Cognitive Impairments and Subjective Cognitive Complaints in Fabry Disease: A Nationwide Study and Review of the Literature

  • Josefine Loeb
  • Ulla Feldt-Rasmussen
  • Christoffer Valdorff Madsen
  • Asmus VogelEmail author
Research Report
Part of the JIMD Reports book series (JIMD, volume 41)


Fabry disease is a rare progressive X-linked lysosomal storage disorder which leads to neuropathic pain, organ dysfunction and cerebral pathology. Few studies have investigated cognitive impairment in Fabry disease and these previous studies are difficult to compare due to heterogeneous methodological designs and small cohorts. The objective was to investigate the frequency of cognitive impairment in the Danish nationwide cohort of Fabry patients. Further, we examined if subjective cognitive complaints were associated with objective cognitive performances in this patient group. Neuropsychological tests (17 measures) and evaluation of subjective complaints with the Perceived Deficits Questionnaire (PDQ) were applied in 41 of 63 patients. According to an a priori definition, 12 patients (29.3%) were cognitively impaired. Tests tapping psychomotor speed, attention and executive functions had the highest frequency of impairment. In general, disease related variables as Mainz Severity Score Index, enzyme activity and years since onset and depression did not have a significant impact on the categorisation of patients as being cognitively impaired or non-impaired. Thus, cognitive impairment in Fabry disease does not seem to occur solely by having symptoms for many years or by having high disease burden. However, impaired neuropsychological test results were significantly more common in patients with cerebrovascular disease. Only three patients had scores in the abnormal range of the PDQ scale and subjective perceptions of cognition were not associated with cognitive performances. The levels of subjective cognitive complaints were generally very low in the studied patients demonstrating that the absence of subjective cognitive complaints does not exclude the presence of objective cognitive problems.


Cognition Fabry disease Memory Neuropsychology Subjective symptoms 



The authors would like to thank the Danish Health Foundation and the Danish Ministry of Health for support to the Danish Dementia Research Centre. The study was supported by an unrestricted research grant from Genzyme. Specialist nurse Ira Hagen is thanked for excellent assistance in the accrual of clinical data from the patients and Casper Kok is thanked for excellent technical assistance. The Danish Fabry Team is thanked for continuous update of Fabry patient data.


