NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Spinal Muscular Atrophy, X-Linked Infantile

Synonym: XL-SMA

, PhD, FACMG, , MD, and , MS.

Author Information

Initial Posting: ; Last Update: September 13, 2012.

Estimated reading time: 19 minutes


Clinical characteristics.

X-linked infantile spinal muscular atrophy (XL-SMA) is characterized by congenital hypotonia and areflexia and evidence of degeneration and loss of anterior horn cells (i.e., lower motor neurons) in the spinal cord and brain stem. Often congenital contractures and/or fractures are present. Intellect is normal. Life span is shortened because of progressive ventilatory insufficiency resulting from chest muscle involvement.


The diagnosis of XL-SMA is based on clinical findings; evidence of degeneration and loss of anterior horn cells in the spinal cord and brain stem; normal SMN1 molecular genetic testing; and family history consistent with X-linked inheritance. UBA1 is the only gene currently known to be associated with XL-SMA.


Treatment of manifestations: Assure adequate caloric intake by caloric supplementation and/or gastrostomy feedings as necessary; manage constipation with diet; provide rigorous pulmonary toilet, supplemental oxygen, and noninvasive ventilatory support; discuss "do not attempt to resuscitate" status with the family before respiratory failure occurs. Orthopedic consultation and physical and occupational therapy to manage contractures.

Prevention of secondary complications: Precautions against infection.

Surveillance: Routine evaluations by a multidisciplinary team, including neurologic evaluation; assessment of pulmonary function, caloric intake, and weight gain; evaluation for scoliosis and/or kyphosis.

Genetic counseling.

XL-SMA is inherited in an X-linked manner. Carrier females have a 50% chance of transmitting the pathogenic variant with each pregnancy. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be affected. Affected males do not reproduce. Carrier testing for family members at risk and prenatal testing for at-risk pregnancies are available if the UBA1 pathogenic variant has been identified in the family.


Clinical Diagnosis

The diagnosis of X-linked infantile spinal muscular atrophy (XL-SMA) should be considered in children who meet the following criteria:

  • Congenital hypotonia and areflexia on physical examination
  • Congenital contractures and/or fractures
  • Digital contractures at birth. These usually remain throughout the child's life.
  • Evidence of degeneration and loss of anterior horn cells (i.e., lower motor neurons) in the spinal cord and brain stem
  • Male gender in a simplex case (i.e., a single occurrence in a family) or X-linked pattern of inheritance in families with more than one affected individual


Electromyogram (EMG) should demonstrate findings of denervation.

Molecular Genetic Testing

Gene. UBA1 (previously referred to as UBE1) is the only gene in which mutation is known to cause XL-SMA.

Evidence for locus heterogeneity. Linkage to the X chromosome region Xp11.3-q11.1 has been demonstrated in families with X-linked SMA without pathogenic variants observed in UBA1 [Kobayashi et al 1995, Dressman et al 2007].

Clinical testing. Sequence analysis of select exons (exon 15) or of the entire coding region

Table 1.

Molecular Genetic Testing Used in X-Linked Infantile Spinal Muscular Atrophy

Gene 1MethodVariants Detected 2Variant Detection Frequency by Method 3
Affected Males 4Carrier Females
UBA1Sequence analysis 5Sequence variantsUnknownUnknown 6

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


Five families detected so far with UBA1 pathogenic variants with complete cosegregation of the disease [Dressman et al 2007, Ramser et al 2008]


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Sequence analysis of genomic DNA cannot detect (multi)exon or whole-gene deletions on the X chromosome in carrier females.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Molecular genetic testing of SMN1 to rule out autosomal recessive SMA
  • Sequence analysis of select exons (exon 15) or of the entire coding region of UBA1
    Note: To date, all pathogenic variants detected have been in exon 15.

Carrier testing for at-risk relatives requires prior identification of the pathogenic variant in the family.

