Pseudoxanthoma elasticum overlaps hereditary spastic paraplegia type 56.

PURPOSE: Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene(s) to solve the ABCC6-negative patients. METHODS: First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients. RESULTS: 6.4% of ABCC6-negative PXE patients (n = 3) harboured biallelic pathogenic variants in CYP2U1. PXE skin lesions with histological confirmation, eye lesions including maculopathy or angioid streaks, and various neurological symptoms were present. CYP2U1 missense variants were confirmed to impair protein function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%) presented some phenotypic overlap with PXE. CONCLUSION: CYP2U1 pathogenic variants are found in unsolved PXE patients with neurological findings, including spastic paraplegia, expanding the SPG56 phenotype and highlighting its overlap with PXE. The pathophysiology of ABCC6 and CYP2U1 should be explored to explain their respective role and potential interaction in ectopic mineralization.

Hereditary spastic paraplegia: More than an upper motor neuron disease.

Hereditary spastic paraplegias (HSPs) are a group of rare inherited neurological diseases characterized by extreme heterogeneity in both their clinical manifestations and genetic backgrounds. Based on symptoms, HSPs can be divided into pure forms, presenting with pyramidal signs leading to lower-limb spasticity, and complex forms, when additional neurological or extraneurological symptoms are detected. The clinical diversity of HSPs partially reflects their underlying genetic backgrounds. To date, 76 loci and 58 corresponding genes [spastic paraplegia genes (SPGs)] have been linked to HSPs. The genetic diagnosis is further complicated by the fact that causative mutations of HSP can be inherited through all possible modes of transmission (autosomal-dominant and -recessive, X-linked, maternal), with some genes showing multiple inheritance patterns. The pathogenic mutations of SPGs primarily lead to progressive degeneration of the upper motor neurons (UMNs) comprising corticospinal tracts. However, it is possible to observe lower-limb muscle atrophy and fasciculations on clinical examination that are clear signs of lower motor neuron (LMN) involvement. The purpose of this review is to classify HSPs based on their degree of motor neuron involvement, distinguishing forms in which only UMNs are affected from those involving both UMN and LMN degeneration, and to describe their differential diagnosis from diseases such as amyotrophic lateral sclerosis.

Clinical and genetic heterogeneity in hereditary spastic paraplegias: from SPG1 to SPG72 and still counting.

Hereditary spastic paraplegias (HSPs) are genetically determined neurodegenerative disorders characterized by progressive weakness and spasticity of lower limbs, and are among the most clinically and genetically heterogeneous human diseases. All modes of inheritance have been described, and the recent technological revolution in molecular genetics has led to the identification of 76 different spastic gait disease-loci with 59 corresponding spastic paraplegia genes. Autosomal recessive HSP are usually associated with diverse additional features (referred to as complicated forms), contrary to autosomal dominant HSP, which are mostly pure. However, the identification of additional mutations and families has considerably enlarged the clinical spectra, and has revealed a huge clinical variability for almost all HSP; complicated forms have also been described for primary pure HSP subtypes, adding further complexity to the genotype-phenotype correlations. In addition, the introduction of next generation sequencing in clinical practice has revealed a genetic and phenotypic overlap with other neurodegenerative disorders (amyotrophic lateral sclerosis, neuropathies, cerebellar ataxias, etc.) and neurodevelopmental disorders, including intellectual disability. This review aims to describe the most recent advances in the field and to provide genotype-phenotype correlations that could help clinical diagnoses of this heterogeneous group of disorders.

Consensus paper: pathological mechanisms underlying neurodegeneration in spinocerebellar ataxias.

Intensive scientific research devoted in the recent years to understand the molecular mechanisms or neurodegeneration in spinocerebellar ataxias (SCAs) are identifying new pathways and targets providing new insights and a better understanding of the molecular pathogenesis in these diseases. In this consensus manuscript, the authors discuss their current views on the identified molecular processes causing or modulating the neurodegenerative phenotype in spinocerebellar ataxias with the common opinion of translating the new knowledge acquired into candidate targets for therapy. The following topics are discussed: transcription dysregulation, protein aggregation, autophagy, ion channels, the role of mitochondria, RNA toxicity, modulators of neurodegeneration and current therapeutic approaches. Overall point of consensus includes the common vision of neurodegeneration in SCAs as a multifactorial, progressive and reversible process, at least in early stages. Specific points of consensus include the role of the dysregulation of protein folding, transcription, bioenergetics, calcium handling and eventual cell death with apoptotic features of neurons during SCA disease progression. Unresolved questions include how the dysregulation of these pathways triggers the onset of symptoms and mediates disease progression since this understanding may allow effective treatments of SCAs within the window of reversibility to prevent early neuronal damage. Common opinions also include the need for clinical detection of early neuronal dysfunction, for more basic research to decipher the early neurodegenerative process in SCAs in order to give rise to new concepts for treatment strategies and for the translation of the results to preclinical studies and, thereafter, in clinical practice.

