Kennedy type spinobulbar muscular atrophy

from Wikipedia, the free encyclopedia
Classification according to ICD-10
G12.2 Motor neuron disease
ICD-10 online (WHO version 2019)

The spinal and bulbar muscular atrophy ( SBMA ), and Kennedy disease called, is a rare X-linked - recessive inherited disease from the group of trinucleotide repeat disorder . It is a special hereditary form of spinal muscular atrophy . Kennedy Disease is to be distinguished from Foster Kennedy Syndrome , which is often just called Kennedy Syndrome , which is a completely different disease.

description

SBMA is a slowly progressing ( progressive ) neuromuscular disease. The degeneration of the lower motor neurons leads to muscle hypotonia (muscle weakness), muscle atrophy (muscle wasting) and fasciculations (involuntary movements, "twitches", very small muscle groups). Muscle weakness and muscle atrophy mainly affect the leg muscles near the hips, the shoulder girdle and the facial, tongue and throat muscles, whereby the symptoms can begin in one of these areas and progress over years to decades. The fasciculations typically occur on the extremities and mimic muscles. The impairment of the tongue and throat muscles can lead to speech disorders ( dysarthria ) and swallowing disorders. The ability to walk is retained for a long time.

Due to the x-linked inheritance , only men are affected by the disease. Many patients also have gynecomastia (enlargement of the mammary gland) and testicular atrophy (shrunken testicles). Fertility is significantly reduced due to the androgen insensitivity. Gynecomastia or the inability to conceive may well be the first symptom.

In contrast, women who carry the genetic defect heterozygous do not become ill . There is a 50% chance that they will pass the disease on to their male offspring. In contrast, the sons of the sick fathers are always healthy because they carry the maternal X chromosome. In the statistically very rare case of homozygosity of the defective AR gene in women - i.e. both parents carried the defect in the AR gene - the symptoms in the affected patients are significantly weaker than in hemizygous male SBMA patients.

As a rule, the SBMA manifests itself between the ages of 20 and 40. In contrast to related amyotrophic lateral sclerosis (ALS) and most other forms of spinal muscular atrophy, the life expectancy of patients is normal. A differential diagnosis from other forms of motor neuron disease is therefore important.

Prevalence and diagnosis

In Europe, a prevalence of 1 in 36,000 is assumed. However, it can be significantly higher locally. In the Finnish region around Vaasa , for example, a prevalence of 1 in 6,500 was found. Based on the analysis of the genetic data, it is assumed that the SBMA first appeared in western Finland about 20 generations ago. Analysis of the haplotype suggests a common ancestor for most Scandinavian SBMA patients.

Even before muscular degeneration can be detected, the SBMA manifests itself - due to the peripheral androgen resistance - as gynecomastia. The SBMA can be reliably detected by molecular diagnostics via the number of CAG repeats in the androgen receptor gene on the X chromosome - even prenatally .

Etiology and Genetics

Spinobulbar muscular atrophy is caused by a trinucleotide expansion in the AR gene that codes for the androgen receptor . Affected is exon 1. While healthy people have between 10 and 36 repeating CAG units ( cytosine , adenine and guanine ), which encode the amino acid glutamine, in their genome, SBMA patients have 38 to 62 of these units Form polyglutamine . The affected gene is located on the X chromosome gene locus q11-q12. So far, no clear connection between the severity of the disease and the number of repeating CAG units has been established. In contrast, a slight correlation was found between the chain length of the polyglutamic acid and the age at the onset of the disease (longer chain leads to earlier disease).

therapy

There is currently no effective treatment for spinobulbar muscular atrophy. Various therapeutic approaches with the administration of androgens are currently being investigated. In animal models show different substances, such as a histone deacetylase inhibitor (HDAC1), leuprolide and curcumin - derivative , a potential efficacy. Until the approval of an on effectiveness tested drug it but experience shows that lasts for many years.

Initial description

Kennedy's disease is named after the American neurologist William R. Kennedy , who first described the SBMA in 1968 together with two colleagues. Before Kennedy, four Japanese authors may have described the SBMA. In 1991, the molecular genetic cause of the disease was determined by an increased number of CAG units in exon 1 of the affected AR gene.

Individual evidence

  1. ^ AE Harding et al: X-linked recessive bulbospinal neuronopathy: a report of ten cases. In: J. Neurol. Neurosurg. Psychiatry. 45, 1982, pp. 1012-1019. PMID 6890989 .
  2. ^ BJ Schmidt et al .: Expression of X-linked bulbospinal muscular atrophy (Kennedy disease) in two homozygous women. In: Neurology 59, 2002, pp. 770-772. PMID 12221177 .
  3. ↑ G. Kuhlenbäumer et al.: The X-linked recessive spinobulbar muscle atrophy (Kennedy type) Description of a family, clinic, molecular genetics, differential diagnosis and therapy. In: Der Nervenarzt 69, 1998, pp. 660-665. doi : 10.1007 / s001150050325 .
  4. ↑ Kennedy type spinobulbar muscular atrophy. In: Orphanet (Rare Disease Database). , accessed December 19, 2008.
  5. ↑ a b B. Udd et al .: High prevalence of Kennedy's disease in western Finland: is the syndrome underdiagnosed? In: Acta Neurol. Scand. 98, 1998, pp. 128-133. PMID 9724012 .
  6. ↑ a b A. Lund et al .: Founder effect in spinal and bulbar muscular atrophy (SBMA) in Scandinavia. In: Europ. J. Hum. Genet. 8, 2000, pp. 631-636. PMID 10951525 .
  7. ↑ I. Georgiou include: Preimplantation genetic diagnosis for spinal and bulbar muscular atrophy (SBMA). In: Hum. Genet. 108, 2001, pp. 494-498. PMID 11499674 .
  8. ↑ M. Minamiyama et al .: Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. In: Hum. Molec. Genet. 13, 2004, pp. 1183-1192. PMID 15102712 .
  9. ↑ M. Katsuno et al .: Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy. In: Nature Med 9, 2003, pp. 768-773. PMID 12754502 .
  10. ↑ Z. Yang et al .: ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor. In: Nature Med 13, 2007, pp. 348-353. PMID 17334372 .
  11. ^ WR Kennedy et al .: Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. In: Neurology 18, 1968, S, 671-680. PMID 4233749 .
  12. ↑ K. Takikawa: A pedigree of progressive bulbar paralysis appearing in sex-linked recessive inheritance. In: Jpn. J. Hum. Genet. 28, 1953, p. 116.
  13. ^ U. Murakami: Clinico-genetic study of hereditary disorders of the nervous system, especially on problems of pathogenesis. In: Folia Psychiat. Neurol. Jpn. 1, 1957, pp. 1-209.
  14. ^ LT Kurland: Epidemiologic investigations of amyotrophic lateral sclerosis. III. A genetic interpretation of incidence and geographic distribution. In: Mayo Clin. Proc. 32, 1957, pp. 449-462.
  15. ↑ H. Tsukagoshi et al: Hereditary, proximal, neurogenic muscular atrophy in adult. In: Arch. Neurol. 12, 1965, pp. 597-603. PMID 14295959 .
  16. ↑ Spinal and bulbar muscular atrophy, x-linked 1; SMAX1.  In: Online Mendelian Inheritance in Man . (English), accessed December 19, 2008.
  17. ↑ AR La Spada et al .: Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. In: Nature 352, 1991, pp. 77-79. PMID 2062380 .

literature

Web links