Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive, neurodegenerative disease associated with a wide variety of progressive neurological manifestations. Miglustat is indicated for the ...treatment of progressive neurological manifestations in both adults and children. Since approval in 2009 there has been a vast growth in clinical experience with miglustat. The effectiveness of miglustat has been assessed using a range of measures.
Comprehensive review of published data from studies of cellular neuropathological markers and structural neurological indices in the brain, clinical impairment/disability, specific clinical neurological manifestations, and patient survival.
Cranial diffusion tensor imaging and magnetic resonance spectroscopy studies have shown reduced levels of choline (a neurodegeneration marker), and choline/N-acetyl aspartate ratio (indicating increased neuronal viability) in the brain during up to 5 years of miglustat therapy, as well as a slowing of reductions in fractional anisotropy (an axonal/myelin integrity marker). A 2-year immunoassay study showed significant reductions in CSF-calbindin during treatment, indicating reduced cerebellar Purkinje cell loss. Magnetic resonance imaging studies have demonstrated a protective effect of miglustat on cerebellar and subcortical structure that correlated with clinical symptom severity. Numerous cohort studies assessing core neurological manifestations (impaired ambulation, manipulation, speech, swallowing, other) using NP-C disability scales indicate neurological stabilization over 2-8 years, with a trend for greater benefits in patients with older (non-infantile) age at neurological onset. A randomized controlled trial and several cohort studies have reported improvements or stabilization of saccadic eye movements during 1-5 years of therapy. Swallowing was also shown to improve/remain stable during the randomized trial (up to 2 years), as well as in long-term observational cohorts (up to 6 years). A meta-analysis of dysphagia - a potent risk factor for aspiration pneumonia and premature death in NP-C - demonstrated a survival benefit with miglustat due to improved/stabilized swallowing function.
The effects of miglustat on neurological NP-C manifestations has been assessed using a range of approaches, with benefits ranging from cellular changes in the brain through to visible clinical improvements and improved survival.
Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that primarily affects females, resulting in severe cognitive and physical disabilities, and is one of the most prevalent causes of ...intellectual disability in females. More than fifty years after the first publication on Rett syndrome, and almost two decades since the first report linking RTT to the
gene, the research community's effort is focused on obtaining a better understanding of the genetics and the complex biology of RTT and Rett-like phenotypes without
mutations. Herein, we review the current molecular genetic studies, which investigate the genetic causes of RTT or Rett-like phenotypes which overlap with other genetic disorders and document the swift evolution of the techniques and methodologies employed. This review also underlines the clinical and genetic heterogeneity of the Rett syndrome spectrum and provides an overview of the RTT-related genes described to date, many of which are involved in epigenetic gene regulation, neurotransmitter action or RNA transcription/translation. Finally, it discusses the importance of including both phenotypic and genetic diagnosis to provide proper genetic counselling from a patient's perspective and the appropriate treatment.
Classical Rett syndrome (RTT) is a neurodevelopmental disorder where most of cases carry
MECP2
mutations. Atypical RTT variants involve mutations in
CDKL5
and
FOXG1
. However, a subset of RTT ...patients remains that do not carry any mutation in the described genes. Whole exome sequencing was carried out in a cohort of 21 female probands with clinical features overlapping with those of RTT, but without mutations in the customarily studied genes. Candidates were functionally validated by assessing the appearance of a neurological phenotype in
Caenorhabditis elegans
upon disruption of the corresponding ortholog gene. We detected pathogenic variants that accounted for the RTT-like phenotype in 14 (66.6 %) patients. Five patients were carriers of mutations in genes already known to be associated with other syndromic neurodevelopmental disorders. We determined that the other patients harbored mutations in genes that have not previously been linked to RTT or other neurodevelopmental syndromes, such as the ankyrin repeat containing protein
ANKRD31
or the neuronal acetylcholine receptor subunit alpha-5 (CHRNA5). Furthermore, worm assays demonstrated that mutations in the studied candidate genes caused locomotion defects. Our findings indicate that mutations in a variety of genes contribute to the development of RTT-like phenotypes.
Mucopolysaccharidosis type VII (Sly syndrome) is an ultra-rare neurometabolic disorder caused by inherited deficiency of the lysosomal enzyme beta-glucuronidase. Precise data regarding its ...epidemiology are scarce, but birth prevalence is estimated to vary from 0.02 to 0.24 per 100,000 live births. The clinical course and disease progression are widely heterogeneous, but most patients have been reported to show signs such as skeletal deformities or cognitive delay. Additionally, detection criteria are not standardized, resulting in delayed diagnosis and treatment. We present a cohort of 9 patients with mucopolysaccharidosis VII diagnosed in the Iberian Peninsula, either in Spain or Portugal. The diagnostic approach, genetic studies, clinical features, evolution and treatment interventions were reviewed. We found that skeletal deformities, hip dysplasia, hydrops fetalis, hepatosplenomegaly, hernias, coarse features, respiratory issues, and cognitive and growth delay were the most common features identified in the cohort. In general, patients with early diagnostic confirmation who received the appropriate treatment in a timely manner presented a more favorable clinical evolution. This case series report helps to improve understanding of this ultra-rare disease and allows to establish criteria for clinical suspicion or diagnosis, recommendations, and future directions for better management of patients with Sly syndrome.
