Huntington's disease (HD) is a progressive neurodegenerative disease, characterised by motor disturbances and non-motor (i.e., psychiatric) symptoms. Motor symptoms are the hallmark features of HD ...and take many forms. Their emergence is related to alterations in striatal dopaminergic neurotransmission: dopamine levels increase in the early stages of the disease, while more advanced stages are characterised by reduced dopamine levels. Such a biphasic change potentially explains the alterations in motor symptoms: increased dopamine-production induces hyperkinetic movements early in the disease course, while depleted dopamine storage leads to hypokinetic symptoms in the advanced phase. Dopamine D2-D3 partial agonists could be a promising treatment option in HD, as they have the potential to either elevate or lower the surrounding dopamine levels if the levels are too low or too high, respectively, potentially offering symptom-relief across the illness-course. Therefore, the present study aimed at exploring the effects of cariprazine, a dopamine D2-D3 partial agonist with high affinity to D3 receptors, on motor symptoms associated with HD. This was a single-centre, retrospective study where sixteen patients received off-label cariprazine treatment for 12 weeks (1.5-3 mg/day). Motor symptoms were evaluated using the Motor Assessment of the Unified Huntington's Disease Rating Scale. Least Square (LS) Mean Changes from Baseline (BL) to Week 8 and Week 12 in the Total Motor Score (TMS) were analysed using the Mixed Model for Repeated Measures method. In addition, improvement from BL to Week 8 and 12 was calculated for all motor items. Data of 16 patients were collected, but data of only 15 patients were analysed as one patient dropped out due to non-compliance. Significant changes were observed from BL to Week 8 (LS Mean Change: -9.4, p < 0.0001) and to Week 12 (LS Mean Change: -12.8, p < 0.0001) in the TMS. The improvement was captured in the majority of motor functions, excluding bradykinesia and gait. Mild akathisia was the most commonly reported side-effect, affecting 3 patients. This is the first study investigating the effectiveness of a D2-D3 partial agonist, cariprazine, in the treatment of HD. The findings of this study revealed that cariprazine was effective in the treatment of a wide range of motor symptoms associated with HD.
Background and purpose
Seven thousand rare diseases have been identified; most of them are of genetic origin. The diagnosis of a neurogenetic disease is difficult, and management and training ...programs are not well defined through Europe. To capture and assess care needs, the Neurogenetics Panel of the European Academy of Neurology (EAN) has performed an explorative survey.
Methods
The survey covering multiple topics of neurogenetics was sent to all neurologists and neuropediatricians affiliated with the EAN practicing in Europe.
Results
We collected answers from 239 members based in 40 European member states. Even though most of the responders were aware of neurogenetic diseases, when we came to amenability of carrying out a complete genetic diagnosis, almost one‐third of the responders declared they were not happy with the current way of ordering genetic analyses in their countries. Furthermore, although single‐gene analysis is diffusely present in Europe, whole exome and genome sequencing are not easily accessible, with considerable variabilities among countries. Almost 10% of the responders did not know if presymptomatic and prenatal diagnosis was available in their countries, and 47.3% were not aware of which newborn screening programs were available. Finally, 96.3% of responders declared that there is a need for education and training in neurogenetics.
Conclusions
We believe that this survey may be of importance for all European stakeholders in neurogenetics in identifying key priorities, targeting areas to encourage education/travel fellowships, and educational seminars in the future, because this area will only accelerate, and diagnostic requirements will expand.
The diagnosis of a neurogenetic disease is difficult, and management and training programs are not well defined through Europe. To capture and assess care needs, the Neurogenetics Panel of the European Academy of Neurology has performed an explorative survey. We believe that this survey may be of importance for all European stakeholders in neurogenetics in identifying key priorities.
