脊髓性肌萎缩症(Spinal Muscular Atrophy 缩写：SMA)是指一组遗传性的神经性肌肉疾病。各型都会对控制随意肌运动的叫作运动神经元的神经细胞构成影响。SMA会造成位于脑底和脊髓的下级运动神经元分裂，从而使其无法发出肌肉进行正常活动所依赖的化学及电信号。SMA主要影响患者的近端肌，即最靠近人体躯干部的肌肉。控制胃、肠和膀胱等器官运动的非随意肌不会受到影响。I型和一些II型患者可能还会伴有一种叫作肌纤维自发性收缩的异常舌部颤动。SMA患者的听觉及视力正常，并且有正常的感官、情感和智力活动。而且研究者还发现，患有SMA的孩子通常都比较聪明。
Spinal muscular atrophy
From Wikipedia, the free encyclopedia
Spinal Muscular Atrophy (SMA) is a neuromuscular disease characterized by degeneration of motor neurons, resulting in progressive muscular atrophy (wasting away) and weakness. The clinical spectrum of SMA ranges from early infant death to normal adult life with only mild weakness. These patients often require comprehensive medical care involving multiple disciplines, including pediatric pulmonology, pediatric neurology, pediatric orthopedic surgery, pediatric critical care, and physical medicine and rehabilitation; and physical therapy, occupational therapy, respiratory therapy, and clinical nutrition. Genetic counseling is also helpful for the parents and family members.
The term "juvenile spinal muscular atrophy" refers to Kugelberg-Welander syndrome.
In all of its forms, the primary feature of SMA is muscle weakness, accompanied by atrophy of muscle. This is the result of denervation, or loss of the signal to contract, that is transmitted from the spinal cord. This is normally transmitted from motor neurons in the spinal cord to muscle via the motor neuron's axon, but either the motor neuron with its axon, or the axon itself, is lost in all forms of SMA.
The features of SMA are strongly related to its severity and age of onset. SMA caused by mutation of the SMN gene has a wide range, from infancy to adult, fatal to trivial, with different affected individuals manifesting every shade of impairment between these two extremes. Many of the symptoms of SMA relate to secondary complications of muscle weakness, and as such can be at least partially remediated by prospective therapy.
Infantile SMA is the most severe form. Some of the symptoms include:
* muscle weakness
* poor muscle tone
* weak cry
* weak cough
* limpness or a tendency to flop
* difficulty sucking or swallowing
* accumulation of secretions in the lungs or throat
* bell shaped torso, caused by breathing using muscles around the tummy area
* clenched fists with sweaty hands
* flickering/vibrating of the tongue
* head often tilted to one side, even when lying down
* legs that tend to be weaker than the arms
* legs lying in the "frogs leg" position
* hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells
* feeding difficulties
* increased susceptibility to respiratory tract infections
* bowel/bladder weakness
* lower-than-normal weight
* developmental milestones, such as lifting the head or sitting up, can't be reached
In order to be diagnosed with Spinal Muscular Atrophy, symptoms need to be present. In most cases a diagnosis can be made by the SMN gene test, which determines whether there is at least one copy of the SMN1 gene by looking for its unique sequences (that distinguish it from the almost identical SMN2) in exons 7 and 8. In some cases, when the SMN gene test is not possible or does not show any abnormality, other tests such as an EMG electromyography (EMG) or muscle biopsy may be indicated.
Caused by mutation of the SMN gene
Main article: Survival motor neuron spinal muscular atrophy
The most common form of SMA is caused by mutation of the SMN gene, and manifests over a wide range of severity affecting infants through adults.
SMA Caused by mutation of other genes
Other forms of spinal muscular atrophy are caused by mutation of other genes, some known and others not yet defined. All forms of SMA have in common weakness caused by denervation, that is, muscle weakens because muscle fibers lose the connection from the spinal cord that communicates when to contract.
Nam OMIM Gene Locus
Hereditary Bulbo-Spinal SMA Kennedy's disease, "SMAX1" 313200 Androgen receptor Xq11-q12
X-linked spinal muscular atrophy 2, "SMAX2" 301830 UBE1 Xp11.23
Spinal Muscular Atrophy with Respiratory Distress (SMARD 1) or Autosomal recessive distal spinal muscular atrophy 1 "DSMA1" 604320 IGHMBP2 11q13.3
Distal SMA with upper limb predominance or "HMN5" 600794 glycyl tRNA synthase 7p15
Spinal muscular atrophy only affects motor nerves. The term spinal muscular atrophy thus refers to atrophy of muscles due to loss of motor neurons within the spinal cord.
By contrast, heritable disorders that cause both weakness due to motor denervation along with sensory impairment due to sensory denervation are known by the inclusive label Charcot-Marie-Tooth or hereditary motor and sensory neuropathy (HMSN).
Individuals with SMA are living longer and fuller lives with the help of assistive technology such as ventilators, power wheelchairs, and modified access to computers. These mitigate the effects of SMA upon the individuals' daily lives, allowing them to participate in the community like anyone else.
Ventilation is especially important. The course of SMA is directly related to the severity of weakness. Infants with the severe form of SMA frequently succumb to respiratory disease due to weakness of the muscles that support breathing. Children with milder forms of SMA naturally live much longer although they may need extensive medical support, especially those at the more severe end of the spectrum.
Due to molecular biology, there is a better understanding of SMA. Many experimental treatments are being tested, including gene replacement, stem-cell replacement of motor neurons, and most promising therapies intended to increase the expression of the SMN 2 gene or increase the percentage of mRNA transcript from SMN 2 that is spliced to the full length form. Other potential therapies are directed to drugs that might enhance residual SMN function, or compensate for its loss. Significant progress has been made in preclincial research towards an effective treatment.
Several drugs have been identified in laboratory experiments that hold promise for patients. To evaluate if these drugs benefit SMA patients, clinical trials are needed. In a clinical trial a new medication is tested while the patients are carefully monitored for their safety and for any possible drug effects, positive or negative.
Some drugs under clinical investigation for the treatment of SMA:
* Valproic acid
Other compounds have been identified that increase SMN gene expression or the percentage of full length SMN transcript spliced from SMN2. These compounds are undergoing further pre-clinical development prior to beginning clinical trials.
Presently, treatment for SMA consists of prevention and management of the secondary effect of chronic motor unit loss. Given that much of the mortality is caused by treatable complications, this is important and may be, even in the long run, as important to maintaining overall function as specific treatment of SMN levels.