Note: Carriers are heterozygotes for this X-linked disorder and are usually unaffected.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Clinical Characteristics

Clinical Description

X-linked infantile spinal muscular atrophy (XL-SMA) is characterized by severe hypotonia and areflexia with loss of anterior horn cells in the spinal cord (i.e., lower motor neurons). The disease course is similar to that in the most severe forms of classic autosomal recessive SMA caused by mutation of SMN1: SMA type 0 (SMA0) and SMA type I (SMA1) (see Spinal Muscular Atrophy). In SMA0, prenatal onset of weakness and poor intrauterine movement results in congenital contractures. In SMA1, motor skills regress before age six months; affected children are never able to sit independently.

The weakness of XL-SMA is often prenatal in onset, manifest as polyhydramnios and poor movement in utero that results in congenital contractures. (Note: The term "arthrogryposis" is used to describe the presence of multiple congenital contractures of any cause.) Some neonates with XL-SMA are born with fractures that are perhaps related to poor fetal movement and subsequent bone fragility.

The most consistent features of XL-SMA are anterior horn cell disease and contractures (especially digital contractures) with or without fractures.

The weakness of XL-SMA is progressive. Affected infants may achieve some early motor milestones, but the extent varies among families.

Other features of XL-SMA that are variably present include mild micrognathia, digital contractures, kyphosis, scoliosis, and cryptorchidism.

Cognitive ability, observed during an often-limited life span, appears to be normal in those with documented XL-SMA.

As in SMA1, the greatest morbidity in XL-SMA may be restrictive lung disease, which is usually in proportion to the child's weakness and can be further complicated by aspiration and infection [Iannaccone 2007].

Children with XL-SMA usually die from respiratory failure by age two years; however, the age at death ranges from the neonatal period to adolescence, the latter in those exceptional cases in which extensive respiratory and medical support are provided.

Note: Individuals with a clinical picture consistent with SMA type II or type III have not been tested for pathogenic variants in UBA1; thus, it is not yet known if individuals with milder SMA phenotypes have UBA1 pathogenic variants.

Female carriers of XL-SMA are usually unaffected.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are evident.


Evidence suggests that the disorder is fully penetrant in hemizygous males.


XL-SMA has also been called:


The prevalence of XL-SMA is unknown. To date, 14 multigenerational families with affected family members have been identified throughout North America, Europe, Mexico, and Thailand [Author, personal observation]. This includes the family described by Greenberg et al [1988].

Differential Diagnosis

The differential diagnosis of X-linked infantile spinal muscular atrophy (XL-SMA) caused by mutation of UBA1 includes classic autosomal recessive SMA caused by mutation of SMN1 and the genetically heterogeneous category of arthrogryposis (Table 2).

Table 2.

Features of X-Linked SMA Compared to SMN1-Related SMA and Isolated Non-Progressive Arthrogryposis

FeaturesXL-SMAAutosomal Recessive SMA TypeArthrogryposis 1
Multiple contractures++----+
Muscle weakness++++++±
Motor regression+±++±--
Normal cognition+++++++
Absent tendon reflexes++++ (70%)±±±
Myopathic facies±±-----
Neurogenic atrophy++++++±
Denervation by EMG++++++±
Anterior horn cell loss++++++±

Isolated non-progressive

SMA Types by Inheritance Pattern

Classic Autosomal Recessive Spinal Muscular Atrophy

SMA, caused by pathogenic variants in SMN1, is characterized by loss of anterior horn cells with secondary muscle loss and weakness. SMA is classified by age of onset and maximum function achieved:

  • SMA1 (onset age <6 months)
  • SMA2 (onset age 6-12 months)
  • SMA3 (onset age >12 months)
  • SMA4 (adult onset)

SMA0 has been proposed for prenatal onset with severe joint contractures. Expression of SMN1 pathogenic variants is modified by the copy number of SMN2.

Other Autosomal Recessive SMA (non-SMN)

Lethal congenital contracture syndrome (LCCS) is characterized by fetal akinesia sequence leading to multiple joint contractures and death in utero typically before 32 weeks' gestation. Pathologic findings are anterior horn motor neuron degeneration and degeneration of descending tracts in the spinal cord. The highest gene frequency is in a genetically isolated subpopulation in northeastern Finland [Mäkelä-Bengs et al 1998]. Candidate gene screening of a linkage region on 9q34 led to identification of a single-base pair substitution in GLE1 in 29 unrelated Finnish families diagnosed with LCCS1 [Nousiainen et al 2008]. GLE1 pathogenic variants are also causative of LAAHD (lethal arthrogyposis with anterior horn cell disease), a disorder that is allelic to LCCS1 [Nousiainen et al 2008]. LCCS differs from SMA in that the descending tracts in the spinal cord are preserved in SMA.

