ABSTRACT
OBJECTIVE: Hereditary spastic paraplegias (HSPs) are genetically driven disorders with the hallmark of progressive spastic gait disturbance. To investigate the phenotypic spectrum, prognostic factors, and genotype-specific differences, we analyzed baseline data from a continuous, prospective cohort. METHODS: We recruited 608 HSP cases from 519 families of mostly German origin. Clinical severity was assessed by the Spastic Paraplegia Rating Scale. Complicating symptoms were recorded by a standardized inventory. RESULTS: Family history indicated dominant (43%), recessive (10%), and simplex (47%) disease. We observed a significant male predominance, particularly in simplex cases without a genetic diagnosis. Disease severity increased with disease duration. Earlier disease onset was associated with less severe disease. Specific complicating features including cognitive impairment, extrapyramidal or peripheral motor involvement, and ataxia were associated with worse disease severity. Disease severity also depended on the genotype. HSP cases maintained the ability to walk independently for a median disease duration of 22 years. Early onset cases were able to maintain free walking significantly longer and were at less risk to become wheelchair dependent. INTERPRETATION: This cross-sectional cohort study provides the first large-scale data on disease manifestation, progression, and modifying factors, with relevance for counseling of HSP families and planning of future cross-sectional and natural history studies. Later age of onset, specific complicating features, and the SPG11 genotype are strongly associated with more severe disease. Future interventional studies will require stratification for modifiers of disease progression identified in this study. Prospective longitudinal studies will verify progression rates calculated in this baseline analysis.
Subject(s)
Severity of Illness Index , Spastic Paraplegia, Hereditary , Adult , Aged , Cross-Sectional Studies , Female , Germany/epidemiology , Humans , Male , Middle Aged , Pedigree , Spastic Paraplegia, Hereditary/epidemiology , Spastic Paraplegia, Hereditary/genetics , Spastic Paraplegia, Hereditary/physiopathologyABSTRACT
The hereditary spastic paraplegias (HSPs) are heterogeneous neurodegenerative disorders with over 50 known causative genes. We identified a recurrent mutation in KCNA2 (c.881G>A, p.R294H), encoding the voltage-gated K(+) -channel, KV 1.2, in two unrelated families with HSP, intellectual disability (ID), and ataxia. Follow-up analysis of > 2,000 patients with various neurological phenotypes identified a de novo p.R294H mutation in a proband with ataxia and ID. Two-electrode voltage-clamp recordings of Xenopus laevis oocytes expressing mutant KV 1.2 channels showed loss of function with a dominant-negative effect. Our findings highlight the phenotypic spectrum of a recurrent KCNA2 mutation, implicating ion channel dysfunction as a novel HSP disease mechanism. Ann Neurol 2016.
Subject(s)
Ataxia/genetics , Intellectual Disability/genetics , Kv1.2 Potassium Channel/genetics , Spastic Paraplegia, Hereditary/genetics , Adult , Animals , Ataxia/physiopathology , Child , Exome , Female , Humans , Intellectual Disability/physiopathology , Male , Middle Aged , Mutation , Oocytes/metabolism , Pedigree , Spastic Paraplegia, Hereditary/physiopathology , Xenopus laevis , Young AdultABSTRACT
