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Genetics and metabolic disorders
Published in Jagdish M. Gupta, John Beveridge, MCQs in Paediatrics, 2020
Jagdish M. Gupta, John Beveridge
3.33 Which of the following inborn errors of metabolism is X-linked in inheritance?Tay Sachs disease.Fabry disease.Glucose-6-phosphate dehydrogenase deficiency.Menkes disease.Lowe syndrome.
Patterns of Inheritance: Mendelian and Non-Mendelian
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Merlin G. Butler, Michael Begleiter, Shannon Lillis, Molly Lund, F. John Meaney
Because females have two copies of the X chromosome and males are hemizygous, most X-linked conditions are more common in males than females. Geneticists divide X-linked conditions into two categories depending on whether the X-linked gene is dominant or recessive which is based on the affected status of the females. In X-linked recessive conditions, female carriers are usually not affected but in the X-linked dominant conditions females are consistently affected. Pedigrees for X-linked recessive genetic diseases have characteristics that are clearly distinguishable from autosomal dominant and recessive genetic diseases. These are illustrated by the pedigree in Fig. 10. Since a father can only transmit a Y chromosome to his sons, X-linked genes are not passed from father to son. Thus, male-to-male transmission is never seen in X-linked traits unlike autosomal dominant conditions. An affected father has no affected sons yet all of his daughters will be carriers of the X-linked condition. If a female carrier has a son, there is a 50% chance that he will be affected. If a female carrier has a daughter, there is a 50% that she will be a carrier. An X-linked recessive genetic disease may be passed through generations of carrier females before it is expressed in a male. Thus, affected males in a family are related through females. Lowe or oculo-cerebrorenal syndrome (Fig. 11) is an example of an X-linked recessive condition which primarily affects the eyes, central nervous system, and kidneys. Affected males have congenital cataracts and impaired vision, and almost all affected males have some degree of intellectual impairment. They also have some degree of proximal tubular renal dysfunction. Lowe syndrome is caused by markedly reduced activity of the enzyme, inositol polyphosphate 5-phosphatase (OCRL-1) which is encoded by the OCRL gene.
Lowe syndrome with extremely short stature: growth hormone deficiency may be the pathogeny
Published in Growth Factors, 2019
Chengjun Dai, Liying Wang, Youli Li, Zhichao Zheng, Jieqi Qian, Chaoban Wang, Zishuo Liu, Xiaoou Shan
Lowe syndrome is usually characterized by congenital cataracts, mental retardation and proximal renal tubular dysfunction with progressive renal failure (Bokenkamp and Ludwig 2016; Kim et al. 2014). Congenital bilateral cataracts are manifested at birth and are considered as the sign of Lowe syndrome. Over half of the patients need cataract surgery in early infancy. For some patients, this can be complicated by glaucoma, nystagmus, corneal scarring and keloids, often resulting in vision loss. The relevant symptoms are manifested in both central nervous system and peripheral nervous system, with hypotonia being the most common form. Other symptoms may include mental retardation and seizure, as well as behavioral abnormalities such as stereotypic hand-clapping. Besides, temper tantrums have also been discovered in some patients. The main manifestation of renal lesions is proximal tubular dysfunction (Maia et al. 2010). Nevertheless, dissimilar from congenital cataracts, proximal tubular dysfunction occurs in early childhood on a frequent basis rather than at birth. Low-molecular-weight (LMW) proteinuria, aminoaciduria, hypercalciuria, acidosis, phosphaturia and glycosuria are commonly observed among these patients and are closely associated with progressive renal failure. End-stage renal disease often occurs in the second to fourth decades of patients’ life (Bockenhauer et al. 2008). In addition to classic oculo-cerebro-renal manifestations, both growth failure and bone abnormalities are made noticeable in some cases.
Hypotonia and delayed motor development as an early presentation of Lowe syndrome: case report and literature review
Published in Acta Clinica Belgica, 2019
Sara David, Kathleen De Waele, Bram De Wilde, Franny Faes, Olivier Vanakker, Sophie Walraedt, Agnieszka Prytuła
The combination of these features in this evolving phenotype led to the clinical suspicion of Lowe syndrome (LS) (OMIM #309000). Genetic analysis of the OCRL gene, showed a missense substitution in exon 13: c.1250T>A, p.Val417Asp. In silico analysis revealed the variant to be absent in the gnomAD database of genomic variation. Prediction tools (SIFT, PolyPhen-2, MutationTaster, PhyloP) unanimously coined this a pathogenic variant. Maternal analysis of the OCRL gene did not reveal the variant, which suggests it to have occurred de novo, though germline mosaicism cannot be excluded.