Pontocerebellar hypoplasia with spinal muscular atrophy (pontocerebellar hypoplasia type 1) is characterized by hypoplasia of the olivary nuclei, pons, and cerebellum and progressive anterior horn cell loss. Hypotonia and weakness are usually noted in the newborn period and can be associated with congenital joint contractures and areflexia. Early presence of tongue fasciculations is similar to SMA1; however, ocular, bulbar, and facial abnormalities are distinct from classic SMA. Most die of respiratory failure in the first year of life. Survivors have failure to thrive and intellectual disability. Spinal cord pathology shows anterior horn cell loss; demyelination may also be present. Affected sibling pairs and occasional parental consanguinity suggests autosomal recessive inheritance [Ryan et al 2000, Rudnik-Schöneborn et al 2003]. See EXOSC3-Related Pontocerebellar Hypoplasia.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is characterized by diaphragmatic paralysis in the first few months of life. Most affected infants have intrauterine growth retardation; many are born prematurely. Many have decreased fetal movement, and some have congenital foot contractures. All have early respiratory failure with a normally shaped thorax and diaphragmatic eventration. Weakness starts distally in the limbs, and extends to full paralysis. Nerve biopsy may show axonal degeneration; muscle biopsy shows neurogenic changes with fiber hypertrophy and atrophy. Mutation of IGHMBP2 encoding the immunoglobulin micro-binding protein 2 is causative [Grohmann et al 2003].

Autosomal Dominant SMA

Autosomal dominant (AD) SMA with onset in childhood and AD SMA with onset in adulthood are usually considered two separate entities. AD SMA is extremely rare in childhood, accounting for less than 2% of childhood SMA; however, up to 30% of adult-onset SMA may be transmitted in an AD manner [Rietschel et al 1992].

Childhood-onset AD SMA usually presents between birth and age eight years. The course is usually mild, but with variable expression. Affected individuals lose the ability to walk at varying ages, often not for several decades. Life expectancy may be significantly diminished. Unlike adult-onset AD SMA, the symptoms are not limited to proximal muscles.

One type of adult-onset AD SMA is proximal SMA, which presents with marked proximal muscle involvement. Onset is usually between ages 30 and 40 years, and does not occur before age 20 years. The disease course of adult-onset AD SMA tends to be much more rapid than that of childhood-onset AD SMA, with most affected individuals losing the ability to run within five years of onset. Life expectancy averages 20 years after onset; thus, life span is shortened to about age 50 or 60 years.

Both childhood- and adult-onset AD SMA have nearly complete penetrance. However, some families have members with childhood onset and others with adult onset, suggesting that in some families the same underlying pathogenic variant may be responsible for both early and late onset [Rietschel et al 1992].

Scapuloperoneal spinal muscular atrophy, an AD form of SMA, which is allelic to hereditary motor and sensory neuropathy type IIC (HMSNIIC), also known as Charcot-Marie-Tooth disease type 2C (CMT2C), results from mutation of TRPV4, the gene encoding transient receptor potential cation channel subfamily V member 4 [Deng et al 2010]. Scapuloperoneal disorders are characterized by progressive weakness in a scapular and peroneal distribution, and severe fiber-type grouping and atrophy of both type 1 and type 2 fibers [Deng et al 2010]. AD transmission with variable expressivity and possible anticipation in subsequent generations have been observed. Other features include congenital absence of muscles, laryngeal palsy, and progressive distal weakness and atrophy [DeLong & Siddique 1992].

Congenital benign spinal muscular atrophy is described as congenital non-progressive atrophy and weakness of the lumbar paraspinal muscles and lower limb musculature associated with contractures [Frijns et al 1994]. Some children present with poor running and jumping, whereas others in the same family have congenital contractures. Involvement of upper limb and cranial musculature is variable. Although some affected individuals have normal nerve conduction velocities and action potentials, some have had concentric needle investigations that indicate neurogenic abnormalities such as reduced interference pattern, giant motor unit potentials in some muscle groups, and signs of denervation and reinnervation. In affected family members serum CK concentrations ranged between normal to twice the upper limit of normal. Muscle biopsy from the index case showed evidence for a neurogenic disorder, with group fiber atrophy with type 1 fiber predominance. The inheritance pattern was most consistent with AD but could also be X-linked or mitochondrial. Linkage analysis excluded linkage to SMN1.

