Familial Danish dementia
Other namesFDD, ADan amyloidosis, Heredopathia ophthalmootoencephalica, HOOE, ITM2B amyloidosis, Cerebellar ataxia, cataract, deafness, and dementia or psychosis[1]
SpecialtyNeurology
SymptomsCataracts, Deafness, Progressive ataxia, Dementia,[2]
Usual onset20-30 years old[3]
Causesmutations of the BRI2 gene [4]
Diagnostic methodFamily history, symptoms, and genetic testing [4]

Familial Danish Dementia is an extremely rare, neurodegenerative disease characterized by progressive cataracts, loss of hearing, cerebellar ataxia, paranoid psychosis, and dementia. Neuropathological hallmarks include extensive atrophy of all areas of the brain, chronic diffuse encephalopathy, and the presence of exceedingly thin and nearly totally demyelinated cranial nerves.[1]

FDD is an autosomal dominant disorder caused by a mutation in the BRI2 gene on chromosome 13.[4] FDD is one of the two types of hereditary, cerebral amyloid angiopathy, alongside familial British dementia.[5]

Signs and Symptoms

Vision problems are one of the earliest symptoms of FDD with cataracts usually appearing before age 30.[6] However, the development of cataracts can appear as early as age 20.[7] The median age for visual symptoms is 27.[6] Other ocular disorders including hemorrhages can also be present.[4]

Impaired hearing manifests as severe or total perceptive loss of hearing and typically presents 10 to 20 years after the onset of ocular symptoms, whereas cerebellar ataxia appears soon after the age of 40.[4]

In most cases, paranoid psychosis occurs after the age of 50, followed by dementia. The majority of patients die in their fifties or sixties.[4]

FDD patients also have extensive brain atrophy, particularly in the cerebellum, cerebral cortex, and white matter, as well as very thin and virtually demyelinated cranial nerves.

Cerebral amyloid angiopathy in this disorder is severe.[8] CAA is present in all regions of the central nervous system.[9]

Other symptoms include intention tremor, neurofibrillary tangles, spasticity,[10] apathy, hyperorality, early dyscalculia, and stereotyped behavior.[11]

Causes

FDD is caused by a 10-nucleotide duplication prior to the stop codon of the BRI2/ITM2B gene. In healthy people, BRI2 is produced as an immature type-II membrane protein (imBRI2), which is cleaved at the C-terminus by a pro-protein convertase to create mature BRI2 (mBRI2) and a 23aa soluble C-terminal fragment (Bri23). However, in FDD patients, a longer C-terminal fragment, the ADan peptide, is formed from the Danish mutant protein (BRI2-ADan), which exhibits amyloidogenic features. ADan causes amyloid angiopathy in the cerebrum, choroid plexus, cerebellum, spinal cord, and retinas. [12]

Mutations in Cystatin C have also been suggested to be a cause of the disorder.[13]

Diagnosis

Due to the rarity of FDD, it is usually diagnosed based on family history and symptoms. Mutations in the BRI2 gene can be identified by genetic testing.[4]

FDD shares similar neuropathological characteristics with Alzheimer disease, including extensive cerebrovascular amyloidosis, parenchymal amyloid and preamyloid lesions, and neurofibrillary degeneration. Surprisingly, a detailed anti-Aβ  immunohistochemical survey of various brain areas from all available FDD autopsy cases clearly identified a co-deposited with ADan primarily in vascular and perivascular amyloid lesions, although co-deposition was also found on a smaller scale in parenchymal preamyloid deposits.[14]

Differential diagnosis includes Begger syndrome and Refsum disease.[15]

Prognosis

Most people with this condition die when they reach their fifties or sixties,[2] with the median age of death being 58.[6] The most common cause of death in FDD is complications from pneumonia, diarrhea, and strokes.[15]

Epidemiology

Familial Danish Dementia has been reported in a single family spanning three generations,[16] with there being nine reported cases as of 2014.[7] Males and females are equally affected by the disorder.[6]

History

In 1970, Strömgren et al. first described Familial Danish Dementia as heredopathia opthalmo-oto-encephalica. It was discovered in 9 members of a Danish family spanning three generations.[4]

Histopathologically FDD was characterized by severe cerebral amyloid angiopathy with neurofibrillary tangle deposition in the limbic system and the neocortex.[17] It is also neuropathologically characterized by diffuse atrophy of cerebellum, cranial nerves, and the spinal cord.[18]