【Adults with SMA】
Although SMA can result in death during childhood, many people with SMA survive into adulthood and even old age. Actual lifespan depends greatly on the severity of SMA in each individual, and the three major types of SMA provide only a rough diagnostic guide. The slowing of the rate of degeneration has a major influence on survival overall, and even some individuals diagnosed with type-1 SMA can survive to adulthood. Intellectual ability is unaffected by SMA. Many children and adults with SMA benefit greatly from the use of assistive technology, such as speech recognition or Switch Access software. Such devices allow people with even very limited mobility to use a computer to read, write, communicate, play video games, and access environmental controls. Sexual response and reproductive functions are also unaffected by SMA; individuals with SMA can enjoy active sex lives and have given birth to children.
【'Baby MB' Case】
On March 15 2006, the High Court of Justice of England and Wales ruled that 17 month old "Baby MB" (identity withheld) was to be kept alive, contrary to 14 medical professionals' advice - one of the medics 'Dr. S' stating "I think that the cumulative effect of the condition's effects is that he has an intolerable life" . The judge said that "he felt the child gained enough pleasure from life to outweigh the medical evidence of his condition" . Baby MB died nine months later, in December 2006.
Spinal muscular atrophy
【What is spinal muscular atrophy?】
Spinal muscular atrophy is a disorder that affects the control of muscle movement. It is caused by a loss of specialized nerve cells, called motor neurons, in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). The loss of motor neurons leads to weakness and wasting (atrophy) of muscles used for activities such as crawling, walking, sitting up, and controlling head movement. In severe cases of spinal muscular atrophy, the muscles used for breathing and swallowing are affected. Spinal muscular atrophy is divided into subtypes based on the severity of the disease and the age when symptoms appear.
Four types of spinal muscular atrophy affect children before the age of 1. Type I spinal muscular atrophy (also called Werdnig-Hoffman disease) is a severe form of the disorder that is evident at birth or within the first few months of life. Typically, affected infants have difficulty breathing and swallowing and are unable to sit without support.
Type II spinal muscular atrophy is characterized by muscle weakness that develops in children between ages 6 and 12 months. Children with type II can sit without support, although they cannot stand or walk unaided.
X-linked infantile spinal muscular atrophy has features that are very similar to type I, except that children with this type are typically born with joint deformities (contractures) that impair movement. In severe cases, affected infants are born with broken bones. Poor muscle tone before birth may contribute to the contractures and broken bones seen in these children.
The fourth type of spinal muscular atrophy that appears in infancy is called distal spinal muscular atrophy type 1. This form of the disorder is characterized by progressive muscle weakness in the hands and feet that eventually spreads to the limbs. Affected individuals also develop paralysis of the muscle that separates the abdomen from the chest cavity (the diaphragm), which leads to respiratory failure. The signs and symptoms of distal spinal muscular atrophy type 1 typically appear between ages 6 weeks and 6 months. Rarely, people with this condition do not show symptoms until late childhood or adolescence.
Three other types of spinal muscular atrophy can affect people in early childhood and adulthood. Type III spinal muscular atrophy (also called Kugelberg-Welander disease or juvenile type) is a milder form of the disorder than types I or II, or the X-linked form. Symptoms appear between early childhood and early adulthood. Individuals with type III spinal muscular atrophy can stand and walk unaided, but usually lose this ability later in life. Two types of spinal muscular atrophy, type IV and Finkel type, usually occur after age 30. Symptoms of these adult-onset types of spinal muscular atrophy are typically mild to moderate and include muscle weakness, tremor, and twitching.
【How common is spinal muscular atrophy?】
Spinal muscular atrophy affects 1 in 6,000 to 1 in 10,000 people.
【What genes are related to spinal muscular atrophy? 】
Mutations in the SMN1, UBA1, VAPB, and IGHMBP2 genes cause spinal muscular atrophy. Extra copies of the SMN2 gene modify the severity of spinal muscular atrophy.
The SMN1 and SMN2 genes provide instructions for making a protein called the survival motor neuron (SMN) protein. The SMN protein is important for the maintenance of specialized nerve cells called motor neurons. Motor neurons are located in the spinal cord and the brainstem; they control muscle movement.
Several different versions of the SMN protein are produced from the SMN2 gene, but only one version is full size and functional. Most functional SMN protein is produced from the SMN1 gene, with a SMAll amount produced from the SMN2 gene.
Mutations in the SMN1 gene cause spinal muscular atrophy types I, II, III, and IV. SMN1 mutations lead to a shortage of the SMN protein, which is needed for the survival of motor neurons. Without SMN protein, motor neurons die, and nerve impulses are not passed between the brain and muscles. As a result, some muscles cannot perform their normal functions, leading to weakness and impaired movement.
Some people with type II, III, or IV spinal muscular atrophy have three or more copies of the SMN2 gene in each cell. These multiple copies of the SMN2 gene can modify the course of spinal muscular atrophy. Extra SMN2 genes can help replace some of the SMN protein that is lost due to mutations in the SMN1 genes. In general, symptoms are less severe and begin later in life as the number of copies of the SMN2 gene increases.
Mutations in the UBA1 gene cause X-linked infantile spinal muscular atrophy. The UBA1 gene provides instructions for making the ubiquitin-activating enzyme E1. This enzyme is involved in a process that targets proteins to be broken down (degraded) within cells. UBA1 gene mutations lead to reduced or absent levels of functional enzyme, which disrupt the process of protein degradation. A buildup of proteins in cells can cause the cell to die; motor neurons are particularly susceptible to damage from protein buildup.
Finkel type spinal muscular atrophy is caused by a mutation in the VAPB gene. The VAPB gene provides instructions for making a protein that is found in cells throughout the body. Little is known about the function of the VAPB protein. Researchers suggest that this protein may play a role in preventing the buildup of unfolded or misfolded proteins within cells. It is unclear how a VAPB gene mutation leads to the loss of motor neurons. An impaired VAPB protein might cause misfolded and unfolded proteins to accumulate and impair the normal function of motor neurons.
Mutations in the IGHMBP2 gene cause distal spinal muscular atrophy type 1. The IGHMBP2 gene provides instructions for making a protein that is thought to be involved in copying (replicating) DNA; producing RNA, a chemical cousin of DNA; and producing proteins. IGHMBP2 gene mutations that cause distal spinal muscular atrophy type 1 interfere with the protein's ability to aid in DNA replication and RNA and protein production. Alpha-motor neurons, which are motor neurons located in the brainstem and spinal cord, are particularly sensitive to a disruption in IGHMBP2 function. Over time, these neurons become damaged and die, leading to the progressive muscle weakness seen in people with distal spinal muscular atrophy type 1.