We present a male patient carrying a pathogenic MECP2 p. Arg179Trp variant with predominant negative psychiatric features and multilevel evidence of mitochondrial dysfunction who responded to the ...cariprazine treatment. He had delayed speech development and later experienced severe social anxiety, learning disabilities, cognitive slowing, and predominant negative psychiatric symptoms associated with rigidity. Clinical examinations showed multisystemic involvement. Together with elevated ergometric lactate levels, the clinical picture suggested mitochondrial disease, which was also supported by muscle histopathology. Exploratory transcriptome analysis also revealed the involvement of metabolic and oxidative phosphorylation pathways. Whole-exome sequencing identified a pathogenic MECP2 variant, which can explain both the dopamine imbalance and mitochondrial dysfunction in this patient. Mitochondrial dysfunction was previously suggested in classical Rett syndrome, and we detected related phenotype evidence on multiple consistent levels for the first time in a MECP2 variant carrier male. This study further supports the importance of the MECP2 gene in the mitochondrial pathways, which can open the gate for more personalized therapeutic interventions. Good cariprazine response highlights the role of dopamine dysfunction in the complex psychiatric symptoms of Rett syndrome. This can help identify the optimal treatment strategy from a transdiagnostic perspective instead of a classical diagnostic category.
Background and purpose
Hormonal replacement therapy (HRT) is used for symptomatic treatment of menopause. Some evidence suggests a proconvulsant effect of estrogen and an anticonvulsant role of ...progesterone. Thus, the use of exogenous sex steroid hormones might influence the course of epilepsy in peri‐ and postmenopausal women with epilepsy (WWE). We conducted a systematic review on the impact of HRT on the frequency of seizures of WWE.
Methods
PubMed and Scopus were searched for articles published from inception until August 2022. s from the past 5 years from the European Academy of Neurology and European Epilepsy Congresses were also reviewed. Article reference lists were screened, and relevant articles were retrieved for consultation. Interventional and observational studies on WWE and animal models of estrogen deficiency were included. Critical appraisal was performed using the revised Cochrane risk‐of‐bias tool for randomized trials and ROBINS‐E tool.
Results
Of 497 articles screened, 13 studies were included, including three human studies. One cross‐sectional study showed a decrease in seizure frequency in WWE using combined HRT, a case–control study showed an increase in comparison with controls, and a randomized clinical trial found a dose‐dependent increase in seizure frequency in women with focal epilepsy taking combined HRT. Ten studies addressing the impact of HRT in rat models were also included, which showed conflicting results.
Conclusions
There is scarce evidence of the impact of HRT in WWE. Further studies should evaluate the harmful potential, and prospective registries are needed for monitoring this population.
Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry ...disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m
/year who had received agalsidase beta for ≥1 year.
Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms.
Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m
and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m
/year. At 2 years, the difference between median eGFR slopes was -0.36 mL/min/1.73 m
/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths.
Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions.
NCT02795676.
In Huntington's disease (HD), the main clinical symptoms include depression, apathy, cognitive deficits, motor deficiencies and involuntary movements. Cognitive, mood and behavioral changes may ...precede motor symptoms by up to 15 years. The treatment of these diverse symptoms is challenging. Tetrabenazine and deutetrabenazine are the only medications specifically approved for Huntington's chorea, but they do not affect the non-motor symptoms. For these, antidepressants, antipsychotics, and benzodiazepines have demonstrated benefit in some cases and can be used off-label. These drugs, due to sedative side effects, may negatively influence cognition. Sixteen patients having HD received a 12-week off-label cariprazine (CAR) treatment (1.5-3 mg/day). Cognitive performance and behavioral changes were measured by the Addenbrooke Cognitive Examination (ACE) test, the Cognitive and Behavioral part of the Unified Huntington's Disease Rating Scale (UHDRS), and the Beck Depression Inventory (BDI). Mixed model for repeated measures was fitted to the data, with terms of visit, baseline (BL) and their interaction. Cariprazine treatment resulted in the following changes from BL to week 12, respectively: the mean score of BDI decreased from 17.7 ± 10.7 to 10.0 ± 10.7 (
<0.0097), while the Behavioral Assessment score of the UHDRS decreased from 54.9 ± 11.3 to 32.5 ± 15.4 (
< 0.0001); ACE score increased from 75.1 ± 11.0 to 89.0 ± 9.3 (
< 0.0001); Cognitive Verbal Fluency score from 6.2 ± 2.5 to 7.7 ± 2.7 (
< 0.0103); Symbol Digit Test from 9.2 ± 6.9 to 12.3 ± 8.9 (
< 0.0009). Mild akathisia was the most frequent side effect, presenting in 2 out of 16 patients (12.5%). We conclude that CAR had a positive effect on depressive mood, apathy and cognitive functions in patients with early stage of HD. Based on the neurobiological basis of these symptoms, CAR can improve the dopamine imbalance of the prefrontal cortex. This draws attention to the transdiagnostic approach which supports the further understanding of the similar symptomatology of different neuropsychiatric disorders and helps to identify new indications of pharmaceutical compounds.