Other X-Linked Forms of SMA

X-linked distal SMA (DSMAX), described by Takata et al [2004], has features similar to Charcot Marie Tooth hereditary neuropathy, including distal weakness; atrophy of the muscles of the lower limbs, particularly in the tibioperoneal compartment; and pes cavus. Symptoms start in the first decade and progress slowly. Muscle weakness and atrophy of the upper extremities, predominantly the hands, occurs later. Affected males remain ambulatory. Electrophysiologic studies show a distal neurogenic EMG pattern; muscle biopsy shows a mixed neurogenic and myogenic pattern; sural nerve biopsy is normal [Takata et al 2004]. Kennerson et al [2010] identified two pathogenic variants in ATP7A in affected males from two families. ATP7A encodes a copper-transporting P-type ATPase. The pathogenic variants are located in a conserved region in the carboxyl half of ATP7A and are not part of the copper transporter's known critical functional domains. Pathogenic variants in ATP7A have previously been associated with Menkes disease. They are loss-of-function variants, including splice-site variants, deletions, nonsense and missense variants within the critical functional domain of ATP7A, or variants that cause misfolding of the protein [Hsi & Cox 2004].

Other Non-SMN Disorders with SMA Phenotype

Other individuals who meet diagnostic criteria for SMA, but have normal SMN1 testing, have been described, suggesting the presence of an SMA type that is not associated with SMN1 pathogenic variants and that may be inherited in an autosomal recessive or X-linked manner [Nevo et al 1998, Felderhoff-Mueser et al 2002]. It is also known, based on previous DNA linkage studies in suspected XL-SMA families, that at least one phenocopy of this disorder does not map to the UBA1 region and may well be a very rare autosomal recessive disease mimicking SMA [Gerritsen et al 2003].


Arthrogryposis is defined as multiple congenital contractures and absent flexion creases.

Arthrogryposis multiplex congenita is etiologically heterogeneous: underlying etiologies can include central nervous system causes, neurogenic effects, fetal constraint, and intrauterine vascular disruption (e.g., amyoplasia). In addition, congenital myasthenic syndromes are genetic disorders of the neuromuscular junction that may present with arthrogryposis. Arthrogryposis is often classified by affected body area (e.g., distal arthrogryposis); generalized arthrogryposis is referred to as arthrogryposis multiplex congenita. It is typically considered non-progressive, although the clinical course of arthrogryposis of neurogenic etiology follows that of the underlying condition. Inheritance pattern varies by etiology; many genes are known to be associated with different arthrogryposis types.

X-linked arthrogryposis. Of the many cases of X-linked arthrogryposis described in the literature, some may have been caused by mutation of UBA1 and perhaps other unknown genes. X-linked arthrogryposis has traditionally been classified by clinical severity [Hall et al 1982]:

  • Type I (severe lethal) X-linked arthrogryposis was described in males with severe congenital contractures, scoliosis, chest deformities, hypotonia, and characteristic facies who died in the first three months of life from respiratory insufficiency. Autopsy demonstrated a quantitative decrease in the number of lateral anterior horn cells [Kizilates et al 2005, Dressman et al 2007]. A UBA1 pathogenic variant was subsequently identified in one of these families (Family #4) [Ramser et al 2008].
  • Type II (moderately severe) X-linked arthrogryposis was described in males with severe contractures, bilateral ptosis, inguinal hernias, and cryptorchidism. These males had normal intellect [Hall et al 1982].
    A few males with severe X-linked arthrogryposis have demonstrated muscle histology with ultrastructural changes with membranous bodies. These individuals had severe psychomotor retardation, in contrast to individuals with the milder types, who had normal development [Hennekam et al 1991].
  • Type III (resolving) X-linked arthrogryposis was described in males with mild to moderate contractures at birth that improved significantly over time. At birth, carrier females had contractures that were milder than in males; they resolved by the second decade of life [Hall et al 1982].

