal, which is marked by a decreased mean cell volume (MCV). The mean cell hemoglobin concentration (MCHC) tends to be high, which is a reflection of the overall decrease in the cell volume. Ektacytometry is a

hereditary Spherocytosis,

Spina bifida

specialized test that can demonstrate the fragility of the red blood cell membrane by placing the cells under stress and identifying increased levels and specific patterns of hemolysis. Another specialized test called the rapid flow cytometric test has recently been developed. This test can determine differences in fluorescent staining patterns that distinguish normal red blood cells from those that are characteristic of HS. This test is highly sensitive and specific for HS and should aid in its rapid diagnosis.

Treatment and management

Most individuals with HS do not have symptoms that are severe enough to require treatment. For those with the more severe forms, blood transfusion therapy can effectively improve symptoms until a child is old enough for total or partial removal of the spleen, the organ responsible for most of the red blood cell destruction. Splenectomy most often eliminates HS complications. However, there is some risk remaining for ongoing chronic anemia or acute anemic events, particularly those caused by viruses and other factors that can temporarily halt red blood cell production. Splenectomy can also lead to an increased risk for blood clots, as well as life-threat- ening bacterial infection given the spleen’s role in fighting bacterial infections. Studies have shown that partial, as opposed to total, splenectomy can be effective at ameliorating HS symptoms while also maintaining the bacte- rial-fighting capacity of the spleen and decreasing the chance for blood clots. Prophylactic antibiotics (i.e. penicillin) and additional vaccinations for common bacterial infections also play a role in decreasing negative sideeffects of partial or total splenectomy. Surgery may be needed to remove gallstones that become symptomatic, which usually does not occur until after age 10 years.

Prognosis

Prognosis is very good for all types of HS, particularly the more mild forms. Treatment is very effective for the more severe forms. There is only a small number of affected individuals who still experience anemia and other symptoms following splenectomy.

Resources

BOOKS

Glader, B., and L. Naumovski. “Other Hereditary Red Blood Cell Disorders.” In Emery and Rimoin’s Principles and Practice of Medical Genetics. 3rd ed. New York: Churchill Livingston, 1997.

PERIODICALS

Bader-Meunier, B., et al. “Long-term Evaluation of the Beneficial Effect of Subtotal Splenectomy for Management of Hereditary Spherocytosis.” Blood 97, no. 2 (January 15, 2001): 399–403.

Campanile, R., et al. “Low Frequency of Ankyrin Mutations in Hereditary Spherocytosis: Identification of Three Novel Mutations.” Human Mutation 378 (2000).

Gallagher, P.G., et al. “Short Reports: A Recurrent Frameshift Mutation of the Ankyrin Associated with Severe Hereditary Spherocytosis.” British Journal of Haematology 111, no. 4 (December 2000): 1190–1193.

King, M.J., et al. “Rapid Flow Cytometric Test for the Diagnosis of Membrane Cytoskeleton-association Haemolytic Anaemia.” British Journal of Haematology 111, no. 3 (December 2000): 924–933.

Miraglia del Giudice, E., et al. “Clinical and Molecular Evaluation of Non-dominant Hereditary Spherocytosis.”

British Journal of Haematology 112, no. 1 (January 2001): 42–47.

WEBSITES

McKusick, V. “Spherocytosis, Hereditary; HS.” Entry #182900.

Online Mendelian Inheritance in Man. http://www3

.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?182900 . (20 Oct. 2000).

McKusick, V. “Spherocytosis, Autosomal Recessive.” Entry #270970. Online Mendelian Inheritance in Man.

http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/ dispmim?270970 . (12 Mar. 1994).

Jennifer D. Bojanowski, MS, CGC

Sphingomyelin lipidosis see Niemann-Pick disease

Sphingomyelinease deficiency see

Niemann-Pick disease

Spielmeyer-Vogt-Sjögren-Batten disease see

Batten disease

I Spina bifida

Definition

Spina bifida is a serious birth abnormality in which the spinal cord is malformed and lacks its usual protective skeletal and soft tissue coverings.

Description

Spina bifida may appear in the body midline anywhere from the neck to the buttocks. In its most severe form, termed spinal rachischisis, the entire spinal canal is open, exposing the spinal cord and nerves. More commonly, the abnormality appears as a localized mass on

the back that is covered by skin or by the meninges, the three-layered membrane that envelopes the spinal cord. Spina bifida is usually readily apparent at birth because of the malformation of the back and paralysis below the level of the abnormality.

