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Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the most common causes of early-onset dementia (EOD). The epidemiology and genetic etiology of EOD are rather unknown. The main genetic causes of AD and FTD are mutations in the APP, PSEN1, PSEN2, MAPT and GRN genes and the hexanucleotide repeat expansion of C9orf72, which is the main genetic cause of FTD in Finland. However, autosomal dominant mutations explain only a minority of familial EOD cases, whereas rare and low-frequency gene variants related to neurodegenerative diseases increase the risk of EOD and may be involved in the etiology of EOD. The epidemiology of FTD in Northern Ostrobothnia, Finland, was determined using the hospital discharge register from Oulu University Hospital and the population statistics for 2006–2010. The genes previously associated with AD, FTD and PD were screened from the EOD patients (n=39) with familial dementia, atypical onset or rapidly progressive disease using next-generation sequencing. The presence of C9orf72 repeat expansion was excluded. The rare and low-frequency variants of genes related to PD were screened in an additional large EOD cohort (n=279). The five-year incidence of FTD was 5.5/100000 in 2006–2010, with a prevalence of 20.5/100000 (age group of 45–65 years). Two pathogenic mutations, PSEN1 p.His163Arg and MAPT p.Arg406Trp, were identified from the selected EOD cohort (n=39). The possible risk-increasing variants of PSEN1, PSEN2, TREM2, BIN1, APP, UBQLN2, GRN, MAPT, TMEM106B, LRRK2, SNCAIP, PARK2 and GBA were identified. After excluding two patients with pathogenic PSEN1 and MAPT mutations, 24% (n=9) of the remaining cohort (n=37) and 15% (n=47) of all screened EOD patients (n=316) carried rare, low-frequency variants of PD-related genes. This research adds to the literature on the epidemiology of FTD and the genetics of EOD. The incidence and prevalence of FTD in Finland are high compared to other countries worldwide. Screening for pathoge, Tiivistelmä Alzheimerin tauti (AT) ja otsa-ohimolohkorappeuma (frontotemporal dementia, FTD) ovat kaksi yleisintä varhain (alle 65-vuotiaana) alkavaa muistisairautta. Näiden epidemiologiaa on tutkittu vähän. Suomessa otsa-ohimolohkorappeuman yleisin tunnettu geneettinen syy on C9orf72 toistojakson laajentuma. Autosomissa dominantisti periytyvien tekijöiden lisäksi lukuisien väestössä harvinaisten geenivarianttien on viime vuosina osoitettu lisäävän muistisairauksien riskiä. Kuitenkin yhä merkittävä osa sairastuneista jää ilman geneettistä selitystä, vaikka sukuhistoriakin puoltaisi perinnöllistä sairautta. Otsa-ohimolohkorappeumien ilmaantuvuus ja esiintyvyys tutkittiin käyttäen Oulun yliopistollisen sairaalan hoidonpäättämisrekisteriä vuosilta 2006–2010. Tunnetut AT:iin, otsa-ohimolohkorappeumiin sekä Parkinsonin tautiin (PT) liitetyt geenit tutkittiin tarkkaan valikoidusta varhain alkavaa muistisairautta sairastavien potilaiden kohortista (n=39) käyttäen uuden sukupolven sekvensointia (next generation sequencing, NGS). C9orf72 toistojaksomutaation kantajat oli poissuljettu. Kohortista löydetyt PT:iin liitettyjen geenien variantit seulottiin lisäksi valikoimattomilta varhain alkavaa muistisairautta sairastavilta potilailta (n=279). Otsa-ohimolohkorappeumien viiden vuoden ilmaantuvuus 45–65-vuotiaiden ikäryhmässä oli 5.5/100000 ja esiintyvyys 20.5/100000. Valikoidusta kohortista löydettiin kaksi tautia aiheuttavaa mutaatiota (PSEN1 p.His163Arg ja MAPT p.Arg406Trp). Harvinaisia variantteja todettiin geeneissä PSEN1, PSEN2, TREM2, BIN1, APP, UBQLN2, GRN, MAPT, TMEM106B, LRRK2, SNCAIP, PARK2 ja GBA. PT:iin liitettyjen geenien variantteja ilmeni enemmän valikoiduilla kuin kaikilla seulotuilla potilailla (24 % vs. 15 %). Otsa-ohimolohkorappeumien ilmaantuvuus ja esiintyvyys Pohjois-Pohjanmaalla ovat korkeita verrattuna aiemmin maailmalla kuvattuihin tuloksiin. Tautia aiheuttavia mutaatioita löytyy nuorilta, valikoiduilta potilailta. Patogeeniset PSEN1 ja MAPT mutaatiot l