Novel SPG10 mutation associated with dysautonomia, spinal cord atrophy, and skin biopsy abnormality.

BACKGROUND: SPG10 is a rare form of autosomic dominant hereditary spastic paraplegia (HSP) caused by mutations in the KIF5A gene, which may be involved in axonal transport. METHODS: We report the characteristics of a French family with a novel missense mutation c.580 G>C in exon 7 of the KIF5A gene. RESULTS: The proband and his sister presented with an adult onset HSP, a sensory spinal cord-like syndrome, dysautonomia, and severe axonal polyneuropathy. Contrary to the proband, his sister presented a secondary improvement in spasticity and walking. In the proband, MRI findings consisted in spinal cord atrophy and symmetric cerebral demyelination, whereas the skin biopsy suggested a defect in the number of vesicles and synaptophysin density at the pre-synaptic membrane. CONCLUSION: This study extends the phenotype of SPG10 and argues for abnormalities in the axonal vesicular transport.

SCA14 in Norway, two families with autosomal dominant cerebellar ataxia and a novel mutation in the PRKCG gene.

OBJECTIVES: Despite a similar prevalence of autosomal dominant cerebellar ataxia (ADCA) in Norway compared to other European countries, less than 10% of the families are explained by the CAG trinucleotide expansions. We wanted to find the occurence of SCA14 in the dominant ataxia population and describe the phenotype. METHODS: We screened a large dominant cerebellar ataxia cohort for mutations in the PRKCG gene. Patients were evaluated according to a standard clinical protocol for ataxia patients. RESULTS: A novel mutation was found in two families, a C to A transversion altering Histidine to a Glutamine at codon 139, located in a highly concerved region in the gene. It completely co-segregated with the affected family members and was not seen in 576 control chromosomes. Genetic analysis revealed common alleles at three microsatellite markers between these two families suggesting a shared ancestral chromosome. Affected subjects displayed a mild, slowly progressive cerebellar syndrome that included gait and limb ataxia and saccadic pursuit and head tremor in one. Age at onset ranged from 10 to 45 years. CONCLUSIONS: These are the first families with SCA14 reported from Scandinavia and a new mutation in the PRKCG gene. The occurrence in the Norwegian dominant ataxia cohort is 3.5%.

Autosomal dominant cerebellar ataxias.

Cerebellar ataxias with autosomal dominant transmission (ADCA) are far rarer than sporadic cases of cerebellar ataxia. The identification of genes involved in dominant forms has confirmed the genetic heterogeneity of these conditions and of the underlying mechanisms and pathways. To date, at least 28 genetic loci and, among them, 20 genes have been identified. In many instances, the phenotype is not restricted to cerebellar dysfunction but includes more complex multisystemic neurological deficits. Seven ADCA (SCA1, 2, 3, 6, 7, 17, and dentatorubro-pallido-luysian atrophy) are caused by repeat expansions in the corresponding proteins; phenotype-genotype correlations have shown that repeat size influences the progression of the disease, its severity and clinical differences among patients, including the phenomenon of anticipation between generations. All other ADCA are caused either by non-coding repeat expansions, conventional mutations or large rearrangements in genes with different functions. This review will focus on the genetic features of ADCA and on the clinical differences among the different forms.

Familial cortical myoclonic tremor with epilepsy: the third locus (FCMTE3) maps to 5p.

