J.R.M. Cruysberg

Mobius syndrome redefined: a syndrome of rhombencephalic maldevelopment.

Objective: To investigate the variable clinical picture of Möbius syndrome (MIM no. 157900) and to further understand the pathogenesis of the disorder. Methods: A standardized questionnaire was submitted to 37 Dutch patients with Möbius syndrome. All underwent standardized neurologic examination with special attention to cranial nerve functions, motor skills, and facial and limb anomalies. Results: Of 37 patients with facial paresis, 97% had bilateral and 3% had unilateral ocular abduction weakness. Further analysis showed isolated abducens nerve palsy in 9%, a conjugated horizontal gaze paresis in 48%, features of Duane retraction syndrome in 34%, and congenital fibrosis of the extraocular muscles in 9%. Other signs included lingual involvement (77%), dysfunction of palate and pharynx (56%), general motor disability (88%), poor coordination (83%), and respiratory abnormalities (19%). Conclusion: Möbius syndrome is more than a cranial nerve or nuclear developmental disorder. It is a syndrome of rhombencephalic maldevelopment involving predominantly motor nuclei and axons, as well as traversing long tracts. The authors also noted gaze palsies, Duane retraction syndrome, feeding and respiratory problems, and poor motor development, suggesting a regional developmental disorder.

Retinal vein occlusion: A form of venous thrombosis or a complication of atherosclerosis? A meta-analysis of thrombophilic factors

Previous studies have shown an increased risk of retinal vein occlusion (RVO) in patients with hypertension, hypercholesterolemia and diabetes mellitus. Literature on the association between thrombophilic factors and RVO consists of small studies and case reports. The objective was to determine the relationship between thrombophilic risk factors and RVO. Thrombophilic risk factors analyzed were hyperhomocysteinemia, MTHFR gene mutation, factor V Leiden mutation, protein C and S deficiency, antithrombin deficiency, prothrombin gene mutation, anticardiolipin antibodies and lupus anticoagulant. For all currently known thrombophilic risk factors odds ratios for RVO were calculated as estimates of relative risk. The odds ratios were 8.9 (95% CI 5.7 - 13.7) for hyperhomocysteinemia, 3.9 (95% CI 2.3 - 6.7) for anticardiolipin antibodies, 1.2 (95% CI 0.9 - 1.6) for MTHFR, 1.5 (95% CI 1.0 - 2.2) for factor V Leiden mutation and 1.6 (95% CI 0.8 - 3.2) for prothrombin gene mutation. In conclusion, regarding thrombophilic risk factors and RVO there is only evidence for an association with hyperhomocysteinemia and anticardiolipin antibodies, factors that are known as risk factors for venous thrombosis as well as for arterial vascular disease. The minor effect of factor V Leiden mutation and the protrombin gene mutation (risk factors for venous thrombosis only) suggests that atherosclerosis might be an important factor in the development of CRVO.

Genotype–phenotype studies in nail-patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy

Nail-patella syndrome (NPS) is characterized by developmental defects of dorsal limb structures, nephropathy, and glaucoma and is caused by heterozygous mutations in the LIM homeodomain transcription factor LMX1B. In order to identify possible genotype–phenotype correlations, we performed LMX1B mutation analysis and comprehensive investigations of limb, renal, ocular, and audiological characteristics in 106 subjects from 32 NPS families. Remarkable phenotypic variability at the individual, intrafamilial, and interfamilial level was observed for different NPS manifestations. Quantitative urinanalysis revealed proteinuria in 21.3% of individuals. Microalbuminuria was detected in 21.7% of subjects without overt proteinuria. Interestingly, nephropathy appeared significantly more frequent in females. A significant association was established between the presence of clinically relevant renal involvement in an NPS patient and a positive family history of nephropathy. We identified normal-tension glaucoma (NTG) and sensorineural hearing impairment as new symptoms associated with NPS. Sequencing of LMX1B revealed 18 different mutations, including six novel variants, in 28 families. Individuals with an LMX1B mutation located in the homeodomain showed significantly more frequent and higher values of proteinuria compared to subjects carrying mutations in the LIM domains. No clear genotype–phenotype association was apparent for extrarenal manifestations. This is the first study indicating that family history of nephropathy and mutation location might be important in precipitating individual risks for developing NPS renal disease. We suggest that the NPS phenotype is broader than previously described and that NTG and hearing impairment are part of NPS. Further studies on modifier factors are needed to understand the mechanisms underlying phenotypic heterogeneity.

