Motoneuronerkrankungen

Familiäre ALS, SMA, HMN

Motor neuron diseases

Familial ALS, SMA and HMN

Zusammenfassung

Motoneuronenerkrankungen (MNE) sind eine Gruppe neurodegenerativer Erkrankungen, die eine klinische, prognostische und genetische Diversität aufweisen. Die häufigsten MNE sind die amyotrophe Lateralsklerose (ALS), die proximale spinale Muskelatrophie (SMA) und hereditäre und sporadische Vorderhornerkrankungen einschließlich der hereditären motorischen Neuropathien (HMN). Für die ALS und für proximale und distale spinale Muskelatrophien sind familiäre und „sporadische“ Verlaufsformen bekannt. Die wesentlichen pathogenetischen Erkenntnisse der MNE sind durch molekularbiologische Untersuchungen der hereditären MNE-Formen entstanden. Ein übereinstimmendes neuropathologisches Merkmal bei der ALS sind intraneuronale Proteininklusionen, die durch Aggregationen von TDP-43, FUS, SOD1 oder Ataxin-2 entstehen. TDP-43, FUS und Ataxin-2 sind multifunktionale DNA/RNA-Bindungsproteine, die an der Transkriptionsregulation beteiligt sind. Die SMA und HMN sind mit verschiedenen Genen assoziiert, deren Genprodukte ebenfalls an der RNA-Prozessierung beteiligt sein können. Möglicherweise ist eine Störung der RNA-Regulation ein überlappendes pathophysiologisches Merkmal bei den MNE. Die Aufklärung übereinstimmender Abschnitte der neuronalen Schädigungskaskade ist ein wesentlicher Ansatz zur Entwicklung einer molekulargenetisch definierten Therapiestrategie sowohl bei der ALS als auch bei hereditären und sporadischen Vorderhornerkrankungen.

Summary

Motor neuron diseases (MND) are a group of neurodegenerative disorders which are present in clinical, prognostic and genetic diversity. The most common MND are amyotrophic lateral sclerosis (ALS), proximal spinal muscular atrophy (SMA) and various forms of hereditary and sporadic lower motor neuron syndromes including hereditary motor neuropathies (HMN). Familial and „sporadic“ forms of ALS and lower motor neuron syndromes are known. The essential pathogenic findings in MND have emerged from molecular biological examinations of the hereditary forms of MND. In ALS, one consistent neuropathological feature is intraneuronal protein inclusions which arise from TDP-43, FUS, SOD1 or ataxin-2 aggregations. TDP-43, FUS, SOD1 and ataxin-2 are multifunctional DNA/RNA-binding proteins which are involved in transcription regulation. SMA and HMN are associated with different genes whose gene products may also be involved in RNA processing. A disturbance in the regulation of RNA possibly represents an overlapping pathophysiological characteristic in MND. The elucidation of common pathways in the cascade of motor neuron degeneration is an essential point of departure for molecular genetically defined treatment strategies both in ALS and in hereditary and sporadic lower motor neuron syndromes.

This is a preview of subscription content, access via your institution.

Abb. 1
Abb. 2
Abb. 3
Abb. 4

Literatur

  1. 1.

    Arai T, Hasegawa M, Nonoka T et al (2010) Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy. Neuropathology 30:170–181

    PubMed  Article  Google Scholar 

  2. 2.

    Byrne S, Walsh C, Lynch C et al (2010) Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry [Epub ahead of print]

  3. 3.

    Chattopadhyay M, Valentine JS (2009) Aggregation of copper-zinc superoxide dismutase in familial and sporadic ALS. Antioxid Redox Signal 11:1603–1614

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Carvalho M de, Swash M (2007) Monomelic neurogenic syndromes: a prospective study. J Neurol Sci 263:26–34

    PubMed  Article  Google Scholar 

  5. 5.

    Deng HX, Zhai H, Bigio EH et al (2010) FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis. Ann Neurol 67:739–748

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Dierick I, Baets J, Irobi J et al (2008) Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study. Brain 131:1217–1227

    PubMed  Article  Google Scholar 

  7. 7.