BACKGROUND: Familial cortical myoclonic tremor with epilepsy (FCMTE) is defined by autosomal dominant adult-onset cortical myoclonus (CM) and seizures in 40% of patients. Two loci, 8q23.3-q24.11 (FAME1/FCMTE1) and 2p11.1-q12.2 (FAME2/FCMTE2), were previously reported without an identified gene. Unlinked families argue for a third mutated gene. METHODS: A genome-wide scan was performed in a large FCMTE family using Linkage-12 microarrays (Illumina). Refinement of the locus on 5p was performed by genotyping 13 polymorphic microsatellite markers in the 45 available family members. RESULTS: This large French FCMTE family included 16 affected relatives. The first symptoms were CM in 5 patients (31.2%), seizures in 5 patients (31.2%), and both at the same time in 6 patients (37.5%). A total of 12.5% (2/16) had only CM without seizures. The genome-wide scan identified a single region on 5p15.31-p15, with a multipoint lod score of 3.66. Further genotyping of all family members confirmed that the region spans 9.31 Mb between D5S580 and D5S2096, 2-point lod scores reaching 6.3 at theta = 0 for D5S486. Sequencing of the SEMA5A and CTNND2 genes failed to detect mutations. CONCLUSIONS: We report the clinical and genetic characteristics of a large familial cortical myoclonic tremor with epilepsy family. The third gene maps to 5p15.31-p15. Identification of the mutated gene is ongoing.

SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum.

OBJECTIVE: Hereditary spastic paraplegias (HSPs) are very heterogeneous inherited neurodegenerative disorders. Our group recently identified ZFYVE26 as the gene responsible for one of the clinical and genetic entities, SPG15. Our aim was to describe its clinical and mutational spectra. METHODS: We analyzed all exons of SPG15/ZFYVE26 gene by direct sequencing in a series of 60 non-SPG11 HSP subjects with associated mental or MRI abnormalities, including 30 isolated cases. The clinical data were collected through the SPATAX network. RESULTS: We identified 13 novel truncating mutations in ZFYVE26, 12 of which segregated at the homozygous or compound heterozygous states in 8 new SPG15 families while 1 was found at the heterozygous state in a single family. Two of 3 splice site mutations were validated on mRNA of 2 patients. The SPG15 phenotype in 11 affected individuals was characterized by early onset HSP, severe progression of the disease, and mental impairment dominated by cognitive decline. Thin corpus callosum and white matter hyperintensities were MRI hallmarks of the disease in this series. CONCLUSIONS: The mutations are truncating, private, and distributed along the entire coding sequence of ZFYVE26, which complicates the analysis of this gene in clinical practice. In our series of patients with hereditary spastic paraplegia-thin corpus callosum, the largest analyzed so far, SPG15 was the second most frequent form (11.5%) after SPG11. Both forms share similar clinical and imaging presentations with very few distinctions, which are, however, insufficient to infer the molecular diagnosis when faced with a single patient.

Tunisian hereditary spastic paraplegias: clinical variability supported by genetic heterogeneity.

Hereditary spastic paraplegias (HSP) constitute a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower extremities. We performed the first clinical, epidemiological and genetic study of HSP in Southern Tunisia. We investigated 88 patients belonging to 38 unrelated Tunisian HSP families. We could establish the minimal prevalence of HSP in the district of Sfax at 5.75/100,000. Thirty-one percent of the families had a pure HSP, whereas 69% had a complicated form. The mode of inheritance was almost exclusively compatible with an autosomal recessive trait (97%, 37/38). Taking into account previously published results and new data generated in this work, genetic studies revealed significant or putative linkage to known HSP loci in 13 families (34.2%) to either SPG11 (7/38, 18.4%), SPG15 (4/38, 10.5%) or to SPG4 and SPG5 in one family each. The linkage results could be validated through the identification of two recurrent truncating mutations (R2034X and M245VfsX246) in the SPG11 gene, three different mutations (Q493X, F683LfsX685 and the novel S2004T/r.?) in the SPG15 gene, the recurrent R499C mutation in the SPG4 gene as well as the new R112X mutation in the SPG5 gene. SPG11 and SPG15 are the major responsible HSP genes in Tunisia.

SPG11--the most common type of recessive spastic paraplegia in Norway?

BACKGROUND: Hereditary spastic paraplegias (HSP) are neurodegenerative diseases mainly characterized by lower limb spasticity with additional neurological symptoms and signs in complicated forms. Among the many autosomal recessive forms, SPG11 appears to be one of the most frequent. OBJECTIVE: Our objective was to select potential SPG11 patients based on phenotypes in our material, identify eventual disease-causing variants with the collaboration of laboratories abroad, estimate the frequency and spectrum of SPG11-mutations and describe their associated phenotypes. MATERIAL AND METHODS: Two isolated cases and two affected members of one family with cognitive impairment and confirmed thin corpus callosum on magnetic resonance imaging were selected from our database for inclusion into a multicenter study. Results - Mutations were found in the two isolated cases but not in the proband of the family. CONCLUSION: We present the first SPG11-HSP in the Norwegian population. SPG11 should be suspected in patients with isolated or recessive HSP, thin corpus callosum and mental retardation.

