X-linked spinal muscular atrophy type 2 (SMAX2, XLSMA), also known as arthrogryposis multiplex congenita X-linked type 1 (AMCX1), is a rare neurological disorder involving death of

motor neurons A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirectly ...

in the

anterior horn of spinal cord The anterior grey column (also called the anterior cornu, anterior horn of spinal cord, motor horn or ventral horn) is the front column of grey matter in the spinal cord. It is one of the three grey columns. The anterior grey column contains motor ...

resulting in generalised muscle wasting (

atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...

). The disease is caused by a

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

in ''

UBA1 Ubiquitin-like modifier activating enzyme 1 (UBA1) is an enzyme which in humans is encoded by the ''UBA1'' gene. UBA1 participates in ubiquitin#ubiquitination, ubiquitination and the NEDD8 pathway for protein folding and Biodegradation, degradati ...

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

and is passed in an

X-linked recessive X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one Y ...

manner by carrier mothers to affected sons. Affected babies have general muscle weakness, weak cry and floppy limbs; consequently, the condition is usually apparent at or even before birth. Symptoms resemble the more severe forms of the more common

spinal muscular atrophy Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic ...

(SMA); however, SMAX2 is caused by a different genetic defect and only

genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

can correctly identify the disease. The disorder is usually fatal in infancy or early childhood due to progressive

respiratory failure Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise ...

, although survival into teenage years has been reported. As with many

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

s, there is no known cure to SMAX2. Appropriate

palliative care Palliative care (derived from the Latin root , or 'to cloak') is an interdisciplinary medical caregiving approach aimed at optimizing quality of life and mitigating suffering among people with serious, complex, and often terminal illnesses. Wit ...

may be able to increase quality of life and extend lifespan.

Signs and symptoms

XL-SMA is characterized by severe

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...

and

areflexia Hyporeflexia is the reduction or absence of normal bodily reflexes (areflexia). It can be detected through the use of a reflex hammer and is the opposite of hyperreflexia. Hyporeflexia is generally associated with a deficit in the lower motor neu ...

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). 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, manifests as polyhydramnios and poor movement in utero that results in congenital contractures. Moreover, the weakness of XL-SMA is progressive. Below is a list of known symptoms of XL-SMA: * Face : ** Myopathic Facies ** Facial weakness * Mouth : ** Tongue fasciculations * Respiratory : ** Insufficiency due to muscle weakness * Chest : ** Chest deformities * Genitourinary : ** External Genitalia (Male) ***

Hypospadias Hypospadias is a common variation in fetal development of the penis in which the urethra does not open from its usual location in the head of the penis. It is the second-most common birth abnormality of the male reproductive system, affecting abou ...

** Internal Genitalia (Male) ***

Cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek () 'hidden' and () 'testicle'. It is the most common birth defect of the male genital tract. About 3% of ...

* Skeletal : **

Arthrogryposis Arthrogryposis (AMC) describes congenital joint contracture in two or more areas of the body. It derives its name from Greek, literally meaning "curving of joints" (', "joint"; ', late Latin form of late Greek ', "hooking"). Children born with one ...

** Multiple joint contractures ** Bone fractures (at birth and postnatal) *** ''Skull-'' **** Dysmorphic Skull *** ''Hands-'' **** Digital contractures Note: Clinical diagnosis of X-linked spinal muscular atrophy type 2 should be considered for children who exhibit the following: * Evidence of degeneration and loss of

anterior horn cells The anterior grey column (also called the anterior cornu, anterior horn of spinal cord, motor horn or ventral horn) is the front column of grey matter in the spinal cord. It is one of the three grey columns. The anterior grey column contains motor ...

in the spinal cord and brain stem * Normal ''

SMN1 Survival of motor neuron 1 (''SMN1''), also known as component of gems 1 or ''GEMIN1'', is a gene that encodes the SMN protein in humans. Gene ''SMN1'' is the telomeric copy of the gene encoding the SMN protein; the centromeric copy is term ...

