Calcitriol Treatment Is Safe and Increases Frataxin Levels in Friedreich Ataxia Patients.

BACKGROUND: Calcitriol, the active form of vitamin D (also known as 1,25-dihydroxycholecalciferol), improves the phenotype and increases frataxin levels in cell models of Friedreich ataxia (FRDA). OBJECTIVES: Based on these results, we aimed measuring the effects of a calcitriol dose of 0.25 mcg/24h in the neurological function and frataxin levels when administered to FRDA patients for a year. METHODS: 20 FRDA patients where recluted and 15 patients completed the treatment for a year. Evaluations of neurological function changes (SARA scale, 9-HPT, 8-MWT, PATA test) and quality of life (Barthel Scale and Short Form (36) Health Survey [SF-36] quality of life questionnaire) were performed. Frataxin amounts were measured in isolated platelets obtained from these FRDA patients, from heterozygous FRDA carriers (relatives of the FA patients) and from non-heterozygous sex and age matched controls. RESULTS: Although the patients did not experience any observable neurological improvement, there was a statistically significant increase in frataxin levels from initial values, 5.5 to 7.0 pg/µg after 12 months. Differences in frataxin levels referred to total protein levels were observed among sex- and age-matched controls (18.1 pg/µg), relative controls (10.1 pg/µg), and FRDA patients (5.7 pg/µg). The treatment was well tolerated by most patients, and only some of them experienced minor adverse effects at the beginning of the trial. CONCLUSIONS: Calcitriol dosage used (0.25 mcg/24 h) is safe for FRDA patients, and it increases frataxin levels. We cannot rule out that higher doses administered longer could yield neurological benefits. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.

BACKGROUND: The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis. METHODS: We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines. RESULTS: In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of FGF14, which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA]≥250). There was significant association between FGF14 (GAA)≥250 expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95% confidence interval [CI], 31.09 to 334.20; P<0.001) and in the German series (odds ratio, 8.76; 95% CI, 3.45 to 20.84; P<0.001). The repeat expansion was present in 61%, 18%, 15%, and 10% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an FGF14 (GAA)≥250 expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein. CONCLUSIONS: A dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.).

Heterozygous STUB1 mutation causes familial ataxia with cognitive affective syndrome (SCA48).

OBJECTIVE: To describe a new spinocerebellar ataxia (SCA48) characterized by early cerebellar cognitive-affective syndrome (CCAS) and late-onset SCA. METHODS: This is a descriptive study of a family that has been followed for more than a decade with periodic neurologic and neuropsychological examinations, MRI, brain SPECT perfusion, and genetic analysis. Whole exome sequencing was performed in 3 affected and 1 unaffected family member and subsequently validated by linkage analysis of chromosome 16p13.3. RESULTS: Six patients fully developed cognitive-affective and complete motor cerebellar syndrome associated with vermian and hemispheric cerebellar atrophy, suggesting a continuum from a dysexecutive syndrome slowly evolving to a complete and severe CCAS with late truncal ataxia. Three presymptomatic patients showed focal cerebellar atrophy in the vermian, paravermian, and the medial part of cerebellar lobes VI and VII, suggesting that cerebellar atrophy preceded the ataxia, and that the neurodegeneration begins in cerebellar areas related to cognition and emotion, spreading later to the whole cerebellum. Among the candidate variants, only the frameshift heterozygous c.823_824delCT STUB1 (p.L275Dfs*16) pathogenic variant cosegregated with the disease. The p.L275Dfs*16 heterozygous STUB1 pathogenic variant leads to neurodegeneration and atrophy in cognition- and emotion-related cerebellar areas and reinforces the importance of STUB1 in maintaining cognitive cerebellar function. CONCLUSIONS: We report a heterozygous STUB1 pathogenic genetic variant causing dominant cerebellar ataxia. Since recessive mutations in STUB1 gene have been previously associated with SCAR16, these findings suggest a previously undescribed SCA locus (SCA48; MIM# 618093).

A randomized, controlled, single-blind, 6-month pilot study to evaluate the efficacy of MS-Line!: a cognitive rehabilitation programme for patients with multiple sclerosis.

BACKGROUND: MS-Line! was created to provide an effective treatment for cognitive impairment in multiple sclerosis (MS) patients. OBJECTIVE: To assess the efficacy of MS-Line!. METHODS: A randomized, controlled, single-blind, 6-month pilot study. Patients were randomly assigned to an experimental group (cognitive rehabilitation with the programme) or to a control group (no cognitive rehabilitation). Randomization was stratified by cognitive impairment level. Cognitive assessment included: selective reminding test, 10/36 spatial recall test (10/36 SPART), symbol digit modalities test, paced auditory serial addition test, word list generation (WLG), FAS test, subtests of WAIS-III, Boston naming test (BNT), and trail making test (TMT). RESULTS: Forty-three patients (22 in the experimental group, 21 in the control group) were analyzed. Covariance analysis showed significant differences in 10/36 SPART (P=0.0002), 10/36 SPART delayed recall (P=0.0021), WLG (P=0.0123), LNS (P=0.0413), BNT (P=0.0007) and TMT-A (P=0.010) scores between groups. CONCLUSIONS: The study showed a significant improvement related to learning and visual memory, executive functions, attention and information processing speed, and naming ability in those patients who received cognitive rehabilitation. The results suggest that MS-Line! is effective in improving cognitive impairment in MS patients.