【How do people inherit spinal muscular atrophy?】
Spinal muscular atrophy types I, II, III, IV and distal spinal muscular atrophy type 1 are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
Finkel type spinal muscular atrophy is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
X-linked infantile spinal muscular atrophy is inherited in an X-linked pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked disorders much more frequently than females. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
Spinal muscular atrophy
Spinal muscular atrophy is a group of inherited diseases that cause progressive muscle degeneration and weakness, eventually leading to death.
Spinal muscular atrophy (SMA) is a collection of different muscle diseases. Grouped together, it is the second leading cause of neuromuscular disease. Most of the time, a person must get the defective gene from both parents to be affected. Approximately 4 out of every 100,000 people have the condition.
The most severe form is SMA type I, also called Werdnig-Hoffman disease. Infants with SMA type II have less severe symptoms during early infancy, but they become progressively weaker with time. SMA type III is the least severe form of the disease.
Rarely, SMA may begin in adulthood. This is usually a milder form of the disease.
A family history of spinal muscular atrophy is a risk factor for all types of the disorder.
Infants with SMA type 1 are born with very little muscle tone, weak muscles, and feeding and breathing problems. With SMA type III, symptoms may not appear until the second year of life.
Often, weakness is first noted in the shoulder muscles and proximal leg muscles. Weakness gets worse over time and will eventually become severe.
Symptoms in an infant:
* Breathing difficulty
* Feeding difficulty
* Floppy infant (poor muscle tone)
* Lack of head control
* Little spontaneous movement
* Progressive weakness (older infant to toddler)
* Very weak infant
Symptoms in a child:
* Frequent, increasingly severe respiratory infections
* Nasal speech
* Worsening posture
【Exams and Tests】
The health care provider will take a careful history and perform a brain/nervous system (neurologic) examination to find out if there is:
* A family history of neuromuscular disease
* Floppy (flaccid) muscles
* No deep tendon reflexes
* Twitches (muscle fasciculation) of tongue muscle
* CPK levels
* DNA testing to confirm diagnosis
* MRI of the spine
* Muscle biopsy
There is no treatment for the progressive weakness caused by the disease. Supportive care is important. Attention must be paid to the respiratory system, because affected people have difficulty clearing secretions. Respiratory complications are common.
Physical therapy is important to prevent contractions of muscles and tendons and abnormal curvature of the spine (scoliosis). Bracing may be necessary.
【Outlook (Prognosis) 】
The lifespan in SMA type 1 is seldom longer than 2 - 3 years. Survival time with type II is longer, but the disease kills most of those affected while they are still children. Children with type III disease may survive into early adulthood. However, people with all forms of the disease have worsening weakness and debility.
【Possible Complications 】
* Contractions of muscles and tendons
* Respiratory infections
【When to Contact a Medical Professional】
Call your health care provider if your child:
* Appears weak
* Develops any other symptoms of spinal muscular atrophy
* Has difficulty feeding
Breathing difficulty can rapidly become an emergency condition.
Genetic counseling is recommended for prospective parents with a family history of spinal muscular atrophy.
【Alternative Names 】
Kliegman RM, Behrman RE, Jenson HB, Stanton BF. The hip. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF. Nelson Textbook of Pediatrics. 18th ed. Philadelphia, Pa: Elsevier;2007:chap 606.
Update Date: 12/17/2008
Updated by: Neil K. Kaneshiro, MD, MHA, Clinical Assistant Professor of Pediatrics, University of Washington School of Medicine; and Daniel B. Hoch, PhD, MD, Assistant Professor of Neurology, Harvard Medical School, Department of Neurology, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.
Spinal Muscular Atrophy
【Disease characteristics】Spinal muscular atrophy (SMA) is characterized by progressive muscle weakness resulting from degeneration and loss of the anterior horn cells (i.e., lower motor neurons) in the spinal cord and the brain stem nuclei. Onset ranges from before birth to adolescence or young adulthood. Poor weight gain, sleep difficulties, pneumonia, scoliosis, and joint contractures are common complications. Before the genetic basis of SMA was understood, it was classified into clinical subtypes; however, it is now apparent that the phenotype of SMA associated with disease-causing mutations of the SMN1 gene spans a continuum without clear delineation of subtypes. Nonetheless, classification by age of onset and maximum function achieved is useful for prognosis and management; subtypes include: SMA O (proposed), with prenatal onset and severe joint contractures, facial diplegia, and respiratory failure; SMA I, with onset before six months of age; SMA II, with onset between six and 12 months; SMA III, with onset in childhood after 12 months; and SMA IV, with adult onset.
【Diagnosis/testing】The diagnosis of SMA is based on molecular genetic testing. The two genes associated with SMA are SMN1 and SMN2. The SMN1 (survival motor neuron 1) gene is believed to be the primary disease-causing gene. About 95-98% of individuals with SMA are homozygous for the absence of exons 7 and 8 of SMN1 and about 2-5% are compound heterozygotes for absence of exons 7 and 8 of SMN1 and a point mutation in SMN1.
Carrier detection relies upon determining the number of exon 7-containing SMN1 gene copies present in an individual. SMA carrier testing, a PCR-based dosage assay available on a limited clinical basis, allows determination of the number of SMN1 gene copies. SMA carrier testing results can be difficult to interpret because some carriers have the normal number of SMN1 gene copies caused by the presence either of two SMN1 gene copies in cis configuration on one chromosome or of a SMN1 point mutation. Furthermore, 2% of individuals with SMA have one de novo mutation, meaning that only one parent is a carrier. Because of these difficulties in SMA carrier test interpretation, SMA carrier testing should be provided in the context of formal genetic counseling.
【Management】When nutrition is a concern in SMA, placement of a gastrostomy tube is appropriate. As respiratory function deteriorates, tracheotomy or non-invasive respiratory support is offered. Sleep disorder breathing can be treated with nighttime use of continuous positive airway pressure. Surgery for scoliosis in individuals with SMA II and SMA III can be carried out safely if the forced vital capacity is greater than 40%. A power chair and other equipment may improve quality of life. Surveillance includes evaluation every six months or more frequently for children who are weak to assess nutritional state, respiratory function, and orthopedic status (spine, hips, and joint range of motion).
【Genetic counseling】SMA is inherited in an autosomal recessive manner. Each pregnancy of a couple who have had a child with SMA has an approximately 25% chance of producing an affected child, an approximately 50% chance of producing an asymptomatic carrier, and an approximately 25% chance of producing an unaffected child who is not a carrier. These recurrence risks deviate slightly from the norm for autosomal recessive inheritance because in about 2% of cases, the affected individual has a de novoSMN1 mutation on one allele; because only one parent is a carrier of a SMN1 mutation, the sibs are not at increased risk for SMA. Prenatal testing is available.