Various forms of spina bifida are known as meningomyelocele, myelomeningocele, spina bifida aperta, open spina bifida, myelodysplasia, spinal dysraphism, spinal rachischisis, myelocele, and meningocele. The term meningocele is used when the spine malformation contains only the protective covering (meninges) of the spinal cord. The other terms indicate involvement of the spinal cord and nerves in the malformation. A related term, spina bifida occulta, indicates that one or more of the bony bodies in the spine are incompletely hardened, but that there is no abnormality of the spinal cord itself.

Genetic profile

Spina bifida may occur as an isolated abnormality or in the company of other malformations. As an isolated abnormality, spina bifida is caused by the combination of genetic factors and environmental influences that bring about malformation of the spine and spinal column. The specific genes and environmental influences that contribute to the many-factored causes of spina bifida are not completely known. An insufficiency of folic acid is known to be one influential nutritional factor. Changes (mutations) in genes involving the metabolism of folic acid are believed to be significant genetic risk factors. The recurrence risk after the birth of an infant with isolated spina bifida is 3-5%. Recurrence may be for spina bifida or another type of spinal abnormality.

Spina bifida may arise because of chromosome abnormalities, single gene mutations, or specific environmental insults such as maternal diabetes mellitus or prenatal exposure to certain anticonvulsant drugs. The recurrence risk varies with each of these specific causes.

Demographics

Spina bifida occurs worldwide, but there has been a steady downward trend in occurrence rates over the past 50-70 years, particularly in regions of high prevalence. The highest prevalence rates, about one in 200 pregnancies, have been reported from certain northern provinces in China. Intermediate prevalence rates, about one in 1,000 pregnancies, have been found in Central and South America. The lowest prevalence rates, less than one in 2,000 pregnancies, have been found in the European countries. The highest regional prevalence in the United States of about one in 500 pregnancies has occurred in the Southeast.

K E Y T E R M S

Chiari II anomaly—A structural abnormality of the lower portion of the brain (cerebellum and brain stem) associated with spina bifida. The lower structures of the brain are crowded and may be forced into the foramen magnum, the opening through which the brain and spinal cord are connected.

Fetus—The term used to describe a developing human infant from approximately the third month of pregnancy until delivery. The term embryo is used prior to the third month.

Hydrocephalus—The excess accumulation of cerebrospinal fluid around the brain, often causing

Signs and symptoms

In most cases, spina bifida is obvious at birth because of malformation of the spine. The spine may be completely open, exposing the spinal cord and nerves. More commonly, the spine abnormality appears as a mass on the back covered by membrane (meninges) or skin. Spina bifida may occur anywhere from the base of the skull to the buttocks. About 75% of abnormalities occur in the lower back (lumbar) region. In rare instances, the spinal cord malformation may occur internally, sometimes with a connection to the gastrointestinal tract.

In spina bifida, many complications arise, dependent in part on the level and severity of the spine malformation. As a rule, the nerves below the level of the abnormality develop in a faulty manner and fail to function, resulting in paralysis and loss of sensation below the level of the spine malformation. Since most abnormalities occur in the lumbar region, the lower limbs are paralyzed and lack sensation. Furthermore, the bowel and bladder have inadequate nerve connections, causing an inability to control bowel and bladder function. Most infants also develop hydrocephaly, an accumulation of excess fluid in the four cavities of the brain. At least one of every seven cases develop findings of Chiari II malformation, a condition in which the lower part of the brain is crowded and may be forced into the upper part of the spinal cavity.

There are a number of mild variant forms of spina bifida, including multiple vertebral abnormalities, skin dimples, tufts of hair, and localized areas of skin deficiency over the spine. Two variants, lipomeningocele and lipomyelomeningocele, typically occur in the lower back area (lumbar or sacral) of the spine. In these conditions,

bifida Spina

a tumor of fatty tissue becomes isolated among the nerves below the spinal cord, which may result in tethering of the spinal cord and complications similar to those with open spina bifida.

Diagnosis

Few disorders are to be confused with open spina bifida. The diagnosis is usually obvious based on the external findings at birth. Paralysis below the level of the abnormality and fluid on the brain (hydrocephaly) may contribute to the diagnosis. Other spine abnormalities such as congenital scoliosis and kyphosis, or soft tissue tumors overlying the spine, are not likely to have these accompanying findings. In cases in which there are no external findings, the diagnosis is more difficult and may not become evident until neurological abnormalities or hydrocephaly develop weeks, months, or years following birth.

