Anderson-Fabry Disease: A Rare Cause of Levodopa-Responsive Early-Onset Parkinsonism.

Abstract

Early-onset parkinsonism is defined when the onset of symptoms occurs before age 50. The differential diagnosis is broad, and it encompasses not only monogenic parkinsonism gene variants but also a few treatable causes.1 A 45-year-old woman came to our attention because of involuntary posturing of both of her feet when walking. She had a positive family history for ischemic heart disease (her father), chronic kidney disease leading twice to kidney transplant (1 sister), and vascular dementia (1 sister). Examination in June 2011 showed steppage on the right lower limb when walking, “en griffe” posture of the toes of the right foot, and mild slowness without decrement in the right hand (Video 1). On follow-up 1 year later, she had clear right-side parkinsonism (Video 2). She reported constipation, pain localized distally to her hands and feet, and worsening of preexisting anxiety and depression. Early-onset parkinsonism was diagnosed, and she was started on pramipexole up to 1.5 mg/day. Because of the development of excessive sleepiness and minor visual hallucinations, pramipexole was discontinued after a few months, and levodopa (l-dopa; 300 mg/daily) was initiated. At 3 years after onset, she started to complain of worsening of painful episodes in her feet, which occurred at night. During the disease course, she displayed a good and sustained response to l-dopa, with the development of nonmotor fluctuations characterized by anxiety at the 4-year follow-up. She did not develop significant dyskinesia. Neuropsychological testing administered at onset and at the last follow-up in 2019 did not disclose any cognitive abnormality. Auditory, somatosensory, visual-evoked potentials, and nerve conduction studies and electromyography were normal. Urinalysis revealed microalbuminuria on repeated samples. All other laboratory investigations including copper and ceruloplasmin were normal. An echocardiogram showed left ventricular hypertrophy. Single-photon emission computed tomography of the dopamine transporter (age 47) showed bilateral nigrostriatal degeneration (Fig. 1A). Brain magnetic resonance imaging (age 50) revealed a few inframillimetric white matter changes in the centrum semiovale. She tested negative for the parkin and glucocerebrosidase gene variants. Genetic analysis of the α-galactosidase A (GLA) gene detected a heterozygous likely pathogenic variant (c.337 T > A) and confirmed the diagnosis of Anderson-Fabry disease (AFD). On family genetic screening, the same gene variant was found in 5 family members, 2 of whom were asymptomatic (Fig. 1B). The proband was started on enzyme replacement therapy with agalsidase alfa at age 51. At the last videotaped follow-up 18 months later, she did not have significant progression or onset of additional neurological signs (Video 3). This is a case of l-dopa–responsive parkinsonism in a heterozygous female carrying a pathogenic AFD gene variant. AFD is a rare, X-linked lysosomal storage disease caused by absent or minimal enzymatic activity of α-galactosidase A. It classically affects males, in whom it has full penetrance. The most frequent neurological features associated are small-fiber neuropathy and early cerebrovascular events. Parkinsonism is a very rare presentation of AFD, particularly in the absence of cerebral small vessel disease.2, 3 Yet, slower gait and impaired fine manual dexterity as well as nonmotor symptoms (pain, depression, excessive daytime sleepiness) have been reported in the absence of clear parkinsonism in heterozygous females and hemizygous males with pathogenic GLA variants.4 This case of AFD expands the spectrum of lysosomal diseases associated with l-dopa–responsive parkinsonism.5 It also highlights the need for the careful assessment of family history and systemic features in patients with early-onset parkinsonism and consideration of gene variants not classically associated with monogenic parkinsonism. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript: A. Writing of the First Draft, B. Review and Critique. I.C.: 1C, 2A, 2B C.S.: 1C, 2B A.T.: 1C, 2B F.M.: 1A,1B, 1C, 2B We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. We also guarantee that patient have given her consent to anonymously report her clinical reports and videos in accordance with current ethical standards. This study did not receive any industry funding. The authors do not have any conflicts to report. Ioana Cociasu, Chiara Sorbera, and Antonino Tuttolomondo have no disclosures to report. Francesca Morgante reports the following: speaking honoraria from Abbvie, Medtronic, Bial, Merz, and International Parkinson's Disease and Movement Disorder Society; advisory board fees from Merz and Bial; consultancy fees from Boston Scientific; research support from Boston Scientific, Merz, and Global Kynetic; royalties for the book Disorders of Movement from Springer; and member of the editorial boards of Movement Disorders, Movement Disorders Clinical Practice, and European Journal of Neurology.