● Clinical Diagnosis
The diagnosis of spinal muscular atrophy (SMA) is established in individuals with the following:
* Evidence of degeneration and loss of anterior horn cells (i.e., lower motor neurons) in the spinal cord and brainstem
* A history of motor difficulties
* Evidence of motor unit disease on physical examination
* Diagnostic changes in the SMN1 gene
The following classification of SMA is based on age of onset and maximum function attained.
* Arthrogryposis multiplex congenita (i.e., congenital joint contractures involving at least two regions of the body) [Bingham et al 1997]
* Weakness at birth
* Facial weakness: minimal
* Onset 0-6 months
* Poor muscle tone
* Muscle weakness
* Lack of motor development; never achieves ability to sit without support
* Facial weakness: minimal or absent
* Fasciculation of the tongue: seen in most but not all affected individuals [Byers & Banker 1961, Iannaccone et al 1993]
* Postural tremor of the fingers: seen occasionally [Spiro 1970, Fredericks & Russman 1979]
* Mild contractures: often at the knees, rarely at the elbows
* Absence of tendon reflexes
* No sensory loss
* Alert appearance
* Normal cerebral function including intellect
* Onset of muscle weakness usually after six months of age; achieves ability to sit independently when placed in a sitting position
* Finger trembling: almost invariably present
* Low muscle tone (flaccidity) [Moosa & Dubowitz 1973, Fredericks & Russman 1979]
* Absence of tendon reflexes in approximately 70% of individuals [Iannaccone et al 1993]
* Average intellectual skills during the formative years and above average by adolescence [von Gontard et al 2002]
* Onset usually after ten months of age but in some cases earlier; achieves ability to walk at least 25 meters
* Weakness manifest as frequent falls or trouble walking up and down stairs at age two to three years
* Proximal limb weakness; the legs more severely affected than the arms
SMA IV. "Adult" onset of muscle weakness
The following testing has been used in the past to establish the diagnosis of SMA but currently has little role in the diagnosis of most individuals with SMA and is used primarily if molecular genetic testing of the SMN1 gene is normal.
【Electromyography (EMG).】EMG reveals denervation and diminished motor action potential amplitude. The EMG regular spontaneous motor unit activity, a unique feature in SMA, is seen most commonly in SMA I and occasionally in SMA II, but not in SMA III [Buchthal & Olsen 1970, Hausmanowa-Petrusewicz & Karwanska 1986]. A reduced interference pattern is seen with maximal effort; polyphasic waves, positive sharp waves, and fibrillations are present in all individuals with SMA.
【Nerve conduction velocities (NCV) 】Motor and sensory NCVs are normal.
【Muscle histology】Muscle biopsy reveals group atrophy of type 1 and type 2 muscle fibers as opposed to the normal checkerboard pattern. Rare angulated and large type 1 fibers are scattered throughout (Dubowitz muscle biopsy).
【Nerve histology】Hypomyelination of the peripheral nerve is observed in the prenatal form; otherwise, the nerves show normal histology [Korinthenberg et al 1997, MacLeod et al 1999, Hergersberg et al 2000].
Molecular Genetic Testing
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
The two genes associated with SMA are SMN1 and SMN2. The two genes are adjacent to each other. The SMN2 gene copy number (arranged in tandem in cis configuration on each chromosome) is variable, ranging from zero to five.
SMN1 and SMN2 differ by five base pairs; none of these differences change the amino acids encoded by the genes.
* SMN1. The SMN1 (survival motor neuron) gene is believed to be the primary SMA disease-causing gene.
* SMN2The presence of three or more copies of SMN2 is correlated with a milder phenotype [Prior et al 2004, Yamashita et al 2004, Soler-Botija et al 2005, Swoboda et al 2005]. See Genotype-Phenotype Correlations.
Molecular genetic testing: Clinical uses
* Diagnostic testing
* Prognostication (See Genotype-Phenotype Correlations)
* Carrier testing
* Prenatal diagnosis
Molecular genetic testing: Clinical methods
* SMN1 targeted mutation analysis. Targeted mutation analysis is used to detect deletion of exons 7 and 8 of SMN1.
Approximately 95-98% of individuals with a clinical diagnosis of SMA lack exon 7 in both copies of SMN1 (i.e., they are homozygous for the deletion) [Bussaglia et al 1995, Lefebvre et al 1995, Parsons et al 1996, Hahnen et al 1997, McAndrew et al 1997, Talbot et al 1997, Parsons et al 1998, Ogino & Wilson 2002].
Approximately 2-5% of individuals with a clinical diagnosis of SMA are compound heterozygotes for deletion of SMN1 exon 7 and an intragenic mutation of SMN1.
* SMN1 sequence analysis. Sequence analysis of all SMN1 exons and intron/exon borders may be used to identify the intragenic SMN1 mutations present in the 2-5% of individuals who are compound heterozygotes. The SMN1 and SMN2 genes are very large and exonic regions must be individually amplified; therefore, sequence analysis does not detect exonic deletions or duplications.
* Duplication analysis to determine SMN2 copy number. The number of copies of the SMN2 gene ranges from zero to five. Quantitative PCR is currently used for the accurate determination of SMN2 copy number [Anhuf et al 2003].
* SMA carrier testing: gene dosage analysis. Targeted mutation analysis is not reliable for carrier detection as it does not quantitate the number of SMN1 gene copies. A PCR-based dosage assay, called "SMA carrier testing" or "SMN gene dosage analysis," can determine the number of SMN1 gene copies, thus permitting highly accurate carrier detection.
* Linkage analysis. Linkage analysis is available for families in which direct DNA testing (mutation analysis and/or sequence analysis) is not informative. It may be used for confirmation of carrier testing and prenatal testing results.
★ Clinical Description
【SMA phenotypes】SMA is characterized by muscle weakness and atrophy resulting from progressive degeneration and loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brainstem nuclei. The onset of weakness ranges from before birth to adolescence or young adulthood. The weakness is almost always symmetric and progressive. Before the advent of molecular diagnosis, attempts were made to classify SMA into discrete subtypes; however, it is now apparent that the phenotype of SMA associated with disease-causing mutations of the SMN gene spans a broad continuum without clear delineation of subtypes.
【Congenital axonal neuropathy】Congenital axonal neuropathy manifests as severe weakness of prenatal onset, joint contractures, facial diplegia, ophthalmoplegia, and respiratory failure at birth requiring immediate endotracheal intubation and ventilation. Decreased fetal movement and polyhydramnios are common [Korinthenberg et al 1997].
