Kjellin syndrome: long-term neuro-ophthalmologic follow-up and novel mutations in the SPG11 gene.

OBJECTIVE: Kjellin's syndrome is a hereditary neuro-ophthalmologic syndrome. We describe the clinical phenotypes of 7 patients, identifying the responsible mutations for 4 of them. A 10-year ophthalmologic and neurologic follow-up of 5 patients allowed us to describe the disease's characteristics, early symptoms and progression, associated ocular signs, and retinal changes in carriers. DESIGN: Retrospective clinical study and molecular genetics investigation. PARTICIPANTS: The records of 7 patients with Kjellin's syndrome were analyzed retrospectively. METHODS: All patients underwent full neurologic and ophthalmologic examinations. The neurologic examinations included assessments of initial symptoms, intelligence quotient tests, psychologic tests, and either magnetic resonance imaging or computed tomography. The ophthalmologic examinations included visual acuity on an Early Treatment Diabetic Retinopathy Study chart, intraocular pressure color vision assessment, slit-lamp and fundus examination, Goldmann perimetry, fundus autofluorescence, optical coherence tomography and fluorescein angiography, electro-oculography, electroretinography, and flash visual evoked potentials. Direct sequencing of the SPG11 and SPG15 genes and gene-dosage analysis for the former were performed for 4 of these index patients. MAIN OUTCOME MEASURES: Identification of new mutations in the SPG11 gene, validating its implication in Kjellin's syndrome. RESULTS: The first signs appear before the age of 10 years, with late verbal development and difficulty running and walking. Life expectancy is between 30 and 40 years. The secondary ophthalmologic symptoms only moderately affect visual acuity. In addition to the classic symptoms, 3 of the 7 patients displayed small whitish lens opacities, and 3 neurologically unaffected parents (father or mother), all heterozygous carriers, exhibited whitish retinal dots. All the patients who were tested carried SPG11, not SPG15, mutations. CONCLUSIONS: Neurologic signs of SPG11 mutations emerge in early infancy, with walking and language difficulties. Onset of paraplegia occurs at the end of the first decade or during the second decade. Retinal changes, an integral part of SPG11 mutations in this series of patients, are only observed once the paraplegia has become apparent.

Dopamine receptor D3 gene and essential tremor in large series of German, Danish and French patients.

The genetic causes of essential tremor (ET) seem to be heterogeneous. Recently, ET has been found associated with a functional variant (Ser9Gly) of the dopamine D(3) receptor (DRD3), located in the ETM1 locus on chromosome 3q13.3 described for the first time in 1997. We examined this variant in three different populations from Germany, Denmark and France. We undertook an association study of the Ser9Gly variant in 202 cases with a familial history from unrelated families with ET, 97 cases with isolated non-familial ET and 528 healthy controls. In addition, linkage and segregation analyses were carried out in 22 ET families. The distribution of genotypes and allele frequencies showed no significant differences in the whole sample and in a subanalysis of familial and sporadic cases. Age at onset of tremor, tremor duration and tremor severity did not show an association with the genotype. In addition, the DRD3 variant was not found linked to the disease in a subset of informative ET families. We did not find a significant association of the DRD3 variant with ET nor linkage to the DRD3 receptor in German, Danish and French ET patients and families, suggesting that it is unlikely to be a causal factor for ET.

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.

Hereditary spastic paraplegia with mental impairment and thin corpus callosum in Tunisia: SPG11, SPG15, and further genetic heterogeneity.

OBJECTIVE: To perform a clinical and genetic study of Tunisian families with autosomal recessive (AR) hereditary spastic paraplegia with thin corpus callosum (HSP-TCC). DESIGN: Linkage studies and mutation screening. SETTING: Reference Center for Neurogenetics in South and Center Tunisia. PARTICIPANTS: Seventy-three subjects from 33 "apparently" unrelated Tunisian families with AR HSP. MAIN OUTCOME MEASURES: Families with AR HSP-TCC were subsequently tested for linkage to the corresponding loci using microsatellite markers from the candidate intervals, followed by direct sequencing of the KIAA1840 gene in families linked to SPG11. RESULTS: We identified 8 Tunisian families (8 of 33 [24%]), including 19 affected patients, fulfilling the clinical criteria for HSP-TCC. In 7 families, linkage to either SPG11 (62.5%) or SPG15 (25%) was suggested by haplotype reconstruction and positive logarithm of odds score values for microsatellite markers. The identification of 2 recurrent mutations (R2034X and M245VfsX) in the SPG11 gene in 5 families validated the linkage results. The neurological and radiological findings in SPG11 and SPG15 patients were relatively similar. The remaining family, characterized by an earlier age at onset and the presence of cataracts, was excluded for linkage to the 6 known loci, suggesting further genetic heterogeneity. CONCLUSIONS: Autosomal recessive HSP-TCC is a frequent subtype of complicated HSP in Tunisia and is clinically and genetically heterogeneous. SPG11 and SPG15 are the major loci for this entity, but at least another genetic form with unique clinical features exists.

