The association of hypogonadism and cerebellar ataxia was first recognized in 1908 by Gordon Holmes. Since the seminal description, several heterogeneous phenotypes have been reported, differing for ...age at onset, associated features, and gonadotropins levels. In the last decade, the genetic bases of these disorders are being progressively uncovered. Here, we review the diseases associating ataxia and hypogonadism and the corresponding causative genes. In the first part of this study, we focus on clinical syndromes and genes (
RNF216, STUB1, PNPLA6, AARS2, SIL1, SETX
) predominantly associated with ataxia and hypogonadism as cardinal features. In the second part, we mention clinical syndromes and genes (
POLR3A, CLPP, ERAL1, HARS, HSD17B4, LARS2, TWNK, POLG, ATM, WFS1, PMM2, FMR1
) linked to complex phenotypes that include, among other features, ataxia and hypogonadism. We propose a diagnostic algorithm for patients with ataxia and hypogonadism, and we discuss the possible common etiopathogenetic mechanisms.
Background
So far, mutations in genes encoding lysosomal enzymes have been associated with Parkinson’s disease (PD). Fabry disease (FD) is an X-linked lysosomal storage disease caused by ...alpha-galactosidase A (α-GAL) deficiency, leading to deposition of globotriaosylceramide in the nervous system and other organs. We aimed to screen for FD a case series of PD patients from Southern Italy and to review the literature.
Methods
One hundred and forty-four consecutive unrelated PD subjects were enrolled. The α-GAL activity was measured in all men and, in case of pathological values, subsequent determination of globotriaosylsphingosine (lyso-Gb3) and
GLA
gene sequencing were also performed. All the women underwent
GLA
gene sequencing.
Results
α-GAL levels resulted low in fifteen men, whereas lyso-Gb3 testing showed values within the reference range in all of them.
GLA
gene variants were not detected in any tested subjects. One pathological study, six case series, and five case reports are currently reported in literature.
Conclusions
The few studies reviewed are heterogeneous, and the results are controversial. An unknown significance variant in
GLA
gene was detected in PD patients in one large study, whereas decreased α-GAL activity was observed in PD subjects in two other researches, but without confirmation by lyso-Gb3 assessment or genetic analysis. Vascular parkinsonism was associated to FD in five case reports. We found no association between PD and FD in our population. However, it is not possible to draw definitive conclusions due to limited sample size. Furthermore, controls would have been missing in case of a positive finding.
Objective:
Despite cognitive tests have been validated in multiple sclerosis (MS), a neuropsychological evaluation is not implemented in the Expanded Disability Status Scale (EDSS) scoring.
Methods:
...We used the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and orientation tests (OTs) to measure the cerebral functional system (CFS) score and to evaluate its impact on the EDSS. We compared EDSS calculated as usual (Native-EDSS) and after the use of the BICAMS and OT (NPS-EDSS).
Results:
We tested 604 MS patients with BICAMS, OTs, and EDSS. In all, 384 patients (63.6%) had at least one altered test at the BICAMS. Older age, lower education, higher Native-EDSS, and male gender were independently associated with at least one impaired BICAMS test. Native-EDSS was different from NPS-EDSS (−0.112; p < 0.001) in 99 patients (16%). When considering patients with a Native-EDSS ⩽ 4.0, the proportion of miscalculated EDSS was 25%.
Conclusion:
The use of brief neuropsychological tests leads to a more accurate CFS assessment in two-thirds of MS patients, and a more accurate EDSS calculation in 25% of patients with a score ⩽4.0. This may help clinicians to better recognize cognitive impairment in everyday clinical practice, especially in the case of isolated cognitive worsening.
To explore the feasibility of upper limbs cardiopulmonary exercise test (CPET) in Friedreich ataxia (FRDA) patients and to compare the results with sex, age, and body mass index (BMI) matched cohort ...of healthy controls (HC).
Cardiopulmonary exercise test was performed using an upper limbs cycle ergometer on fasting subjects. Peak oxygen uptake (peak VO2) was recorded as the mean value of VO2 during a 20 s period at the maximal effort of the test at an appropriate respiratory exchange rate. The ventilatory anaerobic threshold (AT) was detected by the use of the V-slope method. We performed echocardiography with an ultrasound system equipped with a 2.5 MHz multifrequency transducer for complete M-mode, two-dimensional, Doppler, and Tissue Doppler Imaging analyses. We studied 55 FRDA and 54 healthy matched controls (HC). Peak VO2 showed a significant 31% reduction in FRDA patients compared to HC (15.2 ± 5.7 vs. 22.0 ± 6.1 mL/kg/min; P < 0.001). Peak workload was reduced by 41% in FRDA (42.9 ± 12.5 vs. 73.1 ± 21.2 W; P < 0.001). In FRDA patients, peak VO2 is inversely correlated with the Scale for Assessment and Rating of Ataxia score, disease duration, and 9HPT performance, and directly correlated with activities of daily living. The AT occurred at 48% of peak workload time in FRDA patients and at 85% in HC (P < 0.001).
Upper limb CPET is useful in the assessment of exercise tolerance and a possible tool to determine the functional severity of the mitochondrial oxidative defect in patients with FRDA. The cardiopulmonary exercise test is an ideal functional endpoint for Phases II and III trials through a simple, non-invasive, and safe exercise test.
Objective
Friedreich ataxia (FRDA) is an inherited neurological disease defined by progressive movement incoordination. We undertook a comprehensive characterization of the spatial profile and ...progressive evolution of structural brain abnormalities in people with FRDA.