Background: Fatigue is a prominent and disabling symptom of multiple sclerosis (MS), impairing quality of life. The disease course of relapsing remitting MS (RRMS) is individual. Objectives: We aimed to study the effects of demographic and clinical characteristics, as well as lifestyle risk factors on experienced fatigue and health-related quality of life (HRQoL) among RRMS patients, comparing benign and severe disease types. Methods: Altogether 198 Finnish RRMS patients were recruited for this real-life cross-sectional study. Self-reported questionnaires were used to evaluate fatigue and HRQoL by using Fatigue Scale for Motor and Cognitive Functions and 15D health-related quality of life questionnaires. Patients were categorized into subgroups based on the current disability status measured by the Expanded Disability Status Scale (EDSS) cut-off value of 4.5, and by retrospective clinical course divided into benign and aggressive RRMS. Results: All in all, 73% of the RRMS patients suffered from fatigue. Lower HRQoL had a strong correlation with more prominent fatigue (r = -0.719). Higher EDSS was associated with more prominent fatigue and lower HRQoL in the whole RRMS cohort. Older age at the disease onset was associated with more prominent fatigue and decreased HRQoL in the groups of aggressive RRMS and EDSS > 4.5. In the groups of EDSS ≤ 4.5 and benign RRMS, a higher number of used disease-modifying treatments (DMTs) was associated with more pronounced fatigue and reduced HRQoL. In addition, higher BMI was associated with lower HRQoL in patients with benign RRMS. Side effects (45 %) and lack of efficacy (26 %) were the most common reasons for discontinuing a DMT. Cessation due to side effects was the only reason that was significantly associated with more prominent fatigue and lower HRQoL. Use of nicotine products, gender, or disease duration were not associated with fatigue or HRQoL. Conclusions: Individuals with severe RRMS and higher EDSS scores are

Tiivistelmä Väestön vanhetessa muistisairauksien varhaiseen tunnistamiseen perusterveydenhuollossa tarvitaan paljon lisää resursseja. Kognitiivinen tehtäväsarja CERAD on osoittautunut hyvin toimivaksi välineeksi Alzheimerin taudin ensivaiheen arvioinnissa. Koulutus ja ikä vaikuttavat kognitiivisissa testeissä suoriutumiseen, joten ne on tärkeää huomioida tulosten tulkinnassa. Tehtäväsarjaan on päivitetty koulutustason huomioivat katkaisurajat sekä uutena kokonaispistemäärän käyttö.

Background: Due to the significant presence of neuropsychiatric symptoms in patients with frontotemporal dementia (FTD) spectrum disorders, psychiatric misdiagnoses, diagnostic delay, and use of psychiatric treatments are common prior to the FTD diagnosis. Furthermore, treatment of diagnosed FTD patients mainly relies on off-label psychopharmacological approaches. Currently, limited real-world data are available regarding the actual use of psychopharmacological medications in FTD. Objective: To evaluate psychopharmacological medication use at the time of FTD diagnosis. Methods: Psychopharmacological medication use was evaluated in a Finnish FTD cohort containing 222 FTD patients, including the major clinical disease phenotypes (behavioral, language, and motor variants) and genetic patients carrying the C9orf72 repeat expansion. A cohort of 214 Alzheimer’s disease (AD) patients was used as a neurodegenerative disease reference group. Results: Active use of psychopharmacological medications at the time of diagnosis was significantly more common in FTD compared to AD, especially in the case of antidepressants (26.1% versus 15.0%, OR = 2.01, p = 0.008), antipsychotics (23.9% versus 9.3%, OR = 3.15, p < 0.001), and mood-stabilizers (6.3% versus 1.9%, OR = 2.93, p = 0.085; not statistically significant), whereas the use of cholinesterase inhibitors or memantine was nearly nonexistent in FTD patients. Female gender and behavioral variant of FTD phenotype alongside with depressive and psychotic symptoms were the most prominent factors associating with the use of these medications among the FTD spectrum patients. Conclusions: Use of off-label psychopharmacological medication and polypharmacy is substantially common at the time of FTD diagnosis. This likely reflects the challenges in using symptom-driven treatment approaches, especially prior to the eventual diagnosis.

