DiagnosisClinical 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 fracturesDigital 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 Normal SMN1 molecular genetic testing to rule out autosomal recessive spinal muscular atrophyMale 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 individualTestingElectromyogram (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 mutations observed in UBA1 [Kobayashi et al 1995, Dressman et al 2007].Clinical testingSequence analysis of select exons (exon 15) or of the entire coding regionTable 1. Summary of Molecular Genetic Testing Used in X-Linked Infantile Spinal Muscular AtrophyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test Availability Affected Males 2Carrier FemalesUBA1Sequence analysisSequence variants 3UnknownUnknown 4Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Five families detected so far with UBA1 mutations with complete cosegregation of the disease [Dressman et al 2007, Ramser et al 2008]3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.4. Sequence analysis of genomic DNA cannot detect exonic, multiexonic, or whole-gene deletions on the X chromosome in carrier females.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a probandMolecular genetic testing of SMN1 to rule out autosomal recessive SMASequence analysis of select exons (exon 15) or of the entire coding region of UBA1 (Note: To date, all pathologic variants detected have been in exon 15.)Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation 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 disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in UBA1.}

Natural History 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 mutations in 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 mutations in UBA1; thus, it is not yet known if individuals with milder SMA phenotypes have UBA1 mutations. Female carriers of XL-SMA are usually unaffected.

Genotype-Phenotype Correlations No genotype-phenotype correlations are evident.

Differential DiagnosisThe differential diagnosis of X-linked infantile spinal muscular atrophy (XL-SMA) caused by mutations in UBA1 includes classic autosomal recessive SMA caused by mutations in 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 ArthrogryposisView in own windowFeaturesXL-SMA Autosomal Recessive SMA TypeArthrogryposis ^{10IIIIIIIVMultiple contractures++----+Fractures±±----±Hypotonia +++++-±Muscle weakness++++++±Motor regression+±++±--Normal cognition+++++++Absent tendon reflexes++++ (70%)±±±Myopathic facies±±-----Neurogenic atrophy++++++±Denervation by EMG++++++±Anterior horn cell loss++++++±1. Isolated non-progressiveSMA Types by Inheritance PatternClassic Autosomal Recessive Spinal Muscular AtrophySMA, caused by mutation 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 disease-causing mutations 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 mutations 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]. 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. Mutations in IGHMBP2 encoding the immunoglobulin micro-binding protein 2 are causative [Grohmann et al 2003].Autosomal Dominant SMAAutosomal 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 mutation 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 mutations in 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 SMAX-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 mutations in ATP7A in affected males from two families. ATP7A encodes a copper-transporting P-type ATPase. The mutations 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. Mutations in ATP7A have previously been associated with Menkes disease. Those mutations are loss of function mutations, including splice-site mutations, deletions, nonsense and missense mutations within the critical functional domain of ATP7A, or mutations that cause misfolding of the protein [Hsi & Cox 2004].Other Non-SMN Disorders with SMA PhenotypeOther 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 mutations 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]. ArthrogryposisArthrogryposis 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 mutations in 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 mutation 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 mutations are associated with these syndromes is yet to be determined. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).}

Management 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 contracturesNeurologic evaluation to assess muscle tone and help guide supportive management [Iannaccone 2007]Genetics consultationTreatment of Manifestations Management is similar to that for classic, SMN mutation-positive SMA type 0 and SMA type I. See Spinal Muscular Atrophy.Feeding/growthIf 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). RespiratoryProvide 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 ComplicationsStandard precautions against infection are appropriate. Surveillance 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 medical 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 managementEvaluation by a pulmonologist for evidence of progression of restrictive airway diseaseMonitoring of caloric intake and weight, linear growth, head circumference, and growth velocity Monitoring for scoliosis and kyphosisEvaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDUBA1Xp11​.23Ubiquitin-like modifier-activating enzyme 1UBA1 @ LOVDUBA1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Spinal Muscular Atrophy, X-Linked Infantile (View All in OMIM) View in own window 301830SPINAL MUSCULAR ATROPHY, X-LINKED 2; SMAX2 314370UBIQUITIN-LIKE MODIFIER-ACTIVATING ENZYME 1; UBA1Normal allelic variants. 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. Pathologic allelic variants. See Table 3. To date, all pathologic variants detected have been in exon 15. Exon 15 encodes part of a highly conserved protein domain that interacts with gigaxonin. Table 3. UBA1 Pathologic Allelic Variants Discussed in This GeneReview View in own windowDNA Nucleotide Change Protein Amino Acid Change Reference Sequencec.1617G>Tp.Met539IleNM_003334​.3
NP_003325​.2c.1639A>Gp.Ser547Glyc.1731C>Tp.Asn577AsnRamser et al [2008]See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).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 less methylated C nucleotide compared to normal. The complete disease mechanism related to the change in methylation is not yet understood [Ramser et al 2008].