Autosomal dominant leukodystrophy with autonomic disease

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Autosomal dominant leukodystrophy with autonomic disease
Other namesAutosomal dominant adult-onset demyelinating leukodystrophy, ADLD, Adult-onset autosomal dominant demyelinating leukodystrophy, Adult-onset autosomal dominant leukodystrophy, Leukodystrophy, demyelinating, adult-onset, autosomal dominant, Pelizaeus-Merzbacher disease, autosomal dominant or late-onset type, Multiple sclerosis-like disorder[1]
SpecialtyMedical genetics
SymptomsCognitive deficits, ataxia, and dysfunctions of the autonomic system
ComplicationsWalking difficulties
Usual onsetAdulthood
DurationLifelong
CausesGenetic mutation
Diagnostic methodGenetic testing
Differential diagnosisMultiple sclerosis
Preventionnone
PrognosisBad, but quality of life can be improved with treatment
Frequencyrare, at least 70 people on Earth have been diagnosed with the condition
DeathsInevitable in patients with this condition

Autosomal dominant leukodystrophy with autonomic disease is a rare neurological condition of genetic origin which is characterized by gradual demyelination of the central nervous system which results in various impairments, including ataxia, mild cognitive disability and autonomic dysfunction.[2][3][4] It is part of a group of disorders called "leukodystrophies".[5][6]

Signs and symptoms[edit]

Unlike other leukodystrophy syndromes, whose typical age of onset is during childhood, individuals with this condition typically start showing symptoms between their early 40s and late 50s, once they appear, they slowly progress in severity and new symptoms start appearing.[7]

These symptoms first start out with dysfunctions of the autonomic nervous system which result in symptoms such as abnormal functioning of both the bladder and bowel, recurrent blood pressure drops whenever patients stand up, and male erectile dysfunction.[8][9][10]

Rarely, anhidrosis might also occur alongside these symptoms.[9][8][11][10]

After these symptoms start, movement impairments develop; they start off at the legs but then progress and move to the arms and the face, these impairments include either muscular spasticity or weakness, intention tremors, ataxia, dysmetria, and dysdiadochokinesis.[9][8][11][10]

In some individuals, progressive dementia is present.[8][9][11]

Complications[edit]

There are various complications associated with the symptoms that ADLD causes.

Due to the ataxia and it's associated coordination impairments, people might have difficulties with movements such as walking by themselves.[12]

Treatment[edit]

Treatment is focused on the symptoms themselves

The ataxic movement impairments can be treated with walking support systems such as canes or wheelchairs, physical therapy, and speech therapy.[13]

Diagnosis[edit]

This condition is diagnosed mainly through MRIs[14][15] and genetic testing of the LMNB gene and the areas surrounding it,[16] although symptom examination is also important for the diagnosis.[17]

Causes[edit]

This condition is caused by a duplication of the LMNB1 gene, this gene takes part in the production of the lamin B1 protein, which is essential for determining the nucleus' shape within the cells, the replication of DNA, and the way certain genes express themselves.[18][19][20][21][22][23][24]

When the gene is duplicated (as seen in patients with ADLD), there is an excess of lamin B1 protein, this leads to the underexpression of genes that are important for the production of myelin and an increased hardening of the nuclear envelope, which results in a progressive reduction of myelin production and maintenance as one ages.[18]

Like the name of the condition implies, this condition is inherited following an autosomal dominant pattern, which means that only one copy of a certain mutation (in this case, the duplication of the LMNB1 gene) is needed for a trait or disorder to be expressed, in familial cases, offspring have a 1 in 2, or 50% chance of inheriting a copy of said mutation from one of their affected parents.[18]

Although very rarely, this disorder can be caused by deletions near the LMNB1 gene, only one such family has been described in medical literature: they had a deletion upstream the same gene.[25]

Pathophysiology[edit]

In patients with the condition, demyelination (that is, a loss of myelin) starts occurring in both the brain and the spinal cord years before symptoms show up, this abnormality has been identified to be a contributing factor to the development of the first symptoms individuals with this condition show during the early stages of it.[8]