The genetic diagnosis in inherited optic neuropathies often remains challenging, and the emergence of complex neurological phenotypes that involve optic neuropathy is puzzling. Here we unravel two novel principles of genetic mechanisms in optic neuropathies: deep intronic OPA1 mutations, which explain the disease in several so far unsolved cases; and an intralocus OPA1 modifier, which explains the emergence of syndromic 'optic atrophy plus' phenotypes in several families. First, we unravelled a deep intronic mutation 364 base pairs 3' of exon 4b in OPA1 by in-depth investigation of a family with severe optic atrophy plus syndrome in which conventional OPA1 diagnostics including gene dosage analyses were normal. The mutation creates a new splice acceptor site resulting in aberrant OPA1 transcripts with retained intronic sequence and subsequent translational frameshift as shown by complementary DNA analysis. In patient fibroblasts we demonstrate nonsense mediated messenger RNA decay, reduced levels of OPA1 protein, and impairment of mitochondrial dynamics. Subsequent site-specific screening of >360 subjects with unexplained inherited optic neuropathy revealed three additional families carrying this deep intronic mutation and a base exchange four nucleotides upstream, respectively, thus confirming the clinical significance of this mutational mechanism. Second, in all severely affected patients of the index family, the deep intronic mutation occurred in compound heterozygous state with an exonic OPA1 missense variant (p.I382M; NM_015560.2). The variant alone did not cause a phenotype, even in homozygous state indicating that this long debated OPA1 variant is not pathogenic per se, but acts as a phenotypic modifier if it encounters in trans with an OPA1 mutation. Subsequent screening of whole exomes from >600 index patients identified a second family with severe optic atrophy plus syndrome due to compound heterozygous p.I382M, thus confirming this mechanism. In summary, we provide genetic and functional evidence that deep intronic mutations in OPA1 can cause optic atrophy and explain disease in a substantial share of families with unsolved inherited optic neuropathies. Moreover, we show that an OPA1 modifier variant explains the emergence of optic atrophy plus phenotypes if combined in trans with another OPA1 mutation. Both mutational mechanisms identified in this study-deep intronic mutations and intragenic modifiers-might represent more generalizable mechanisms that could be found also in a wide range of other neurodegenerative and optic neuropathy diseases.
Subject(s)
GTP Phosphohydrolases/genetics , Genome, Human/genetics , Mutation/genetics , Optic Atrophy, Autosomal Dominant/genetics , Adolescent , Adult , Aged , Exons/genetics , Female , Gene Dosage/genetics , Genetic Loci/genetics , Genetic Variation , Humans , Male , Middle Aged , Optic Atrophy, Autosomal Dominant/classification , Optic Atrophy, Autosomal Dominant/pathology , Pedigree , Phenotype , SyndromeABSTRACT
Hereditary spastic paraplegias (HSPs) comprise a group of genetically heterogeneous neurodegenerative disorders characterized by spastic weakness of the lower extremities. We have generated a Drosophila model for HSP type 10 (SPG10), caused by mutations in KIF5A. KIF5A encodes the heavy chain of kinesin-1, a neuronal microtubule motor. Our results imply that SPG10 is not caused by haploinsufficiency but by the loss of endogenous kinesin-1 function due to a selective dominant-negative action of mutant KIF5A on kinesin-1 complexes. We have not found any evidence for an additional, more generalized toxicity of mutant Kinesin heavy chain (Khc) or the affected kinesin-1 complexes. Ectopic expression of Drosophila Khc carrying a human SPG10-associated mutation (N256S) is sufficient to disturb axonal transport and to induce motoneuron disease in Drosophila. Neurofilaments, which have been recently implicated in SPG10 disease manifestation, are absent in arthropods. Impairments in the transport of kinesin-1 cargos different from neurofilaments are thus sufficient to cause HSP-like pathological changes such as axonal swellings, altered structure and function of synapses, behavioral deficits, and increased mortality.
