Elsevier

Ophthalmology

Volume 118, Issue 3, March 2011, Pages 564-573
Ophthalmology

Original article
Kjellin Syndrome: Long-term Neuro-ophthalmologic Follow-up and Novel Mutations in the SPG11 Gene

https://doi.org/10.1016/j.ophtha.2010.07.024Get rights and content

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.

Financial Disclosure(s)

The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Section snippets

Materials and Methods

The present retrospective study was approved by the institutional review board of Lille University Hospital. All the patients were examined at this hospital. These patients had been referred to our clinic from 1987 to 2009 with a diagnosis of spastic paraplegia. The criteria for the clinical diagnosis of Kjellin's syndrome were maculopathy and neurologic signs, including spasmodic paraplegia. All the participants agreed to undergo neurologic and eye examinations, together with a questionnaire,

Case 1

This female patient had displayed spastic paraparesis since the age of 14 years. She was the second of 2 children (Fig 1, available at http://aaojournal.org). Her parents did not display any neurologic disorders and were not consanguineous, although they did originate from villages just 4 to 5 km apart in the remote Portuguese countryside. A far cousin on the mother's side, V14, and 2 other cousins, V16 and V17, were affected by spastic paraplegia. This distant family was studied in Portugal,

Molecular Genetics

We identified 5 (3 novel) truncating mutations in the SPG11 gene in all 4 sampled cases, in either the homozygous or the compound heterozygous state, indicating that they were the cause of the disease in these patients. They were absent from 192 French and 96 North-African unrelated healthy individuals. Two of these mutations had already been reported: The heterozygous truncating c.6832_6833delAG/p.S2278LfsX61 (exon 37) mutation found in case 7 had been reported to be segregating in affected

Discussion

Kjellin's syndrome is rare but not exceptional. Our 7 patients, all of whom carried mutations in SPG11, belonged to 6 families with a total of 14 affected members. We detected these patients in a general population of 4 million inhabitants (Nord-Pas-de-Calais Region in Northern France) over a period of 16 years. During a similar period in the same population, we identified a similar number of patients with Refsum disease.14

From a neurologic point of view, and on the basis of our observations,

References (19)

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    Similar to ABCA4 retinopathy, electrophysiological changes may not be easily predicted from the anatomical changes, as those with widespread flecks may have normal results, or show reduction in full field ERG a wave amplitude with increased latency. Despite many similarities, Kjellin syndrome is not confused with Stargardt disease as neurological signs and symptoms predate the retinal changes (Puech et al., 2011). Recently two genes, ZFYVE26 and SPG11, have been identified where bi-allelic mutation results in Kjellin syndrome (Hanein et al., 2008; Orlen et al., 2009).

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Manuscript no. 2009-1345.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Funding: French National Research Agency (ANR) grants to G. Stevanin: A05221DS, R09148DS, and R07077DS. The funding organization had no role in the design or conduct of this research.

The first 3 authors contributed equally to this work.

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