A new cognitive rehabilitation programme for patients with multiple sclerosis: the 'MS-line! Project'.

BACKGROUND: Cognitive rehabilitation is often delayed in multiple sclerosis (MS). OBJECTIVE: To develop a free and specific cognitive rehabilitation programme for MS patients to be used from early stages that does not interfere with daily living activities. METHODS: MS-line!, cognitive rehabilitation materials consisting of written, manipulative and computer-based materials with difficulty levels developed by a multidisciplinary team. RESULTS: Mathematical, problem-solving and word-based exercises were designed. Physical materials included spatial, coordination and reasoning games. Computer-based material included logic and reasoning, working memory and processing speed games. CONCLUSIONS: Cognitive rehabilitation exercises that are specific for MS patients have been successfully developed.

Central nervous system drug consumption depending on the time between symptom onset and the diagnosis of Alzheimer's disease: an analysis by the Registry of Dementias of Girona.

AIMS: To describe central nervous system (CNS) drug consumption patterns depending on the time to diagnosis of Alzheimer's disease (AD), and to check whether the cases diagnosed later are associated with greater severity and consuming more CNS drugs. METHODS: Cross-sectional study using 952 cases of the Registry of Dementias of Girona. A binary logistic regression was used to detect variables associated with the use of CNS drugs depending on the time to diagnosis. RESULTS: CNS drugs were consumed by 95.8% of the AD patients. Only antipsychotics presented a statistically significant increase in the frequency of prescription to patients with longer time elapsed from symptom onset to AD diagnosis. CONCLUSION: Longer time elapsed from the onset of symptoms to the diagnosis resulted in increased probability of antipsychotic consumption.

Ataxia rating scales--psychometric profiles, natural history and their application in clinical trials.

We aimed to perform a comprehensive systematic review of the existing ataxia scales. We described the disorders for which the instruments have been validated and used, the time spent in its application, its validated psychometric properties, and their use in studies of natural history and clinical trials. A search from 1997 onwards was performed in the MEDLINE, LILACS, and Cochrane databases. The web sites ClinicalTrials.gov and Orpha.net were also used to identify the endpoints used in ongoing randomized clinical trials. We identified and described the semiquantitative ataxia scales (ICARS, SARA, MICARS, BARS); semiquantitative ataxia and non-ataxia scales (UMSARS, FARS, NESSCA); a semiquantitative non-ataxia scale (INAS); quantitative ataxia scales (CATSYS 2000, AFCS, CCFS and CCFSw, and SCAFI); and the self-performed ataxia scale (FAIS). SARA and ICARS were the best studied and validated so far, and their reliability sustain their use. Ataxia and non-ataxia scores will probably provide a better view of the overall disability in long-term trials and studies of natural history. Up to now, no clear advantage has been disclosed for any of them; however, we recommend the use of specific measurements of gait since gait ataxia is the first significant manifestation in the majority of ataxia disorders and comment on the best scales to be used in specific ataxia forms. Quantitative ataxia scales will be needed to speed up evidence from phase II clinical trials, from trials focused on the early phase of diseases, and for secondary endpoints in phase III trials. Finally, it is worth remembering that estimation of the actual minimal clinically relevant difference is still lacking; this, together with changes in quality of life, will probably be the main endpoints to measure in future therapeutic studies.

High-frequency stimulation of the ventrolateral thalamus regulates gene expression in hippocampus, motor cortex and caudate-putamen.

High-frequency stimulation (HFS) of the ventrolateral (VL) thalamus is effective in treating the resting tremor of Parkinson's disease (PD). PD is a movement disorder that involves neurodegeneration, predominantly of the substantia nigra, but also in other brain areas, such as the motor cortex and hippocampus. The mechanisms of action of HFS on remote brain areas at the molecular level are largely unknown. Here, we investigated gene expression profiles using oligonucleotide microarrays and quantitative real-time PCR in rat hippocampi. We showed that chronic (14days) HFS modulates the expression of 176 hippocampal genes. Our results showed that genes involved in proliferation and neurogenesis-related biological functions were specifically regulated by HFS, including nestin (Nes) and doublecortin (Dcx), which are expressed in neural progenitor cells and immature neurons, respectively, as well as genes encoding proteins that may support neural differentiation or migration, such as Timp1, Ccl2, S100a4 and Angpt2. Next, we used quantitative real-time PCR (RT-PCR) to profile these six genes in the motor cortex and the caudate-putamen, which included the subventricular zone (CPu-SVZ). Interestingly, HFS increased Dcx expression in the motor cortex whereas Nes was upregulated in the CPu-SVZ but not in the motor cortex. In the CPu-SVZ Timp1 and Ccl2 were highly upregulated by HFS. In conclusion, our findings suggest that HFS may enhance neuroplasticity at the molecular level in several remote brain areas such as the CPu-SVZ, motor cortex and hippocampus.

