Donald T. Whelan

Smith-Lemli-Opitz syndrome: phenotypic extreme with minimal clinical findings.

Smith-Lemli-Opitz syndrome (SLO) is caused by inherited enzymatic deficiency of 7-dehydrocholesterol-delta7-reductase and resultant cholesterol deficiency. It comprises a characteristic combination of facial features, malformations, and mental retardation. We report on three related patients (two brothers and their first cousin) with mental retardation and minimal physical signs in whom the diagnosis of SLO was delayed for a number of years. The presence of a third-degree relative in the absence of consanguinity in this family supports the proposed high population carrier frequency. Our report suggests that cases of mild SLO remain undiagnosed and untreated, and that awareness of this common cause of mental retardation is low.

Incidence of Smith-Lemli-Opitz syndrome in Ontario, Canada.

1. The authors stated that their study is ‘‘the first prospective determination of incidence of SLOS using the biochemical diagnosis test in North America’’. However, to perform a prospective study aimed to calculate the frequency (better than incidence) of SLOS in a population, based on biochemical data, it is necessary to perform the biochemical diagnostic test in all the newborn infants,during a pre-determined period of time. Then, those infants presenting the anomaly should be followed up for clinical diagnosis. This does not seem to be the methodology followed by these authors, although it is not clearly explained in the paper. It appears that they studied all those infants clinically diagnosed and referred to their laboratory for biochemical test. Thus, we believe that this study is not ‘‘prospective’’. 2. Why did Nowaczyk et al. consider that they have estimated the ‘‘incidence’’ of SLOS? The real incidence of SLOS (as for the majority of congenital defects) is always unknown due to the spontaneous abortions of fetuses with the syndrome. In our opinion, they only obtained aminimal estimation of the prevalence in their population. This is so because many cases died soon after birth and, as also stated by these authors, the clinical diagnosis of mild and atypical cases of SLOS are often not clinically identified before the first birthday, and many cases of females with less severe phenotypes are not diagnosed. Nevertheless, it is possible to estimate the frequency of SLOS in newborn infants (that could be considered as the ‘‘incidence in newborns’’). But to do this, it is necessary to examine in the same manner all the newborn infants in the way we stated above.Smith-Lemli-Opitz syndrome (OMIM 270400) (SLOS) is caused by inherited enzymatic deficiency of 3beta-hydroxysterol-Delta7-reductase (7-dehydrocholesterol-Delta7-reductase, DHCR7). SLOS is diagnosed clinically by the demonstration of elevated levels of 7-dehydrocholesterol (7DHC) in body fluids or tissues. SLOS is associated with mental retardation of variable degree and severe behavior abnormalities. The physical abnormalities range from minor facial anomalies to lethal malformations of the central nervous system, heart, kidneys, and other organs. The exact incidence of SLOS is not known. Although there exist estimates of the incidence of SLOS ranging from 1 in 20,000 to 1 in 60,000, no prospective studies of the incidence of SLOS, based on the clinical data and biochemical diagnosis of SLOS, have been performed. Five unrelated cases of SLOS were diagnosed in Ontario during a 12-month period. The diagnoses were made based on the demonstration of elevated 7DHC in plasma or amniotic fluid. The birth rate for Ontario for that period was 132,000 births. The incidence of SLOS in Ontario was at least 1 in 26,500 pregnancies in 1999-2000. Given that 86% of the population of Ontario is of European origin, the incidence of SLOS in the Ontario population of European origin was at least 1 in 22,700. As infants with mild forms of SLOS born during this period may remain undiagnosed, these numbers likely are underestimates. This observation has implications for prenatal and newborn screening for this potentially treatable inherited disorder.

Fumaric aciduria: a new organic aciduria, associated with mental retardation and speech impairment

Two siblings are described who present with fumaric aciduria, a hitherto unreported organic aciduria. The results of our analytical investigations using gas chromatography/mass spectrometry, and the clinical presentation of the patients, are consistent with the notion that the fumaric aciduria is caused by an inherited defect which leads to a net secretion of fumaric acid by the renal tubules.

Paternal transmission of fragile X syndrome.

We present a family in which a fragile X mosaic male, who carries both premutation and full mutation alleles in his peripheral blood leukocytes, has a daughter with both premutation and partially methylated full mutation alleles and a significant developmental disability. To our knowledge, this is the first report of such an occurrence and it challenges current thinking about the expansion and transmission of unstable FMR1 alleles from men to their daughters. It is currently accepted that neither males with premutations nor full mutations are at risk for having daughters with full mutations and fragile X syndrome. The sperm cells of full mutation males are thought to carry only premutation alleles. These alleles, when transmitted through a male, regardless of his cognitive status, are thought to be unable to expand to full mutations in the next generation. In effect, the expansion from premutation to full mutation has only been observed through female meioses. The sperm cells in the father in this family have been shown to contain only alleles in the premutation range. Since his daughter has both premutation and full mutation alleles the expansion to full mutation in this case must have occurred postzygotically.