  1. Bolsover FE, Murphy E, Cipolotti L, Werring DJ, Lachmann RH (2014) Cognitive dysfunction and depression in Fabry disease: a systematic review. J Inherit Metab Dis 37:177–187CrossRefGoogle Scholar
  2. Buschke H, Fuld PA (1974) Evaluating storage, retention, and retrieval in disordered memory and learning. Neurology 24:1019–1025CrossRefGoogle Scholar
  3. Christodoulou C, Melville P, Scherl WF et al (2005) Perceived cognitive dysfunction and observed neuropsychological performance: longitudinal relation in persons with multiple sclerosis. J Int Neuropsychol Soc 11:614–619CrossRefGoogle Scholar
  4. Cole AL, Lee PJ, Hughes DA, Deegan PB, Waldek S, Lachmann RH (2007) Depression in adults with Fabry disease: a common and under-diagnosed problem. J Inherit Metab Dis 30:943–951CrossRefGoogle Scholar
  5. Echevarria L, Benistan K, Toussaint A et al (2016) X-chromosome inactivation in female patients with Fabry disease. Clin Genet 89:44–54CrossRefGoogle Scholar
  6. Elstein D, Doniger GM, Altarescu G (2012) Cognitive testing in Fabry disease: pilot using a brief computerized assessment tool. Isr Med Assoc J 14:624–628PubMedGoogle Scholar
  7. Fledelius HC, Sandfeld L, Rasmussen AK, Madsen CV, Feldt-Rasmussen U (2015) Ophthalmic experience over 10 years in an observational nationwide Danish cohort of Fabry patients with access to enzyme replacement. Acta Ophthalmol 93:258–264CrossRefGoogle Scholar
  8. Germain DP (2010) Fabry disease. Orphanet J Rare Dis 5:1–49CrossRefGoogle Scholar
  9. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62CrossRefGoogle Scholar
  10. Korsholm K, Feldt-Rasmussen U, Granqvist H et al (2015) Positron emission tomography and magnetic resonance imaging of the brain in Fabry disease: a nationwide, long-time, prospective follow-up. PLoS One 10:e0143940CrossRefGoogle Scholar
  11. Lelieveld IM, Bottcher A, Hennermann JB, Beck M, Fellgiebel A (2015) Eight-year follow-up of neuropsychiatric symptoms and brain structural changes in Fabry disease. PLoS One 10:e0137603CrossRefGoogle Scholar
  12. Lohle M, Hughes D, Milligan A et al (2015) Clinical prodromes of neurodegeneration in Anderson-Fabry disease. Neurology 84:1454–1464CrossRefGoogle Scholar
  13. Longato N, Kleitz C, Bitonto LD, Jung B, Noel E, Blanc F (2011) Cognitive impairments in Fabry’s disease conference cognitive impairments in Fabry’s disease. BarcelonaGoogle Scholar
  14. Low M, Nicholls K, Tubridy N et al (2007) Neurology of Fabry disease. Intern Med J 37:436–447CrossRefGoogle Scholar
  15. Madsen CV, Bundgaard H, Rasmussen AK et al (2017) Echocardiographic and clinical findings in patients with Fabry disease during long-term enzyme replacement therapy: a nationwide Danish cohort study. Scand Cardiovasc J 51:207–216CrossRefGoogle Scholar
  16. Meyers JE, Meyers KR (1995) Rey complex figure test and recognition trial. PAR, LutzGoogle Scholar
  17. Mortensen EL, Gade A (1993) On the relation between demographic variables and neuropsychological test performance. Scand J Psychol 34:305–317CrossRefGoogle Scholar
  18. Nelson HE, O’Connell A (1978) Dementia: the estimation of premorbid intelligence levels using the New Adult Reading Test. Cortex 14:234–244CrossRefGoogle Scholar
  19. Prabakaran T, Birn H, Bibby BM et al (2014) Long-term enzyme replacement therapy is associated with reduced proteinuria and preserved proximal tubular function in women with Fabry disease. Nephrol Dial Transplant 29:619–625CrossRefGoogle Scholar
  20. Raven J, Raven JC, Court JH (2003) Manual for Raven’s progressive matrices and vocabulary scales. Harcourt Assessment, San AntonioGoogle Scholar
  21. Reitan RM (1955) The relation of the trail making test to organic brain damage. J Consult Psychol 19:393–394CrossRefGoogle Scholar
  22. Rolfs A, Dudesek A, Lukas J, Böttcher T (2010) Neurological manifestations in Fabry disease. In: Elstein D, Altarescu G, Beck M (eds) Fabry disease. Springer, DordrechtGoogle Scholar
  23. Schermuly I, Muller MJ, Muller KM et al (2011) Neuropsychiatric symptoms and brain structural alterations in Fabry disease. Eur J Neurol 18:347–353CrossRefGoogle Scholar
  24. Segal P, Kohn Y, Pollak Y, Altarescu G, Galili-Weisstub E, Raas-Rothschild A (2010) Psychiatric and cognitive profile in Anderson-Fabry patients: a preliminary study. J Inherit Metab Dis 33:429–436CrossRefGoogle Scholar
  25. Sigmundsdottir L, Tchan MC, Knopman AA, Menzies GC, Batchelor J, Sillence DO (2014) Cognitive and psychological functioning in Fabry disease. Arch Clin Neuropsychol 29:642–650CrossRefGoogle Scholar
  26. Smith A (1982) Symbol digit modalities test: manual. PAR, LutzGoogle Scholar
  27. Stroop JR (1935) Studies of interference in serial verbal reactions. J Exp Psychol 18:1–20CrossRefGoogle Scholar
  28. Sullivan M, Edgley K, Dehoux E (1990) A survey of multiple sclerosis. Part 1: Perceived cognitive problems and compensatory strategy use. Can J Rehabil 4:99–105Google Scholar
  29. Vinther-Jensen T, Larsen IU, Hjermind L et al (2014) A clinical classification acknowledging neuropsychiatric and cognitive impairment in Huntington’s disease. Orphanet J Rare Dis 9:1–9CrossRefGoogle Scholar
  30. Vogel A, Elberling TV, Hording M et al (2007) Affective symptoms and cognitive functions in the acute phase of Graves’ thyrotoxicosis. Psychoneuroendocrinology 32:36–43CrossRefGoogle Scholar
  31. Vogel A, Bhattacharya S, Larsen JL, Jacobsen S (2011) Do subjective cognitive complaints correlate with cognitive impairment in systemic lupus erythematosus? A Danish outpatient study. Lupus 20:35–43CrossRefGoogle Scholar
  32. Wadley VG, McClure LA, Warnock DG et al (2015) Cognitive function in adults aging with Fabry disease: a case-control feasibility study using telephone-based assessments. JIMD Rep 18:41–50CrossRefGoogle Scholar
  33. Zarate YA, Hopkin RJ (2008) Lysosomal storage disease 3 – Fabry’s disease. Lancet 372:1427–1435CrossRefGoogle Scholar

Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018

Authors and Affiliations

  • Josefine Loeb
    • 1
  • Ulla Feldt-Rasmussen
    • 1
  • Christoffer Valdorff Madsen
    • 1
  • Asmus Vogel
    • 2
    • 3
    Email author
  1. 1.Department of Medical EndocrinologyRigshospitalet, University of CopenhagenCopenhagenDenmark
  2. 2.Danish Dementia Research Center, Department of NeurologyRigshospitalet, University of CopenhagenCopenhagenDenmark
  3. 3.Department of PsychologyUniversity of CopenhagenCopenhagenDenmark

Personalised recommendations