Spinal Muscular Atrophy, X-Linked Infantile

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.

Diagnosis/testing.

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.

Management.

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
• 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
• 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 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.

Penetrance

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

Nomenclature

XL-SMA has also been called:

• X-linked lethal infantile SMA
• Infantile X-linked SMA
• X-linked arthrogryposis multiplex congenita
• Distal X-linked AMC
• X-linked arthrogryposis type I, AMCX1
• 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: 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.

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. 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

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.