【AMC-SMA association (arthrogryposis multiplex congenita-spinal muscular atrophy)】AMC-SMA manifests as severe weakness of prenatal onset and AMC (i.e., congenital joint contractures involving at least two regions of the body). Decreased fetal movement, polyhydramnios, and breech presentation are common. Typically, affected infants have absence of movement except for extraocular and facial movement. Death usually occurs from respiratory failure before one month of age [Banker 1985, Burglen et al 1996, Bingham et al 1997]. However, one report describes a child who is not ventilator-dependent at five years of age [Falsaperla et al 2001].
【SMA I (acute spinal muscular atrophy; Werdnig-Hoffmann disease)】SMA I manifests as severe weakness before age six months. Affected children are not able to sit without support at any time. Proximal, symmetric muscle weakness, lack of motor development, and poor muscle tone are the major clinical manifestations. Mild contractures are often noted at the knees and, rarely, at the elbows. In the neonatal period or during the first few months, the infants with the gravest prognosis have problems sucking or swallowing and often show abdominal breathing. The muscles of the face are relatively spared; the diaphragm is not involved until late in the course of disease. The heart is normal. Of note, a peculiar tremor of the electrocardiographic baseline has been attributed to fasciculation of limb and chest wall muscles [Russman & Fredericks 1979, Coletta et al 1989].
Fasciculation of the tongue is seen in most but not all individuals [Byers & Banker 1961, Iannaccone et al 1993]. A postural tremor of the fingers is seen only occasionally in SMA I [Spiro 1970, Fredericks & Russman 1979]. Most individuals die before age two years [Ignatius 1994, Thomas & Dubowitz 1994]. However, on occasion, individuals whose weakness was thought to have started before age six months are still sitting in adolescence or adulthood [Iannaccone et al 1993, Zerres & Rudnik-Schoneborn 1995].
Those individuals who have chosen to receive respiratory support may live longer than age two years [Bach et al 2002].
【SMA II (chronic spinal muscular atrophy; Dubowitz disease)】SMA II manifests as onset usually between six and 12 months of age. Maximum motor milestone attained is the ability to sit independently when placed. Although poor muscle tone may be evident at birth or within the first few months of life, individuals with SMA II may gain motor milestones slowly [Iannaccone et al 1993]. Often concerns are not raised until a child is not sitting independently by age nine to 12 months or is not standing by age one year. Finger trembling and general flaccidity are common [Moosa & Dubowitz 1973, Fredericks & Russman 1979]. Affected individuals on average lose the ability to sit independently by the mid-teens [Russman et al 1996].
【SMA III (juvenile spinal muscular atrophy; Kugelberg-Welander disease)】SMA III manifests after one year of age. Individuals with SMA III walk independently but may fall frequently or have trouble walking up and down stairs at age two to three years. The legs are more severely affected than the arms. Prognosis generally correlates with the maximum motor function attained [Russman et al 1983]. Individuals with SMA III who have never climbed stairs without using a rail lose walking ability by the mid-teens [Russman et al 1996]. Individuals who develop normal walking skills prior to the onset of weakness can maintain this ability until the third or fourth decade of life.
【SMA IV】The onset of muscle weakness is usually in the second or third decade of life. The findings are similar to those described for SMA III [Brahe et al 1995, Clermont et al 1995, Zerres et al 1995].
【Complications of SMA】Poor weight gain, sleep difficulties, pneumonia, scoliosis, and joint contractures are common complications of SMA.
An unexplained potential complication of SMA is severe metabolic acidosis with dicarboxylic aciduria and low serum carnitine levels during periods of intercurrent illness or fasting [Kelley & Sladky 1986, Crisp et al 1989]. Whether these metabolic abnormalities are primary or secondary to the underlying defect in SMA is unknown. Some investigators have suggested that underweight individuals with SMA with minimum muscle mass are at risk for recurrent hypoglycemia or ketosis [Bruce et al 1995, Tein et al 1995]. The problem is self-limiting; individuals typically recover in two to four days.
【Life expectancy and prognosis of SMA】Whether the loss of function observed in all individuals with SMA is caused by loss of motor units or other factors such as scoliosis, progressive contractures, and pulmonary insufficiency is difficult to determine [Hausmanowa-Petrusewicz et al 1992]. Of the individuals studied by Russman et al (1992) over a period of 18 months, none lost strength in the individual muscle groups studied, but four lost functional abilities. In a cross-sectional study of 120 individuals with SMA, Merlini et al (2004) noted that individuals no longer ambulant were weaker than those who were still ambulant, concluding that loss of muscle strength correlated with loss of function. Given the study design these conclusions need be considered tentative.
In a physiological outcome study, Swoboda et al (2005) showed a correlation between motor unit number estimation (MUNE) and disease severity. In addition to MUNE, the measurement of compound motor action potential can be used to determine outcome.
A review of life expectancy of 569 individuals with SMA II and SMA III from Germany and Poland found that 68% of individuals with SMA II were alive at 25 years of age and that life expectancy of individuals with SMA III was not different from that of the general population [Zerres et al 1997].
【Pregnancy】Women with SMA may experience exacerbation of muscle weakness during pregnancy [Rudnik-Schoneborn et al 1992]. Complications of pregnancy in ten of 12 women with SMA included premature labor in four, prolonged labor in three, and delayed post-partum recovery in six. No deleterious effects were observed in the offspring.
【Neuropathology】Studies reveal a decreased number of motor neurons (and varying stages of chromatolysis and acute degeneration of anterior horn cells) and gliosis in the anterior horns of the spinal cord as well as a decreased number of lower cranial motor neurons.
Severe SMA or SMA I is still called Werdnig-Hoffmann disease by many [Werdnig 1891, Hoffmann 1892].
SMA II was called chronic SMA prior to the current classification.
SMA III has had the eponym juvenile SMA or Kugelberg-Welander disease [Kugelberg & Welander 1956].
【Arthrogryposis multiplex congenita (AMC)】Although some individuals with AMC have SMN mutations [Burglen et al 1996, Bingham et al 1997], other infants with various types of AMC do not.
【Congenital axonal neuropathy】Korinthenberg et al (1997) indicated that three siblings with SMN disease-causing mutations reported by them were the same infants reported by others to have congenital hypomyelination neuropathy or axonopathy [Vital et al 1989, Boylan & Cornblath 1992].
