Hereditary spastic paraplegias (HSP) are a group of neurodegenerative diseases sharing spasticity in lower limbs as common symptom. There is a large clinical variability in the presentation of ...patients, partly underlined by the large genetic heterogeneity, with more than 60 genes responsible for HSP. Despite this large heterogeneity, the proteins with known function are supposed to be involved in a limited number of cellular compartments such as shaping of the endoplasmic reticulum or endolysosomal function. Yet, it is difficult to understand why alteration of such different cellular compartments can lead to degeneration of the axons of cortical motor neurons. A common feature that has emerged over the last decade is the alteration of lipid metabolism in this group of pathologies. This was first revealed by the identification of mutations in genes encoding proteins that have or are supposed to have enzymatic activities on lipid substrates. However, it also appears that mutations in genes affecting endoplasmic reticulum, mitochondria, or endolysosome function can lead to changes in lipid distribution or metabolism. The aim of this review is to discuss the role of lipid metabolism alterations in the physiopathology of HSP, to evaluate how such alterations contribute to neurodegenerative phenotypes, and to understand how this knowledge can help develop therapeutic strategy for HSP.
Neurofilament light chain (NfL) is a marker of brain atrophy and predictor of disease progression in rare diseases such as Huntington Disease, but also in more common neurological disorders such as ...Alzheimer's disease. The aim of this study was to measure NfL longitudinally in autosomal dominant spinocerebellar ataxias (SCAs) and establish correlation with clinical and imaging parameters. We enrolled 62 pathological expansions carriers (17 SCA1, 13 SCA2, 19 SCA3, and 13 SCA7) and 19 age-matched controls in a prospective biomarker study between 2011 and 2015 and followed for 24 months at the Paris Brain Institute. We performed neurological examination, brain 3 T MRI and plasma NfL measurements using an ultrasensitive single-molecule array at baseline and at the two-year follow-up visit. We evaluated NfL correlations with ages, CAG repeat sizes, clinical scores and volumetric brain MRIs. NfL levels were significantly higher in SCAs than controls at both time points (p < 0.001). Age-adjusted NfL levels were significantly correlated at baseline with clinical scores (p < 0.01). We identified optimal NfL cut-off concentrations to differentiate controls from carriers for each genotype (SCA1 16.87 pg/mL, SCA2, 19.1 pg/mL, SCA3 16.04 pg/mL, SCA7 16.67 pg/mL). For all SCAs, NfL concentration was stable over two years (p = 0.95) despite a clinical progression (p < 0.0001). Clinical progression between baseline and follow-up was associated with higher NfL concentrations at baseline (p = 0.04). Of note, all premanifest carriers with NfL levels close to cut off concentrations had signs of the disease at follow-up. For all SCAs, the higher the observed NfL, the lower the pons volume at baseline (p < 0.01) and follow-up (p = 0.02). Higher NfL levels at baseline in all SCAs predicted a decrease in cerebellar volume (p = 0.03). This result remained significant for SCA2 only among all genotypes (p = 0.02). Overall, plasma NfL levels at baseline in SCA expansion carriers predict cerebellar volume change and clinical score progression. NfL levels might help refine inclusion criteria for clinical trials in carriers with very subtle signs.
•NfL levels were sustainably higher in SCAs than controls over a two-year period.•Optimal plasma NfL cut-off concentrations was identified for each SCA genotype.•Plasma NfL concentrations predicted cerebellar volume loss at two years in SCAs.•Clinical progression was associated with higher NfL concentrations at baseline.•Premanifest carriers with NfL levels close to cut off had signs of the disease.
Abstract
Huntington’s disease (HD) is a monogenic, fully penetrant neurodegenerative disorder. Widespread white matter damage affects the brain of patients with HD at very early stages of the ...disease. Fixel-based analysis (FBA) is a novel method to investigate the contribution of individual crossing fibers to the white matter damage and to detect possible alterations in both fiber density and fiber-bundle morphology. Diffusion-weighted magnetic resonance spectroscopy (DW-MRS), on the other hand, quantifies the motion of brain metabolites in vivo, thus enabling the investigation of microstructural alteration of specific cell populations. The aim of this study was to identify novel specific microstructural imaging markers of white matter degeneration in HD, by combining FBA and DW-MRS. Twenty patients at an early stage of HD and 20 healthy controls were recruited in a monocentric study. Using diffusion imaging we observed alterations to the brain microstructure and their morphology in patients with HD. Furthermore, FBA revealed specific fiber populations that were affected by the disease. Moreover, the mean diffusivity of the intra-axonal metabolite
N
-acetylaspartate, co-measured with
N
-acetylaspartylglutamate (tNAA), was significantly reduced in the corpus callosum of patients compared to controls. FBA and DW-MRS of tNAA provided more specific information about the biological mechanisms underlying HD and showed promise for early investigation of white matter degeneration in HD.
The field of inherited metabolic diseases (IMD) has initially emerged and developed over decades in pediatric departments. Still, today, about 50% of patients with IMD are adults, and adult metabolic ...medicine (AMM) is getting more structured at national and international levels. There are several domains in which pediatricians can learn from AMM. First, long-term evolution of IMD patients, especially those treated since childhood, is critical to determine nutritional and neuropsychiatric outcomes in adults so that these outcomes can be better monitored, and patient care adjusted as much as possible from childhood. Conversely, the observation of attenuated phenotypes in adults of IMD known to present with severe phenotypes in children calls for caution in the development of newborn screening programs and, more largely, in the interpretation of next-generation sequencing data. Third, it is important for pediatricians to be familiar with adult-onset IMD as they expand our understanding of metabolism, including in children, such as oxysterols and glycogen metabolism. Last, the identification of common molecular and cellular mechanisms in neurodevelopment and neurodegeneration opens the way to synergistic therapeutic developments that will benefit both fields of pediatric and adult medicine. Overall, these observations underline the need of strong interdisciplinarity between pediatricians and adult specialists for the diagnosis and the treatment of IMD well beyond the issues of patient transition from pediatric to adult medicine.
