Paola S. Denora

Mutations in SPG11 , encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum

Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is a common and clinically distinct form of familial spastic paraplegia that is linked to the SPG11 locus on chromosome 15 in most affected families. We analyzed 12 ARHSP-TCC families, refined the SPG11 candidate interval and identified ten mutations in a previously unidentified gene expressed ubiquitously in the nervous system but most prominently in the cerebellum, cerebral cortex, hippocampus and pineal gland. The mutations were either nonsense or insertions and deletions leading to a frameshift, suggesting a loss-of-function mechanism. The identification of the function of the gene will provide insight into the mechanisms leading to the degeneration of the corticospinal tract and other brain structures in this frequent form of ARHSP.

SPG11 spastic paraplegia. A new cause of juvenile parkinsonism.

Autosomal recessive hereditary spastic paraplegia (AR HSP) with thin corpus callosum (TCC) is a rare neurodegenerative disorder often caused by mutations in the gene encoding for spatacsin at the SPG11 locus on chromosome 15q. The disease is characterized by progressive spastic paraparesis and mental retardation which occur during the first two decades of life and frequently with peripheral neuropathy. Brain magnetic resonance imaging (MRI) reveals typical TCC with periventricular white matter changes. We describe two patients, of Turkish descent, from the same consanguineous family and affected with SPG11 in association with unusual early-onset parkinsonism. Parkinsonism occurred during the very early stages of SPG11 in both patients, being in one the inaugural symptom of the disease presented as a resting tremor with akinesia, rigidity and expressing an initial moderate levodopa-response that progressively weakened. The second patient presented a resting tremor with mild akinesia and no levodopa-response. Both patients were affected with progressive spastic paraparesis which had initially occurred at 15 and 12 years of age, respectively, in association with mild mental retardation and an axonal polyneuropathy. TCC with periventricular white matter changes (PWMC) was evident by MRI and 123I-ioflupane SPECT was abnormal. Genetic analysis detected for both patients a new c.704_705delAT, p.H235RfsX12 homozygous mutation in SPG11. This report provides evidence that parkinsonism may initiate SPG11-linked HSP TCC and that SPG11 may cause juvenile parkinsonism.

Screening of ARHSP-TCC patients expands the spectrum of SPG11 mutations and includes a large scale gene deletion.

Autosomal recessive spastic paraplegia with thinning of corpus callosum (ARHSP‐TCC) is a complex form of HSP initially described in Japan but subsequently reported to have a worldwide distribution with a particular high frequency in multiple families from the Mediterranean basin. We recently showed that ARHSP‐TCC is commonly associated with mutations in SPG11/KIAA1840 on chromosome 15q. We have now screened a collection of new patients mainly originating from Italy and Brazil, in order to further ascertain the spectrum of mutations in SPG11, enlarge the ethnic origin of SPG11 patients, determine the relative frequency at the level of single Countries (i.e., Italy), and establish whether there is one or more common mutation. In 25 index cases we identified 32 mutations; 22 are novel, including 9 nonsense, 3 small deletions, 4 insertions, 1 in/del, 1 small duplication, 1 missense, 2 splice‐site, and for the first time a large genomic rearrangement. This brings the total number of SPG11 mutated patients in the SPATAX collection to 111 cases in 44 families and in 17 isolated cases, from 16 Countries, all assessed using homogeneous clinical criteria. While expanding the spectrum of mutations in SPG11, this larger series also corroborated the notion that even within apparently homogeneous population a molecular diagnosis cannot be achieved without full gene sequencing.

Cellular distribution and subcellular localization of spatacsin and spastizin, two proteins involved in hereditary spastic paraplegia.

Truncating mutations in the SPG11 and SPG15 genes cause complicated spastic paraplegia, severe neurological conditions due to loss of the functions of spatacsin and spastizin, respectively. We developed specific polyclonal anti-spatacsin (SPG11) and anti-spastizin (SPG15) antisera, which we then used to explore the intracellular and tissue localizations of these proteins. We observed expression of both proteins in human and rat central nervous system, which was particularly strong in cortical and spinal motor neurons as well as in retina. Both proteins were also expressed ubiquitously and strongly in embryos. In cultured cells, these two proteins had similar diffuse punctate, cytoplasmic and sometimes nuclear (spastizin) distributions. They partially co-localized with multiple organelles, particularly with protein-trafficking vesicles, endoplasmic reticulum and microtubules. Spastizin was also found at the mitochondria surface. This first study of the endogenous expression of spatacsin and spastizin shows similarities in their expression patterns that could account for their overlapping clinical phenotypes and involvement in a common protein complex.

