M.R. Rivera-Vega

Unusual clinical presentation in two cases of multiple sulfatase deficiency

Multiple sulfatase deficiency (MSD) is an inborn error of metabolism that combines the clinical features of late infantile metachromatic leukodystrophy and mucopolysaccharidosis. The characteristic biochemical abnormality is a reduction in the activities of several sulfatases, with consequent tissue accumulation of sulfatides, sulfated glycosaminoglycans, sphingolipids, and steroid sulfates. In this study we present two unusual cases of MSD with variable enzymatic deficiency of arylsulfatases A, B, and C. Both patients had ichthyosis, broad thumbs and index fingers, an unusually slow progression of the neurologic symptoms, and lacked the hepatosplenomegaly that is typical of MSD. Olivopontocerebellar atrophy was present and one patient had a large retrocerebellar cyst. Mucopolysaccharides were not detected in the urine from either subject. Leukocyte arylsulfatase A activity in patient 1 was 0.46 nmol/mg protein/hr and in patient 2 was 0.0 nmol/mg protein/hr (normal 0.7–5.0 nmol/mg protein/hr). Leukocyte arylsulfatase B activity in patient 1 was 24 nmol/mg protein/hr and in patient 2 was 22 nmol/mg protein/hr (normal 115–226 nmol/mg protein/hr). Leukocyte arylsulfatase C in patient 1 was 0.30 pmol/mg protein/hr and in patient 2 was 0.28 pmol/mg protein/hr (normal 0.84 pmol/mg protein/hr). In conclusion, these two patients with MSD had mild clinical presentations not previously reported and variable enzymatic deficiency of arylsulfatases A, B, and C.

Molecular analysis of the CYP1B1 gene: identification of novel truncating mutations in patients with primary congenital glaucoma.

Background: Mutations and polymorphisms have been identified in the CYP1B1 gene; while mutations that affect the conserved core structures of cytochrome P4501B1 result in primary congenital glaucoma (PCG), mutations in other regions hold the potential to define differences in estrogen metabolism. In the present study, we analyzed the CYP1B1 gene in Mexican patients with PCG and described four novel mutations. Materials and Methods: The sample included 12 nonrelated cases with PCG. Analysis of coding regions of the CYP1B1 gene was performed through PCR and DNA sequencing analysis from genomic DNA. Results and Discussion: Molecular analysis of the CYP1B1 gene showed the following molecular defects: (1) a novel single-base pair deletion within codon 370 (1454delC) that produces a substitution of leucine instead of proline and a premature stop codon 57 amino acids after the last original amino acid; this family also harbored a novel polymorphic variant of the cytochrome P4501B1 with six single-nucleotide polymorphisms (142C→G; 355G→T; 729G→C; 4326C→G; 4360C→G and 4379C→T); (2) a novel single-base pair deletion within codon 277 (1176delT) that results in a premature stop codon; (3) a novel single-base pair deletion within codon 179 (880delG) that produces a substitution of arginine instead of alanine and a premature stop codon 17 amino acids downstream from the last original amino acid, and (4) a duplication (or insertion) of ten base pairs within codon 404 (1556dupATGCCACCAC) that results in a premature stop codon 26 amino acids after the last original amino acid. We also observed in 2 nonrelated patients a deletion of 13 bp (1410_1422delGAGTGCAGGCAGA) previously reported for other populations. Conclusion: We reported four novel mutations and a novel polymorphic variant in the CYP1B1 gene in PCG in the Mexican population; it has important implications in diagnosis and genetic counseling.

Satoyoshi syndrome with unusual skeletal abnormalities and parental consanguinity.

Satoyoshi syndrome (SS) (OMIM 600705) is a rare multisystemic disorder of unknown etiology characterized by progressive painful intermittent muscle spasm, alopecia universalis, diarrhea, short stature, amenorrhea, and secondary skeletal abnormalities mimicking a metaphyseal chondrodysplasia. To date all reported cases have been sporadic. We describe a 26‐year‐old Mexican woman, a product of consanguineous parents with clinical characteristics of SS. Our patient, also showed skeletal anomalies not previously reported that seems to be a coincidental finding.