Abstract
Identifying diseases displaying chronic low plasma Coenzyme Q
10
(CoQ) values may be important to prevent possible cardiovascular dysfunction. The aim of this study was to retrospectively ...evaluate plasma CoQ concentrations in a large cohort of pediatric and young adult patients. We evaluated plasma CoQ values in 597 individuals (age range 1 month to 43 years, average 11 years), studied during the period 2005–2016. Patients were classified into 6 different groups: control group of healthy participants, phenylketonuric patients (PKU), patients with mucopolysaccharidoses (MPS), patients with other inborn errors of metabolism (IEM), patients with neurogenetic diseases, and individuals with neurological diseases with no genetic diagnosis. Plasma total CoQ was measured by reverse-phase high-performance liquid chromatography with electrochemical detection and ultraviolet detection at 275 nm. ANOVA with Bonferroni correction showed that plasma CoQ values were significantly lower in the PKU and MPS groups than in controls and neurological patients. The IEM group showed intermediate values that were not significantly different from those of the controls. In PKU patients, the Chi-Square test showed a significant association between having low plasma CoQ values and being classic PKU patients. The percentage of neurogenetic and other neurological patients with low CoQ values was low (below 8%). In conclusión, plasma CoQ monitoring in selected groups of patients with different IEM (especially in PKU and MPS patients, but also in IEM under protein-restricted diets) seems advisable to prevent the possibility of a chronic blood CoQ suboptimal status in such groups of patients.
Niemann-Pick disease type C (NP-C) is a lysosomal storage disease in which impaired intracellular lipid trafficking leads to excess storage of cholesterol and glycosphingolipids in the brain and ...other tissues. It is characterized clinically by a variety of progressive, disabling neurological symptoms including clumsiness, limb and gait ataxia, dysarthria, dysphagia and cognitive deterioration (dementia). Until recently, there has been no disease-modifying therapy available for NP-C, with treatment limited to supportive measures. In most countries, NP-C is managed through specialist centers, with non-specialist support provided locally. However, effective patient support is hampered by the absence of national or international clinical management guidelines. In this paper, we seek to address this important gap in the current literature. An expert panel was convened in Paris, France in January 2009 to discuss best care practices for NP-C. This commentary reviews current literature on key aspects of the clinical management of NP-C in children, juveniles and adults, and provides recommendations based on consensus between the experts at the meeting.
Despite the growing interest and the potential benefits of idebenone as a repurposed drug for different orphan conditions, data regarding its monitoring are scarce. Our main goal was to report plasma ...idebenone values in a cohort of Friedreich’s ataxia (FRDA) patients during a long-term follow-up. Taking advantage of this, we also assessed cardiological and neurological status together with idebenone values and genetic background.
Long-term follow-up retrospective study in 27 FRDA patients with a disease onset at the paediatric age treated with idebenone by compassionate use. Plasma idebenone was measured by HPLC with electrochemical detection.
Median plasma idebenone values increased when doses were increased, but apparently linearity was lost in the highest dose group. Marked intraindividual and interindividual differences were observed among patients. We did not find a consistent positive effect after analysis of paired data at the beginning and the end of the study. We only found a correlation between some cardiological measures and the duration of idebenone therapy at high doses, but with uncertain significance.
The large variations observed among the different individuals involved in this study should be considered for optimization of individual dosage regimens.
•Despite the growing interest and the potential benefits of idebenone, data regarding its monitoring are scarce.•We report plasma idebenone values of a cohort of 27 Friedreich’s ataxia patients during a long-term follow-up period.•Large interindividual and intraindividual variability in plasma idebenone concentrations was observed.•These large variations should be considered for optimization of individual dosage regimens.
Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder leading to dopaminergic depletion and early‐onset Parkinsonism. Affected children present with either a severe form that does not ...respond to L‐Dopa treatment (THD‐B) or a milder L‐Dopa responsive form (THD‐A). We generated induced pluripotent stem cells (iPSCs) from THD patients that were differentiated into dopaminergic neurons (DAn) and compared with control‐DAn from healthy individuals and gene‐corrected isogenic controls. Consistent with patients, THD iPSC‐DAn displayed lower levels of DA metabolites and reduced TH expression, when compared to controls. Moreover, THD iPSC‐DAn showed abnormal morphology, including reduced total neurite length and neurite arborization defects, which were not evident in DAn differentiated from control‐iPSC. Treatment of THD‐iPSC‐DAn with L‐Dopa rescued the neuronal defects and disease phenotype only in THDA‐DAn. Interestingly, L‐Dopa treatment at the stage of neuronal precursors could prevent the alterations in THDB‐iPSC‐DAn, thus suggesting the existence of a critical developmental window in THD. Our iPSC‐based model recapitulates THD disease phenotypes and response to treatment, representing a promising tool for investigating pathogenic mechanisms, drug screening, and personalized management.