Clinical and biochemical effects of zileuton in patients with the Sjögren-Larsson syndrome

Abstract. The Sjögren-Larsson syndrome (SLS) is an inborn error of lipid metabolism, characterised clinically by congenital ichthyosis, mental retardation and spasticity. Patients also suffer from severe pruritus. The degradation of leukotriene (LT) B4 is one of the defective metabolic routes in SLS. Zileuton inhibits the synthesis of LTB4 and the cysteinyl leukotrienes. Five SLS patients were treated with zileuton for 3 months. Favourable effects were found on pruritus score (P=0.006), general well-being, and background activity of electroencephalographic studies. Neuropsychological test results did not change significantly. There was, however, a clinically important trend towards improvement in the speed of information processing. Results of cerebral MRI and proton magnetic resonance spectroscopy did not change during therapy. Urinary concentrations of LTB4 and ω-OH-LTB4 decreased significantly (P=0.02 and P=0.003 respectively), while their concentrations in CSF were normal at baseline and remained so after therapy. Conclusion: patients with Sjögren-Larsson syndrome might benefit from treatment with zileuton, especially with respect to the agonising pruritus. The findings reported here, point to a crucial role for leukotriene B4 in the pathogenesis of pruritus.

Juvenile macular dystrophy associated with deficient activity of fatty aldehyde dehydrogenase in Sjögren-Larsson syndrome.

PURPOSE To report the ocular manifestations associated with the Sjögren-Larsson syndrome in a series of patients with proven fatty aldehyde dehydrogenase deficiency. To emphasize the clinical importance of the ophthalmological features of the Sjögren-Larsson syndrome. To discuss the metabolic disturbances that might give rise to the ophthalmological picture. METHODS Fifteen patients with Sjögren-Larsson syndrome underwent a standardized ophthalmological examination. In patients of appropriate age, and who were able to cooperate, additional investigations were performed. RESULTS All patients exhibited bilateral, glistening yellow-white crystalline deposits that were located in the innermost retinal layers and appeared during the first 2 years of life. Repeated fundus photography in individual patients showed that the dots became more numerous as the patients got older. Photophobia, subnormal visual acuity, myopia, and astigmatism were found in most of the patients. Fluorescein angiography was performed in three patients and showed a mottled hyperfluorescence of the retinal pigment epithelium, without leakage. Color vision, electroretinography, and electro-oculography could be performed in only a small number of patients and showed no abnormalities. Visual evoked potentials were found to be abnormal in six of eight patients. CONCLUSIONS In Sjögren-Larsson syndrome, patients exhibit highly characteristic bilateral, glistening yellow-white retinal dots from the age of 1 to 2 years onward. The number of dots increases with age. The extent of the macular abnormality does not correlate with the severity of the ichthyosis or with the severity of the neurological abnormalities. A high percentage of patients shows additional ocular signs and symptoms, notably marked photophobia.

Sjögren-Larsson syndrome: clinical and MRI/MRS findings in FALDH-deficient patients

Objective: To determine the spectrum of clinical and MRI/1H MRS features of patients with fatty aldehyde dehydrogenase (FALDH) deficiency. Background: The Sjögren–Larsson syndrome (SLS) was originally defined as a clinical triad consisting of ichthyosis, spastic di- or tetraplegia, and mental retardation, with autosomal recessive inheritance. By now, both the deficiency of the enzyme FALDH, and the genetic mutations on chromosome 17 responsible for this deficiency, have been identified. SLS, defined by fibroblast FALDH deficiency, seems to be a much broader syndrome. Methods: The clinical findings of 11 FALDH-deficient patients of different ages and one patient with the characteristic SLS-like ichthyosis, but without FALDH deficiency, were evaluated in relation to their cerebral MRI, and to 1H MRS in six patients. Results: The severity of neurologic symptoms showed considerable variation. Fundoscopic perifoveal glistening dots and the characteristic SLS-like ichthyosis were present in all patients. Serial MRI findings showed evidence of retarded myelination and a variable degree of dysmyelination. 1H MRS showed an accumulation of free lipids in the periventricular white matter, even before the stage of visible dysmyelination. Conclusions: The neurologic consequences of FALDH deficiency show considerable variation. The characteristic pattern of ichthyosis and retinal degeneration are seen consistently, yet they are not pathognomonic. MRI and 1H MRS findings suggest an accumulation of long-chain fatty alcohol intermediates, resulting in retarded myelination and dysmyelination.

Patients with Sjogren-Larsson syndrome lack macular pigment.