A family with hereditary hyperferritinaemia cataract syndrome: evidence of incomplete penetrance and clinical heterogeneity

Ferritin, the major intracellular iron store protein, consists of 24 subunits of two types, H (heavy) and L (light) encoded in chromosomes 11 and 19, respectively (Worwood, 1982). Ferritin synthesis is regulated by iron intracellular levels; when the supply of iron to the cell is limited, ferritin translation is inhibited, conversely, when cellular iron is abundant ferritin synthesis takes place. The binding of the 5¢ untranslated region (5¢-UTR) of FTL mRNA to trans-acting iron regulatory proteins (IRPs) prevents the binding of the translation initiation complex and thus blocks translation of the ferritin protein (Muckenthaler et al, 1998). Mutations in the 5¢UTR of the FTL gene produce elevated serum ferritin and clinically result in hereditary hyperferritinaemia cataract syndrome (HHCS), an autosomal dominant disease characterized by early onset bilateral cataract. The present study analyzed a family with bilateral cataract and marked hyperferritinaemia. Genomic DNA was isolated from peripheral blood with conventional methods and the FTL gene, including IRE (Iron Regulatory Element) region, was amplified as described elsewhere (Allerson et al, 1999). DNA sequencing analysis was performed in ABI PRISM 310 genetic analyzer (Applied Biosystems, Foster City, CA) according supplier’s conditions. The family with hyperferitinaemia was detected through a oneyear screening programme of patients with early onset cataract (50 non-related patients or families). All assays were performed two times with a normal control included. Clinical characteristics of lens opacities were analyzed through slitlamp. The affected family was referred to the General Hospital of Mexico. The protocol was approved by the Ethics Committee and patients gave informed consent to the study. We analyzed a three-generation Mexican family segregating autosomal

A Novel 23.1 Mb Interstitial Deletion Involving 7q22.3q32.1 in a Girl with Short Stature, Motor Delay, and Craniofacial Dysmorphism

Interstitial deletions of 7q show a wide phenotypic spectrum that varies with respect to the location and size of the deleted region. They lead to craniofacial dysmorphism with intellectual disability, growth retardation, and various congenital defects. Here, a Mexican girl with microcephaly, facial dysmorphism, short stature, hand anomalies, and intellectual disability was analyzed by CytoScan HD array. Her phenotype was associated with a de novo 7q22.3q32.1 deletion involving 109 loci, 57 of them listed in the OMIM database. This novel deletion increases the knowledge of the variability in the rupture sites of the region and expands the spectrum of molecular and clinical defects of the 7q deletion syndrome.

Inguinal Hernia in Recessive X-Linked Ichthyosis

To the Editor: Recessive X-linked ichthyosis (XLI) is a genetic entity which affects the skin. Its principal features consist of dark and adhesive scales on the neck, trunk and extremities (1). Patients and carriers of XLI may have corneal opacities (2). Cryptorchidism in patients (3) and delayed labor with low serum steroid levels in carriers (4) are also reported. Currently, we are interested in studying the clinical and biochemical features of XLI patients. We observed ten unrelated patients with XLI in the Genetics Department of the General Hospital of Mexico that had been referred for ichthyosis. The initial diagnosis was based on the characteristics of the scales and affected areas of the skin and confirmed through the steroid sulfatase (STS) assay, which was performed as described elsewhere (5) in leucocytes from the patients and their possible carrier mothers. The enzymatic activity was undetectable in all XLI cases (pmol 8H-DHEA/mg protein/h) and was deeply reduced in nine of the ten mothers from the levels in normal female controls as previously reported (6). The carriers ranged from 0.17 to 0.25 pmol/mg protein/h, and the control average is reported to be 1.21 ± 0.23 pmol/mg protein/h. The STS assay confirmed the XLI diagnosis and identified the carrier state. The clinical features in the XLI patients and a review of the medical reports of the pregnancy of their mothers showed the presence of inguinal hernia in three patients, two on the left and one bilateral, which is a higher incidence than in the normal population. These three cases needed surgical treatment and, in two patients, the inguinal hernia was the initial reason for requesting medical assistance. The medical reports showed that four mothers had transvaginal bleeding during the first trimester of their pregnancies, which is a very high incidence of this complication. In fact, complete rest was prescribed in two cases. Never985