Abnormal corticospinal tract modulation of the soleus H reflex in patients with pure spastic paraparesis.

Central motor conduction time (CMCT) is usually abnormally prolonged in leg muscles of patients with pure hereditary spastic paraparesis (PHSP). One consequence of such abnormality should be an abnormal timing in the modulation of segmental reflexes, which might be more relevant for the pathophysiology of spasticity-related gait disturbances than just the CMCT delay. We examined the effects of transcranial magnetic stimulation (TMS) on the soleus H reflex in 13 control subjects and 11 PHSP patients using a conditioning (TMS) and test (H reflex) paradigm. Interstimulus interval (ISI) was 0-100 ms in steps of 10 ms. The amplitude of the H reflex at each interval was expressed as percentage of the control H reflex and the conditioned curves were compared between control subjects and patients. In control subjects, TMS-induced facilitation of the H reflex with two well-defined phases: early (ISIs 10 and 20 ms) and late (ISIs 70-90 ms). In patients, the early phase of facilitation was significantly reduced, while there was facilitation at 40 ms that was not present in control subjects. However, neither the characteristics of the MEP nor the differential modulation of the H reflex correlated significantly with clinical measures of motor dysfunction. Our results indicate an abnormal effect of TMS on the H reflex in PHSP patients. This suggests that the excitability of interneurons and soleus motoneurons is not modified in tune with the arrival of descending inputs. Desynchronization of the descending volley may contribute to both the lack of early facilitation and the presence of abnormal facilitatory phases.

Giant SCA8 alleles in nine children whose mother has two moderately large ones.

We report here a family in which each of nine children has inherited giant SCA8 CTG expansions from a homozygous mother who has two moderately large SCA8 CTG alleles. In contrast, three homozygous male individuals and a case of coexistence of two expansions of the FRDA gene and one of SCA8, all of them with moderately large alleles, have transmitted their respective SCA8 expanded alleles with minor changes, as usually occurs in heterozygous male transmissions.

Decreased hypocretin-1 (Orexin-A) levels in the cerebrospinal fluid of patients with myotonic dystrophy and excessive daytime sleepiness.

STUDY OBJECTIVE: Myotonic dystrophy type 1 is a multisystem disorder with myotonia, muscle weakness, cataracts, endocrine dysfunction, and intellectual impairment. This disorder is caused by a CTG triplet expansion in the 3' untranslated region of the DMPK gene on 19q13. Myotonic dystrophy type 1 is frequently associated with excessive daytime sleepiness, sharing with narcolepsy a short sleep latency and the presence of sleep-onset rapid eye movement periods during the Multiple Sleep Latency Test. Since narcolepsy is characterized by a dysfunction of the hypothalamic hypocretin system, we investigated whether patients with myotonic dystrophy type 1 with excessive daytime sleepiness have abnormalities in the hypocretin system. DESIGN/PARTICIPANTS: Six patients with myotonic dystrophy type 1 complaining of excessive daytime sleepiness and 13 healthy controls without a sleep disorder were included. The patients with myotonic dystrophy type 1 were evaluated using clinical interviews, nocturnal polysomnograms, and Multiple Sleep Latency Tests. All patients had a confirmed genetic diagnosis for DM1 and were HLA typed. Cerebrospinal fluid hypocretin-1 levels were measured using a direct radioimmunoassay in patients and controls. SETTING: University hospital sleep laboratory. INTERVENTIONS: N/A. MEASUREMENT AND RESULTS: The mean sleep latency on Multiple Sleep Latency Tests was abnormal in all patients (< 5 minutes in 2, < or = 8 in 4) and 2 sleep-onset rapid eye movement periods were observed in 2 subjects. All patients were HLA-DQB1*0602 negative. Hypocretin-1 levels were significantly lower in patients versus controls (p < 0.001); 1 case with 2 sleep-onset rapid eye movement periods had hypocretin-1 levels in the range generally observed in narcolepsy (< 110 pg/mL). Three cases had intermediate levels (110-200 pg/mL). Hypocretin-1 levels did not correlate clinically with disease severity or duration or with subjective or objective sleepiness reports. CONCLUSIONS: A dysfunction of the hypothalamic hypocretin system may mediate sleepiness and abnormal Multiple Sleep Latency Test results in patients with myotonic dystrophy type 1.