Clinical and molecular findings of 13 families from Saudi Arabia and a family from Sudan with homocystinuria.

Homocystinuria due to cystathionine beta synthase (CBS) deficiency results in elevated plasma homocysteine and methionine levels, which are associated with multiple organ pathologies, including vascular, respiratory, musculoskeletal, nervous, and ocular tissues. This autosomal recessive disorder is caused by homozygous or compound heterozygous mutations in the CBS gene encoding for the CBS. Although homocystinuria is observed in Arab and North African patients, their clinical presentations have not been described and molecular causes remained largely uninvestigated. In this study, we describe the clinical presentations of 22 homocystinuria patients from 13 Saudi Arabian families and 1 North African Sudanese family. Cardinal biochemical features of homocystinuria manifested in all patients, but heterogeneity of expression was observed for other associated phenotypes. One patient developed Legg-Calvé-Perthes disease that has not been previously described in homocystinuria. In the Saudi families, a novel nonsense mutation, p.Trp323X, and recurrent p.Arg336Cys and p.Gly153Arg mutations were identified in the CBS gene. The p.Trp323X mutation was found in 10 of the 13 unrelated Saudi families. In the Sudanese family, the p.Thr257Met mutation in the CBS gene, previously described in Italian and Spanish patients, was found. This study shows that the spectrum of CBS gene mutations in Saudi homocystinuria patients is quite different than the Arab patients from Qatar and Israel. This study is the only detailed phenotypic and genetic depiction of homocystinuria patients from Saudi Arabia and Sudan. The data are useful for diagnosis and management of Saudi patients.

Novel mutation in GLRB in a large family with hereditary hyperekplexia.

Hereditary hyperekplexia (HH) is a disorder of the inhibitory glycinergic neurotransmitter system. Mutations in five genes have been reported to cause the disease. However, only single mutation in GLRB, the gene encoding beta-subunit of the glycine receptor, in a singleton patient with HH has been found to date. In this study, 13 patients with HH were identified through neurology and genetic clinics. Formal clinical examinations, linkage analysis, homozygosity mapping, in-mutation screening of GLRB and in silico functional analyses were carried out. A novel mutation in GLRB among nine patients was identified. This c.596 T>G perturbation results in the change of the highly conserved methionine at position 177 to arginine. Besides the classical HH phenotype, seven patients had esotropia and few of them had behavioral problems. This study presents a large family with HH as a result of homozygous mutation in GLRB and expands the clinical spectrum of HH to include eye misalignment disorder. Moreover, the report of these familial cases supports the previous evidence in a single patient of an autosomal recessive inheritance of HH because of defects in GLRB.

Smith-Lemli-Opitz syndrome among Arabs.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of variable presentation caused by the deficiency of the 3ß- hydroxycholesterol Δ(7) - reductase. Over the past 10 years, our biochemical laboratory has screened 191 plasma samples for possible SLOS, measuring the plasma cholesterol and 7-dehydrocholesterol using gas chromatography-mass spectrometry (GC-MS). The SLOS was confirmed in only five Arab patients with growth retardation, global developmental delay, dysmorphic features, and 2-3 toe syndactyly, among other findings. All cases represented moderate to severe form of SLOS. One patient had a unique cardiovascular malformation (cor triatriatum with significant obstruction of the right pulmonary veins). Two previously reported N287K (861 C>A) and R352Q (1055 G>A) and a novel R352L (1055 G>T) mutations were identified in the DHCR7 gene in these patients. The paper sheds light on this rare disease among Arabs and reviews all reported SLOS cases in the Arab population.

Biplane transesophageal color Doppler echocardiography for assessment of mitral valve area with mitral inflow jet widths.

Biplane transesophageal color Doppler echocardiography can image the mitral valve orifice in two orthogonal views. If the maximal stenotic jet width through the mitral valve obtained with the vertical transducer represents the major axis, the stenotic jet width dissected by the horizontal transducer should be the minor axis of the mitral orifice. Thus the mitral valve area can be calculated assuming an oval shape of mitral orifice. Nineteen patients with mitral stenosis were investigated. Maximal mitral stenotic jet width (JW1) was searched on a vertical plane and the jet width from the orthogonal view (JW2) was obtained on a horizontal plane. Mitral valve areas from the color Doppler jet widths were calculated by pi.JW1/2.JW2/2 and compared with those derived from Gorlin's formula. Adequate quality of echocardiographic images could be obtained in all patients for transesophageal color Doppler jet width measurements or Doppler pressure half-time determinations and in 16 of 19 patients for transthoracic planimetery of the mitral orifice at the parasternal short axis. Mitral valve areas derived from biplane transesophageal color Doppler imaging (1.31 +/- 0.53 cm2) were not different from those calculated according to Gorlin's formula from the catheterization data (1.25 +/- 0.50 cm2), those determined by transthoracic echocardiographic planimetery (1.38 +/- 0.5 cm2), or those calculated from the Doppler pressure half-time method (1.32 +/- 0.41 cm2) (difference not significant by analysis of variance). There was a very strong correlation between transesophageal echocardiographic mitral valve areas and those derived from catheterization data (r = 0.94; standard error of the estimate = 0.13 cm2). A similar correlation was obtained for the planimetric echocardiographic method (r = 0.94; standard error of the estimate = 0.14 cm2). A slightly less strong correlation was found between mitral valve areas derived from the Doppler pressure half-time method and those derived from Gorlin's formula (r = 0.83; standard error of the estimate = 0.24 cm2). The pressure half-time method accurately predicted the mitral valve area in most (15/19) patients, but it significantly (> 0.4 cm2) overestimated mitral valve area in two patients with aortic regurgitation and underestimated (< 0.4 cm2) mitral valve area in two patients with left ventricular hypertrophy. Determination of mitral valve area by color Doppler biplane transesophageal echocardiography is an alternative for accurate estimation of mitral valve area and may be most useful in intraoperative monitoring during surgical or balloon mitral commissurotomy or in the case of inadequate imaging quality of transthoracic echocardiography.