Phenotype-genotype[edit]

In a 2018 study done by Naomi Mezaki and 18 other colleagues, it was found that ADLD patients with a deletion near the LMNB1 gene (2 patients from a single family) started showing symptoms at an earlier age, had less autonomic dysfunctions and had more noticeable cognitive deficits than other ADLD patients with duplication of the LMNB1 gene (4 patients from 3 families).[26]

Prognosis[edit]

This condition is progressive and fatal.[27]

While the quality of life might be improved with treatment, the life expectancy can't be improved easily: individuals diagnosed with ADLD typically live for another 10 to 20 years after their diagnosis before their death.[28][29]

Prevalence[edit]

At least 70 cases from 35 families around the world have been described in medical literature,[30] most of these were from families of Caucasian descent.[31]

History[edit]

This condition was first discovered in 1964 by E Zerbin-Rüdin et al. when they described (what they thought to be) a familial autosomal dominant variant of Pelizaeus-Merzbacher disease with onset in adulthood.[32]

In 2006, Padiath et al. found the LMNB1 duplication involved in ADLD in 4 families, of which 1 was previously described in medical literature. Haplotype studies revealed that the family mentioned beforehand and another Irish-American family shared a common ancestor. The lamin B1 protein was found to be overly expressed in brain tissues of family members affected with ADLD.[33]

See also[edit]

References[edit]

