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

• 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 atrophy

• 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

Testing

Electromyogram (EMG) should demonstrate findings of denervation.

Testing Strategy

To confirm/establish the diagnosis in a proband

• Molecular genetic testing of SMN1 to rule out autosomal recessive SMA

• Testing for UBA1 mutations

  Note: Such testing is available in research laboratories only. (2) Clinical confirmation of mutations identified in a research laboratory may be available for families in which a disease-causing mutation has been identified in a research laboratory.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations 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) Disorders

No 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 never are 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 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, 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 yet 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.

Penetrance

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

Nomenclature

XL-SMA has also been called:

• X-linked lethal infantile SMA

• X-linked arthrogryposis multiplex congenita

• SMAX2

  Note: SMAX1 is Kennedy disease (spinal and bulbar muscular atrophy), an unrelated X-linked, adult-onset disease.

Prevalence

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].

SMA Types by Inheritance Pattern

Arthrogryposis

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

Arthrogryposis multiplex congenita is etiologically heterogeneous, i.e., has many etiologies. 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, such as distal arthrogryposis, or, if generalized, 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].

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

  • Physical examination to assess respiratory rate, work of breathing, presence of paradoxical breathing, chest wall shape, and skin perfusion

  • Baseline pulmonary studies to determine extent of restrictive airway disease and cough efficiency

  • 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]

Treatment of Manifestations

Management is similar to that for classic, SMN-mutation-positive SMA type 0 and SMA type I.

Feeding/growth

• 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).

Respiratory

• 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 disorders. 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.

Surveillance

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 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

Testing of Relatives at Risk

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

Therapies Under Investigation

Search 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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

• The father of an affected male will not have the disease nor will he be a carrier of the mutation.

• In a family with more than one affected individual, the mother of an affected male is an obligate carrier.

• If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo gene mutation, in which case the mother is not a carrier.

• When an affected male is the only affected individual in the family, the following possibilities regarding his mother's carrier status need to be considered:

  • He has a de novo disease-causing mutation in UBA1 and his mother is not a carrier.

  • His mother has a de novo disease-causing mutation in UBA1, either (a) as a "germline mutation" (i.e., present at the time of her conception and therefore in every cell of her body); or (b) as "germline mosaicism" (i.e., present in some of her germ cells only).

  • His mother has a disease-causing mutation that she inherited from a maternal female ancestor.

Sibs of the proband

• The risk to sibs depends on the carrier status of the mother.

• If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation 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 disease-causing mutation 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 may be available from laboratories offering clinical confirmation of mutations identified in research laboratories if the disease-causing mutation in a specific gene has been identified in the family. See .

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when molecular genetic testing is available on a research basis only. See for a list of laboratories offering DNA banking.

Prenatal Testing

No laboratories offering molecular genetic testing for prenatal diagnosis of XL-SMA caused by a UBA1 mutation are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified. For laboratories offering custom prenatal testing, see .

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see .

Literature Cited

1. 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]
2. 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]
3. Frijns CJM, Van Deutekom JV, Frants R, Jennekens F. Dominant congenital benign spinal muscular atrophy. Muscle Nerve. 1994;17:192–7. [PubMed: 8114789]
4. Gerritsen J, Estrella E., Ahearn ME, Yariz KO, Baumbach L (2003). 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? American Society of Human Genetics, Annual Meeting, Abstract 1743.
5. 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]
6. 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]
7. Hall J, Reed S, Scott C, Rogers J, Jones K, Camarano A. Three distinct types of X-linked arthrogryposis seen in 6 families. Clin Genet. 1982;21:81–97. [PubMed: 7200838]
8. Hennekam R, Barth P, Van Lookeren Campagne W, De Visser M, Dingemans K. A family with severe X-linked arthrogryposis. Eur J Pediatr. 1991;150:656–60. [PubMed: 1915520]
9. Iannaccone ST. Modern management of spinal muscular atrophy. J Child Neurol. 2007;22:974–8. [PubMed: 17761652]
10. Isozumi K, DeLong R, Kaplan J, Deng HX, Iqbal Z, Hung WY, Wilhelmsen KC, Hentati A, Pericak-Vance MA, Siddique T. Linkage of scapuloperoneal spinal muscular atrophy to chromosome 12q24.1-q24.31. Hum Mol Genet. 1996;5:1377–82. [PubMed: 8872481]
11. 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]
12. 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]
13. 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]
14. 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]
15. 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]
16. Rietschel M., Rudnik-Schoneborn S., Zerres K. Clinical variability of autosomal dominant spinal muscular atrophy. J Neurol Sci. 1992;107:65–73. [PubMed: 1578236]
17. 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]
18. Ryan MM, Cooke-Yarborough CM, Procopis PG, Ouvrier RA. Anterior horn cell disease and olivopontocerebellar hypoplasia. Pediatr Neurol. 2000;23:180–4. [PubMed: 11020648]
19. Takata RI, Speck Martins CE, Passosbueno MR, Abe KT, Nishimura AL, Da Silva MD, Monteiro A, 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]
20. 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]

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Reading

1. Dubowitz V. Chaos in classification of the spinal muscular atrophies of childhood. Neuromuscul Disord. 1991;1:77–80. [PubMed: 1845352]

Acknowledgments

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, 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 Paytons 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

• 30 October 2008 (me) Review posted live

• 10 July 2008 (lbr) Original submission