Acta Clin Croat 2018; 57:780-784 Case Report doi: 10.20471/acc.2018.57.04.23 MULTIPLE SCLEROSIS OR FABRY DISEASE – PROS AND CONS Iris Zavoreo, Miljenka-Jelena Jurašić, Marijana Lisak, Ana Jadrijević Tomas and Vanja Bašić Kes Department of Neurology, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia SUMMARY – Fabry disease is a rare X-linked inherited lysosomal storage disease aff ecting mul- tiple organ systems, presenting in the central nervous system (CNS) as white matter lesions with underlying cerebral vasculopathy and autoinfl ammatory changes of the choroid plexus and leptomen- inges. We present a young female patient (age 36 years) admitted to our department due to visual loss on the left eye. Magnetic resonance imaging (MRI) showed demyelinating lesions in the frontal and parietal lobe, periventricularly, in mesencephalon and right cerebellar hemisphere, and left optic neu- ritis; MR angiography was normal. Her medical history revealed renal dysfunction, hypothyroidism, and miscarriage in the 6th month of pregnancy due to eclampsia and Fabry disease in the family (mother). Cerebrospinal fl uid analysis showed mild pleocytosis, normal blood brain barrier function and oligoclonal bands type 3. Visual evoked potentials showed prechiasmal dysfunction of the left optic nerve. Genetical testing for Fabry disease was positive (two heterozygous mutations), with de- creased alpha galactosidase activity values and increased Lyso GB3 values. Th e patient received corti- costeroid therapy (methylprednisolone) 1 g for 5 days, which led to regression of visual disturbances on the left eye. After this acute treatment, there was a question of defi nitive diagnosis and further treatment of the underlying cause. Considering renal dysfunction, miscarriage, arterial hypertension, positive genetic and biochemical testing for Fabry disease, as well as MRI fi ndings showing lesions in posterior circulation, we concluded that the patient probably had Fabry disease with autoinfl amma- tory changes in the CNS and should be treated with enzyme replacement therapy. Still, there was a question of optic neuritis on the left eye and positive oligoclonal bands favoring the diagnosis of multiple sclerosis. Th erefore, further clinical and neuroradiological follow up was needed to distin- guish multiple sclerosis and Fabry disease in this patient. Key words: Fabry disease; Multiple sclerosis – therapy; Croatia; Case reports Introduction of the GLA enzymes is to break down globotriaosyl- ceramide (GL-3 or Gb3), lyso-GL-3/Gb3 and related Fabry disease is an X-linked inherited lysosomal glycolipids by removing terminal galactose sugar from storage disease caused by mutations (or alterations) in the end of these glycolipid molecules. Th e enzyme de- the a-Gal A (GLA) gene that result in insuffi cient ac- fi ciency causes continuous build-up of GL-3/Gb3 and tivity of the a-Gal A enzyme. Lysosomes are primary related glycolipids in the body cells, resulting in cell digestive units within cells, therefore they are enriched abnormalities and organ dysfunction1-3. Due to X- with enzymes which break down or digest particular linked inheritance pattern, males are typically more compounds and intracellular structures. Th e function severely aff ected than females. Females have a more variable course and may be asymptomatic or as severe- Correspondence to: Assist. Prof. Iris Zavoreo, MD, PhD, Depart- ly aff ected as males due to so-called lyonization, i.e. ment of Neurology, Sestre milosrdnice University Hospital Centre, Vinogradska c. 29, HR-10000 Zagreb, Croatia females have two copies of the X chromosome, one of E-mail: [email protected] which is inactivated randomly, thus they have no phe- Received November 21, 2016, accepted December 28, 2016 notypic expression. Th erefore, there is always lower 780 Acta Clin Croat, Vol. 57, No. 4, 2018 Iris Zavoreo et al. Multiple sclerosis or Fabry disease GLA enzyme level in plasma, while in females GLA frontal and parietal lobe, periventricularly, in mesen- enzyme activity levels depend not only on GLA muta- cephalon and right cerebelar hemisphere, and left op- tions of the X chromosome, but also on the lyonization tic neuritis; MR angiography was normal. Th e patient’s eff ect4,5. history revealed renal dysfunction, hypothyroidism, Fabry disease is estimated to aff ect 1 in 40,000 to and miscarriage in the 6th month of pregnancy due to 60,000 males. Th is disorder also occurs in females, al- eclampsia and genetically confi rmed Fabry disease in though the prevalence is unknown. Milder, late-onset the family (mother and one sister). Cerebrospinal fl uid forms of the disorder are probably more common than analysis showed mild pleocytosis, normal blood brain the classic, severe form. Th e average