Prenatal diagnosis may be made in most cases with ultrasound examination after 12-14 weeks of pregnancy. Many cases are also detected by the testing of the mother’s blood for the level of alpha-fetoprotein at about 16 weeks of pregnancy. If the spine malformation is not skin covered, alpha-fetoprotein from the fetus’ circula-

tion may leak into the surrounding amniotic fluid, a small portion of which is absorbed into the mother’s blood.

Treatment and management

Aggressive surgical and medical management have improved the survival and function of infants with spina bifida. Initial surgery may be carried out during the first days of life, providing protection against injury and infection. Subsequent surgery is often necessary to protect against excessive curvature of the spine, and in the presence of hydrocephaly, to place a mechanical shunt to decrease the pressure and amount of cerebrospinal fluid in the cavities of the brain. Because of weakness or paralysis below the level of the spine abnormality, most children will require physical therapy, bracing, and other orthopedic assistance to enable them to walk. A variety of approaches including periodic bladder catheterization, surgical diversion of urine, and antibiotics are used to protect urinary function.

Although most individuals with spina bifida have normal intellectual function, learning disabilities or mental impairment has occured. This may result, in part, from hydrocephaly and/or infections of the nervous system.

Children so affected may benefit from early educational intervention, physical therapy, and occupational therapy. Counseling to improve self-image and lessen barriers to socialization becomes important in late childhood and adolescence.

Open fetal surgery has been performed for spina bifida during the last half of pregnancy. After direct closure of the spine malformation, the fetus is returned to the womb. By preventing chronic intrauterine exposure to mechanical and chemical trauma, prenatal surgery improves neurological function and leads to fewer complications after birth. Fetal surgery is considered experimental, and results have been mixed.

Prevention of isolated spina bifida and other spinal abnormalities has become possible during recent decades. The major prevention is through the use of a B vitamin, folic acid, for several months prior to and following conception. The Centers for Disease Control and Prevention recommend the intake of 400 micrograms of synthetic folic acid every day for all women of childbearing years.

Prognosis

More than 80% of infants born with spina bifida survive with surgical and medical management. Although complications from paralysis, hydrocephaly, Chiari II malformation, and urinary tract deterioration threaten the well-being of the survivors, the outlook for normal intellectual function is good.

Resources

PERIODICALS

Sells, C.J., and J.G. Hall, guest eds. Neural Tube Defects, in

Mental Retardation and Developmental Disabilities

Research Reviews. Volume 4, Number 4. New York: Wiley-Liss, 1998.

ORGANIZATIONS

March of Dimes Birth Defects Foundation. 1275 Mamaroneck Ave., White Plains, NY 10605. (888) 663-4637. resourcecenter@modimes.org. http://www.modimes

.org .

National Birth Defects Prevention Network. Atlanta, GA (770) 488-3550. http://www.nbdpn.org .

Shriners Hospitals for Children. International Shrine Headquarters, 2900 Rocky Point Dr., Tampa, FL 33607-1460. (813) 281-0300.

Spina Bifida Association of America. 4590 MacArthur Blvd. NW, Suite 250, Washington, DC 20007-4226. (800) 6213141 or (202) 944-3285. Fax: (202) 944-3295.

WEBSITES

Spina Bifida Association of America. http://www.sbaa.org .

Shriners Hospitals for Children, International Shrine Headquarters. http://www.shrinershq.org .

March of Dimes Birth Defects Foundation. http://www

.modimes.org .

National Birth Defects Prevention Network.

http://www.nbdpn.org/NBDPN .

Roger E. Stevenson, MD

Spinal and bulbar muscular atrophy see

Kennedy disease

I Spinal muscular atrophy

Definition

Spinal muscular atrophy (SMA) is a disease characterized by degradation of the anterior horn cells of the spinal cord and has similar characteristics to Spinobulbar muscular atrophy (SBMA). SBMA differs from SMA in its mode of inheritance, the disease-determining gene, the mutational events that trigger disease and the cellular specificity of the disease pathology.

