A 51-year-old male initially presented with pain in the distal extremities in childhood. At the age of 20 years, a routine annual health check-up revealed LVH and proteinuria. At the age of 37 years, he was definitively diagnosed with classical FD accompanied by renal biopsy findings, including lamellated myelin-like inclusions in the cytoplasm of glomerular and tubular cells, and lower levels of leukocyte GLA activity (0.2 nmol/h/mg protein, normal range: 49.8–116.4). At that time, lacunar brain infarction, opacified lens, and angiokeratoma, were also detected. Subsequent investigation revealed that his younger brother was previously diagnosed with classical FD. Moreover, a remarkable family history of genetic disorder was noted (Fig. 1). Specifically, his grandmother died due to stroke and heart disease; three of her four daughter (including the patient’s mother) were heterozygous. His two sons of the patient refused further examination for diagnosis of FD because they had been worried by the peculiar metamorphosed behavior of their father reflecting his psychosocial burden. ERT with agalsidase alfa (Replagal®, 0.2 mg/kg once every 2 weeks) was initiated in this patient from the age of 38 years. A detailed description of the process from diagnosis to the initiation of ERT has been previously published [7].

Genealogical tree of the family of this patient. III-6 is an index case of this report. His mother (II-7) is hemizygote and cardiac variant. His uncle (II-9) and his brother (III-7) are classical Fabry disease. His two sons (IV-1 and IV-2) were reluctant to undergo genetic investigation for a definitive diagnosis. Detail information of III-1, III-2, III-3, and III-4was not obtained

At the age of 42 years, he experienced a cerebral infarction (left internal capsule) with simultaneous detection of multiple asymptomatic brain infarctions (Figs. 2a–c). Conservative daily treatment with oral medications, namely azilsartan (10 mg), clopidogrel (75 mg), rosuvastatin (2.5 mg), cilostazol (50 mg), and carbamazepine (400 mg), was initiated and did not leave sequalae. The estimated glomerular filtration rate was gradually declined from 65.2 ml/min/1.73 m2 at the time of ERT introduction to levels denoting end-stage renal failure. At the age of 47 years, an arteriovenous fistula was created on the left forearm for blood access; however, acute occlusion occurred. After subcutaneously fixing the superficial left brachial artery, hemodialysis was initiated. At the age of 48 years, repeated brain infarction was recorded thrice every 2 months. The first attack was characterized by numbness of the left upper and lower limbs. The second attack was characterized by the numbness of the left upper limb, and magnetic resonance imaging (MRI) revealed right cerebral cortex infarction and micro bleeding. Two months later, MRI demonstrated new infarctions at the left pons and bilateral cerebral cortex without obvious symptoms (Figs. 2d–f). The serial events resulted in permanent damage, which manifested as numbness of the left side of the body and opposite tendon hyperreflexia but no motion impairment. In terms of communication, vocabulary use, and comprehension decreased. In addition, stubbornness and low morale gradually developed, leading to voluntary termination of employment. Thereafter, his daily life was limited to the vicinity of his residence.

Magnetic resonance imaging. a Diffusion-weighted scan and (b, c) fluid-attenuated inversion recovery (FLAIR): Images revealed a new left internal capsule infarction and multiple asymptomatic brain infarctions at the age of 42 years. d, e Diffusion-weighted scan and (f) T2-weighted scan: the last images of consecutive episodes at the age of 48 years; new infarctions in the bilateral cerebral hemispheres and left pons were detected. There were wide-spread periventricular high-intensity lesions in the parietal cerebral area with different time phases

At the age of 48 years, the patient continued maintenance hemodialysis at our hospital, which is located near his residence. For the subsequent 3 years, he displayed perplexed utterance and behavior, and his psychosocial burden was raised (Table 1). Due to the impairment of attention and disorientation, it was necessary for medical staff to monitor his behavior before, during, and after each hemodialysis session. He repeatedly interfered with the blood access needle, and, on one occasion, he removed the needle during the hemodialysis session. In addition, disorientation resulted in visiting our hospital at midnight although the next hemodialysis session was scheduled for the next morning. On another day, he was wondering around town after the hemodialysis session and could not return home. He gradually became reclusive, and his family tended to avoid interaction with him. He often expressed objective cognitive complaints, such as awareness of dementia, and appeared conflicted and depressed.

The cognitive function of this patient was monitored on an annual basis using Hasegawa dementia rating scale-revised (HDS-R; maximum: 30 points) and mini-mental state examination (MMSE; maximum: 30 points) at the age of 49, 50, and 51 years (Fig. 3) [8, 9]. The score of HDS-R was 6, 4, and 4 points, while that of MMSE was 15, 17, and 10 points, respectively. Dementia had progressed to severe levels. For a detail analysis of a profile of cognitive performance by domain rather than a global score of functioning, we performed neurobehavioral Cognitive Status Examination (COGNISTAT). This examination was performed on the basis of the instruction provided in the manual [10]. Standardized scores of 10 cognitive domains were obtained, comprising Orientation, Attention, Comprehension, Repetition, Naming, Constructional Ability, Memory, Calculation, Similarities, and Judgement. Scores were standardized as mean = 1 and standard deviation = 1. Lower scores (i.e., 0–9) denoted worse cognitive ability, and scores > 9 were considered normal. Remarkable declines in Orientation, Language (Comprehension, Naming), Construction, Memory, Calculations and Reasoning (Similarities, Judgement) were observed. A relatively good score was maintained for Attention and Language Repetition. Sensitive diagnostic imaging with the Voxel-based Specific Regional Analysis System for Alzheimer’s Disease [11] yielded a Z-score of 0.49, denoting no specific loss of gray matter selectivity in bilateral hippocampal regions. Moreover, the reduction in whole brain gray matter volume was 6.02%, indicating the absence of atrophy despite his multiple brain infarctions.

Results of neurophysical examinations of cognitive function. a The points of Hasegawa dementia rating scale-revised (HDS-R; maximum: 30 points; blue bar) and mini-mental state examination (MMSE; maximum: 30 points; red bar) demonstrated moderate-to-severe cognitive impairment, which worsened with ageing. b Cognitive Status Examination (COGNISTAT) demonstrated severe decline in Orientation, Language (Comprehension, Naming), Construction, Memory, Calculations, and Reasoning (Similarities, Judgement). y.o.: year old

At the age of 51 years, he received coverage from Public Nursing Care Insurance and began to use short-term residential care at the nursing home for 3 days per week. Gradually, the patient did not show interest in any aspect of life.