Refinement of the SPG9 locus on chromosome 10q23.3-24.2 and exclusion of candidate genes.

BACKGROUND AND PURPOSE: The hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders, characterized by a progressive spasticity of the lower limbs. So far, 33 different loci (SPGs) have been mapped and the 15 genes responsible have been identified. We mapped a locus responsible for a form of spastic paraplegia, complicated by bilateral cataracts, gastroesophageal reflux with persisting vomiting and amyotrophy to chromosome 10q23.3-q24.2, in an Italian family. The critical region was in a 12 cm chromosomal interval between markers D10S564 and D10S603 (SPG9, MIM601162). In the same region, two other forms of HSP have been recently mapped: SPG27 and SPG33. In the latter case, the gene responsible has been identified. MATERIALS AND METHODS: To better characterize this region, we genotyped individuals from SPG9-linked families using additional markers and reduced the candidate region to a 4.8 Mb, excluding several genes by positional cloning. RESULTS: The refined SPG9 locus is positioned completely within SPG27 and does not include the SPG33 gene. DISCUSSION: Fifty-two transcripts are present in the refined critical region and 25 strong candidates have been excluded as disease causing genes by direct sequencing. Six of them were also excluded as responsible for SPG27.

Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism?

BACKGROUND: Autosomal dominant parkinsonism (ADP) is caused in a large percentage of familial and sporadic cases by mutations in the LRRK2 gene, particularly G2019S. It is also caused by mutations in genes associated with autosomal dominant cerebellar ataxia (ADCA), notably CAG/CAA repeat expansions in SCA2. METHODS: We screened 164 families with ADP for expansions in the SCA2, 3, and 17 genes and for the G2019S mutation in LRRK2. The SCA2 CAG/CAA repeat expansion was sequenced to determine its structure. The phenotypes of patients with ADP caused by the SCA2, LRRK2, and unknown mutations were compared, as well as those of SCA2 patients with interrupted or uninterrupted expansions of the same size. RESULTS: Three French ADP families had SCA2 mutations. The expansions ranged from 37 to 39 repeats and were interrupted and stable upon transmission. All patients (n = 9) had levodopa-responsive parkinsonism without cerebellar signs. They had significantly more symmetric signs and less rigidity than ADP caused by the G2019S mutation in LRRK2 or by unknown mutations. Interestingly, two sisters carrying both the SCA2 and the G2019S LRRK2 mutations had markedly earlier onset than their mother with only SCA2. In contrast, similar-sized but uninterrupted repeats were associated with ADCA in which cerebellar ataxia was constant and associated only rarely with one or more mild parkinsonian signs. CONCLUSION: These results suggest that the configuration of the SCA2 CAG/CAA repeat expansions plays an important role in phenotype variability. Uninterrupted SCA2 repeat expansions found in families with autosomal dominant cerebellar ataxia result in somatic mosaicism and produce large hairpin RNAs, which may interact with double-stranded RNA-binding proteins. These characteristics are modified by interruption of the SCA2 repeat expansion as found in families with autosomal dominant parkinsonism.

A new locus for autosomal recessive spastic paraplegia (SPG32) on chromosome 14q12-q21.

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders characterized by progressive spasticity of the lower limbs. Here, we performed a genome-wide linkage analysis on a consanguineous family presenting an autosomal recessive form of HSP associated with mild mental retardation, brainstem dysraphia, and clinically asymptomatic cerebellar atrophy. We have mapped the disease locus SPG32 to chromosome 14q12-q21 within a 30-cM interval, which excludes the atlastin gene.

[Familial spastic paraplegia with severe amyotrophy of the hands. (Silver syndrome?)]. / Paraplégie spastique familiale avec amyotrophie sévère des mains (syndrome de Silver?).