    Dipti S, Childs AM, Livingston JH et al (2005) Brown-Vialetto-Van Laere syndrome; variability in age at onset and disease progression highlighting the phenotypic overlap with Fazio-Londe disease. Brain Dev 27:443–446

    PubMed  Article  Google Scholar 

  8. 8.

    Elden AC, Kim HJ, Hart MP et al (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466:1069–1075

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Feldkotter M, Schwarzer V, Wirth R et al (2002) Quantitative analyses of SMN1 and SMN2 based on real-time lightcycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet 70:358–368

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Forman MS, Trojanowski JQ, Lee VM (2007) TDP-43: a novel neurodegenerative proteinopathy. Curr Opin Neurobiol 17:548–555

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Frijns CJ, Van Deutekom J, Frants RR et al (1994) Dominant congenital benign spinal muscular atrophy. Muscle Nerve 17:192–197

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Gdynia HJ, Sperfeld AD, Flaith L et al (2007) Classification of phenotype characteristics in adult-onset spinal muscular atrophy. Eur Neurol 58:170–176

    PubMed  Article  Google Scholar 

  13. 13.

    Harding AE, Thomas PK (1980) The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 103:259–280

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Harding AE, Thomas PK (1980) Hereditary distal spinal muscular atrophy. A report on 34 cases and a review of the literature. J Neurol Sci 45:337–348

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Hirayama K (1993) Juvenile muscular atrophy of the distal upper limb – three decades of description and it’s treatment. Rinsho Shinkeigaku 33:1235–1243

    PubMed  CAS  Google Scholar 

  16. 16.

    Kabashi E, Valdmanis PN, Dion P et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Kassubek J, Juengling FD, Sperfeld AD (2007) Widespread white matter changes in Kennedy disease: a voxel based morphometry study. J Neurol Neurosurg Psychiatry 78:1209–1212

    PubMed  Article  Google Scholar 

  18. 18.

    Katsuno M, Banno H, Suzuki K et al (2010) Clinical features and molecular mechanisms of spinal and bulbar muscular atrophy (SBMA). Adv Exp Med Biol 685:64–74

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Katsuno M, Banno H, Suzuki K et al (2010) Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 9:875–884

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Kausch K, Muller CR, Grimm T et al (1991) No evidence for linkage of autosomal dominant proximal spinal muscular atrophies to chromosome 5q markers. Hum Genet 86:317–318

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Kennedy WR, Alter M, Sung JH (1968) Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology 18:671–680

    PubMed  CAS  Google Scholar 

  22. 22.

    Kurland L, Moulder D (1955) Epidemiologic investigations of amyotrophic lateral sclerosis. Familial aggregation indicative of dominant inheritance. Neurology 5:182–196

    PubMed  CAS  Google Scholar 

  23. 23.

    Kwiatkowski TJ Jr, Bosco DA, Leclerc AL et al (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    La Spada AR, Wilson EM, Lubahn DB et al (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352:77–79

    Article  Google Scholar 

  25. 25.

    Lagier-Tourenne C, Cleveland DW (2010) Neurodegeneration: An expansion in ALS genetics. Nature 466:1052–1053

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Lagier-Tourenne C, Polymenidou M, Cleveland DW (n d) TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum Mol Genet 19:R46–R64

  27. 27.

    Lai SL, Abramzon Y, Schymick JC et al (2010) FUS mutations in sporadic amyotrophic lateral sclerosis. Neurobiol Aging [Epub ahead of print]

  28. 28.

    Lorson CL, Androphy EJ (2000) An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. Hum Mol Genet 9:259–265

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Mackenzie IR, Bigio EH, Ince PG et al (2007) Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 61:427–434

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Mackenzie IR, Feldman HH (2005) Ubiquitin immunohistochemistry suggests classic motor neuron disease, motor neuron disease with dementia, and frontotemporal dementia of the motor neuron disease type represent a clinicopathologic spectrum. J Neuropathol Exp Neurol 64:730–739

    PubMed  Article  Google Scholar 

  31. 31.