In addition to the three types described by Hall et al [1982], Zori et al [1998] reported a five-generation family in which multiple males were affected with a relatively mild form of non-progressive arthrogryposis affecting only the lower limbs. All had involvement of the knee joint, with either a flexion or extension defect; about half had involvement of the hip joint, including one with dislocated hips; and all but two had involvement of the ankle joints. The contractures resulted in gait impairment, but all affected individuals were ambulatory. Skeletal muscle biopsies from two affected individuals were essentially normal, and nerve conduction studies from one affected individual were normal. No female family members were affected. Zori et al [1998] noted that the phenotype in this family was most consistent with type III X-linked arthrogryposis described by Hall et al [1982].

In summary, over the last two decades, knowledge regarding X-linked clinical syndromes in which arthrogryposis is part of the clinical spectrum has grown tremendously. A number of these syndromes have associated hypotonia (for further review, see Hall [2007] and Hall [2010]). Further discussion of these syndromes is beyond the scope of this review. The degree to which UBA1 pathogenic variants are associated with these syndromes is yet to be determined.


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with X-linked infantile spinal muscular atrophy (XL-SMA), the following evaluations are recommended:

  • Nutrition/feeding
    • Determine if caloric intake is adequate.
    • Determine if dysphagia and/or fatigue during feeding are present [Iannaccone 2007]; consider swallowing evaluation, especially if aspiration is suspected [Wang et al 2007].
    • Determine if gastrostomy tube placement and fundoplication are indicated.
  • Respiratory function
    • Assess respiratory rate, work of breathing, presence of paradoxic breathing, chest wall shape, and skin perfusion.
    • Perform baseline pulmonary studies to determine extent of restrictive airway disease and cough efficiency.
    • Perform sleep evaluation to assess for sleep-disordered breathing including nocturnal hypoventilation and oxygen desaturation [Wang et al 2007].
  • Orthopedic evaluation to assess contractures
  • Neurologic evaluation to assess muscle tone and help guide supportive management [Iannaccone 2007]
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Management is similar to that for classic SMA type 0 and SMA type I, caused by mutation of SMN. See Spinal Muscular Atrophy.


  • If oral intake is not adequate, consider higher-calorie feeds and fat supplementation.
  • If weight gain is inadequate or the child cannot feed appropriately, consider nasogastric and possibly gastrostomy-tube placement.
  • Watch for swallowing dysfunction and consider a formal swallowing evaluation, especially if coughing or choking and/or recurrent pneumonias are evident as they may be signs of aspiration.
  • Manage gastroesophageal reflux disorder in the standard manner.
  • Manage constipation (resulting from weak abdominal musculature and poor motility) with diet (fiber and water content).


  • Provide rigorous pulmonary toilet, supplemental oxygen, and noninvasive ventilatory support.
  • Assist cough through mechanical devices or other means if the patient has ineffective cough.
  • Secretion mobilization may be achieved through chest physiotherapy and postural drainage.
  • Use oral suctioning as needed.
  • Use oximetry to monitor the patient's oxygen exchange status [Wang et al 2007].
  • In some cases artificial ventilation and tracheostomy may be employed.
  • As in classic SMA, discuss "do not attempt to resuscitate" status with the family before respiratory failure occurs. This discussion may begin earlier, but is appropriate when abdominal breathing is present and/or the forced vital capacity is less than 30%. See Spinal Muscular Atrophy for further discussion of respiratory support in SMA.

Sleep. Perform a sleep study if sleep-disordered breathing is suspected. Manage accordingly.

Orthopedic. Orthopedic management and physical and occupational therapy are indicated to manage contractures and prevent development of further contractures related to muscle weakness.

Prevention of Secondary Complications

Standard precautions against infection are appropriate.


The guidelines described below closely follow those presented in the consensus statement for standard care in spinal muscular atrophy [Wang et al 2007].

Individuals with XL-SMA should be followed regularly by a physician familiar with this condition (e.g., a clinical geneticist). Other subspecialists involved in ongoing care include the neurologist, pulmonologist, orthopedist, physical and occupational therapists, nutritionist, and gastroenterologist as needed.