Familial spastic paraplegia (FSP) with severe muscular atrophy of hands and feet is exceptional. Autosomal dominant forms were initially described by Silver in 1966. We report two cases, from the same Tunisian family, presenting FSP with severe amyotrophy of the hands. A brother and his sister, aged respectively 37 and 36 years old, presented practically the same clinical picture. Their parents were cousins. The female patient was hospitalized. Both patients developed gait disorders around the age of three years. Muscular atrophy of the hands arose much later, around the age of 20 years. The neurological examination disclosed a spastic gait with distal amyotrophy, severe in the hands and moderate in the feet. Sensitivity was preserved and there was no fasciculation. The spinal cord and cerebral MRI was normal. Electromyography (EMG) showed a neurogenic pattern in the distal muscles. Stimulation of the median, ulnar and sciatica nerves was ineffective. The somatosensory evoked potentials (EP) were delayed (upper limb) or desynchronised (lower limb). The auditory and visual EP were normal. The cerebrospinal fluid contained 1 mononuclear cell/mm3 and 10 mg protein/100 ml. Abnormalities of the cranio-vertebral junction, Arnold-Chiari malformation, syringomyelia and familial juvenile amyotrophic lateral sclerosis (ALS) were excluded and the diagnosis of Silver's syndrome was evoked.

Predominant dystonia with marked cerebellar atrophy: a rare phenotype in familial dystonia.

BACKGROUND: Dystonia syndromes constitute a heterogeneous group of phenotypes that may be caused by different heredodegenerative, metabolic, or genetic diseases. OBJECTIVE: To describe the characteristics of an unusual dystonia-plus phenotype associated with cerebellar atrophy. METHODS: We selected patients with predominant dystonia and cerebellar atrophy among the 861 families referred to us for genetic testing from 1992 to 2003. The main secondary heredodegenerative causes and the major genes responsible for hereditary dystonias and autosomal dominant or recessive ataxias were excluded. RESULTS: We identified 12 patients in 8 families with an unusual dystonia-plus phenotype characterized by dystonia and cerebellar atrophy on brain MRI. The mean age at onset was 27.3 +/- 11.5 years (range: 9 to 42 years) and the mean disease duration 14.7 +/- 7.7 years (range: 4 to 30). At onset, dystonia was focal or multifocal, mainly affecting vocal cords (n = 8) and upper limbs (n = 2). During the disease course spasmodic dysphonia became severe in five patients, leading to complete aphonia in two. Dystonia became generalized in five. Cerebellar ataxia was limited to unsteadiness in most patients and progressed very slowly. The paucity of clinical cerebellar signs contrasted with the marked cerebellar atrophy on brain MRI in most patients. Four families with two affected sibs support the hypothesis of an autosomal recessive disorder. However, X-linked inheritance is possible since only men were affected. CONCLUSION: We have characterized an unusual familial phenotype associating dystonia and cerebellar atrophy in 12 male patients.

Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia.

BACKGROUND: Mutations in the SPG7 gene, which encodes paraplegin, are responsible for an autosomal recessive hereditary spastic paraplegia (HSP). OBJECTIVE: To screen the SPG7 gene in a large population of HSP families compatible with autosomal recessive transmission. METHODS: The authors analyzed 136 probands with pure or complex HSP for mutations in the SPG7 using denaturation high-performance liquid chromatography and direct sequencing. RESULTS: The authors identified 47 variants including 6 mutations, 27 polymorphisms, and 14 changes with unknown effects. In one family from Morocco, compound c.850_851delTTinsC and c.1742_1744delTGG heterozygous mutations were shown to be causative. This family had complex HSP with cerebellar impairment. Progression of the disease was rapid, resulting in a severe disease after 8 years of duration. Also detected were 20 families with one heterozygous mutation that was not found in a large control population. The mutations produced highly defective proteins in four of these families, suggesting that they were probably causative. Direct sequencing of all exons and reverse transcription PCR experiments demonstrated the absence of a second mutation. However, the p.Ala510Val missense substitution previously described as a polymorphism was shown to be significantly associated with HSP, suggesting that it had a functional effect. CONCLUSION: SPG7 mutations account for less than 5% of hereditary spastic paraplegia (HSP) families compatible with autosomal recessive inheritance. Cerebellar signs or cerebellar atrophy on brain imaging were the most frequent additional features in patients with SPG7 HSP. Rare nucleotide variants in SPG7 are frequent, complicating routine diagnosis.

SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years.

Seven families with six different SPG3A mutations were identified among 106 with autosomal dominant hereditary spastic paraplegia (HSP). Two mutations were novel (T162P, C375R). SPG3A was twice as frequent as SPG4 in patients with onset before age 10 years (31.8%). Later onset was not observed. The phenotype was pure HSP, but disease duration was longer than in non-SPG3A/SPG4 patients, leading ultimately to greater handicap.