    Mariotti C, Castellotti B, Pareyson D et al (2000) Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families. Neuromuscul Disord 10:391–397

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Maruyama H, Morino H, Ito H et al (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465:223–226

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Pasinelli P, Brown RH (2006) Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci 7:710–723

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Ralser M, Albrecht M, Nonhoff U et al (2005) An integrative approach to gain insights into the cellular function of human ataxin-2. J Mol Biol 346:203–214

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Rosen DR (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 364:362

    PubMed  CAS  Google Scholar 

  37. 37.

    Rudnik-Schoneborn S, Forkert R, Hahnen E et al (1996) Clinical spectrum and diagnostic criteria of infantile spinal muscular atrophy: further delineation on the basis of SMN gene deletion findings. Neuropediatrics 27:8–15

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Rudnik-Schoneborn S, Sztriha L, Aithala GR et al (2003) Extended phenotype of pontocerebellar hypoplasia with infantile spinal muscular atrophy. Am J Med Genet A 117A:10–17

    PubMed  Article  Google Scholar 

  39. 39.

    Russman BS (2007) Spinal muscular atrophy: clinical classification and disease heterogeneity. J Child Neurol 22:946–951

    PubMed  Article  Google Scholar 

  40. 40.

    Schroder R, Keller E, Flacke S et al (1999) MRI findings in Hirayama’s disease: flexion-induced cervical myelopathy or intrinsic motor neuron disease? J Neurol 246:1069–1074

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Soukup GR, Sperfeld AD, Uttner I et al (2009) Frontotemporal cognitive function in X-linked spinal and bulbar muscular atrophy (SBMA): a controlled neuropsychological study of 20 patients. J Neurol 256:1869–1875

    PubMed  Article  Google Scholar 

  42. 42.

    Sperfeld AD, Hanemann CO, Ludolph AC et al (2005) Laryngospasm: an underdiagnosed symptom of X-linked spinobulbar muscular atrophy. Neurology 64:753–754

    PubMed  Google Scholar 

  43. 43.

    Sperfeld AD, Karitzky J, Brummer D et al (2002) X-linked bulbospinal neuronopathy: Kennedy disease. Arch Neurol 59:1921–1926

    PubMed  Article  Google Scholar 

  44. 44.

    Sreedharan J, Blair IP, Tripathi VB et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Takata RI, Speck Martins CE, Passosbueno MR et al (2004) A new locus for recessive distal spinal muscular atrophy at Xq13.1-q21. J Med Genet 41:224–229

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Traynor BJ, Codd MB, Corr B et al (2000) Amyotrophic lateral sclerosis mimic syndromes: a population-based study. Arch Neurol 57:109–113

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Unrath A, Muller HP, Riecker A et al (2010) Whole brain-based analysis of regional white matter tract alterations in rare motor neuron diseases by diffusion tensor imaging. Hum Brain Mapp 31:1727–1740

    PubMed  Google Scholar 

  48. 48.

    Valdmanis PN, Rouleau GA (2008) Genetics of familial amyotrophic lateral sclerosis. Neurology 70:144–152

    PubMed  Article  Google Scholar 

  49. 49.

    Van Berg-Vos RM den, Visser J, Kalmijn S et al (2009) A long-term prospective study of the natural course of sporadic adult-onset lower motor neuron syndromes. Arch Neurol 66:751–757

    Article  Google Scholar 

  50. 50.

    Vance C, Rogelj B, Hortobagyi T et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211

    PubMed  Article  CAS  Google Scholar 

  51. 51.

    Wirth B (2000) An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 15:228–237

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Zerres K, Rudnik-Schoneborn S (1995) Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol 52:518–523

    PubMed  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Prof. Dr. S. Petri.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Petri, S., Meyer, T. Motoneuronerkrankungen. Nervenarzt 82, 697–706 (2011). https://doi.org/10.1007/s00115-010-2967-y

Download citation

Schlüsselwörter

  • Motoneuronerkrankungen
  • Amotrophe Lateralsklerose
  • Spinale Muskelatrophie
  • Hereditäre motorische Neuropathien
  • Pathogenetik

Keywords

  • Motor neuron diseases
  • Amyotrophic lateral sclerosis
  • Spinal muscular atrophy
  • Hereditary motor neuropathies
  • Pathogenetics