Background and purpose
Primary mitochondrial diseases (PMDs) are common inborn errors of energy metabolism, with an estimated prevalence of one in 4300. These disorders typically affect tissues with ...high energy requirements, including heart, muscle and brain. Epilepsy may be the presenting feature of PMD, can be difficult to treat and often represents a poor prognostic feature. The aim of this study was to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy.
Methods
A panel of 24 experts in mitochondrial medicine, pharmacology and epilepsy management of adults and/or children and two patient representatives from seven countries was established. Experts were members of five different European Reference Networks, known as the Mito InterERN Working Group. A Delphi technique was used to allow the panellists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two rounds with predetermined levels of agreement.
Results
A high level of consensus was reached regarding the safety of 14 out of all 25 drugs reviewed, resulting in endorsement of National Institute for Health and Care Excellence guidelines for seizure management, with some modifications. Exceptions including valproic acid in POLG disease, vigabatrin in patients with γ‐aminobutyric acid transaminase deficiency and topiramate in patients at risk for renal tubular acidosis were highlighted.
Conclusions
These consensus recommendations describe our intent to improve seizure control and reduce the risk of drug‐related adverse events in individuals living with PMD‐related epilepsy.
Abstract Background Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases with progressive lower limb spasticity and weakness. The ...aim of this study is to determine the frequency of different SPG mutations in Hungarian patients, and to provide further genotype-phenotype correlations for the known HSP causing genes. Methods We carried out genetic testing for 58 probands with clinical characteristics of HSP. For historical reasons, three different approaches were followed in different patients: 1) Sanger sequencing of ATL1 and SPAST genes, 2) whole exome, and 3) targeted panel sequencing by next generation sequencing. Results Genetic diagnosis was established for 20 probands (34.5%). We detected nine previously unreported mutations with high confidence for pathogenicity. The most frequently affected gene was SPAST with pathogenic or likely pathogenic mutations in 10 probands. The most frequently detected variant in our cohort was the SPG7 p.Leu78*, observed in four probands. Altogether five probands were diagnosed with SPG7. Additional mutations were detected in SPG11 , ATL1 , NIPA1 , and ABCD1. Conclusion This is the first comprehensive genetic epidemiological study of patients with HSP in Hungary. Next generation sequencing improved the yield of genetic diagnostics in this disease group even when the phenotype was atypical. However, considering the frequency of the HSP-causing gene defects, SPG4, the most common form of the disease, should be tested first to be cost effective in this economic region.
Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive disease caused by biallelic pathogenic variants in the sphingomyelin phosphodiesterase-1 (
) gene. Acid sphingomyelinase deficiency ...is characterized by a spectrum of disease and is broadly divided into three types (ASMD type A, ASMD type A/B, and ASMD type B). More than 220 disease-associated
variants have been reported, and genotype/phenotype correlations are limited. Here we report the first description of all six diagnosed acid sphingomyelinase deficiency cases in Hungary. Nine
variants are present in this cohort, including 3
variants (G247D, M384R, and F572L), which have only been described in Hungarian patients. All described variants are deemed to be pathogenic. Eight of the variants are missense, and one is a frameshift variant. The treatment of an ASMD type A/B patient in this cohort using hematopoietic stem cell transplantation is also detailed. This study may help to support diagnosis, patient genetic counseling, and management of acid sphingomyelinase deficiency.
PDF