An approved definition of the term leukodystrophy does not currently exist. The lack of a precise case definition hampers efforts to study the epidemiology and the relevance of genetic white matter ...disorders to public health.
Thirteen experts at multiple institutions participated in iterative consensus building surveys to achieve definition and classification of disorders as leukodystrophies using a modified Delphi approach.
A case definition for the leukodystrophies was achieved, and a total of 30 disorders were classified under this definition. In addition, a separate set of disorders with heritable white matter abnormalities but not meeting criteria for leukodystrophy, due to presumed primary neuronal involvement and prominent systemic manifestations, was classified as genetic leukoencephalopathies (gLE).
A case definition of leukodystrophies and classification of heritable white matter disorders will permit more detailed epidemiologic studies of these disorders.
•Leukodystrophies are a heterogeneous group of disorders with variable clinical manifestations and pathologic mechanisms•Lack of a precise definition for leukodystrophies hampers efforts to study the epidemiology and the relevance to public health•A consensus definition was achieved, based on the specific involvement of the white matter of the central nervous system•30 distinct disorders were defined as leukodystrophies based on the proposed definition•A class of genetic leukoencephalopathies was characterized that may or may not include leukodystrophies
Hereditary spastic paraplegias are heterogeneous neurological disorders characterized by a pyramidal syndrome with symptoms predominantly affecting the lower limbs. Some limited pyramidal involvement ...also occurs in patients with an autosomal recessive neurocutaneous syndrome due to ALDH18A1 mutations. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), an enzyme that catalyses the first and common step of proline and ornithine biosynthesis from glutamate. Through exome sequencing and candidate gene screening, we report two families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic paraplegia with marked cognitive impairment, without any cutaneous abnormality. More interestingly, we also identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic paraplegia, as well as in two sporadic patients. Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency. Glutamine loading tests in two fibroblast cultures from two related affected subjects confirmed a metabolic block at the level of P5CS in vivo. Besides expanding the clinical spectrum of ALDH18A1-related pathology, we describe mutations segregating in an autosomal dominant pattern. The latter are associated with a potential trait biomarker; we therefore suggest including amino acid chromatography in the clinico-genetic work-up of hereditary spastic paraplegia, particularly in dominant cases, as the associated phenotype is not distinct from other causative genes.
Dominant mutations of ATP1A3, a neuronal Na,K-ATPase α subunit isoform, cause neurological disorders with an exceptionally wide range of severity. Several new mutations and their phenotypes are ...reported here (p.Asp366His, p.Asp742Tyr, p.Asp743His, p.Leu924Pro, and a VUS, p.Arg463Cys). Mutations associated with mild or severe phenotypes rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), or early infantile epileptic encephalopathy (EIEE) were expressed in HEK-293 cells. Paradoxically, the severity of human symptoms did not correlate with whether there was enough residual activity to support cell survival. We hypothesized that distinct cellular consequences may result not only from pump inactivation but also from protein misfolding. Biosynthesis was investigated in four tetracycline-inducible isogenic cell lines representing different human phenotypes. Two cell biological complications were found. First, there was impaired trafficking of αβ complex to Golgi apparatus and plasma membrane, as well as changes in cell morphology, for two mutations that produced microcephaly or regions of brain atrophy in patients. Second, there was competition between exogenous mutant ATP1A3 (α3) and endogenous ATP1A1 (α1) so that their sum was constant. This predicts that in patients, the ratio of normal to mutant ATP1A3 proteins will vary when misfolding occurs. At the two extremes, the results suggest that a heterozygous mutation that only impairs Na,K-ATPase activity will produce relatively mild disease, while one that activates the unfolded protein response could produce severe disease and may result in death of neurons independently of ion pump inactivation.
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•Mutations in ATP1A3 cause disease ranging widely from newborn- to adult-onset.•Loss of activity cannot explain the severity of phenotype.•Protein misfolding and ER retention did correlate with clinical severity here.•Misfolding also affected the ratio between good and bad alleles, by competition.
The pattern of cerebral dopamine (DA) abnormalities in Huntington disease (HD) is complex, as reflected by the variable clinical benefit of both DA antagonists and agonists in treating HD symptoms. ...In addition, little is known about serotonin metabolism despite the early occurrence of anxiety and depression in HD. Post-mortem enzymatic changes are likely to interfere with the in vivo profile of biogenic amines. Hence, in order to reliably characterize the regional and chronological profile of brain neurotransmitters in a HD mouse model, we used a microwave fixation system that preserves in vivo concentrations of dopaminergic and serotoninergic amines. DA was decreased in the striatum of R6/2 mice at 8 and 12 weeks of age while DA metabolites, 3-methoxytyramine and homovanillic acid, were already significantly reduced in 4-week-old motorically asymptomatic R6/2 mice. In the striatum, hippocampus and frontal cortex of 4, 8 and 12-week-old R6/2 mice, serotonin and its metabolite 5-hydroxyindoleacetic acid were significantly decreased in association with a decreased turnover of serotonin. In addition, automated high-resolution behavioural analyses displayed stress-like behaviours such as jumping and grooming and altered spatial learning in R6/2 mice at age 4 and 6 weeks respectively. Therefore, we describe the earliest alterations of DA and serotonin metabolism in a HD murine model. Our findings likely underpin the neuropsychological symptoms at time of disease onset in HD.
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