X-linked spinal muscular atrophy type 2

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X-linked spinal muscular atrophy type 2
Other namesSpinal muscular atrophy with arthrogryposis
X-linked recessive.svg
This condition is inherited in an X-linked recessive manner
Specialty Neurology

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 in the anterior horn of spinal cord resulting in generalised muscle wasting (atrophy). The disease is caused by a mutation in UBA1 gene and is passed in an X-linked recessive manner by carrier mothers to affected sons. [1] [2]

Contents

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 (SMA); however, SMAX2 is caused by a different genetic defect and only genetic testing can correctly identify the disease.[ citation needed ]

The disorder is usually fatal in infancy or early childhood due to progressive respiratory failure, although survival into teenage years has been reported. [3] As with many genetic disorders, there is no known cure to SMAX2. Appropriate palliative care may be able to increase quality of life and extend lifespan.[ citation needed ]

Signs and symptoms

XL-SMA is characterized by severe hypotonia and areflexia with loss of anterior horn cells in the spinal cord (i.e., lower motor neurons). [4] 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). [4] In SMA0, prenatal onset of weakness and poor intrauterine movement results in congenital contractures. [4] In SMA1, motor skills regress before age six months; affected children are never able to sit independently. [4]

The weakness of XL-SMA is often prenatal in onset, manifests as polyhydramnios and poor movement in utero that results in congenital contractures. [4] Moreover, the weakness of XL-SMA is progressive.

Below is a list of known symptoms of XL-SMA: [5]

Note: Clinical diagnosis of X-linked spinal muscular atrophy type 2 should be considered for children who exhibit the following: [4]

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. [6] 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.[ citation needed ]

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. [6] Moreover, in a sixth family, neither of the two missense mutations or the synonymous substitution was identified. [6] 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. [1] [6] Thus, SMAX2 is one of several neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway. [6] 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, [7] 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 genetic testing 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: [8]

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: [8]

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.[ citation needed ]

The nutrition and feeding evaluations are focused on determining if: [8]

The respiratory evaluations are used to: [8]

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. [8]

Overall treatment aims at alleviating the symptoms and may include mechanical ventilation, feeding tube, gastrostomy, and orthopedic interventions.[ citation needed ]

Epidemiology

X-linked spinal muscular atrophy type 2 is considered a rare disorder, and its prevalence is unknown. [9] Currently, only 14 multigenerational families with affected family members have been identified throughout North America, Europe, Mexico, and Thailand. [10]

See also

Related Research Articles

Spinal muscular atrophies Wikipedia list article

Spinal muscular atrophies (SMAs) are a genetically and clinically heterogeneous group of rare debilitating disorders characterised by the degeneration of lower motor neurons and subsequent atrophy (wasting) of various muscle groups in the body. While some SMAs lead to early infant death, other diseases of this group permit normal adult life with only mild weakness.

Arthrogryposis Medical condition

Arthrogryposis, describes congenital joint contracture in two or more areas of the body. It derives its name from Greek, literally meaning "curving of joints".

Oculopharyngeal muscular dystrophy Medical condition

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X-linked recessive inheritance Mode of inheritance

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 and in females who are homozygous for the gene mutation, see zygosity. Females with one copy of the mutated gene are carriers.

Spinal and bulbar muscular atrophy Medical condition

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Hereditary inclusion body myopathies (HIBM) are a group of rare genetic disorders which have different symptoms. Generally, they are neuromuscular disorders characterized by muscle weakness developing in young adults. Hereditary inclusion body myopathies comprise both autosomal recessive and autosomal dominant muscle disorders that have a variable expression (phenotype) in individuals, but all share similar structural features in the muscles.

Farber disease Medical condition

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Congenital muscular dystrophy Medical condition

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Emery–Dreifuss muscular dystrophy Medical condition

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Spinal muscular atrophy Rare congenital neuromuscular disorder

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 cause of infant death. It may also appear later in life and then have a milder course of the disease. The common feature is progressive weakness of voluntary muscles, with arm, leg and respiratory muscles being affected first. Associated problems may include poor head control, difficulties swallowing, scoliosis, and joint contractures.

Kaufman oculocerebrofacial syndrome Medical condition

Kaufman oculocerebrofacial syndrome is an autosomal recessive congenital disorder characterized by mental retardation, brachycephaly, upslanting palpebral fissures, eye abnormalities, and highly arched palate. It was characterized in 1971; eight cases had been identified as of 1995.

Ubiquitin-activating enzyme

Ubiquitin-activating enzymes, also known as E1 enzymes, catalyze the first step in the ubiquitination reaction, which can target a protein for degradation via a proteasome. This covalent bond of ubiquitin or ubiquitin-like proteins to targeted proteins is a major mechanism for regulating protein function in eukaryotic organisms. Many processes such as cell division, immune responses and embryonic development are also regulated by post-translational modification by ubiquitin and ubiquitin-like proteins.

Marden–Walker syndrome Medical condition

Marden–Walker syndrome (MWS) is a rare autosomal recessive congenital disorder. It is characterized by blepharophimosis, microcephaly, micrognathia, multiple joint contractures, arachnodactyly, camptodactyly, kyphoscoliosis and delayed motor development and is often associated with cystic dysplastic kidneys, dextrocardia, Dandy–Walker malformation and agenesis of corpus callosum.