References

  1. 1 2 "ADan amyloidosis - About the Disease". rarediseases.info.nih.gov. Retrieved 22 July 2023.
  2. 1 2 Paul, Robert H. (2007-11-17). Vascular Dementia: Cerebrovascular Mechanisms and Clinical Management. Springer Science & Business Media. p. 42. ISBN 978-1-59259-824-3.
  3. ↑ Sharma, Pankaj; Meschia, James F. (2012-08-27). Stroke Genetics. Springer Science & Business Media. p. 75. ISBN 978-0-85729-209-4.
  4. 1 2 3 4 5 6 7 8 Holton, Janice L.; Lashley, Tammaryn; Ghiso, Jorge; Braendgaard, Hans; Vidal, Ruben; Guerin, Christopher J.; Gibb, Graham; Hanger, Diane P.; Rostagno, Agueda; Anderton, Brian H.; Strand, Catherine (March 2002). "Familial Danish Dementia: A Novel Form of Cerebral Amyloidosis Associated with Deposition of Both Amyloid-Dan and Amyloid-Beta". Journal of Neuropathology & Experimental Neurology. 61 (3): 254–267. doi:10.1093/jnen/61.3.254. ISSN 0022-3069. PMID 11895040.
  5. ↑ "Hereditary cerebral amyloid angiopathy: MedlinePlus Genetics". medlineplus.gov. Retrieved 2021-09-07.
  6. 1 2 3 4 Dickson, Dennis; Weller, Roy O. (2011-09-09). Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. John Wiley & Sons. p. 440. ISBN 978-1-4443-4123-2.
  7. 1 2 Encyclopedia of the Neurological Sciences. Academic Press. 2014-04-29. pp. 163–164. ISBN 978-0-12-385158-1.
  8. ↑ Love, Seth; Louis, David; Ellison, David W. (2008-02-29). Greenfield's Neuropathology Eighth Edition 2-Volume Set. CRC Press. p. 1115. ISBN 978-1-4665-8543-0.
  9. ↑ Clark, Leon V. (2004). Trends in Atherosclerosis Research. Nova Publishers. p. 198. ISBN 978-1-59454-046-2.
  10. ↑ "Dementia, familial Danish | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2021-09-07.
  11. ↑ Husain, Masud; Schott, Jonathan M. (2016). Oxford Textbook of Cognitive Neurology and Dementia. Oxford University Press. pp. 347–348. ISBN 978-0-19-965594-6.
  12. ↑ Matsuda, Shuji; Tamayev, Robert; D’Adamio, Luciano (1 January 2011). "Increased AβPP Processing in Familial Danish Dementia Patients". J Alzheimers Dis. 27 (2): 385–391. doi:10.3233/JAD-2011-110785. PMC 3690758. PMID 21841249.
  13. ↑ Picken, Maria M.; Herrera, Guillermo A.; Dogan, Ahmet (2015-08-17). Amyloid and Related Disorders: Surgical Pathology and Clinical Correlations. Humana Press. p. 126. ISBN 978-3-319-19294-9.
  14. ↑ Tomidokoro, Yasushi; Lashley, Tammaryn; Rostagno, Agueda; Neubert, Thomas A.; Bojsen-Møller, Marie; Braendgaard, Hans; Plant, Gordon; Holton, Janice; Frangione, Blas; Révész, Tamas; Ghiso, Jorge (8 November 2005). "Familial Danish Dementia". Journal of Biological Chemistry. 280 (44): 36883–36894. doi:10.1074/jbc.m504038200. PMID 16091362. Retrieved 22 July 2023.
  15. 1 2 Toriello, Helga V.; Smith, Shelley D. (2013-08-08). Hereditary Hearing Loss and Its Syndromes. OUP USA. p. 489. ISBN 978-0-19-973196-1.
  16. ↑ Wahlund, Lars-Olof; Erkinjuntti, Timo; Gauthier, Serge (2009-02-12). Vascular Cognitive Impairment in Clinical Practice. Cambridge University Press. p. 150. ISBN 978-0-521-87537-0.
  17. ↑ MD, Thomas P. Naidich; MD, Mauricio Castillo; MD, Soonmee Cha; MD, James G. Smirniotopoulos (2012-10-31). Imaging of the Brain: Expert Radiology Series. Elsevier Health Sciences. ISBN 978-1-4160-5009-4.
  18. ↑ Pantoni, Leonardo; Gorelick, Philip B. (May 2014). Cerebral Small Vessel Disease. Cambridge University Press. p. 87. ISBN 978-1-107-03166-1.
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