  1. ^ "Autosomal dominant leukodystrophy with autonomic disease". 16 June 2022.
  2. ^ Finnsson, J.; Melberg, A.; Raininko, R. (2013-08-01). "1H-MR spectroscopy of adult-onset autosomal dominant leukodystrophy with autonomic symptoms". Neuroradiology. 55 (8): 933–939. doi:10.1007/s00234-013-1174-5. ISSN 1432-1920. PMID 23636437. S2CID 915515.
  3. ^ "ADLD". Global Genes. Retrieved 2022-08-16.
  4. ^ "Pruebas genéticas - Leucodistrofia autosómica dominante con enfermedad autónoma (Autosomal dominant leukodystrophy with autonomic disease) - Gen LMNB1. - IVAMI". www.ivami.com. Retrieved 2022-08-16.
  5. ^ "Leukodystrophy - Overview". www.brainandlife.org. Retrieved 2022-08-16.
  6. ^ Resende, Lucas Lopes; de Paiva, Anderson Rodrigues Brandão; Kok, Fernando; da Costa Leite, Claudia; Lucato, Leandro Tavares (2019-01-01). "Adult Leukodystrophies: A Step-by-Step Diagnostic Approach". RadioGraphics. 39 (1): 153–168. doi:10.1148/rg.2019180081. ISSN 0271-5333. PMID 30620693. S2CID 58586821.
  7. ^ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Adult onset autosomal dominant leukodystrophy". www.orpha.net. Retrieved 2022-08-16.{{cite web}}: CS1 maint: numeric names: authors list (link)
  8. ^ a b c d e "Autosomal dominant leukodystrophy with autonomic disease: MedlinePlus Genetics". medlineplus.gov. Retrieved 2022-08-16.
  9. ^ a b c d "Autosomal dominant leukodystrophy with autonomic disease - About the Disease - Genetic and Rare Diseases Information Center". rarediseases.info.nih.gov. Retrieved 2022-08-16.
  10. ^ a b c R, M, QS, Raininko, Gosky, Padiath (2021-07-15). "LMNB1-Related Autosomal Dominant Leukodystrophy". europepmc.org. Retrieved 2022-08-16.{{cite web}}: CS1 maint: multiple names: authors list (link)
  11. ^ a b c "Adult onset autosomal dominant leukodystrophy (ADLD)". Alex - The Leukodystrophy Charity. Retrieved 2022-08-16.
  12. ^ "Ataxia - Symptoms and causes". Mayo Clinic. Retrieved 2022-08-16.
  13. ^ "Ataxia - Treatment". nhs.uk. 2017-10-20. Retrieved 2022-08-16.
  14. ^ Melberg, A.; Hallberg, L.; Kalimo, H.; Raininko, R. (2006-04-01). "MR Characteristics and Neuropathology in Adult-Onset Autosomal Dominant Leukodystrophy with Autonomic Symptoms". American Journal of Neuroradiology. 27 (4): 904–911. ISSN 0195-6108. PMC 8133955. PMID 16611789.
  15. ^ Finnsson, Johannes; Sundblom, Jimmy; Dahl, Niklas; Melberg, Atle; Raininko, Raili (2015-09-01). "L MNB 1-related autosomal-dominant leukodystrophy: Clinical and radiological course". Annals of Neurology. 78 (3): 412–425. doi:10.1002/ana.24452. ISSN 0364-5134. PMC 5054845. PMID 26053668.
  16. ^ Schuster, Jens; Sundblom, Jimmy; Thuresson, Ann-Charlotte; Hassin-Baer, Sharon; Klopstock, Thomas; Dichgans, Martin; Cohen, Oren S.; Raininko, Raili; Melberg, Atle; Dahl, Niklas (2011-02-01). "Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms". Neurogenetics. 12 (1): 65–72. doi:10.1007/s10048-010-0269-y. ISSN 1364-6753. PMID 21225301. S2CID 31170330.
  17. ^ Terlizzi, Rossana; Calandra-Buonaura, Giovanna; Zanigni, Stefano; Barletta, Giorgio; Capellari, Sabina; Guaraldi, Pietro; Donadio, Vincenzo; Cason, Ernesto; Contin, Manuela; Poda, Roberto; Tonon, Caterina; Sambati, Luisa; Gallassi, Roberto; Liguori, Rocco; Lodi, Raffaele (2016-02-01). "A longitudinal study of a family with adult-onset autosomal dominant leukodystrophy: Clinical, autonomic and neuropsychological findings". Autonomic Neuroscience. 195: 20–26. doi:10.1016/j.autneu.2016.02.005. ISSN 1566-0702. PMID 26896090. S2CID 5864535.
  18. ^ a b c "LMNB1 gene: MedlinePlus Genetics". medlineplus.gov. Retrieved 2022-08-16.
  19. ^ "Adult Onset Autosomal Dominant (ADLD) - Causes, Treatment & Symptoms". Hunter's Hope. Retrieved 2022-08-16.