Spastic paraplegia 15: linkage and clinical description of three Tunisian families.

Hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower limbs. The locus designated spastic paraplegia 15 (SPG15), located in a 16-Mb interval on chromosome 14q, is associated with a rare autosomal recessive complicated form of HSP known as Kjellin's syndrome. In this study, we describe three additional families, of Tunisian origin, linked to the SPG15 locus, one of which had a significant multipoint LOD score of 3.46. In accordance with previous reports, the phenotype of our patients consisted of early onset spastic paraparesis associated with mental impairment and severe progression. Retinal degeneration was not observed, however, but we extended the phenotype of this form to include peripheral neuropathy and white matter abnormalities on MRI. Interestingly, like retinal degeneration, thin corpus callosum is not a constant feature in this entity.

Spastic paraplegia 5: Locus refinement, candidate gene analysis and clinical description.

Thirty-three different loci for hereditary spastic paraplegias (HSP) have been mapped, and 15 responsible genes have been identified. Autosomal recessive spastic paraplegias (ARHSPs) usually have clinically complex phenotypes but the SPG5, SPG24, and SPG28 loci are considered to be associated with pure forms of the disease. We performed a genome-wide scan in a large French family. Fine mapping of the refined SPG5 region on chromosome 8q12 was performed in another 17 ARHSP families with additional microsatellite markers. After exclusion of known ARHSP loci, the genome-wide screen provided evidence of linkage with a maximal multipoint lod score of 2.6 in the D8S1113-D8S1699 interval. This interval partially overlapped SPG5 and reduced it to a 5.9 megabase (Mb)-region between D8S1113 and D8S544. In a family of Algerian origin from a series of 17 other ARHSP kindreds, linkage to the SPG5 locus was supported by a multipoint lod score of 2.3. The direct sequencing of the coding exons of seven candidate genes did not detect mutations/polymorphisms in the index cases of both linked families. The phenotype of the two SPG5-linked families consisted of spastic paraparesis associated with deep sensory loss. In several patients with long disease durations, there were also mild cerebellar signs. The frequency of SPG5 was approximately 10% (2/18) in our series of ARHSP families with pure or complex forms. We have refined the SPG5 locus to a 3.8 cM interval and extended the phenotype of this form of ARHSP to include slight cerebellar signs.

New mutations in protein kinase Cgamma associated with spinocerebellar ataxia type 14.

Autosomal dominant cerebellar ataxias (ADCA) are a heterogeneous group of neurological disorders. Point mutations in the gene encoding protein kinase Cgamma (PRKCG) are responsible for spinocerebellar ataxia 14 (SCA14). We screened for mutations in the PRKCG gene, in a large series of 284 ADCA index cases, mostly French (n=204) and German (n=48), in whom CAG repeat expansions in the known SCA genes were previously excluded. Six mutations were found that segregated with the disease and were not detected on 560 control chromosomes, including F643L (exon 18), already reported in another French kindred. Five new missense mutations were identified in exons 4 (C114Y/G123R/G123E), 10 (G360S) and 18 (V692G). All but one (V692G) were located in highly conserved regions of the regulatory or catalytic domains of the protein. All six SCA14 families were French and there was no evidence of reduced penetrance. The phenotype consisted in a very slowly progressive cerebellar ataxia with a mean age at onset of 33.5+/-14.2 years (range 15 to 60 years), occasionally associated with executive dysfunction, myoclonus, myorythmia, tremor or decreased vibration sense. SCA14 represented only 1.5% (7/454) of French ADCA families but none of the German families. It should, however, be considered in patients with slowly progressive ADCA, particularly when myoclonus and cognitive impairment are present.