Ophthalmic features of Joubert syndrome.

PURPOSE: Joubert syndrome (Online Mendelian Inheritance in Man 213300) is a rare autosomal recessive congenital malformation of the brainstem and cerebellar vermis. Diagnosis is based on characteristic clinical features (e.g., hypotonia, episodic hyperpnea, developmental delay, progressive ataxia) and is confirmed by distinctive neuroradiologic findings (e.g., the "molar tooth" sign). Variable ophthalmic features have been mentioned in prior reports; however, most do not detail eye findings and the few that do were before the publication of suggested diagnostic criteria. The objective of the current study is to describe the ophthalmic phenotype in a cohort of patients with Joubert syndrome for whom the diagnosis was made using current diagnostic criteria. DESIGN: Prospective case series. PARTICIPANTS: Eight children diagnosed clinically with radiologic confirmation. METHODS: Ophthalmic examination and visual electrophysiology. MAIN OUTCOME MEASURES: Ocular and oculomotor examination (as allowed by patient cooperation), electroretinography, flash visual-evoked potential (fVEP). RESULTS: Patients' ages ranged from 7 months to 10 years. Saccadic dysfunction was observed in all cooperative patients (6/6); compensatory head thrusts or turns were present in all except the youngest patient (7 months of age). Most patients (5/8) had primary-position nystagmus (see-saw in 3/5). Abnormal pursuit (3/7) and a dystrophic retinal appearance (3/8) were also seen. One patient had bilateral asymmetric ptosis with unilateral lid elevation during ipsilateral abduction. Electroretinography findings were normal for all 8 patients. Seven patients underwent fVEP; 6 were abnormal (asymmetric) and one was not interpretable because of study artifact. CONCLUSIONS: Ophthalmologists should be aware that saccadic dysfunction (typically with head thrusts) and primary position nystagmus (typically see-saw) in a developmentally delayed child suggest the diagnosis of Joubert syndrome, especially if a dystrophic retinal appearance is also present. Our findings of asymmetric fVEPs and see-saw nystagmus suggest an abnormality in optic nerve decussation, consistent with the concept that impaired axonal guidance occurs in patients with Joubert syndrome. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Ethnically diverse causes of Walker-Warburg syndrome (WWS): FCMD mutations are a more common cause of WWS outside of the Middle East.

Walker-Warburg syndrome (WWS) is a genetically heterogeneous autosomal recessive disease characterized by congenital muscular dystrophy, cobblestone lissencephaly, and ocular malformations. Mutations in six genes involved in the glycosylation of á-dystroglycan (POMT1, POMT2, POMGNT1, FCMD, FKRP and LARGE) have been identified in WWS patients, but account for only a portion of WWS cases. To better understand the genetics of WWS and establish the frequency and distribution of mutations across WWS genes, we genotyped all known loci in a cohort of 43 WWS patients of varying geographical and ethnic origin. Surprisingly, we reached a molecular diagnosis for 40% of our patients and found mutations in POMT1, POMT2, FCMD and FKRP, many of which were novel alleles, but no mutations in POMGNT1 or LARGE. Notably, the FCMD gene was a more common cause of WWS than previously expected in the European/American subset of our cohort, including all Ashkenazi Jewish cases, who carried the same founder mutation.

Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome.

Intragenic homozygous deletions in the Large gene are associated with a severe neuromuscular phenotype in the myodystrophy (myd) mouse. These mutations result in a virtual lack of glycosylation of alpha-dystroglycan. Compound heterozygous LARGE mutations have been reported in a single human patient, manifesting with mild congenital muscular dystrophy (CMD) and severe mental retardation. These mutations are likely to retain some residual LARGE glycosyltransferase activity as indicated by residual alpha-dystroglycan glycosylation in patient cells. We hypothesized that more severe LARGE mutations are associated with a more severe CMD phenotype in humans. Here we report a 63-kb intragenic LARGE deletion in a family with Walker-Warburg syndrome (WWS), which is characterized by CMD, and severe structural brain and eye malformations. This finding demonstrates that LARGE gene mutations can give rise to a wide clinical spectrum, similar as for other genes that have a role in the post-translational modification of the alpha-dystroglycan protein.

Determination of urinary S-sulphocysteine, xanthine and hypoxanthine by liquid chromatography-electrospray tandem mass spectrometry.

Molybdenum cofactor and isolated sulphite oxidase deficiencies are two related rare autosomal recessive diseases characterized by severe neurological abnormalities, dislocated lens and mental retardation. Determination of three biochemical markers S-sulphocysteine (SSC), xanthine (XAN) and hypoxanthine (HXAN) in urine is essential for a definitive diagnosis and identification of the exact defect. We developed a rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the analysis of SSC, XAN and HXAN in urine. The analysis was carried out in the negative-ion selected-reaction monitoring mode. The turnaround time for the assay was 7 min. Linear calibration curves for the three biomarkers were obtained in the range of 12-480 micromol/L. The intra- and inter-day assay variations were <2.5%. Mean recoveries of SSC, XAN and HXAN added to urine at two significantly different concentrations were in the range 94.3-107.3%. At a normal SSC urine excretion value of 3.2 micromol/mmol creatinine, the signal-to-noise ratio was 337:1. This stable isotope dilution LC-MS/MS method is specific, rapid and simple, and provides definitive diagnosis for molybdenum cofactor and isolated sulphite oxidase deficiencies in very small volumes of urine. We have identified seven new cases of isolated sulphite oxidase deficiency from four Saudi families and one Sudanese family.