  20. ^ Lynch, David S.; Wade, Charles; Paiva, Anderson Rodrigues Brandão de; John, Nevin; Kinsella, Justin A.; Merwick, Áine; Ahmed, Rebekah M.; Warren, Jason D.; Mummery, Catherine J.; Schott, Jonathan M.; Fox, Nick C.; Houlden, Henry; Adams, Matthew E.; Davagnanam, Indran; Murphy, Elaine (2019-05-01). "Practical approach to the diagnosis of adult-onset leukodystrophies: an updated guide in the genomic era". Journal of Neurology, Neurosurgery & Psychiatry. 90 (5): 543–554. doi:10.1136/jnnp-2018-319481. ISSN 0022-3050. PMC 6581077. PMID 30467211.
  21. ^ Sabetrasekh, Vanderver, Parisa, Adeline (2018-06-01). "Autosomal Dominant Leukodystrophy with Autonomic Disease Synonyms: ADLD, Adult-Onset Autosomal Dominant Leukodystrophy with Autonomic Symptoms, Autosomal Dominant Adult-Onset Demyelinating Leukodystrophy, LMNB1-Related Adult-Onset Autosomal Dominant Leukodystrophy. Bookshelf ID: NBK338165, PMID 26749591". ResearchGate.{{cite web}}: CS1 maint: multiple names: authors list (link)
  22. ^ "ADLD". encyclopedia.pub. Retrieved 2022-08-16.
  23. ^ "leukodystrophy, demyelinating, adult-onset, autosomal dominant".
  24. ^ "Autosomal Dominant Leukodystrophy, Adult Onset". www.nemours.org. Retrieved 2022-08-16.
  25. ^ Giorgio, Elisa; Robyr, Daniel; Spielmann, Malte; Ferrero, Enza; Di Gregorio, Eleonora; Imperiale, Daniele; Vaula, Giovanna; Stamoulis, Georgios; Santoni, Federico; Atzori, Cristiana; Gasparini, Laura; Ferrera, Denise; Canale, Claudio; Guipponi, Michel; Pennacchio, Len A. (2015-06-01). "A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)". Human Molecular Genetics. 24 (11): 3143–3154. doi:10.1093/hmg/ddv065. ISSN 1460-2083. PMC 4424952. PMID 25701871.
  26. ^ Mezaki, Naomi; Miura, Takeshi; Ogaki, Kotaro; Eriguchi, Makoto; Mizuno, Yuri; Komatsu, Kenichi; Yamazaki, Hiroki; Suetsugi, Natsuki; Kawajiri, Sumihiro; Yamasaki, Ryo; Ishiguro, Takanobu; Konno, Takuya; Nozaki, Hiroaki; Kasuga, Kensaku; Okuma, Yasuyuki (2018-12-01). "Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy". Neurology Genetics. 4 (6): e292. doi:10.1212/NXG.0000000000000292. ISSN 2376-7839. PMC 6340331. PMID 30697589.
  27. ^ Padiath, Quasar S. (2019). "Autosomal Dominant Leukodystrophy: A Disease of the Nuclear Lamina". Frontiers in Cell and Developmental Biology. 7: 41. doi:10.3389/fcell.2019.00041. ISSN 2296-634X. PMC 6435485. PMID 30949481.
  28. ^ Association, United Brain. "Autosomal Dominant Leukodystrophy (ADLD)". United Brain Association. Retrieved 2022-08-16.
  29. ^ Zhang, Yanyan; Li, Jie; Bai, Rong; Wang, Jianping; Peng, Tao; Chen, Lijie; Wang, Jingtao; Liu, Yanru; Tian, Tian; Lu, Hong (2019). "LMNB1-Related Adult-Onset Autosomal Dominant Leukodystrophy Presenting as Movement Disorder: A Case Report and Review of the Literature". Frontiers in Neuroscience. 13: 1030. doi:10.3389/fnins.2019.01030. ISSN 1662-453X. PMC 6816284. PMID 31695592.
  30. ^ "Entry - #169500 - LEUKODYSTROPHY, DEMYELINATING, ADULT-ONSET, AUTOSOMAL DOMINANT; ADLD - OMIM". www.omim.org. Retrieved 2022-08-16.
  31. ^ Lin, Shu-Ting; Ptáček, Louis J.; Fu, Ying-Hui (2011-01-26). "Adult-Onset Autosomal Dominant Leukodystrophy: Linking Nuclear Envelope to Myelin". Journal of Neuroscience. 31 (4): 1163–1166. doi:10.1523/JNEUROSCI.5994-10.2011. ISSN 0270-6474. PMC 3078713. PMID 21273400.
  32. ^ Zerbin-Rüdin, E.; Peiffer, J. (1964). "[Genetic contribution to the problem of the late form of Pelizaeus-Merzbacher disease]". Humangenetik. 1 (2): 107–122. doi:10.1007/BF00389627. ISSN 0018-7348. PMID 5869474. S2CID 34057578.
  33. ^ Padiath, Quasar S.; Saigoh, Kazumasa; Schiffmann, Raphael; Asahara, Hideaki; Yamada, Takeshi; Koeppen, Anulf; Hogan, Kirk; Ptácek, Louis J.; Fu, Ying-Hui (2006-10-01). "Lamin B1 duplications cause autosomal dominant leukodystrophy". Nature Genetics. 38 (10): 1114–1123. doi:10.1038/ng1872. ISSN 1061-4036. PMID 16951681. S2CID 25336497.
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