Subject(s)
Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Kinesins/genetics , Spastic Paraplegia, Hereditary/genetics , Animals , Axonal Transport/genetics , Axonal Transport/physiology , Disease Models, Animal , Gene Expression , Humans , Mice , Microtubules/genetics , Microtubules/metabolism , Mutation , Synapses/genetics , Synapses/pathologyABSTRACT
PURPOSE: Psychotic symptoms in Parkinson's disease (PD) caused by dopamimetic treatment are a relevant clinical problem. As clozapine does not cause extrapyramidal side effects, it is suitable for treatment of dopamimetic psychosis. The main aim of the present study was (1) to establish an indication-specific recommendation for therapeutic reference range of clozapine among patients with dopamimetic psychosis in PD and related disorders. Secondary goals were (2) to test whether clozapine therapy is safe and calculable despite pharmacokinetic changes expected in the study population and (3) to assess influencing variables on clozapine serum levels. METHODS: We carried out a retrospective chart review of patients suffering from dopamimetic psychosis as well as Lewy body dementia treated with clozapine. We extracted demographic and clinical data as well as results from therapeutic drug monitoring that was carried out via high-performance liquid chromatography in order to analyse clozapine and norclozapine serum concentrations. RESULTS: n = 35 patients could be identified and were included in the study. Mean age was 72.4 years. Clozapine treatment for patients with dopamimetic psychosis in PD and related disorders seems to be safe and calculable. Mean clozapine serum concentration was 77.9 ng/ml (SD 63.4 ng/ml). Clozapine dose is significantly correlated with serum clozapine concentration (r = 0.35; R (2) = 0.122). Women showed lower clozapine serum concentrations although they received higher weight-corrected clozapine doses. CONCLUSIONS: We suggest an orienting indication-specific therapeutic reference range of 15-141 ng/ml among PD patients with dopamimetic psychosis. Therapeutic drug monitoring is recommended and might help to minimize the risk of adverse events by screening for unexpectedly high serum concentrations of clozapine.
Subject(s)
Antipsychotic Agents/blood , Clozapine/blood , Parkinson Disease/blood , Psychotic Disorders/blood , Aged , Aged, 80 and over , Antipsychotic Agents/pharmacokinetics , Antipsychotic Agents/therapeutic use , Clozapine/pharmacokinetics , Clozapine/therapeutic use , Female , Humans , Male , Middle Aged , Parkinson Disease/drug therapy , Psychotic Disorders/drug therapyABSTRACT
Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder preferentially affecting the longest corticospinal axons. More than 40 HSP genetic loci have been identified, among them SPG10, an autosomal dominant HSP caused by point mutations in the neuronal kinesin heavy chain protein KIF5A. Constitutive KIF5A knockout (KIF5A( -/- )) mice die early after birth. In these mice, lungs were unexpanded, and cell bodies of lower motor neurons in the spinal cord swollen, but the pathomechanism remained unclear. To gain insights into the pathophysiology, we characterized survival, outgrowth, and function in primary motor and sensory neuron cultures from KIF5A( -/- ) mice. Absence of KIF5A reduced survival in motor neurons, but not in sensory neurons. Outgrowth of axons and dendrites was remarkably diminished in KIF5A( -/- ) motor neurons. The number of axonal branches was reduced, whereas the number of dendrites was not altered. In KIF5A( -/- ) sensory neurons, neurite outgrowth was decreased but the number of neurites remained unchanged. In motor neurons maximum and average velocity of mitochondrial transport was reduced both in anterograde and retrograde direction. Our results point out a role of KIF5A in process outgrowth and axonal transport of mitochondria, affecting motor neurons more severely than sensory neurons. This gives pathophysiological insights into KIF5A associated HSP, and matches the clinical findings of predominant degeneration of the longest axons of the corticospinal tract.
Subject(s)
Axonal Transport/genetics , Kinesins/metabolism , Spastic Paraplegia, Hereditary/genetics , Animals , Axons/metabolism , Cells, Cultured , Disease Models, Animal , Gene Knockout Techniques , Kinesins/deficiency , Mice , Mice, Inbred C57BL , Mitochondria/genetics , Mitochondria/metabolism , Motor Neurons/cytology , Motor Neurons/metabolism , Mutation, Missense , Sensory Receptor Cells/cytology , Sensory Receptor Cells/metabolism , Spastic Paraplegia, Hereditary/metabolismABSTRACT
Hereditary spastic paraplegia (HSP) is a neurodegenerative condition defined clinically by lower limb spasticity and weakness. Homozygous mutations in CYP7B1 have been identified in several consanguineous families that represented HSP type 5 (SPG5), one of the many genetic forms of the disease. We used direct sequencing and multiplex ligation-dependent probe amplification to screen for CYP7B1 alterations in apparently sporadic HSP patients (n = 12) as well as index patients from non-consanguineous families with recessive (n = 8) and dominant (n = 8) transmission of HSP. One sporadic patient showing HSP as well as optic atrophy carried a homozygous nonsense mutation. Compound heterozygosity was observed in a recessive family with a clinically pure phenotype. A heterozygous missense change segregated in a small dominant family. We also found a significant association of a known coding polymorphism with cerebellar signs complicating a primary HSP phenotype. Our findings suggest CYP7B1 alterations to represent a rather frequent cause of HSP that should be considered in patients with various clinical presentations.