Mass spectrometry and clinical chemistry

Over the last ten to fifteen years there has been an enormous increase in the sophistication of the analytical instruments used in the clinical chemistry laboratory. That the majority of these instruments is designed for the automated and rapid analysis of body fluids reflects a trend in modern clinical chemistry to invest large amounts of money into capital equipment in order to process large numbers of samples in the least labour-intensive way. Provision of such a service is. however, only one aspect of clinical chemistry. Another responsibility is to provide to smaller patient groups, laboratory services of a more investigative nature which, because of their complexity and limited numbers, do not lend themselves to automation. Also. the discipline and its members should be involved in research into the physiological chemistry of health and disease, and into the application of new methods of analyses to investigate these processes. These responsibilities also require the investment of capital for instrumentation and of time for the investigations. However, since the returns on these investments are different from, and less pecuniary than, those from the automated instrumentation. they are often more difficult to justify. especially in times of fiscal constraint. An example of this type of investment is the use of analytical mass spectrometry in the clinical laboratory. The purpose of this review is to show how this technique has already been successfully adapted to problems in clinical chemistry. On the broader front, it describes one example of how clinical chemistry can carry out the innovative and investigative work alluded to above, which is so crucial to its long-term survival as a scientific discipline. The review will be divided into three sections. The first will describe the types and modes of usage of mass-spectrometer systems that are currently employed in clinical laboratories. The second will review the recent applications of these instruments to clinical chemistry problems. A final. shorter section. will deal with aspects of mass

Oral-facial-digital syndrome VII is oral-facial-digital syndrome I: a clarification.

We report on further clinical findings in the one single family in the literature classified as oral‐facial‐digital (OFD) type VII in order to demonstrate that the diagnosis in this kindred should, in fact, be OFD type I. The mother and the daughter described in the original report have since developed polycystic kidney disease. In addition, the daughter recently had a daughter of her own with central nervous system, oral and digital anomalies. Linkage studies have shown that all the affected women share the same haplotype across the previously identified region Xp22.2p22.3 to which OFD I maps. Although the pedigree was too small for a significant lod score, the combination of clinical and molecular information clearly shows that the disease in this family is OFD I. We report this family in order to clarify and simplify the classification of the oral‐facial‐digital syndrome spectrum and to recommend the removal of OFD VII from the classification system of the oral‐facial‐digital syndromes.

Novel mutations (Asn 484 Lys, Thr 500 Ala, Gly 438 Glu) in Morquio B disease.

Primary deficiency of beta-galactosidase results in GM1 gangliosidosis and Morquio B disease. Of the more than 40 disease-causing mutations described in the Gal gene to date, about 75% are of the missense type and are scattered along the length of the gene. No single, major common mutation has been associated with GM1 gangliosidosis. However, a Trp 273 Leu mutation has been commonly found in the majority of patients with Morquio B disease defined genotypically to date. We now report three new mutations in three Morquio B patients where the Trp 273 Leu mutation is absent. Two of the mutations, C1502G (Asn 484 Lys) and A1548G (Thr 500 Ala), were found in twins (one male, one female) who display a mild form of Morquio B disease and keratan sulfate in the urine. In their fibroblasts, residual activity was 1.9% and 2.1% of controls. On Western blots, the 84-kDa precursor and the 64-kDa mature protein were barely detectable. The occurrence of a 45-kDa degradation product indicates that the mutated protein reached the lysosome but was abnormally processed. In the third case, we identified only a G1363A (Gly 438 Glu) mutation (a major deletion on the second allele has not been ruled out). This female patient too displays a very mild form of the disease with a residual activity of 5.7% of control values. In fibroblasts from this case, the 84-kDa precursor and the 45-kDa degradation product were present, while the mature 64-kDa form was barely detectable. The occurrence of these three mutations in the same area of the protein may define a domain involved in keratan sulfate degradation.

Pregnancy in a healthy woman with untreated citrullinemia

We report the clinical and biochemical data on a second successful pregnancy in a woman with citrullinemia due to argininosuccinate synthetase deficiency (CTLN1). Despite very elevated plasma and urine citrulline and little or no measurable argininosuccinate synthetase enzyme activity on cultured skin fibroblasts, this 29‐year‐old woman, who was identified through newborn screening, has remained asymptomatic throughout her life. Mutation analysis has recently revealed that she is a compound heterozygote for a known and a novel mutation (IVS15‐1G > C and K310Q, respectively). Many newborn screening programs have recently been expanded to include citrullinemia and numerous asymptomatic hypercitrullinemic infants and children have been identified. It is now important to define prognostic indicators that will help with treatment decisions and genetic counseling for these patients. This patient, as the only citrullinemic adult who has been followed prospectively, contributes important information in this regard. In addition, her child was unaffected by the high citrulline levels demonstrated in amniotic fluid and breast milk suggesting that citrulline is not teratogenic. Although pregnancy is an important risk factor for women with CTLN1, it appears that females with citrullinemia can have normal pregnancy outcomes, as long as metabolic crisis is avoided.

Boy with 47,XXY,del(15)(q11.2q13) karyotype and Prader-Willi syndrome: a new case and review of the literature.

We report on a 10‐year‐old boy with a 47,XXY,del(15)(q11.2q13) karyotype and a Prader–Willi syndrome phenotype. His medical history and physical examination conformed to all of the major clinical criteria for Prader–Willi syndrome, but his height was taller than expected based on his hand and foot sizes. The deleted chromosome 15 was paternal in origin and molecular analysis showed maternal origin for the additional X chromosome. These findings suggest that the presence of these two disorders was coincidental in our patient. This supports the findings in the two other 47,XXY and Prader–Willi cases for which parent of origin studies have been published. Given the information from the literature and presented herein, we suggest that genetic counseling for cases of PWS and 47,XXY should address these two conditions separately.

A rare case of mosaic Down syndrome 46,XY/46,XY, -21, +i(21q).

Detailed studies were carried out on a patient with a rare type of mosaicism which gave rise to an effective 21 trisomy. The clinical signs of Down syndrome were minimal. The cytogenetic interpretation is that the abnormal clone had an isochromosome derived from a maternal No. 21. The normal cell line appears to be replacing the abnormal clone.