Distal spinal muscular atrophy type 1 Medical condition

Distal spinal muscular atrophy type 1 (DSMA1), also known as spinal muscular atrophy with respiratory distress type 1 (SMARD1), is a rare neuromuscular disorder involving death of motor neurons in the spinal cord which leads to a generalised progressive atrophy of body muscles.

Lethal congenital contracture syndrome Medical condition

Lethal congenital contracture syndrome 1 (LCCS1), also called Multiple contracture syndrome, Finnish type, is an autosomal recessive genetic disorder characterized by total immobility of a fetus, detectable at around the 13th week of pregnancy. LCCS1 invariably leads to prenatal death before the 32nd gestational week. LCCS1 is one of 40 Finnish heritage diseases. It was first described in 1985 and since then, approximately 70 cases have been diagnosed.

Spinal muscular atrophy with progressive myoclonic epilepsy Rare neurodegenerative disease whose symptoms include slowly progressive muscle wasting

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), sometimes called Jankovic–Rivera syndrome, is a very rare neurodegenerative disease whose symptoms include slowly progressive muscle wasting (atrophy), predominantly affecting proximal muscles, combined with denervation and myoclonic seizures. Only 12 known families are described in scientific literature to have SMA-PME.

Congenital distal spinal muscular atrophy Hereditary condition characterized by muscle wasting

Congenital distal spinal muscular atrophy is a hereditary condition characterized by muscle wasting (atrophy), particularly of distal muscles in legs and hands, and by early-onset contractures of the hip, knee, and ankle. Affected individuals often have shorter lower limbs relative to the trunk and upper limbs. The condition is a result of a loss of anterior horn cells localized to lumbar and cervical regions of the spinal cord early in infancy, which in turn is caused by a mutation of the TRPV4 gene. The disorder is inherited in an autosomal dominant manner. Arm muscle and function, as well as cardiac and respiratory functions are typically well preserved.

Calpainopathy Medical condition

Calpainopathy is the most common type of autosomal recessive limb-girdle muscular dystrophy (LGMD). It preferentially affects the muscles of the hip girdle and shoulder girdle.

Spinal muscular atrophy with lower extremity predominance 2B Rare genetic disease

Spinal muscular atrophy with lower extremity predominance 2B (SMALED2B) is a rare neuromuscular disorder characterised by generalised muscle weakness.

References

  1. 1 2 Ramser, J.; Ahearn, M. E.; Lenski, C.; Yariz, K. O.; Hellebrand, H.; Von Rhein, M.; Clark, R. D.; Schmutzler, R. K.; Lichtner, P.; Hoffman, E. P.; Meindl, A.; Baumbach-Reardon, L. (2008). "Rare Missense and Synonymous Variants in UBE1 Are Associated with X-Linked Infantile Spinal Muscular Atrophy". The American Journal of Human Genetics. 82 (1): 188–193. doi:10.1016/j.ajhg.2007.09.009. PMC   2253959 . PMID   18179898.
  2. Dressman, D.; Ahearn, M. E.; Yariz, K. O.; Basterrecha, H.; Martínez, F.; Palau, F.; Barmada, M. M.; Clark, R. D.; Meindl, A.; Wirth, B.; Hoffman, E. P.; Baumbach-Reardon, L. (2007). "X-linked infantile spinal muscular atrophy: Clinical definition and molecular mapping". Genetics in Medicine. 9 (1): 52–60. doi: 10.1097/GIM.0b013e31802d8353 . PMID   17224690.
  3. Kobayashi, H.; Baumbach, L.; Matise, T. C.; Schiavi, A.; Greenberg, F.; Hoffman, E. (1995). "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". Human Molecular Genetics. 4 (7): 1213–1216. doi:10.1093/hmg/4.7.1213. PMID   8528211.
  4. 1 2 3 4 5 6 Baumbach-Reardon, Lisa; Sacharow, Stephanie J.; Ahearn, Mary Ellen (1993), Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.), "Spinal Muscular Atrophy, X-Linked Infantile", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID   20301739 , retrieved 2021-05-03
  5. "OMIM Clinical Synopsis - #301830 - SPINAL MUSCULAR ATROPHY, X-LINKED 2; SMAX2". www.omim.org. Retrieved 2021-05-04.
  6. 1 2 3 4 5 "OMIM Entry - * 314370 - Ubiquitin-Like Modifier-Activating Enzyme 1; UBA1". OMIM. Retrieved 2021-05-04.
  7. "OMIM Clinical Synopsis - #301830 - SPINAL MUSCULAR ATROPHY, X-LINKED 2; SMAX2". www.omim.org. Retrieved 2021-05-04.
  8. 1 2 3 4 5 Baumbach-Reardon, Lisa; Sacharow, Stephanie J.; Ahearn, Mary Ellen (1993), Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.), "Spinal Muscular Atrophy, X-Linked Infantile", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID   20301739 , retrieved 2021-05-03
  9. "X-linked infantile spinal muscular atrophy: MedlinePlus Genetics". medlineplus.gov. Retrieved 2021-05-03.
  10. Baumbach-Reardon, Lisa; Sacharow, Stephanie J.; Ahearn, Mary Ellen (1993), Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.), "Spinal Muscular Atrophy, X-Linked Infantile", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID   20301739 , retrieved 2021-05-04

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