Subject(s)
Spastic Paraplegia, Hereditary/genetics , Steroid Hydroxylases/genetics , Adolescent , Adult , Age of Onset , Child , Child, Preschool , Chromosomes, Human, Pair 8 , Cytochrome P450 Family 7 , DNA Mutational Analysis , Haplotypes , Humans , Infant , Middle Aged , Polymorphism, Genetic , Young AdultABSTRACT
Facial expressions and voice modulations are among the most important communicational signals to convey emotional information. The ability to correctly interpret this information is highly relevant for successful social interaction and represents an integral component of emotional competencies that have been conceptualized under the term emotional intelligence. Here, we investigated the relationship of emotional intelligence as measured with the Salovey-Caruso-Emotional-Intelligence-Test (MSCEIT) with cerebral voice and face processing using functional and structural magnetic resonance imaging. MSCEIT scores were positively correlated with increased voice-sensitivity and gray matter volume of the insula accompanied by voice-sensitivity enhanced connectivity between the insula and the temporal voice area, indicating generally increased salience of voices. Conversely, in the face processing system, higher MSCEIT scores were associated with decreased face-sensitivity and gray matter volume of the fusiform face area. Taken together, these findings point to an alteration in the balance of cerebral voice and face processing systems in the form of an attenuated face-vs-voice bias as one potential factor underpinning emotional intelligence.
Subject(s)
Emotional Intelligence/physiology , Face , Social Perception , Voice , Adult , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/physiology , Facial Recognition , Female , Gray Matter/diagnostic imaging , Gray Matter/physiology , Humans , Intelligence Tests , Magnetic Resonance Imaging , Male , Visual Perception/physiology , Young AdultABSTRACT
Several studies have shown an association of alcohol dependence with DNA methylation (DNAm), suggesting that environmentally-induced changes on epigenomic variation may play an important role in alcohol dependence. In the present study, we analysed genome-wide DNAm profiles of purified CD3+ T-cells from pre- and post-treatment alcohol dependent patients, as well as closely matched healthy controls. We identified 59 differentially methylated CpG sites comparing patients prior to treatment with healthy controls and were able to confirm 8 of those sites in additional analyses for differentially methylated regions. Comparing patients before and after a 3-week alcohol treatment program we revealed another unique set of 48 differentially methylated CpG sites. Additionally, we found that the mean global DNAm was significantly lower in patients prior to treatment compared to controls, but reverted back to levels similar to controls after treatment. We validated top-ranked hits derived from the epigenome-wide analysis by pyrosequencing and further replicated two of them in an independent cohort and confirmed differential DNAm of HECW2 and SRPK3 in whole blood. This study is the first to show widespread DNAm variation in a disease-relevant blood cell type and implicates HECW2 and SRPK3 DNAm as promising blood-based candidates to follow up in future studies.