Infants with perinatal respiratory distress with diaphragmatic and intercostal muscle weakness who have evidence of denervation on electromyogram and group atrophy on muscle biopsy were described prior to the availability of molecular testing [Schapira & Swash 1985, Bove & Iannaccone 1988]. This entity has been linked to chromosome 11q13-q21 and shown to share common functions for anterior horn cell maintenance with survival motor neuron gene [Grohmann et al 2001]. An autosomal recessive form without respiratory distress has recently been described, linkage being established in the same region as the diaphragmatic form [De Angelis et al 2002].
For SMA I and SMA III, the differential includes other causes of the "floppy infant":
* Central nervous system abnormalities. Cranial imaging may be helpful in identifying these.
* Chromosomal abnormalities and specifically Prader-Willi syndrome need to be considered. High-resolution chromosome analysis and, for Prader-Willi syndrome, methylation analysis can distinguish these.
* Peroxisome biogenesis disorders, Zellweger syndrome spectrum are suspected if the child has lost skills previously acquired or if hepatosplenomegaly is present. Measurement of plasma very-long-chain fatty acid (VLCFA) levels shows elevation of C26:0 and C26:1 and the ratios C24/C22 and C26/C22. Mutations in twelve different PEX genes are causative; molecular genetic testing is available for some.
* Infantile acid maltase deficiency (Pompe disease; glycogen storage disease type II) is suspected when cardiomegaly is present. Biochemical and molecular testing is available.
* Primary diseases of muscle need to be considered. Among these are nemaline myopathy, central core disease, X-linked myotubular myopathy, congenital myotonic dystrophy type 1, and congenital muscular dystrophy. The diagnosis of a specific type of muscle disease rests on the presence of the specific ultrastructural changes on muscle biopsy and/or genetic testing.
* Congenital myasthenia gravis (see Congenital Myasthenic Syndromes) may be recognized by abnormal EMG responses to repetitive nerve stimulation and in some cases genetic testing.
Other disorders to consider are trauma of the cervical spinal cord, especially with breech delivery, spinal muscular atrophy with infantile cerebellar atrophy, and spinal muscular atrophy associated with brain atrophy [Chou et al 1990, Yohannan et al 1991].
Peripheral neuropathies (see Charcot-Marie-Tooth Hereditary Neuropathy Overview) including the Guillain-Barre syndrome are part of the differential diagnosis.
Regression of motor skills associated with intact or exaggerated deep tendon reflexes suggest cerebral white matter diseases such as X-linked adrenoleukodystrophy.
SMA III is considered in the differential diagnosis of Duchenne muscular dystrophy (DMD), which is suspected when serum creatine kinase concentration is ten to 20 times greater than normal. DMD is confirmed by molecular genetic studies of the DMD gene or muscle biopsy.
Congenital myopathies may also present with a clumsy gait and difficulty walking up and down stairs. Metabolic myopathies, including glycogen storage diseases and lipid myopathies, need to be considered.
Other disorders with motor neuron disease may be confused with SMA: X-linked spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease, is a gradually progressive neuromuscular disorder in adult men in which degeneration of lower motor neurons results in proximal muscle weakness, muscle atrophy, and fasciculations beginning between ages 20 and 50 years. Individuals with SBMA often show gynecomastia, testicular atrophy, and reduced fertility as a result of androgen insensitivity. Identification of a CAG trinucleotide repeat expansion in the androgen receptor gene is diagnostic.
Hexosaminidase A deficiency results in lysosomal storage of the specific glycosphingolipid, GM2 ganglioside. The juvenile, chronic, and adult-onset variants have onset after infancy, slow progression, and variable neurologic findings, including progressive dystonia, spinocerebellar degeneration, and lower motor neuron disease. Diagnosis is by enzyme deficiency or molecular testing.
"Monomelic muscular atrophy" is predominantly a cervical form of spinal muscular atrophy. Rarely, the tongue may be affected; other cranial nerves are spared [Goutieres et al 1991, Hageman et al 1993].
Fazio-Londe disease is a motor neuron disease limited to the lower cranial nerves, which starts in the second decade of life and progresses to death in one to five years.
Distal spinal muscular atrophy is characterized by initial weakness and wasting of distal muscles, followed by weakness of other muscle groups. A fascioscapuloperoneal distribution of spinal muscular atrophy, a bulbospinal muscular atrophy in adults, and spinal muscular atrophy with initial involvement of the proximal muscles have also been described.
A congenital form of lower extremity SMA has been described; it is unclear whether the distal muscles are weaker than the proximal muscles. If so, this would be included under the rubric of distal spinal muscular atrophy [Mercuri et al 2004].
Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease involving both the upper motor neurons (UMN) and lower motor neurons (LMN), may begin with pure lower motor neuron signs. Molecular genetic testing is available for at least three genes associated with ALS: SOD1, ALS2, and VAPB.
Evaluations at Initial Diagnosis to Establish the Extent of Disease
The following issues need to be addressed independent of SMA type:
* Nutrition/feeding assessment
――Time required to complete a feeding
――Evidence of fatigue during a feeding/meal
――Weight plotted on standard growth curves
* Respiratory function assessment
――Normal breathing pattern versus abdominal breathing pattern
――Forced vital capacity (FVC); in children over the age four years, the hand-held spirometer is accurate. When FVC is above 40%, decompensation during respiratory infection is less likely than when FVC is less than 40%.
* Sleep asssessment. Consideration of a sleep study if the child snores during sleep or awakes fatigued in the morning
* Activities of daily living. Assessment of equipment needed for independence, such as a power-chair and other equipment in the home to improve the quality of life for the affected individual and the caregiver
* Orthopedic evaluation. Attention to the development of contractures, scoliosis, and hip dislocation
Treatment of Manifestations
【Nutrition/feeding】When there are concerns, a feeding gastrostomy is appropriate and can be removed if oral intake becomes adequate.
【Respiratory function】Inevitably, the respiratory function deteriorates [Samaha et al 1994]. Some children with SMA I can survive beyond two years of age when offered tracheotomy or non-invasive respiratory support [Bach et al 2002].
Options for management including "do not attempt to resuscitate" status should be discussed before respiratory failure occurs [Samaha et al 1994]. This discussion should be initiated when abdominal breathing is noted and/or the forced vital capacity is less than 30%.
Children relying on non-invasive respiratory support have fewer hospitalizations after age five years, may be free from daytime ventilator use, and are able to express themselves verbally. Non-invasive respiratory support is labor intensive, demands commitment, and depends upon the availability of facilities. Bush and colleagues (2005) argue that nighttime nasal intermittent positive pressure (NIPPV) and occasional daytime NIPPV are reasonable; they do not currently recommend full-time NIPPV. Miske et al (2004) use the mechanical in-exsufflator (MI-E) in treatment of neuromuscular conditions. MI-E delivers a positive pressure insufflation followed by an expulsive exsufflation, simulating a normal cough and is helpful in the management of respiratory infections in individuals with SMA.