PURPOSE Sjögren-Larsson syndrome (SLS), an autosomal recessive hereditary disorder with congenital ichthyosis, spastic diplegia or tetraplegia, and mental retardation, reveals a characteristic macular dystrophy with intraretinal crystals and foveal pseudocysts. Ophthalmic symptoms in SLS are reduced visual acuity and photophobia. This article reports the deficiency of macular pigment as a novel finding in this peculiar, congenital maculopathy. DESIGN Cross-sectional, observational case study. PARTICIPANTS Patients with clinically and genetically proven SLS. METHODS Besides general ophthalmologic examination, 2 different methods were used, fundus autofluorescence (FAF) and fundus reflectometry with the macular pigment reflectometer (MPR), for measuring macular pigment (MP). MAIN OUTCOME MEASURES Distribution profiles and quantity of MP in eyes of SLS patients. RESULTS Twenty-eight eyes of 14 patients were included. The technique to measure MP depended on the ability of the mentally handicapped patients to cooperate. Fundus autofluorescence images providing qualitative estimates were obtained from 9 eyes of 5 patients, and MPR measures providing quantitative estimates were obtained from 19 eyes of 10 patients. Fundus autofluorescence images of SLS patients lacked the typical attenuation of macular FAF signal expected in normal eyes. Mean foveal MP levels measured by MPR showed significantly lower values in SLS patients (0.10+/-0.07) than in healthy individuals (0.69+/-0.17; P<0.001, Student t test). CONCLUSIONS The group of SLS patients studied here had significantly reduced levels of foveal MP. The crystalline macular dystrophy in SLS seems to be the first known disease with a genetically caused deficiency of MP.

Ophthalmological abnormalities in children with congenital disorders of glycosylation type I

Background: Children with congenital disorders of glycosylation (CDG) type Ia frequently present with ocular involvement and visual loss. Little is known, however, about the occurrence of ophthalmological abnormalities in other subtypes of CDG syndrome. Methods: We evaluated 45 children sequentially diagnosed with CDG type I for the presence of ocular abnormalities at the time of the diagnosis and during follow-up. We compared the various ophthalmic findings in the different CDG subgroups. Results: Of the 45 patients, 22 had CDG type Ia, nine had CDG type Ic and 14 had a so-far undiagnosed biochemical background (CDG type Ix). We found ocular anomalies in 28 of the 45 children. Three had unique findings, including congenital cataract, retinal coloboma and glaucoma. A few CDG type Ia patients showed a sequential occurrence of symptoms, including retinitis pigmentosa or cataract. Conclusions: Ophthalmic findings are frequent in CDG syndrome involving both the anterior and posterior segment of the eye. The disorder might lead to abnormal development of the lens or the retina, cause diminished vision, alter ocular motility and intraocular pressure. We suggest routine screening and follow-up for ophthalmological anomalies in all children diagnosed with CDG syndrome to provide early treatment and adequate counselling.

3-Methylglutaconic aciduria type I redefined A syndrome with late-onset leukoencephalopathy

Objective: 3-Methylglutaconic aciduria type I is a rare inborn error of leucine catabolism. It is thought to present in childhood with nonspecific symptoms; it was even speculated to be a nondisease. The natural course of disease is unknown. Methods: This is a study on 10 patients with 3-methylglutaconic aciduria type I. We present the clinical, neuroradiologic, biochemical, and genetic details on 2 new adult-onset patients and follow-up data on 2 patients from the literature. Results: Two unrelated patients with the characteristic biochemical findings of 3- methylglutaconic aciduria type I presented in adulthood with progressive ataxia. One patient additionally had optic atrophy, the other spasticity and dementia. Three novel mutations were found in conserved regions of the AUH gene. In both patients, MRI revealed extensive white matter disease. Follow-up MRI in a 10-year-old boy, who presented earlier with isolated febrile seizures, showed mild abnormalities in deep white matter. Conclusion: We define 3-methylglutaconic aciduria type I as an inborn error of metabolism with slowly progressive leukoencephalopathy clinically presenting in adulthood. In contrast to the nonspecific findings in pediatric cases, the clinical and neuroradiologic pattern in adult patients is highly characteristic. White matter abnormalities may already develop in the first decades of life. The variable features found in affected children may be coincidental. Long-term follow-up in children is essential to learn more about the natural course of this presumably slowly progressive disease. Dietary treatment with leucine restriction may be considered.

Phenotype description of a novel DFNA9/COCH mutation, I109T.

Objectives: This is a report of the audiological and vestibular characteristics of a Dutch DFNA9 family with a novel mutation, I109T, in the LCCL domain of COCH. Methods: From the family with the novel I109T COCH mutation, audiometric data were collected and analyzed longitudinally. Results were compared to those obtained in previously identified P51S, G88E, and G87W COCH mutation carriers. Special attention was also given to a comparison of age-related features such as progressive hearing loss and vestibular impairment. Results: A novel mutation (I109T) in COCH segregates with hearing impairment and vestibular dysfunction in the present family. Pure tone thresholds, phoneme recognition scores, and vestibular responses of the I109T mutation carriers were essentially similar to those previously established in P51S, G87W, and G88E mutation carriers. Deterioration of hearing in the I109T mutation carriers started at 43 years of age, and vestibular function deteriorated at least 7 years later. Conclusions: The phenotype associated with the novel COCH (I109T) mutation is largely similar to that associated with P51S and G88E mutation carriers. However, subtle differences in terms of onset age and rate of progression seem to exist.