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.

A novel KIF5A/SPG10 mutation in spastic paraplegia associated with axonal neuropathy.

JO N 2 84 0 5 % of the AD-HSP patients harbor mutations in less common genes (NIPA1/SPG6, KIF5A/SPG10, REEP1/SPG31, BSCL2/SPG17, ZFYVE27/SPG33, KIAA0196/SPG8, HSPD1/SPG13) with possible variations in frequency in different populations [5]. The remaining cases harbor mutations in as yet unknown genes. To determine the relative incidence of less common AD-HSP etiologies, we systematically screened for mutations in a cohort of 25 patients with documented AD-HSP and 50 apparently sporadic cases without prior linkage data information and in whom mutations or rearrangements in SPG4 had been excluded by reported methodologies [2]. SPG3A mutations had also been ruled out in 9 cases where onset was < 10 years. After obtaining written informed consent, we purified genomic DNA from peripheral blood using standard procedures. PCR amplification of exons and flanking intronic sequences using specific primer pairs was followed by dHPLC and direct sequencing of amplified fragments to analyze the coding regions of NIPA1/SPG6, KIF5A/SPG10, REEP1/SPG31, BSCL2/SPG17, HSPD1/SPG13. We identified a novel missense mutation in KIF5A/SPG10 in an Italian family (Fig. 1A). The proposita (II:01) was a 39 year-old woman. Her spastic gait was initially identified at the age of 30 years and has Alessandra Tessa Gabriella Silvestri Maria Fulvia de Leva Anna Modoni Paola S. Denora Marcella Masciullo M. Teresa Dotti Carlo Casali Mariarosa A. B. Melone Antonio Federico Alessandro Filla Filippo M. Santorelli

Spastic paraplegia with thinning of the corpus callosum and white matter abnormalities: Further mutations and relative frequency in ZFYVE26/SPG15 in the Italian population

Spastic paraplegia with thinning of the corpus callosum (ARHSP-TCC) is a relatively frequent form of complicated hereditary spastic paraplegia in which mental retardation and muscle stiffness at onset are followed by slowly progressive paraparesis and cognitive deterioration. Although genetically heterogeneous, ARHSP-TCC is frequently associated with mutations in the SPG11 gene, on chromosome 15q. However, it is becoming evident that ARHSP-TCC can also be the clinical presentation of mutations in ZFYVE26 (SPG15), as shown by the recent identification of eight families with a variable phenotype. Here, we present an additional Italian ARHSP-TCC patient harboring two new, probably loss-of-function mutations in ZFYVE26. This finding, together with the report of a mutation in another Italian family, provides confirmation that ZFYVE26 is the second gene responsible for ARHSP-TCC in the Italian population.

Hereditary spastic paraplegia caused by the novel mutation 1047insC in the SPG7 gene

Spastic paraplegia type 7 (SPG7) is an autosomal recessive form of hereditary spastic paraparesis (ARHSP) caused by mutations in paraplegin, a subunit of an ATP-dependent AAA-protease located within the inner mitochondrial membrane. We have identified a novel paraplegin mutation, c.1047insC, in a non-consanguineous Norwegian family with ARHSP. This is the first description of this disorder in the Norwegian population and, apart from mild ptosis in two siblings, the phenotype was essentially pure and late in onset.

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.

Motor neuron degeneration in spastic paraplegia 11 mimics amyotrophic lateral sclerosis lesions

The most common autosomal recessive spastic paraplegia is caused by mutations in SPG11. Denora et al. report the first postmortem neuropathological analysis of two unrelated patients with SPG11, and demonstrate clinical and pathological overlap between this disease and ALS. Abnormal neuronal lipid accumulation is identified as a hallmark of SPG11.