【Sleep disorders】In a study of seven persons with SMA, Mellies et al (2004) noted that sleep disorder breathing developed prior to respiratory failure. Puruckherr et al (2004) described a 46-year-old man with SMA III whose increasing daytime fatigue caused by snoring and apnea at night resolved with nighttime use of continuous positive airway pressure with a nasal mask.
【Orthopedic】Children with SMA I rarely require orthopedic intervention because they do not live long enough to develop spinal deformity, hip dislocation, or contractures.
Scoliosis is a major problem in SMA II and in half of those with SMA III [Brown et al 1989, Merlini et al 1989, Rodillo et al 1989]. Before age ten years, approximately 50% of children with SMA, especially those who are non-ambulatory, develop spinal curvatures of more than 50 degrees, the threshold for surgery. Scoliosis repair can be carried out safely if the forced vital capacity is greater than 40%. The use of an orthosis does not prevent scoliosis, but does allow the affected individual to be upright rather than recumbent. Although individuals lose some upper extremity function following operative intervention, the advantages of a stable trunk and the opportunity to sit upright unassisted outweigh the disadvantages. Whether scoliosis repair prevents further deterioration of pulmonary function is unclear.
A retrospective review of a large series concluded that surgery is not needed for asymptomatic hip dislocation [Sporer & Smith 2003].
Individuals are evaluated at least every six months; weaker children are evaluated more frequently.
Nutritional state, respiratory function and orthopedic status (spine, hips, and joint range of motion) are assessed at each visit.
Therapies Under Investigation
Pre-clinical evaluation of drugs and other interventions is underway [Escolar et al 2001, Iannaccone & Hynan 2003, Swoboda et al 2005].
Increasing the activity of the SMN2 gene is one of the major strategies under consideration. The following are some medications/chemicals under investigation:
* Histone deacetylase (HDAC) inhibitors can increase the level of fl-SMN [Kernochan et al 2005].
* Valproic acid [Brichta et al 2003, Sumner et al 2003] increases SMN protein in skin fibroblasts.
* Phenylbutyrate, a drug used in the treatment of urea acid cycle disorders, increased full-length SMN2 transcripts in skin fibroblasts [Andreassi et al 2004]. Oral phenylbutyrate increased SMN expression in white blood cells [Brahe et al 2005]. In a pilot trial phenylbutyrate improved function in the short term in ten persons with SMA [Mercuri et al 2004].
* Hydroxyurea, a medication that enhances the expression of human fetal hemoglobin [Stevens 1999] also modifies gene expression and increases SMN levels in skin fibroblasts from individuals with SMA [Grzeschik et al 2005].
* Indoprofen, a non-steroidal anti-inflammatory drug (NSAID), increases SMN2 levels in fibroblasts of individuals with SMA [Lunn et al 2004].
* An open-label pilot trial of Rilutek (Riluzole) in infants with SMA is currently under way at ten participating centers. The Phase 1 trial showed it to be safe, but the power was insufficient to show benefit [Russman et al 2003].
* A multicenter randomized, double-blind study of the effect of gabapentin in individuals with SMA II and III showed benefit to muscle strength but no improvement in motor or respiratory function [Miller et al 2001, Merlini et al 2003]. However, a double-blind one-year study showed that gabapentin was not beneficial in SMA [Miller et al 2001].
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Mode of Inheritance
Spinal muscular atrophy is inherited in an autosomal recessive manner.
Risk to Family Members
【Parents of a proband】
* Approximately 98% of parents of an affected child are heterozygotes and, therefore, carry a disease-causing mutation in the SMN1 gene.
* About 2% of parents are not carriers of a SMN1 mutation as their affected child has a de novo disease-causing mutation [Wirth et al 1997]. The majority of de novo mutations are paternal in origin [Wirth et al 1997].
* Heterozygotes are asymptomatic.
【Sibs of a proband】
* At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
* Even if a child with SMA appears to have inherited one disease-causing allele from a carrier parent and to have a de novo mutation resulting in the other disease-causing mutation, germline mosaicism in the parent without an identifiable mutation needs to be considered [Campbell et al 1998]; therefore, it is reasonable to consider sibs of such an individual to be at risk for SMA.
* Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
【Offspring of a proband】
* Only individuals with the milder forms of SMA are likely to reproduce. All of their offspring are carriers.
* The unrelated reproductive partner of an individual with a mild form of SMA should be offered carrier testing. If the partner shows at least two SMN1 copies, the partner has a one in 670 probability of being a carrier (taking into consideration the 2% frequency of two SMN1 copies on the same chromosome and the small risk of an intragenic SMN1 mutation). Thus, the risk to such a couple of having an affected child is one in 1340.
【Other family members】Each sib of an obligate heterozygote is at a 50% risk of being a carrier.
Carrier detection may be considered for the following individuals:
* Parents of a single affected child with SMA in whom the diagnosis has been confirmed with direct DNA testing. Carrier detection for such parents has three limitations:
――A de novo mutation in the SMN gene, occurring in approximately 2% of individuals [Wirth et al 1995]. This is a high rate when compared to most autosomal recessive disorders.
――The finding of two SMN1 genes on a single chromosome, which occurs in about 4% of the general population [McAndrew et al 1997]. The presence of two SMN1 genes on a single chromosome has serious counseling implications because a carrier with two SMN1 genes on one chromosome is misdiagnosed as a non-carrier by the SMA dosage carrier test.
――Carriers with one normal allele and one intragenic SMN1 gene mutation
Because of de novo mutational events and the presence of two SMN1 genes on a single chromosome, approximately 6% of parents of a single child affected with SMA have normal results of SMN dosage testing. Thus, the finding of normal SMN1 dosage in a parent significantly reduces, but does not eliminate, the risk of the parent being a carrier for SMA. Further study by linkage analysis including other family members may allow clarification of these two situations, since documentation of a de novo mutation in the child reduces the couple's risk of having additional affected children.
* Parents of an affected deceased child with SMA on whom no molecular testing of SMN was performed. Tissue, such as muscle biopsies and paraffin tissue samples, available from deceased individuals can often provide enough DNA for genetic testing; however, if DNA is not available, both parents could be offered SMA carrier (dosage) testing. Issues with test result interpretation include the following:
――If both parents are found to be carriers, the diagnosis of SMA in the proband is most likely and prenatal testing can be offered.