Description

The anterior horn cells control the voluntary muscle contractions from large muscle groups such as the arms and legs. For example, if an individual wants to move his/her arm, electrical impulses are sent from the brain down the anterior horn cells to the muscles of the arm, which then stimulates the arm muscles to contract allowing the arm to move. Degradation is a rapid loss of functional motor neurons. Loss of motor neurons results in progressive symmetrical atrophy of the voluntary muscles. Progressive symmetrical atrophy refers to the loss of function of muscle groups from both sides of the body. For example, both arms and both legs are equally effected to similar degrees of muscle loss and the inability to be controlled and used properly. Progressive loss indicates that muscle loss is not instantaneous, rather, muscle loss occurs consistantly over a period of time. These muscle groups include those skeletal muscles that control large muscle groups such as the arms, legs and torso. The weakness in the legs is generally greater than the weakness in the arms.

Spinal muscular atrophy (SMA) arises primarily from degradation of the anterior horn cells of the spinal cord, resulting in proximal weakness and atrophy of voluntary skeletal muscle. Proximal weakness effects the limbs positioned closer to the body, such as arms and legs, rather than more distant body parts such as hands, feet, fingers, or toes.

Spinal muscular atrophy only affects the motor neurons of the spinal cord and voluntary muscles of the limb

atrophy muscular Spinal

Spinal muscular atrophy

K E Y T E R M S

Anterior horn cells—Subset of motor neurons within the spinal cord.

Atrophy—Wasting away of normal tissue or an organ due to degeneration of the cells.

Degradation—Loss or diminishing.

Dorsal root ganglia—The subset of neuronal cells controlling impulses in and out of the brain.

Intragenic—Occuring within a single gene.

Motor neurons—Class of neurons that specifically control and stimulate voluntary muscles.

Motor units—Functional connection with a single motor neuron and muscle.

Sensory neurons—Class of neurons that specifically regulate and control external stimuli (senses: sight, sound).

Transcription—The process by which genetic information on a strand of DNA is used to synthesize a strand of complementary RNA.

Voluntary muscle—A muscle under conscious control, such as arm and leg muscles.

and trunk. Patients do not display sensory loss, heart problems, or mental retardation. There are numerous secondary complications seen in SMA, including bending of the legs and arms and pneumonia. SMA development involves an initial substantial loss of motor units, followed by a stabilization of the surviving motor units. Motor units refer to an entire motor neuron and the connections within a muscle required for neuronal function.

Clinical subgroups

The childhood form of SMA is subdivided into three main clinical subgroups, Type I, II, and III, depending upon the age of onset and severity. A fourth subgroup, Type O, was recently discovered in London.

Type I

Type I SMA, or Werdnig-Hoffmann disease, is the acute or severe form, characterized by severe muscle atrophy. Guido-Werdig, an Austrian doctor, first identified the disease in 1891. He described two brothers displaying progressive muscle weakness from the age of 10 months, starting in the legs and progressing to the back and arms. The first brother died at the age three years with respiratory problems. The second brother survived to the age of six years.

Symptoms emerge in the first three months of life with the affected children never gaining the ability to sit, stand, or walk. Swallowing and feeding may be difficult and the child may show difficulties with their own secretions. There is general weakness in the intercostals and accessory respiratory muscles (the muscles situated between the ribs). The chest may appear concave (sunken in) due to the diaphragmatic (tummy) breathing.

Type II

Type II SMA was first described in 1964. It is less severe than type I, with clinical symptoms emerging between three and 15 months of age. Most patients can sit but are unable to stand or walk unaided. Feeding and swallowing problems are uncommon in patients with Type II SMA. Again, as with patients diagnosed with type I SMA, the intercostal muscles are affected, with diaphragmatic breathing a main characteristic of children with type II. Most patients will survive beyond the age of four years and, depending upon how their respiratory system is affected, may live through adolescence.

Type III

The chronic form of SMA, Type III (KugelbergWelander disease) was first described in 1956. The clinical symptoms manifest after the age of four. It produces proximal muscle weakness, predominantly in the lower body. Affected individuals can walk unaided and have a normal life span depending upon the extent of respiratory muscles loss.

Type O

Clinicians in London have recently identified a fourth form of the childhood disease; Type 0 SMA. This form appears to have a fetal-onset in that affected individuals display reduced movement within the uterus and are born with severe muscular atrophy with massive motor neuronal cell death. Therefore, these patients have very few functional motor neurons and motor units.