Background: Currently, there are few studies considering possible modifiable risk factors of frontotemporal dementia (FTD). Objectives: In this retrospective case-control study, we evaluated whether a history of traumatic brain injury (TBI) associates with a diagnosis of FTD or modulates the clinical phenotype or onset age in FTD patients. Methods: We compared the prevalence of prior TBI between individuals with FTD (N = 218) and age and sex-matched AD patients (N = 214) or healthy controls (HC; N = 100). Based on the patient records, an individual was categorized to the TBI+ group if they were reported to have suffered from TBI during lifetime. The possible associations of TBI with age of onset and disease duration were also evaluated in the whole FTD patient group or separately in the sporadic and genetic FTD groups. Results: The prevalence of previous TBI was the highest in the FTD group (19.3%) when compared to the AD group (13.1%, p = 0.050) or HC group (12%, p = 0.108, not significant). Preceding TBI was more often associated with the sporadic FTD cases than the C9orf72 repeat expansion-carrying FTD cases (p = 0.003). Furthermore, comparison of the TBI+ and TBI- FTD groups indicated that previous TBI was associated with an earlier onset age in the FTD patients (B = 3.066, p = 0.010). Conclusions: A preceding TBI associates especially with sporadic FTD and with earlier onset of symptoms. The results of this study suggest that TBI may be a triggering factor for the neurodegenerative processes in FTD. However, understanding the precise underlying mechanisms still needs further studies.

Introduction: The biallelic repeat expansion (AAGGG)exp in RFC1 causes cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). Recently, cognitive impairment has been reported in patients with CANVAS and a broader neurodegenerative process associated with RFC1 has been suggested. Furthermore, rare cases of multiple system atrophy, Parkinson’s disease, amyotrophic lateral sclerosis or CANVAS with features of dementia with Lewy bodies have been found. Objective: We hypothesized that the biallelic (AAGGG)exp is associated with neurodegeneration manifested as cognitive symptoms and that atypical RFC1 disease may be found among patients with cognitive disorder. Methods: Clinical data on nine patients with biallelic (AAGGG)exp were reviewed and 564 patients with Alzheimer’s disease or frontotemporal dementia (FTD) were investigated for biallelic RFC1 (AAGGG)exp. Results: Five patients with biallelic (AAGGG)exp were found with a cognitive impairment and in four of them the phenotype resembled FTD. However, biallelic (AAGGG)exp was not detected among patients with Alzheimer’s disease or FTD. Conclusions: Cognitive impairment is a feature in patients with the biallelic (AAGGG)exp, but the pathogenic expansion seems to be rare in patients with dementia. Studies on patients with diverse phenotypes would be useful to further explore the involvement of RFC1 in neuronal degeneration and to identify atypical phenotypes, which should be taken into account in clinical practice.

We aimed to evaluate the feasibility of using real-world register data for identifying persons with mild Alzheimer’s disease (AD) and to describe their cognitive performance at the time of diagnosis. Patients diagnosed with AD during 2010–2013 (aged 60–81 years) were identified from the Finnish national health registers and enlarged with a smaller private sector sample (total n = 1,268). Patients with other disorders impacting cognition were excluded. Detailed clinical and cognitive screening data (the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery [CERAD-nb]) were obtained from local health records. Adequate cognitive data were available for 389 patients with mild AD (31%) of the entire AD group. The main reasons for not including patients in analyses of cognitive performance were AD diagnosis at a moderate/severe stage (n = 266, 21%), AD diagnosis given before full register coverage (n = 152, 12%), and missing CERAD-nb data (n = 139, 11%). The cognitive performance of persons with late-onset AD (n = 284), mixed cerebrovascular disease and AD (n = 51), and other AD subtypes (n = 54) was compared with that of a non-demented sample (n = 1980) from the general population. Compared with the other AD groups, patients with late-onset AD performed the worst in word list recognition, while patients with mixed cerebrovascular disease and AD performed the worst in constructional praxis and clock drawing tests. A combination of national registers and local health records can be used to collect data relevant for cognitive screening; today, the process is laborious, but it could be improved in the future with refined search algorithms and electronic data.