'' molecular genetic testing to rule out autosomal recessive spinal muscular atrophy * Male gender in a simplex case or X-linked pattern of inheritance in families with more than one affected individual

Genetics

X-linked spinal muscular atrophy type 2 is inherited in an X-linked recessive pattern. The gene associated with this disorder, ''UBA1'', is located on the X chromosome at Xp11.3 and contains 27 exons; moreover, translation begins at the second exon. In males, if the X chromosome contains an altered copy of the gene then the male will have the disorder. In females, a mutation of the gene on both X chromosomes would have to occur in order for the female to have the disorder. Since females are unlikely to have two altered copies of the gene, males are affected by this disorder much more frequently than females. A recent study has resulted the in detection of three rare novel variants in exon 15 of UBA1 that segregated with the disease: two missense mutations present in each of one XLSMA family (314370.0001, 314370.0002), and one synonymous C-to-T substitution (314370.0003) identified in another three unrelated families. Moreover, in a sixth family, neither of the two missense mutations or the synonymous substitution was identified. Ramser et al. (2008) demonstrated that the synonymous C-to-T substitution leads to significant reduction of UBA1 expression and alters the methylation pattern of exon 15, implying a plausible role of this DNA element in developmental UBA1 expression in humans. Thus, SMAX2 is one of several neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway. The severity of SMAX2 does not waiver regardless of the type of causative mutation.

Diagnosis

Components that may lead to a diagnosis include the presence of clinical symptoms, evidence of degeneration, and analysis of family history. One notable sign of SMAX2 is the loss of anterior horn cells in the spinal cord and brain stem. SMAX2 is typically confirmed through

that shows a mutation in the ubiquitin-like modifier-activating enzyme 1 gene (''UBA1)''. The UBA1 gene is important to diagnosis as it is the only gene known to correspond with degeneration of XL-SMA. In infancy it is important to look for the following when considering a X-linked spinal muscular atrophy diagnosis: * Congenital hypotonia and areflexia on physical examination * Congenital contractures/fractures * Digital contractures at birth that 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 A child with these symptoms are likely to have X-linked spinal muscular atrophy. In order to confirm this the most practical measures to take next are: * to perform a normal SMN1 molecular genetic testing to rule out autosomal recessive spinal muscular atrophy * perform an analysis to see if it is male gender in a simplex case (i.e., a single occurrence in a family) or find the presence of X-linked pattern of inheritance in families with more than one affected individual

Management

Following a diagnosis of the X-linked infantile spinal muscular atrophy it is recommended for the patient to go through further evaluations to alleviate symptoms as there is currently no known cure to SMAX2. The types of evaluations that are recommended are categorized in nutrition/feeding and respiratory function. The nutrition and feeding evaluations are focused on determining if: * caloric intake is adequate * dysphagia or fatigue while feeding occurs * problems related to swallowing persist * gastronomy tube placement and fundoplication are necessary The respiratory evaluations are used to: * assess respiratory rate, work required to breath, signs of paradoxical breathing, the shape of the chest wall, and skin perfusion * perform baseline pulmonary studies to establish the extent of restive airway disease and cough efficiency * perform sleep evaluations to assess for sleep-disordered breathing Other evaluations include assessing the existing contractures, neurologic evaluation to assess muscle tone and help provide supportive management, and highly recommended consultations with a genetic counselor. Overall treatment aims at alleviating the symptoms and may include

mechanical ventilation Mechanical ventilation, assisted ventilation or intermittent mandatory ventilation (IMV), is the medical term for using a machine called a ventilator to fully or partially provide artificial ventilation. Mechanical ventilation helps move air ...

feeding tube Eating (also known as consuming) is the ingestion of food, typically to provide a heterotrophic organism with energy and to allow for growth. Animals and other heterotrophs must eat in order to survive — carnivores eat other animals, her ...

gastrostomy Gastrostomy is the creation of an artificial external opening into the stomach for nutritional support or gastric decompression. Typically this would include an incision in the patient's epigastrium as part of a formal operation. It can be perfor ...

, and orthopedic interventions.

Epidemiology

X-linked spinal muscular atrophy type 2 is considered a rare disorder, and its prevalence is unknown. Currently, only 14 multigenerational families with affected family members have been identified throughout North America, Europe, Mexico, and Thailand.

References

External links

{{Disorders of translation and posttranslational modification Systemic atrophies primarily affecting the central nervous system X-linked recessive disorders Motor neuron diseases Neuromuscular disorders