Diagnosis

One of the main diagnostic tools is electromyography (EMG). Contraction of voluntary muscle is controlled by electrical impulses originating from the brain. These impulses pass down the motor neurons of the spinal cord to the connecting muscles, where it triggers the contraction. The EMG records this electrical impulse and determines whether the electric current is the same as in normal individuals. Metal needles are inserted into the arms and thigh and the electrical impulse is recorded.

In addition, the speed at which the electric impulse passes down the motor neuron can also be used as a diag-

nostic test. In SMA patients, both the nerve conduction velocity (NVC) and the EMG readings are reduced.

The third test is an invasive procedure called a muscle biopsy. This involves a surgeon removing a small section of muscle. This is then tested for signs of degradation.

Genetic profile

All forms of childhood SMA are autosomal recessive, with both parents needing to be carriers to pass the disease on. If both parents are carriers, there is a 25% chance of their child being affected.

All three forms are caused by a decrease in the production of a protein, termed Survival of Motor Neuron (SMN). The SMN protein is encoded by two nearly identical genes located on chromosome 5; SMN-1 and SMN- 2 (previously referred to as telomeric and centomeric SMN, respectively). Remarkably, only mutations or deletions of SMN-1 result in disease development.

In most individuals who do not have SMA, each chromosome (maternal and paternal) contains one copy of SMN-1 and one copy of SMN-2. Therefore, in most unaffected individuals, there are two SMN-1 and two SMN-2 genes. Importantly, a subset of SMA-causing mutations are intragenic SMN-1 single amino acid substitutions. Intragenic indicates that mutations are within an otherwise intact SMN gene, but that there is a small and very subtle mutation that is only found within the SMN gene. This is in contrast to large genomic deletions that can delete the SMN gene and also neighboring genes. The intragenic or small mutations thereby confirms SMN-1 as the SMA-determining gene.

Signs and symptoms

Research shows that, in SMA, the reduced SMN protein levels result in motor neuronal cell degradation. How, and why this occurs is still not known.

Demographics

Approximately, one in 10,000 live births are affected with SMA, which is slightly lower than expected since the carrier frequency is between one in 40 and one in 50. Since this is a recessive disease, meaning two copies of the abnormal gene must be present for the disease to occur, carriers are unaffected because only one copy of the abnormal gene is present.

The genomic SMN region is remarkably unstable, and de novo mutations (mutations that are new and not inherited from the parents) are quite frequent, accounting for nearly 2% of all SMA cases. In 90% of patients, death

occurs before the age of two due to respiratory failure. In North America and Europe, type I SMA accounts for one in every 25,000 infant mortalities. SMA is the leading genetic cause of infantile death and is the second most common autosomal recessive disorder behind cystic fibrosis. Carrier frequencies and disease frequencies are similar throughout the world, although slight variations can exist. Asian populations have a slightly reduced carrier frequency although it is not known why this discrepancy has occurred.

Treatment and management

To date, there is no treatment for childhood SMA. However, there are possible mechanisms through which treatment could be developed. Gene therapy could be used for SMA to replace the abnormal SMN-1 gene. Such treatment is not yet available or possible at this time though.

Prognosis

In Type I SMA, eating and swallowing can become difficult as the muscles of the face are affected. Due to the degradation of the respiratory muscles breathing can also be labored. It is therefore essential for patients to undergo chest physiotherapy (CPT). CPT is a standard set of procedures designed to trigger and aid coughing in patients. Coughing is important as it clears the patients lungs and throat of moisture and prevents secondary problems, such as pneumonia.

As symptoms progress, patients may require a ventilator to aid breathing. There are two main forms of ventilation systems. Negative Pressure Ventilation can be achieved by placing the patient in a Port-A-Lung. This machine ensures that the air pressure around the patient is lower than the air pressure within the patient’s lungs, enabling easier breathing. The pressure can be raised or lowered if the patients ventilation rate increases or decreases.

The second method is called Bi-Pap (Biphasic Positive Airway Pressure). This procedure involves the insertion of a small tube down the nose into the patient’s lungs, through which oxygen is pumped into the lungs and waste carbon dioxide is removed. This system allows maximum inspiration and expiration levels to be reached.

Of all the forms of childhood SMA, Type II is the most diverse. It is therefore hard to tell when muscle weakness will occur and how severe the disease will be. With the aid of leg braces and walking devices, some children may gain the ability to stand. Unlike Type I SMA, not all children with Type II are affected by respiratory weakness. The main cause of death in patients with Type II is respiratory failure resulting from a

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