Subject(s)
Alcoholism/pathology , CD3 Complex/analysis , DNA Methylation , T-Lymphocyte Subsets/pathology , Adult , Alcoholism/drug therapy , Epigenesis, Genetic/drug effects , Humans , Male , Middle Aged , T-Lymphocyte Subsets/chemistryABSTRACT
Hereditary spastic paraplegias (HSP) are a group of clinically and genetically heterogeneous disorders with the hallmark of progressive spastic gait disturbance. We used advanced neuroimaging to identify brain regions involved in SPG4, the most common HSP genotype. Additionally, we analyzed correlations between imaging and clinical findings. We performed 3T MRI scans including isotropic high-resolution 3D T1, T2-FLAIR, and DTI sequences in 15 adult patients with genetically confirmed SPG4 and 15 age- and sex-matched healthy controls. Brain volume loss of gray and white matter was evaluated through voxel-based morphometry (VBM) for supra- and infratentorial regions separately. DTI maps of axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), fractional anisotropy (FA), and measured anisotropy (MA1) were analyzed through tract-based special statistics (TBSS). VBM and TBSS revealed a widespread affection of gray and white matter in SPG4 including the corpus callosum, medio-dorsal thalamus, parieto-occipital regions, upper brainstem, cerebellum, and corticospinal tract. Significant correlations with correlation coefficients r > 0.6 between clinical data and DTI findings could be demonstrated for disease duration and disease severity as assessed by the spastic paraplegia rating scale for the pontine crossing tract (AD) and the corpus callosum (RD and FA). Imaging also provided evidence that SPG4 underlies a primarily axonal rather than demyelinating damage in accordance with post-mortem data. DTI is an attractive tool to assess subclinical affection in SPG4. The correlation of imaging findings with disease duration and severity suggests AD, RD, and FA as potential progression markers in interventional studies.
Subject(s)
Gray Matter/pathology , Magnetic Resonance Imaging/methods , Severity of Illness Index , Spastic Paraplegia, Hereditary/pathology , White Matter/pathology , Adult , Diffusion Tensor Imaging/methods , Female , Gray Matter/physiopathology , Humans , Male , Middle Aged , White Matter/physiopathologyABSTRACT
Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disease caused by mutations within the colony stimulating factor 1 receptor (CSF1R) gene. While a small number of reports on imaging findings in routine MRI exist, reported imaging findings in DWI and spectroscopy are scarce, and limited to not genetically proven case reports. We assessed MRI including DWI and MR spectroscopy in six patients with HDLS and two asymptomatic mutation carriers. A total of 13 MRIs were evaluated and a score of the white-matter lesion (WML) load was calculated. The course of MR abnormalities was followed for 6-19 months in four patients and 95 months in one carrier. MRI revealed widespread white-matter lesions of patchy or confluent pattern especially in the frontal and occipital lobe. The pyramidal tract was less affected than the surrounding tissue in all symptomatic patients on conventional T2WI. Three of four cases with DWI showed small dots of diffusion restriction within WML. Spectroscopy showed increased levels of mIns, Cho and lactate while NAA was decreased. Asymptomatic mutation carriers had, for the age of the patients, unusually pronounced unspecific WMLs. No diffusion restriction or alterations in metabolite levels could be detected in asymptomatic mutation carriers. Microbleeds were not found in any patient. Diffusion restriction seems to be a typical imaging pattern visible in patients with active disease progression in HDLS. Spectroscopic findings and the absence of microbleeds differ clearly from reported findings in CADASIL and subcortical arteriosclerotic encephalopathy. While the distribution and character of WMLs in asymptomatic cases remain unspecific they are likely to represent subclinical markers of HDLS.
Subject(s)
Brain/pathology , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Receptor, Macrophage Colony-Stimulating Factor/genetics , Adult , Diffusion Magnetic Resonance Imaging , Female , Frontal Lobe/pathology , Heterozygote , Humans , Leukoencephalopathies/diagnosis , Leukoencephalopathies/genetics , Leukoencephalopathies/pathology , Male , Middle Aged , Mutation , Parietal Lobe/pathology , White Matter/pathologyABSTRACT
Hereditary spastic paraplegias (HSP) constitute a rare and highly heterogeneous group of neurodegenerative disorders, defined clinically by progressive lower limb spasticity and pyramidal weakness. Autosomal recessive HSP as well as sporadic cases present a significant diagnostic challenge. Mutations in AP5Z1, a gene playing a role in intracellular membrane trafficking, have been recently reported to be associated with spastic paraplegia type 48 (SPG48). Our objective was to determine the relative frequency and clinical relevance of AP5Z1 mutations in a large cohort of 127 HSP patients. We applied a targeted next-generation sequencing approach to analyze all coding exons of the AP5Z1 gene. With the output of high-quality reads and a mean coverage of 51-fold, we demonstrated a robust detection of variants. One 43-year-old female with sporadic complicated paraplegia showed two heterozygous nonsynonymous variants of unknown significance (VUS3; p.[R292W];[(T756I)]). Thus, AP5Z1 gene mutations are rare, at least in Europeans. Due to its low frequency, systematic genetic testing for AP5Z1 mutations is not recommended until larger studies are performed to add further evidence. Our findings demonstrate that amplicon-based deep sequencing is technically feasible and allows a compact molecular characterization of multiple HSP patients with high accuracy.