――If only one parent is Δ7 SMN1 heterozygous, testing of additional family members of the parent with two SMN1 gene copies may be informative.
――If both parents show at least two SMN1 copies, it is extremely unlikely that the affected child had SMA caused by mutations at the SMN locus.
* At-risk relatives of an individual with SMA who is homozygous for Δ7 SMN1. In this instance, the risk that the dosage test will produce a false negative or uncertain result because of the presence of two SMN1 copies on one chromosome is 4%.
* Unrelated reproductive partners of an individual known to be heterozygous for a familial disease-causing mutation in SMN1or an individual at risk of being heterozygous for a SMNdisease-causing mutation. These unrelated reproductive partners are individuals who are at no known increased risk of being heterozygous for a SMN disease-causing mutation. A reproductive partner showing at least two SMN1 copies has an approximately one-in-670 probability of being a carrier (taking into consideration the 2% frequency of two SMN1 copies on the same chromosome and the small risk of intragenic mutations).
Related Genetic Counseling Issues
【Family planning】The optimal time for determination of genetic risk, clarification of carrier status, and discussion of availability of prenatal testing is before pregnancy.
【DNA banking】Because of the complex nature of the SMN mutations causing SMA, the difficulty in performing molecular genetic testing now, and the likelihood that testing methods will improve in the future, consideration should be given to banking the DNA of any individual known or suspected of having SMA. In this manner, a DNA sample would be available to family members who seek genetic counseling and testing in the future. See DNA Banking for a list of laboratories offering this service.
【High-risk pregnancy】Prenatal diagnosis is possible for fetuses at 25% risk when the disease-causing SMN mutations in both parents are known or when linkage has been established in the family. Analysis of fetal DNA obtained either through chorionic villus sampling (CVS) at about 10-12 weeks' gestation or amniocentesis usually performed at about 15-18 weeks' gestation is possible for the known parental SMN1 gene mutations or for the previously identified linked markers. The situations in which prenatal testing is likely to occur and the issues in test result interpretation are the following:
* The couple are the parents of a child with SMA. It would be predicted that a fetus with the same genotype (i.e., molecular genetic test result) as a previously affected sib would have similar clinical findings.
* One or both parents are heterozygous for SMNdisease-causing mutations detected during testing of relatives and their partners. In this instance, interpretation of test results may be difficult and should be done in the context of formal genetic counseling.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
【Low-risk pregnancy】For the fetus with reduced fetal movement at no known increased risk for SMA, SMA needs to be considered, as do the disorders discussed in Differential Diagnosis [Macleod et al 1999].
【Preimplantation genetic diagnosis (PGD)】 may be available for families in which the disease-causing mutations have been identified in an affected family member in a research or clinical laboratory [Moutou et al 2003, Malcov et al 2004].
★ Molecular Genetics
Molecular Genetic Pathogenesis
SMA may be the result of a genetic defect in the biogenesis and trafficking of the spliceosomal snRNP complexes. The SMN protein interacts with proteins known to be involved in the small nuclear ribonucleoprotein particle complex as well as with the survival motor neuron-interacting protein SIP. Consequently, the motor neurons of individuals with SMA are impaired in their capacity to produce specific mRNAs and as a result become deficient in proteins that are necessary for the growth and function of these cells. Thus, SMA may be a disorder affecting splicing; however, the reasons for specific motor neuron death as a consequence of SMN1 mutations are not yet known. The SMN protein has also been reported to influence several other cellular activities such as transcription, ribosomal assembly, and apoptosis [Strasswimmer et al 1999, Lefebvre et al 2002, Vyas et al 2002].
Despite the few differences in the coding regions between SMN1 and SMN2, the two genes do not encode identical proteins. SMN1 produces full-length transcripts and SMN2 primarily produces transcripts lacking exon 7 because the C-to-T transition in SMN2 exon 7 disrupts an exon-splicing enhancer sequence [Lorson et al 1999]. Therefore, SMA arises because the SMN2 gene cannot fully compensate for the lack of expression of mutated SMN1. However, when the SMN2 copy number is increased, the small amount of full-length transcript generated by SMN2 is often able to produce a milder type II or III phenotype.
【Normal allelic variants】 The SMN region on chromosome 5q12.2-q13.3 is unusually complex, with repetitive sequences, pseudogenes, retrotransposable elements, deletions, and inverted duplications [Biros & Forrest 1999]. Unaffected individuals have two copies of the SMN gene arranged in tandem on each chromosome; these are referred to as SMN1 (telomeric copy) and SMN2 (centromeric copy). Other terms that have been used to identify SMN1 are telSMN, SMNt, and SMNT; other terms that have been used to identify SMN2 are cenSMN, SMNc, c BCD541, and SMNC. Both SMN1 and SMN2 contain nine exons and differ only in eight nucleotides (five are intronic and three are exonic, located within exons 6, 7, and 8) [Biros & Forrest 1999].
The presence of a SMA carrier with two SMN1 copies on one chromosome was definitively proven utilizing hybrids monosomal for human chromosome 5 [Mailman et al 2001].
【Pathologic allelic variants】 It is the loss of the telomeric copy of the SMN(SMN1) gene that leads to development of SMA. Individuals with SMA are either homozygous for a deletion of exon 7 of SMN1 (Δ7 SMN1) or are compound heterozygotes for Δ7 SMN1 and a intragenic mutation of SMN1. Deletions of the SMN1 gene appear to be directly involved in SMA, since exon 7 — or exons 7 and 8 — of SMN1 are undetectable in more than 95% of individuals irrespective of their clinical type, either as a result of homozygous deletions, or because of conversion of sequences of SMN1 into those of the SMN2 gene.
【Normal gene product】Evidence supports a role for SMN in snRNP (small nuclear ribonuclearprotein) biogenesis and function [Fischer et al 1997, Liu et al 1997, Pellizzoni et al 1998]. SMN has been shown to be required for pre-mRNA splicing. Immunofluorescence studies using a monoclonal antibody to the SMN protein have revealed that the SMN protein is localized to novel nuclear structures called 'gems;' gems appear similar to and possibly interact with coiled bodies, which are thought to play a role in the processing and metabolism of small nuclear RNAs [Liu & Dreyfuss 1996]. SnRNPs and possibly other splicing components require regeneration from inactivated to activated functional forms. The function of SMN is in the reassembly and regeneration of these splicing components [Pellizzoni et al 1998].
【Abnormal gene product】 Mutant SMN, such as that found in individuals with SMA, lacks the splicing-regeneration activity of wild-type SMN.