Objective: Only a few studies have evaluated modifiable risk factors for frontotemporal dementia (FTD). Here, we evaluated several modifiable factors and their association with disease phenotype, genotype, and prognosis in a large study population including Finnish and Italian patients with FTD and control groups. Methods: In this case–control study, we compared the presence of several cardiovascular and other lifestyle-related diseases and education between Finnish and Italian patients with familial (n = 376) and sporadic (n = 654) FTD, between different phenotypes of FTD, and between a subgroup of Finnish FTD patients (n = 221) and matched Finnish patients with Alzheimer’s disease (AD) (n = 214) and cognitively healthy controls (HC) (n = 100). Results: Patients with sporadic FTD were less educated (p = 0.042, B = -0.560, 95% CI −1.101 to −0.019) and had more heart diseases (p < 0.001, OR = 2.265, 95% CI 1.502–3.417) compared to patients with familial FTD. Finnish FTD patients were less educated (p = 0.032, B = 0.755, 95% CI 0.064–1.466) compared with AD patients. The Finnish FTD group showed lower prevalence of hypertension than the HC group (p = 0.003, OR = 2.162, 95% CI 1.304–3.583) and lower prevalence of hypercholesterolemia than in the HC group (p < 0.001, OR = 2.648, 95%CI 1.548–4.531) or in the AD group (p < 0.001, OR = 1.995, 95% CI 1.333–2.986). Within the FTD group, clinical phenotypes also differed regarding education and lifestyle-related factors. Interpretation: Our study suggests distinct profiles of several modifiable factors in the FTD group depending on the phenotype and familial inheritance history and that especially sporadic FTD may be associated with modifiable risk factors.

Background: Frontotemporal dementia (FTD) covers a spectrum of neurodegenerative disorders with various clinical and neuropathological subtypes. The two major pathological proteins accumulating in the brains of FTD patients, depending on their genetic background, are TDP-43 and tau. We aimed to evaluate whether total TDP-43 levels measured from the serum associate with the genotype or clinical phenotype of the FTD patients and whether serum TDP-43 provides prognostic or diagnostic value in the FTD spectrum disorders. Methods: The study cohort included 254 participants with a clinical diagnosis of FTD (including all major genotypes and clinical phenotypes) and 105 cognitively healthy controls. Serum total TDP-43 levels measured with a single-molecule array (Simoa) were compared within the FTD group according to the genotype, clinical phenotype, and predicted neuropathological subtype of the patients. We also evaluated the associations between the TDP-43 levels and disease severity or survival in FTD. Results: Total TDP-43 levels in the serum were significantly lower in the FTD group as compared to the healthy control group (275.3 pg/mL vs. 361.8 pg/mL, B = 0.181, 95%CI = 0.014–0.348, p = 0.034). The lowest TDP-43 levels were observed in the subgroup of FTD patients harboring predicted TDP-43 brain pathology (FTD-TDP, 241.4 pg/mL). The low levels in the FTD-TDP group were especially driven by C9orf72 repeat expansion carriers (169.2 pg/mL) and FTD patients with concomitant motoneuron disease (FTD-MND, 113.3 pg/mL), whereas GRN mutation carriers did not show decreased TDP-43 levels (328.6 pg/mL). Serum TDP-43 levels showed no correlation with disease severity nor progression in FTD. Conclusions: Our results indicate that the total levels of TDP-43 in the serum are decreased especially in FTD patients with the C9orf72 repeat expansion or FTD-MND phenotype, both subtypes strongly associated with TDP-43 type B brain pathology. Serum-based measurement of TDP-43 co

Early-onset dementia (EOD) is highly heritable. However, in many EOD cases the genetic etiology remains unknown. Mitochondrial dysfunction is associated with neurodegeneration and the complex I (CI) deficiency is the most common enzyme deficiency in diseases related to oxidative phosphorylation. The X-chromosomal NDUFA1 gene is essential for the activity of CI. Mutations in NDUFA1 are associated with mitochondrial diseases especially with Leigh syndrome. CI deficiency is also associated with neurodegenerative diseases, such as Alzheimer’s disease (AD). The aim of this study was to evaluate the role of NDUFA1 variants in EOD patients. Next-generation sequencing panel was used to screen NDUFA1 variants in a cohort of 37 EOD patients with a family history of dementia or an atypical or rapidly progressive course of disease. We identified a hemizygous p.Gly32Arg variant in two brothers with AD. Subsequent screening of the variant in a larger cohort of EOD patients (n = 279) revealed three additional variant carriers (one male and two heterozygote females), suggesting that NDUFA1 variant p.Gly32Arg may play a role in neurodegenerative dementia.