ABSTRACT
OBJECTIVE: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is caused by autosomal-dominantly inherited mutations in the colony stimulating factor 1 receptor (CSF1R) gene, and is clinically characterized by a progressive cognitive and motor decline leading to death within several years. METHODS: In a continuous series of 25 patients with adult-onset leukoencephalopathy of unknown cause, we genetically confirmed HDLS in 6 families. Affected and nonaffected individuals were examined clinically and by brain MRI studies. RESULTS: HDLS presented as prominent dementia and apraxia, often with extrapyramidal and pyramidal signs, rarely with ataxia. White matter MRI changes were detectable early in the disease course. Family history was negative in 4 of 6 index patients. In 2 of 6 index patients, we could confirm the occurrence of de novo mutations in the CSF1R gene. One family showed possible incomplete penetrance: the 69-year-old father of the index patient carried a CSF1R mutation but was clinically unaffected. In one family, the parents were apparently unaffected and not available for genetic testing. CONCLUSIONS: Typical clinical phenotype and early brain MRI alterations can help to guide the diagnosis of HDLS. Because we confirmed de novo mutations in one-third of patients with CSF1R mutations, this diagnosis should be considered even in the absence of a family history. Furthermore, we present evidence for reduced penetrance of a CSF1R mutation. These results have substantial impact for genetic counseling of asymptomatic individuals at risk and should foster research into disease-modifying factors.
Subject(s)
Mutation/genetics , Adult , Female , Humans , Leukoencephalopathies/diagnosis , Leukoencephalopathies/genetics , Male , Middle Aged , Young AdultABSTRACT
BACKGROUND: Hereditary spastic paraplegias (HSPs) are characterised by lower limb spasticity due to degeneration of the corticospinal tract. We set out for an electrophysiological characterisation of motor and sensory tracts in patients with HSP. METHODS: We clinically and electrophysiologically examined a cohort of 128 patients with genetically confirmed or clinically probable HSP. Motor evoked potentials (MEPs) to arms and legs, somato-sensory evoked potentials of median and tibial nerves, and nerve conduction studies of tibial, ulnar, sural, and radial nerves were assessed. RESULTS: Whereas all patients showed clinical signs of spastic paraparesis, MEPs were normal in 27% of patients and revealed a broad spectrum with axonal or demyelinating features in the others. This heterogeneity can at least in part be explained by different underlying genotypes, hinting for distinct pathomechanisms in HSP subtypes. In the largest subgroup, SPG4, an axonal type of damage was evident. Comprehensive electrophysiological testing disclosed a more widespread affection of long fibre tracts involving peripheral nerves and the sensory system in 40%, respectively. Electrophysiological abnormalities correlated with the severity of clinical symptoms. CONCLUSIONS: Whereas HSP is primarily considered as an upper motoneuron disorder, our data suggest a more widespread affection of motor and sensory tracts in the central and peripheral nervous system as a common finding in HSP. The distribution patterns of electrophysiological abnormalities were associated with distinct HSP genotypes and could reflect different underlying pathomechanisms. Electrophysiological measures are independent of symptomatic treatment and may therefore serve as a reliable biomarker in upcoming HSP trials.