Methods
A coordinated international analysis of regional brain volume using magnetic resonance imaging data charted the whole‐brain profile, interindividual variability, and temporal staging of structural brain differences in 248 individuals with FRDA and 262 healthy controls.
Results
The brainstem, dentate nucleus region, and superior and inferior cerebellar peduncles showed the greatest reductions in volume relative to controls (Cohen d = 1.5–2.6). Cerebellar gray matter alterations were most pronounced in lobules I–VI (d = 0.8), whereas cerebral differences occurred most prominently in precentral gyri (d = 0.6) and corticospinal tracts (d = 1.4). Earlier onset age predicted less volume in the motor cerebellum (rmax = 0.35) and peduncles (rmax = 0.36). Disease duration and severity correlated with volume deficits in the dentate nucleus region, brainstem, and superior/inferior cerebellar peduncles (rmax = −0.49); subgrouping showed these to be robust and early features of FRDA, and strong candidates for further biomarker validation. Cerebral white matter abnormalities, particularly in corticospinal pathways, emerge as intermediate disease features. Cerebellar and cerebral gray matter loss, principally targeting motor and sensory systems, preferentially manifests later in the disease course.
Interpretation
FRDA is defined by an evolving spatial profile of neuroanatomical changes beyond primary pathology in the cerebellum and spinal cord, in line with its progressive clinical course. The design, interpretation, and generalization of research studies and clinical trials must consider neuroanatomical staging and associated interindividual variability in brain measures. ANN NEUROL 2021;90:570–583
Wilson's Disease (WD) is an autosomal recessive disorder caused by excessive copper deposition in liver, brain and other organs. The clinical picture is characterized by hepatic, psychiatric and ...neurological dysfunction. Movement disorders are the core neurological features, although non-motor symptoms (NMS), as cognitive/affective, autonomic and sleep disorders, may occur over time. We aimed to assess the frequency of NMS in WD patients compared with healthy subjects.
Twenty-seven patients affected with genetically proven WD (12 F, 15 M) and 35 healthy controls (Ctrl; 17 F, 18 M), comparable for age and education, were enrolled. Eighteen patients presented with the neurological form of the disease (NV) and nine with the non-neurological variant (NNV). NMS were assessed in all subjects by the following clinical scales: Mini-Mental State Examination (MMSE), Non-Motor Symptoms Scale (NMSS), SCOPA-AUT Questionnaire, Apathy Evaluation Scale (AES), Beck Depression Inventory (BDI), Epworth Sleepiness Scale (ESS), Restless Legs Syndrome Rating Scale (RLSRS), REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP-RS).
We found that the patients showed more severe and frequent NMS and daytime sleepiness, and lower MMSE than Ctrl. In comparison to healthy subjects, NV subjects showed statistically significant higher ESS, NMSS, and RLSRS scores, and a lower MMSE score. Subtle and subclinical extrapyramidal/pyramidal signs and brain MRI signal abnormalities were detected in patients considered as asymptomatic for neurological disturbances.
NMS are common among WD patient, in particular those with NV, likely due to the widespread pathological changes throughout the central nervous system.
•Wilson's Disease (WD) is mostly characterized by motor, psychiatric and cognitive symptoms.•We aimed to assess and characterize other non-motor symptoms (NMS), as affective, sleep, and autonomic disorders.•NMS are more severe and frequent in WD subjects than controls.
Oculomotor deficits are common in hereditary ataxia, but disproportionally neglected in clinical ataxia scales and as outcome measures for interventional trials. Quantitative assessment of oculomotor ...function has become increasingly available and thus applicable in multicenter trials and offers the opportunity to capture severity and progression of oculomotor impairment in a sensitive and reliable manner. In this consensus paper of the Ataxia Global Initiative Working Group On Digital Oculomotor Biomarkers, based on a systematic literature review, we propose harmonized methodology and measurement parameters for the quantitative assessment of oculomotor function in natural-history studies and clinical trials in hereditary ataxia. MEDLINE was searched for articles reporting on oculomotor/vestibular properties in ataxia patients and a study-tailored quality-assessment was performed. One-hundred-and-seventeen articles reporting on subjects with genetically confirmed (
n
=1134) or suspected hereditary ataxia (
n
=198), and degenerative ataxias with sporadic presentation (
n
=480) were included and subject to data extraction. Based on robust discrimination from controls, correlation with disease-severity, sensitivity to change, and feasibility in international multicenter settings as prerequisite for clinical trials, we prioritize a core-set of five eye-movement types: (i) pursuit eye movements, (ii) saccadic eye movements, (iii) fixation, (iv) eccentric gaze holding, and (v) rotational vestibulo-ocular reflex. We provide detailed guidelines for their acquisition, and recommendations on the quantitative parameters to extract. Limitations include low study quality, heterogeneity in patient populations, and lack of longitudinal studies. Standardization of quantitative oculomotor assessments will facilitate their implementation, interpretation, and validation in clinical trials, and ultimately advance our understanding of the evolution of oculomotor network dysfunction in hereditary ataxias.
Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant ...advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2,
n
= 421), SCA3 (
n
= 268), SCA6 (
n
= 117), other SCAs (
n
= 97), Friedreich ataxia (FRDA,
n
= 178), Niemann-Pick disease type C (NPC,
n
= 57), and ataxia-telangiectasia (
n
= 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression (
n
= 2; SCA2) or treatment response (
n
= 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores (
n
= 18 studies (SARA:
n
= 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset;
n
= 17), genetic stratification (
n
= 9), and imaging measures of atrophy (
n
= 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes.
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