Extrapyramidal (EP) symptoms are a known feature in a subpopulation of patients with behavioral variant frontotemporal dementia (bvFTD). Concomitant EP symptoms with FTD-like neuropsychiatric symptoms are also core features in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). This complicates the early diagnosis of these disorders. Our retrospective register study aimed to discover imaging (MRI and FDG-PET) biomarkers to differentiate PSP, CBD, and bvFTD patients with extrapyramidal symptoms (EP +) from bvFTD patients without EP symptoms (EP-). The records of 2751 patients were screened for the diagnoses and presence of EP symptoms. A total of 222 patients were submitted to imaging analysis and applicable imaging data were recovered from 139 patients. Neuroimaging data were analyzed using Freesurfer software. In the whole cohort, EP + patients showed lower volumes of gray matter compared to EP- patients in the putamen (p = 0.002), bilateral globus pallidum (p = 0.002, p = 0.042), ventral diencephalon (p = 0.002) and brain stem (p < 0.001). In the bvFTD subgroup, there was volumetric difference between EP + and EP− patients in the brain stem. FDG-PET scans in the bvFTD patient subgroup showed that EP + patients had comparative hypometabolism of the superior cerebellar peduncle (SCP) and the frontal lobes. We discovered that EP symptoms are linked to brainstem atrophy in bvFTD patients and the whole cohort. Also, evident hypometabolism in the SCP of bvFTD EP + patients was detected as compared to bvFTD EP− patients. This could indicate that the EP symptoms in these diseases have a more caudal origin in the brainstem than in Parkinson’s disease.

Accumulation of amyloid-β is a key neuropathological feature in brain of Alzheimer’s disease patients. Alterations in cerebral haemodynamics, such as arterial impulse propagation driving the (peri)vascular CSF flux, predict future Alzheimer’s disease progression. We now present a non-invasive method to quantify the three-dimensional propagation of cardiovascular impulses in human brain using ultrafast 10 Hz magnetic resonance encephalography. This technique revealed spatio-temporal abnormalities in impulse propagation in Alzheimer’s disease. The arrival latency and propagation speed both differed in patients with Alzheimer’s disease. Our mapping of arterial territories revealed Alzheimer’s disease-specific modifications, including reversed impulse propagation around the hippocampi and in parietal cortical areas. The findings imply that pervasive abnormality in (peri)vascular CSF impulse propagation compromises vascular impulse propagation and subsequently glymphatic brain clearance of amyloid-β in Alzheimer’s disease.

Background: C9orf72 repeat expansion (C9exp) is the most common genetic cause underlying frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). However, detection of the C9exprequires elaborative methods. Objective: Identification of C9exp carriers from genotyped cohorts could be facilitated by using single nucleotide polymorphisms (SNPs) as markers for the C9exp. Methods: We elucidated the potential of the previously described Finnish risk haplotype, defined by the SNP rs3849942, to identify potential C9exp carriers among 218,792 Finns using the FinnGen database. The haplotype approach was first tested in an idiopathic normal pressure hydrocephalus (iNPH) patient cohort (European Alzheimer’s Disease DNA BioBank) containing C9exp carriers by comparing intermediate (15–30) and full-length (> 60 repeats) C9exp carriers (n = 41) to C9exp negative patients (< 15 repeats, n = 801). Results: In this analysis, rs3849942 was associated with carriership of C9exp (OR 8.44, p < 2 × 10–15), while the strongest association was found with rs139185008 (OR 39.4, p < 5 × 10–18). Unbiased analysis of rs139185008 in FinnGen showed the strongest association with FTLD (OR 4.38, 3 × 10–15) and motor neuron disease ALS (OR 5.19, 3 × 10–21). rs139185008 was the top SNP in all diseases (iNPH, FTLD, ALS), and further showed a strong association with ALS in the UK Biobank (p = 9.0 × 10–8). Conclusions: Our findings suggest that rs139185008 is a useful marker to identify potential C9exp carriers in the genotyped cohorts and biobanks originating from Finland.