Affected children should be followed at least monthly until the severity and disease course are more clearly delineated. Affected children frequently die in infancy or early childhood; their clinical status should be followed closely to optimize management, and so that the family has a good understanding of the progression and can make informed decisions.

The following are indicated on a routine basis:

  • Neurologic evaluations to assess muscle tone and help guide supportive management
  • Evaluation by a pulmonologist for evidence of progression of restrictive airway disease
  • Monitoring of caloric intake and weight, linear growth, head circumference, and growth velocity
  • Monitoring for scoliosis and kyphosis

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

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. —ED.

Mode of Inheritance

X-linked infantile spinal muscular atrophy (XL-SMA) is inherited in an X-linked manner.

Risk to Family Members

Parents of the proband

Sibs of the proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant will be carriers and will usually not be affected.

Offspring of the proband

  • Males with a severe phenotype do not generally survive.
  • Males with milder phenotypes will pass the pathogenic variant to all of their daughters and none of their sons.

Other family members of the proband. The proband's maternal aunts may be at risk of being carriers and the aunts' offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the pathogenic variant in the family has been identified.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant has been identified in the family, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for XL-SMA are possible.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Cure SMA
    925 Busse Road
    Elk Grove Village IL 60007
    Phone: 800-886-1762 (toll-free)
  • National Organization for Rare Disorders (NORD)
    55 Kenosia Avenue
    PO Box 1968
    Danbury CT 06813-1968
    Phone: 800-999-6673 (toll-free); 203-744-0100; 203-797-9590 (TDD)
    Fax: 203-798-2291
  • Compassionate Friends
    Supporting Family After a Child Dies
    PO Box 3696
    Oak Brook IL 60522
    Phone: 877-969-0010 (toll free); 630-990-0010
    Fax: 630-990-0246
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
  • National Rehabilitation Information Center (NARIC)
    8201 Corporate Drive
    Suite 600
    Landover MD 20785
    Phone: 800-346-2742 (toll-free); 301-459-5984 (TTY); 301-459-5900
    Fax: 301-459-4263

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Spinal Muscular Atrophy, X-Linked Infantile: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
UBA1Xp11​.3Ubiquitin-like modifier-activating enzyme 1UBA1 @ LOVDUBA1UBA1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Spinal Muscular Atrophy, X-Linked Infantile (View All in OMIM)


Gene structure. Two alternatively spliced transcript variants of UBA1 have been described. The second variant differs in the 5' UTR compared to variant 1. Variants 1 and 2 encode the same protein. The gene consists of 26 exons with an alternative exon1a accounting for the alternative splicing. Translation begins in exon 2. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. See Table 3. To date, all pathogenic variants detected have been in exon 15. Exon 15 encodes part of a highly conserved protein domain that interacts with gigaxonin.

Table 3.

UBA1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequence

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.

Normal gene product. The protein encoded by UBA1 catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation. It comprises 1058 amino acids.

Abnormal gene product. The variant c.1731C>T, which does not alter an amino acid (p.Asn577Asn), has been shown to alter methylation in the CpG dinucleotides of exon 15. Therefore, in the index cases of three families with XL-SMA, this c.1731C>T change results in one fewer methylated C nucleotide compared to normal. The complete disease mechanism related to the change in methylation is not yet understood [Ramser et al 2008].