Synopsis
This is the first proof of principle that iPSC‐derived dopaminergic (DA) neurons from mild (THDA) and severe (THDB) patients reproduce distinct disease‐related features and reveal abnormal morphologies. The study highlights the importance of prenatal treatment with L‐Dopa in cases of THDB.
THDA and THDB‐iPSCs produce fewer DA neurons than control‐iPSCs, as judged by reduced numbers of TH+ cell and TH protein expression.
THDA and THDB‐iPSC‐derived DA neurons exhibit low intracellular DA levels and its metabolites and reduced expression of other DA markers, indicating impaired DA neuron function.
DA neurons generated from both THD patient‐specific iPSCs show altered neuronal morphology (fewer and shorter neurites) compared to healthy controls.
THDA neuronal defects can be recovered with L‐Dopa treatment.
L‐Dopa added at an early stage of neural differentiation leads to prevention of neuronal defects in THDB cells.
This is the first proof of principle that iPSC‐derived dopaminergic (DA) neurons from mild (THDA) and severe (THDB) patients reproduce distinct disease‐related features and reveal abnormal morphologies. The study highlights the importance of prenatal treatment with L‐Dopa in cases of THDB.
Niemann-Pick disease type C (NP-C) is a rare, autosomal-recessive, progressive neurological disease caused by mutations in either the NPC1 gene (in 95% of cases) or the NPC2 gene. This observational, ...multicentre genetic screening study evaluated the frequency and phenotypes of NP-C in consecutive adult patients with neurological and psychiatric symptoms. Diagnostic testing for NP-C involved NPC1 and NPC2 exonic gene sequencing and gene dosage analysis. When available, results of filipin staining, plasma cholestane-3β,5α,6β-triol assays and measurements of relevant sphingolipids were also collected. NPC1 and NPC2 gene sequencing was completed in 250/256 patients from 30 psychiatric and neurological reference centres across the EU and USA median (range) age 38 (18-90) years. Three patients had a confirmed diagnosis of NP-C; two based on gene sequencing alone (two known causal disease alleles) and one based on gene sequencing and positive filipin staining. A further 12 patients displayed either single mutant NP-C alleles (8 with NPC1 mutations and 3 with NPC2 mutations) or a known causal disease mutation and an unclassified NPC1 allele variant (1 patient). Notably, high plasma cholestane-3β,5α,6β-triol levels were observed for all NP-C cases (n = 3). Overall, the frequency of NP-C patients in this study 1.2% (95% CI; 0.3%, 3.5%) suggests that there may be an underdiagnosed pool of NP-C patients among adults who share common neurological and psychiatric symptoms.
Rett syndrome, a serious neurodevelopmental disorder, has been associated with an altered expression of different synaptic-related proteins and aberrant glutamatergic and γ-aminobutyric acid ...(GABA)ergic neurotransmission. Despite its severity, it lacks a therapeutic option. Through this work we aimed to define the relationship between MeCP2 and GABAA.-A1 receptor expression, emphasizing the time dependence of such relationship. For this, we analyzed the expression of the ionotropic receptor subunit in different MeCP2 gene-dosage and developmental conditions, in cells lines, and in primary cultured neurons, as well as in different developmental stages of a Rett mouse model. Further, RNAseq and systems biology analysis was performed from post-mortem brain biopsies of Rett patients. We observed that the modulation of the MeCP2 expression in cellular models (both Neuro2a (N2A) cells and primary neuronal cultures) revealed a MeCP2 positive effect on the GABAA.-A1 receptor subunit expression, which did not occur in other proteins such as KCC2 (Potassium-chloride channel, member 5). In the Mecp2+/− mouse brain, both the KCC2 and GABA subunits expression were developmentally regulated, with a decreased expression during the pre-symptomatic stage, while the expression was variable in the adult symptomatic mice. Finally, the expression of the gamma-aminobutyric acid (GABA) receptor-related synaptic proteins from the postmortem brain biopsies of two Rett patients was evaluated, specifically revealing the GABA A1R subunit overexpression. The identification of the molecular changes along with the Rett syndrome prodromic stages strongly endorses the importance of time frame when addressing this disease, supporting the need for a neurotransmission-targeted early therapeutic intervention.
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