Because α-galactosidase A is ubiquitous throughout the body, in addition to neurologic symptoms, FD involves multiple organ systems, with possible dermatologic, renal, gastrointestinal, cardiac, and cerebrovascular dysfunction. Despite growth in FD research, including the Fabry Outcomes Survey,3 the psychosocial and neuropsychiatric implications of the disease remain unclear.7 Behavioral presentations are idiosyncratic and unstable over time, depending on the structures impacted by progressive glycosphingolipid accumulation. Premature cardiovascular events (onset between age 30 and 40 for women), greater incidence of ischemic stroke or transient ischemic attack (7% to 30%), and frequent evidence of white matter lesions put FD patients at greater risk for developing presenile vascular dementia.1,3 Nearly all male FD patients with dementia show some evidence of stroke or transient ischemic attack; cognitive functioning has not been well explored in female patients.4 In a heterogeneous sample of 15 FD patients age 7 to 61, Segal et al8 noted deficits in attention, processing speed, and executive function .75 to 1.95 standard deviations below normative means. No patients in this study had a history of stroke or transient ischemic attack; neuroimaging studies were not reported. Kolodny and Pastores9 suggested multiple mechanisms for cognitive disruption, suggesting that mild dementia late in the disease course could be secondary to diffuse leukomalacia, multiple strokes, or possibly to lipid storage in hippocampal and frontal lobe neurons.
Psychiatric comorbidity
Psychiatric illness, such as depression or a personality disorder, may be comorbid with FD, although pathologic mechanisms remain unclear.7,10,11 Hypothesized mechanisms include:
- psychosocial stress from chronic disease
- white matter changes
- disruption of impaired L-arginine-nitric oxide pathways.7,12
Crosbie et al13 noted that FD patients presented with greater psychological distress as measured by the Minnesota Multiphasic Personality Inventory-2 than patients with Gaucher disease or chronic heart disease. However, no significant differences were found between patients with FD and those diagnosed with a pain disorder. In the Segal et al study, out of 11 adult FD patients, 4 were diagnosed with major depressive disorder, 1 with schizophrenia, 2 with schizotypal personality disorder, and 1 with borderline personality disorder.8
EVALUATION: Brain abnormalities
Head CT scans (conducted 2 years ago and 6 months ago) revealed prominent cortical sulci likely caused by underlying volume loss, especially in bifrontal areas. A brain MRI performed 2 months ago indicated a moderate degree of subcortical atrophy in bilateral frontal and parietal regions. These radiology findings suggest mild to moderate frontal atrophy, mild degree of white matter changes, and slightly enlarged ventricles. An EEG showed background slowing and lack of an alpha rhythm, indicative of cerebral cortical dysfunction.
Ms. P’s α-galactosidase A level was within normal limits; however, normal enzyme levels frequently are reported in symptomatic and asymptomatic female FD patients.14 A dermatology consult confirmed the presence of skin findings characteristic of FD (ie, multiple cherry red papules extensively distributed throughout Ms. P’s chest, abdomen, and back, as well as upper and lower extremities).
Ms. P completed 2 neuropsychological assessments separated by 5 months. For a summary of the results of these tests, see the table titled “Ms. P’s neuropsychological assessment results”. Both assessments revealed grossly impaired intellectual capacity, memory, processing speed, and motor functioning. During the assessment, Ms. P could understand all directions with minimal changes from standardized protocols. Ms. P became insistent that she would not be able to complete memory tasks successfully. She gave up prematurely on tasks, saying they were too difficult. She admitted to guessing on several items because she did not want to continue the task.
Ms. P’s performance on tasks measuring effort and validity of a person’s neuropsychological presentation was consistent with someone exaggerating neurologic symptoms. A person with true dementia may perform as poorly as Ms. P did. However, Ms. P’s scores likely underestimated her level of functioning, even if she was experiencing dementia. Ms. P could not complete tasks individuals with severe dementia complete successfully, such as simple addition and subtraction and digit repetition. Ms. P recalled several recent and remote events, such as her breakfast menu and location of her first assessment, but could not recall words practiced multiple times. Although Ms. P’s scores on a complex card-sorting task were in the impaired range, a detailed review of her pattern indicated that although Ms. P could not generate any correct sorting categories, she made few repetitive responses and errors. This pattern is consistent with someone who understands task requirements, but deliberately avoids answering correctly. This suggests that she retained some ability for hypotheses generation and problem solving; however, because she exaggerated her symptoms, specific deficits could not be determined.