Subject(s)
Spastic Paraplegia, Hereditary/physiopathology , Adolescent , Adult , Aged , Aged, 80 and over , Electrophysiology , Evoked Potentials, Somatosensory/physiology , Female , Humans , Male , Middle Aged , Motor Neurons/physiology , Neural Conduction/physiology , Peripheral Nerves/physiopathology , Young AdultABSTRACT
BACKGROUND: Mutations in SACS, leading to autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), have been identified as a frequent cause of recessive early-onset ataxia around the world. Here we aimed to enlarge the spectrum of SACS mutations outside Quebec, to establish the pathogenicity of novel variants, and to expand the clinical and imaging phenotype. METHODS: Sequencing of SACS in 22 patients with unexplained early-onset ataxia, assessment of novel SACS variants in 3.500 European control chromosomes and extensive phenotypic investigations of all SACS carriers. RESULTS: We identified 11 index patients harbouring 17 novel SACS variants. 9/11 patients harboured two variants of at least probable pathogenicity which were not observed in controls and, in case of missense mutations, were located in highly conserved domains. These 9 patients accounted for at least 11% (9/83) in our series of unexplained early onset ataxia subjects. While most patients (7/9) showed the classical ARSACS triad, the presenting phenotype reached from pure neuropathy (leading to the initial diagnosis of Charcot-Marie-Tooth disease) in one subject to the absence of any signs of neuropathy in another. In contrast to its name "spastic ataxia", neither spasticity (absent in 2/9=22%) nor extensor plantar response (absent in 3/9=33%) nor cerebellar ataxia (absent in 1/9=11%) were obligate features. Autonomic features included urine urge incontinence and erectile dysfunction. Apart from the well-established MRI finding of pontine hypointensities, all patients (100%) showed hyperintensities of the lateral pons merging into the (thickened) middle cerebellar peduncles. In addition, 63% exhibited bilateral parietal cerebral atrophy, and 63% a short circumscribed thinning of the posterior midbody of the corpus callosum. In 2 further patients with differences in important clinical features, VUS class 3 variants (c.1373C>T [p.Thr458Ile] and c.2983 G>T [p.Val995Phe]) were identified. These variants were, however, also observed in controls, thus questioning their pathogenic relevance. CONCLUSIONS: We here demonstrate that each feature of the classical ARSACS triad (cerebellar ataxia, spasticity and peripheral neuropathy) might be missing in ARSACS. Nevertheless, characteristic MRI features - which also extend to supratentorial regions and involve the cerebral cortex - will help to establish the diagnosis in most cases.
Subject(s)
Genes, Recessive , Muscle Spasticity/genetics , Muscle Spasticity/pathology , Spinocerebellar Ataxias/congenital , Humans , Muscle Spasticity/physiopathology , Mutation, Missense , Phenotype , Spinocerebellar Ataxias/genetics , Spinocerebellar Ataxias/pathology , Spinocerebellar Ataxias/physiopathologyABSTRACT
Axonopathies are a group of clinically diverse disorders characterized by the progressive degeneration of the axons of specific neurons. In hereditary spastic paraplegia (HSP), the axons of cortical motor neurons degenerate and cause a spastic movement disorder. HSP is linked to mutations in several loci known collectively as the spastic paraplegia genes (SPGs). We identified a heterozygous receptor accessory protein 1 (REEP1) exon 2 deletion in a patient suffering from the autosomal dominantly inherited HSP variant SPG31. We generated the corresponding mouse model to study the underlying cellular pathology. Mice with heterozygous deletion of exon 2 in Reep1 displayed a gait disorder closely resembling SPG31 in humans. Homozygous exon 2 deletion resulted in the complete loss of REEP1 and a more severe phenotype with earlier onset. At the molecular level, we demonstrated that REEP1 is a neuron-specific, membrane-binding, and membrane curvature-inducing protein that resides in the ER. We further show that Reep1 expression was prominent in cortical motor neurons. In REEP1-deficient mice, these neurons showed reduced complexity of the peripheral ER upon ultrastructural analysis. Our study connects proper neuronal ER architecture to long-term axon survival.