Literature Cited

  • DeLong R, Siddique T. A large New England kindred with autosomal dominant neurogenic scapuloperoneal amyotrophy with unique features. Arch Neurol. 1992;49:905–8. [PubMed: 1520078]
  • Deng HX, Klein CJ, Yan J, Shi Y, Wu Y, Fecto F, Yau HJ, Yang Y, Zhai H, Siddique N, Hedley-Whyte ET, Delong R, Martina M, Dyck PJ, Siddique T. Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat Genet. 2010;42:165–9. [PMC free article: PMC3786192] [PubMed: 20037587]
  • Dressman D, Ahearn ME, Yariz KO, Basterrecha H, Martínez F, Palau F, Barmada MM, Clark RD, Meindl A, Wirth B, Hoffman EP, Baumbach-Reardon L. X-linked infantile spinal muscular atrophy: clinical definition and molecular mapping. Genet Med. 2007;9:52–60. [PubMed: 17224690]
  • Felderhoff-Mueser U, Grohmann K, Harder A, Stadelmann C, Zerres K, Bührer C, Obladen M. Severe spinal muscular atrophy variant associated with congenital bone fractures. J Child Neurol. 2002;17:718–21. [PubMed: 12503654]
  • Frijns CJM, Van Deutekom JV, Frants R, Jennekens F. Dominant congenital benign spinal muscular atrophy. Muscle Nerve. 1994;17:192–7. [PubMed: 8114789]
  • Gerritsen J, Estrella E., Ahearn ME, Yariz KO, Baumbach L. Fetal akinesia with anterior horn cell loss and congenital malformation in male siblings: Severe X-linked spinal muscular atrophy (XL-SMA) or a new disease entity? Abstract 1743. Los Angeles, CA: American Society of Human Genetics Annual Meeting. 2003.
  • Greenberg F, Fenolio KR, Hejtmancik JF, Armstrong D, Willis JK, Shapira E, Huntington HW, Haun RL. X-linked Infantile Spinal Muscular Atrophy. Am J Dis Child. 1988;142:217–9. [PubMed: 3341327]
  • Grohmann K, Varon R, Stolz P, Schuelke M, Janetzki C, Bertini E, Bushby K, Muntoni F, Ouvrier R, Van Maldergem L, Goemans NM, Lochmüller H, Eichholz S, Adams C, Bosch F, Grattan-Smith P, Navarro C, Neitzel H, Polster T, Topaloğlu H, Steglich C, Guenther UP, Zerres K, Rudnik-Schöneborn S, Hübner C. Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Ann Neurol. 2003;54:719–24. [PubMed: 14681881]
  • Hall JG. Arthrogryposes (multiple congenital contractures). In: Rimoin DL, Connor JM, Pyeritz RE, Korf BR, eds. Emery and Rimoin's Principles and Practice of Medical Genetics. 5 ed. New York, NY: Churchill Livingstone; 2007:3785-856.
  • Hall JG. Arthrogryposis. In: Cassidy SB, Allanson JE, eds. Management of Genetic Syndromes. 3 ed. Hoboken, NJ: Wiley and Sons; 2010:81-96.
  • Hall JG, Reed SD, Scott CI, Rogers JG, Jones KL, Camarano A. Three distinct types of X-linked arthrogryposis seen in 6 families. Clin Genet. 1982;21:81–97. [PubMed: 7200838]
  • Hennekam RC, Barth PG, Van Lookeren Campagne W, De Visser M, Dingemans KP. A family with severe X-linked arthrogryposis. Eur J Pediatr. 1991;150:656–60. [PubMed: 1915520]
  • Hsi G, Cox DW. A comparison of the mutation spectra of Menkes disease and Wilson disease. Hum Genet. 2004;114:165–72. [PubMed: 14579150]
  • Iannaccone ST. Modern management of spinal muscular atrophy. J Child Neurol. 2007;22:974–8. [PubMed: 17761652]
  • Kennerson ML, Nicholson GA, Kaler SG, Kowalski B, Mercer JF, Tang J, Llanos RM, Chu S, Takata RI, Speck-Martins CE, Baets J, Almeida-Souza L, Fischer D, Timmerman V, Taylor PE, Scherer SS, Ferguson TA, Bird TD, De Jonghe P, Feely SM, Shy ME, Garbern JY. Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. Am J Hum Genet. 2010;86:343–52. [PMC free article: PMC2833394] [PubMed: 20170900]
  • Kizilates SU, Talim B, Sel K, Köse G, Caglar M. Severe lethal spinal muscular atrophy variant with arthrogryposis. Pediatr Neurol. 2005;32:201–4. [PubMed: 15730903]
  • Kobayashi H, Baumbach L, Matise TC, Schiavi A, Greenberg F, Hoffman EP. A gene for a severe lethal form of X-linked arthrogryposis (X-linked infantile spinal muscular atrophy) maps to human chromosome Xp11.3-q11.2. Hum Mol Genet. 1995;4:1213–6. [PubMed: 8528211]