age at diagnosis is barrier function, and oligoclonal bands type 3. Visual approximately 30 years. Delayed diagnosis may be due evoked potentials showed prechiasmal dysfunction of to the rarity of the disease and/or the nonspecifi c na- the left optic nerve. Genetic testing for Fabry disease ture of its early symptoms6,7. was positive (two heterozygous mutations), with de- Th ere are two major disease phenotypes, i.e. type 1 creased alpha galactosidase activity values and in- ‘classic’ and type 1 ‘later-onset’ subtypes. Th e signs and creased Lyso GB3 values. Neurological examination symptoms of classic phenotype typically begin in showed loss of visual acuity on the left eye, without any childhood or adolescence. Symptoms increase with age other neurological signs and symptoms. due to the progressive glycolipid accumulation in the Th e patient received corticosteroid therapy (meth- vascular system, kidneys and heart leading to kidney ylprednisolone) 1 g for 5 days, which led to regression failure, heart disease or strokes. Early and progressive of visual disturbances on the left eye. clinical symptoms include acroparesthesias, anhidro- After this acute treatment, there was a question of sis or hypohidrosis, angiokeratomas, gastrointestinal defi nitive diagnosis and further treatment of the un- problems, and corneal dystrophy. Additional symp- derlying cause. Considering renal dysfunction, miscar- toms include chronic fatigue, dizziness, headache, gen- riage, arterial hypertension, positive genetic and bio- eralized weakness, nausea, vomiting, delayed puberty, chemical testing for Fabry disease, as well as MRI lack of or sparse hair growth, and rarely malformation fi ndings showing lesions in posterior circulation (Figs. of the joints of the fi ngers. 1-4), we concluded that the patient probably had Fab- Involvement of the central nervous system (CNS) ry disease with microangiopathy complications (auto- in Fabry disease patients is mainly due to cerebral vas- infl ammatory vasculopathy) of the brain white matter, culopathy aff ecting both small and large cerebral ves- which required treatment with enzyme replacement sels. Macroangiopathy usually leads to ischemic stroke, therapy. Still, there was a question of optic neuritis of while microangiopathy is usually the cause of progres- the left eye and positive oligoclonal bands favoring the sive white matter lesions confi rmed by magnetic reso- diagnosis of MS. Th erefore, further clinical and neuro- nance imaging (MRI) in about 80% of Fabry disease radiological follow up was needed to distinguish MS patients (both genders). Because of its clinical presen- and Fabry disease in this patient. tation, as well as previously mentioned MRI fi ndings, Fabry disease takes an important place in the diff eren- Discussion tial diagnosis of multiple sclerosis (MS). Clinicians should be extremely careful in establishing diagnosis Fabry disease aff ects young people and can have in patients with Fabry disease because intermittent monosymptomatic courses, which only involve CNS Fabry symptoms can be misleading and patient can without any medical history of other classic Fabry fulfi ll Mc Donald criteria for MS, as well as aberra- symptoms such as angiokeratoma, cornea veriticillata, 8,9 tions in cerebrospinal fl uid fi nding suggesting MS . or heart and kidney disease. MS is one of the most common neurologic diseases in young population of Case Report Western countries. Diff erential diagnosis of MS re- quires detailed workup to exclude any other infl amma- We present a young female patient (age 36 years) tory or non-infl ammatory brain white matter diseases admitted to our department due to visual loss on the mimicking clinical and/or MRI features of MS. Over- left eye. MRI showed demyelinating lesions in the presentation or intermittent presentation of cerebellar Acta Clin Croat, Vol. 57, No. 4, 2018 781 Iris Zavoreo et al. Multiple sclerosis or Fabry disease Fig. 1. Horizontal T2 MRI section: Fig. 2. Horizontal T2 MRI section: multiple demyelinating lesions. multiple demyelinating lesions. Fig. 3. Sagittal T1 MRI section: Fig. 4. Sagittal T1 MRI section: multiple demyelinating lesions. multiple demyelinating lesions. and/or brain stem symptoms (ataxia, gait disturbances, ingitis’ or chronic meningitis with mild to moderate double vision, vertigo, posterior vascular territory pleocytosis (76 cells/μL) and slightly elevated total symptoms) in combination with sensory defi cits due protein levels (up to 800 mg/L) suggesting disturbed to small fi ber lesions, as well as white matter lesions on blood brain barrier function, mostly with lympho- MRI, can mislead clinicians in establishing diagnosis monocytic response. Results of the postmortem stud- of MS according to temporal