[show abstract][hide abstract] ABSTRACT: Hereditary spastic paraplegias (HSPs) are genetically and phenotypically heterogeneous disorders. Both "uncomplicated" and "complicated" forms have been described with various modes of inheritance. Sixteen loci for autosomal-recessive "complicated" HSP have been mapped. The SPG15 locus was first reported to account for a rare form of spastic paraplegia variably associated with mental impairment, pigmented maculopathy, dysarthria, cerebellar signs, and distal amyotrophy, sometimes designated as Kjellin syndrome. Here, we report the refinement of SPG15 to a 2.64 Mb genetic interval on chromosome 14q23.3-q24.2 and the identification of ZFYVE26, which encodes a zinc-finger protein with a FYVE domain that we named spastizin, as the cause of SPG15. Six different truncating mutations were found to segregate with the disease in eight families with a phenotype that included variable clinical features of Kjellin syndrome. ZFYVE26 mRNA was widely distributed in human tissues, as well as in rat embryos, suggesting a possible role of this gene during embryonic development. In the adult rodent brain, its expression profile closely resembled that of SPG11, another gene responsible for complicated HSP. In cultured cells, spastizin colocalized partially with markers of endoplasmic reticulum and endosomes, suggesting a role in intracellular trafficking.
The American Journal of Human Genetics 05/2008; 82(4):992-1002. · 11.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG31. In a large collaborative effort, we screened a sample of 535 unrelated HSP patients for REEP1 mutations and copy number variations. We identified 13 novel and 2 known REEP1 mutations in 16 familial and sporadic patients by direct sequencing analysis. Twelve out of 16 mutations were small insertions, deletions or splice site mutations. These changes would result in shifts of the open-reading-frame followed by premature termination of translation and haploinsufficiency. Interestingly, we identified two disease associated variations in the 3'-UTR of REEP1 that fell into highly conserved micro RNA binding sites. Copy number variation analysis in a subset of 133 HSP index patients revealed a large duplication of REEP1 that involved exons 2-7 in an Irish family. Clinically most SPG31 patients present with a pure spastic paraplegia; rare complicating features were restricted to symptoms or signs of peripheral nerve involvement. Interestingly, the distribution of age at onset suggested a bimodal pattern with the appearance of initial symptoms of disease either before the age of 20 years or after the age of 30 years. The overall mutation rate in our clinically heterogeneous sample was 3.0%; however, in the sub-sample of pure HSP REEP1 mutations accounted for 8.2% of all patients. These results firmly establish REEP1 as a relatively frequent autosomal dominant HSP gene for which genetic testing is warranted. We also establish haploinsufficiency as the main molecular genetic mechanism in SPG31, which should initiate and guide functional studies on REEP1 with a focus on loss-of-function mechanisms. Our results should be valid as a reference for mutation frequency, spectrum of REEP1 mutations, and clinical phenotypes associated with SPG31.
[show abstract][hide abstract] ABSTRACT: To investigate the progression of cognitive impairment and its behavioral aspects in patients with SPG4-linked autosomal dominant hereditary spastic paraplegia (SPG4-ADHSP).
Sixteen patients, 45 years or older, from five families with SPG4-ADHSP were prospectively assessed. Eleven of these, from three families, were followed and 10 had two cognitive examinations using the Cambridge Cognitive Assessment (CAMCOG) 2.9 years apart. The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), the Neuropsychiatric Inventory (NPI), and the Nurses' Observation Scale for Geriatric Patients (NOSGER) were completed by close relatives of the 11 patients at the second assessment. Eleven matched control subjects had CAMCOG examinations 3.1 years apart.
The mean CAMCOG score at the initial assessment was lower for the 10 HSP patients (73.5/107) than for 10 control subjects (91.7/107, p = 0.005). After 2.9 years, the HSP patients experienced a fall in the mean CAMCOG by 9.1 points to 64.4/107 (p = 0.008). The mean CAMCOG score for the control subjects (90.8/107) fell by only 0.9 points after 3.1 years (p = 0.36). The CAMCOG scores of two HSP patients moved from the mild (60 to 80) into the moderate dementia category (35 to 59) and in three other patients into the mild dementia range from borderline normal scores (81 to 85). IQCODE scores were abnormal in 9/11 HSP patients and 1/11 controls (p = 0.001). Seven of the 11 HSP patients were considered as having dementia.
This study indicates an active progression of cognitive deterioration and dementia in older patients with SPG4-ADHSP.
[show abstract][hide abstract] ABSTRACT: Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by pro- gressive spasticity of the lower limbs. Five AD-HSP loci have been mapped to chromosomes 14q, 2p, 15q, 8q and 12q. The SPG4 locus at 2p21-p22 has been shown to account for approximately 40% of all AD-HSP families. SPG4 encoding spastin, a putative nuclear AAA protein, has recently been identified. Here, sequence analysis of the 17 exons of SPG4 in 87 unrelated AD-HSP patients has resulted in the detection of 34 novel mutations. These SPG4 mutations are scattered along the coding region of the gene and include all types of DNA modification including missense (28%), nonsense (15%) and splice site point (26.5%) mutations as well as deletions (23%) and insertions (7.5%). The clinical analysis of the 238 mutation carriers revealed a high proportion of both asymptomatic carriers (14/238) and patients unaware of symptoms (45/238), and permitted the redefinition of this frequent form of AD-HSP.
Human Molecular Genetics 04/2000; · 7.69 Impact Factor