  • Mäkelä-Bengs P, Järvinen N, Vuopala K, Suomalainen A, Ignatius J, Sipilä M, Herva R, Palotie A, Peltonen L. Assignment of the disease locus for lethal congenital contracture syndrome to a restricted region of chromosome 9q34, by genome scan using five affected individuals. Am J Hum Genet. 1998;63:506–16. [PMC free article: PMC1377309] [PubMed: 9683599]
  • Nevo Y, Kramer U, Legum C, Shomrat R, Fatal A, Soffer D, Harel S, Shapira Y. SMA type 2 unrelated to chromosome 5q13. Am J Med Genet. 1998;75:193–5. [PubMed: 9450884]
  • Nousiainen HO, Kestilä M, Pakkasjärvi N, Honkala H, Kuure S, Tallila J, Vuopala K, Ignatius J, Herva R, Peltonen L. Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nat Genet. 2008;40:155–7. [PMC free article: PMC2684619] [PubMed: 18204449]
  • Ramser J, Ahearn ME, Lenski C, Yariz K, Hellebrand H, von Rhein M, Clark RD, Schmutzler RK, Lichtner P, Hoffman EP, Meindl A, Baumbach-Reardon L. Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy. Am J Hum Genet. 2008;82:188–93. [PMC free article: PMC2253959] [PubMed: 18179898]
  • Rietschel M, Rudnik-Schoneborn S, Zerres K. Clinical variability of autosomal dominant spinal muscular atrophy. J Neurol Sci. 1992;107:65–73. [PubMed: 1578236]
  • Rudnik-Schöneborn S, Sztriha L, Aithala GR, Houge G, Laegreid LM, Seeger J, Huppke M, Wirth B, Zerres K. Extended phenotype of pontocerebellar hypoplasia with infantile spinal muscular atrophy. Am J Med Genet A. 2003;117A:10–7. [PubMed: 12548734]
  • Ryan MM, Cooke-Yarborough CM, Procopis PG, Ouvrier RA. Anterior horn cell disease and olivopontocerebellar hypoplasia. Pediatr Neurol. 2000;23:180–4. [PubMed: 11020648]
  • Takata RI, Speck Martins CE, Passosbueno MR, Abe KT, Nishimura AL, Da Silva MD, Monteiro A Jr, Lima MI, Kok F, Zatz M. A new locus for recessive distal spinal muscular atrophy at Xq13.1-q21. J Med Genet. 2004;41:224–9. [PMC free article: PMC1735691] [PubMed: 14985388]
  • Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main M, Crawford TO, Trela A., Participants of the International Conference on SMA Standard of Care. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007;22:1027–49. [PubMed: 17761659]
  • Zori RT, Gardner JL, Zhang J, Mullan MJ, Shah R, Osborn AR, Houlden H, Wallace MR, Roberts S, Yang TP. Newly described form of X-linked arthrogryposis maps to the long arm of the human X chromosome. Am J Med Genet. 1998;78:450–4. [PubMed: 9714012]

Chapter Notes


The authors are grateful to the numerous clinicians and families that have supported XL-SMA disease gene discovery efforts through their cooperation throughout the years (especially Dr Louis Elsas), as well as to the laboratories of Drs Alfons Meindl and Eric Hoffman, who share in the XL-SMA disease gene discovery. This work was supported in the United States by funds from the Dr John T Macdonald Center for Medical Genetics at the University of Miami Miller School of Medicine, the University of Miami Miller School of Medicine, the national Muscular Dystrophy Association, the Families of SMA, and Peyton's Pals; and in Europe, by the German Ministry for Research and Education grant and FAZIT-Stiftung, Frankfurt/Main, Germany. The authors would like to dedicate this review in memory of four human geneticists who were fundamental to the early days of this research project: Dr Frank Greenberg, Dr Ronald Haun, Dr Emmanuel Shapira, and especially Dr Victor McKusick, who thought every inherited disorder, common or rare, was worth recognition and further investigation.

Revision History

  • 13 September 2012 (me) Comprehensive update posted live
  • 30 October 2008 (me) Review posted live
  • 10 July 2008 (lbr) Original submission
Copyright © 1993-2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source ( and copyright (© 1993-2020 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK2594PMID: 20301739


Tests in GTR by Gene

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...