Biomarkers sensitive to prodromal or early pathophysiological changes in Alzheimer’s disease (AD) symptoms could improve disease detection and enable timely interventions. Changes in brain hemodynamics may be associated with the main clinical AD symptoms. To test this possibility, we measured the variability of blood oxygen level-dependent (BOLD) signal in individuals from three independent datasets (totaling 80 AD patients and 90 controls). We detected a replicable increase in brain BOLD signal variability in the AD populations, which constituted a robust biomarker for clearly differentiating AD cases from controls. Fast BOLD scans showed that the elevated BOLD signal variability in AD arises mainly from cardiovascular brain pulsations. Manifesting in abnormal cerebral perfusion and cerebrospinal fluid convection, present observation presents a mechanism explaining earlier observations of impaired glymphatic clearance associated with AD in humans.

Background: Natalizumab (NTZ) is widely used for highly active relapsing-remitting multiple sclerosis (MS). Inflammatory disease activity often returns after NTZ treatment discontinuation. We aimed to identify predictive factors for such reactivation in a real-life setting. Methods: We conducted a retrospective survey in four Finnish hospitals. A computer-based search was used to identify all patients who had received NTZ for multiple sclerosis. Patients were included if they had received at least six NTZ infusions, had discontinued treatment for at least three months, and follow-up data was available for at least 12 months after discontinuation. Altogether 89 patients were analyzed with Cox regression model to identify risk factors for reactivation, defined as having a corticosteroid-treated relapse. Results: At 6 and 12 months after discontinuation of NTZ, a relapse was documented in 27.0% and 35.6% of patients, whereas corticosteroid-treated relapses were documented in 20.2% and 30.3% of patients, respectively. A higher number of relapses during the year prior to the introduction of NTZ was associated with a significantly higher risk for reactivation at 6 months (Hazard Ratio [HR] 1.65, p < 0.001) and at 12 months (HR 1.53, p < 0.001). Expanded Disability Status Scale (EDSS) of 5.5 or higher before NTZ initiation was associated with a higher reactivation risk at 6 months (HR 3.70, p = 0.020). Subsequent disease-modifying drugs (DMDs) failed to prevent reactivation of MS in this cohort. However, when subsequent DMDs were used, a washout time longer than 3 months was associated with a higher reactivation risk at 6 months regardless of whether patients were switched to first-line (HR 7.69, p = 0.019) or second-line therapies (HR 3.94, p = 0.035). Gender, age, time since diagnosis, and the number of NTZ infusions were not associated with an increased risk for reactivation. Conclusion: High disease activity and a high level of disability prior to NTZ tr

Objective: We describe the neurologic, neuroradiologic, and ophthalmologic phenotype of 1 Swedish and 1 Finnish family with autosomal dominant ataxia-pancytopenia (ATXPC) syndrome and SAMD9L mutations. Methods: Members of these families with germline SAMD9L c.2956C>T, p.Arg986Cys, or c.2672T>C, p.Ile891Thr mutations underwent structured interviews and neurologic and ophthalmologic examinations. Neuroimaging was performed, and medical records were reviewed. Previous publications on SAMD9L-ATXPC were reviewed. Results: Twelve individuals in both families were affected clinically. All mutation carriers examined had balance impairment, although severity was very variable. All but 1 had nystagmus, and all but 1 had pyramidal tract signs. Neurologic features were generally present from childhood on and progressed slowly. Two adult patients, who experienced increasing clumsiness, glare, and difficulties with gaze fixation, had paracentral retinal dysfunction verified by multifocal electroretinography. Brain MRI showed early, marked cerebellar atrophy in most carriers and variable cerebral periventricular white matter T2 hyperintensities. Two children were treated with hematopoietic stem cell transplantation for hematologic malignancies, and the neurologic symptoms of one of these worsened after treatment. Three affected individuals had attention deficit hyperactivity disorder or cognitive problems. Retinal dysfunction was not previously reported in individuals with ATXPC. Conclusions: The neurologic phenotype of this syndrome is defined by balance or gait impairment, nystagmus, hyperreflexia in the lower limbs and, frequently, marked cerebellar atrophy. Paracentral retinal dysfunction may contribute to glare, reading problems, and clumsiness. Timely diagnosis of ATXPC is important to address the risk for severe hemorrhage, infection, and hematologic malignancies inherent in this syndrome; regular hematologic follow-up might be beneficial.