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Inborn errors of metabolism
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Specific lysosomal enzyme defects have been identified for most disorders in the severe and clinically confusing group of sphingolipidoses, all autosomal recessive, and prenatal diagnosis is feasible in these. Carrier detection is of particular significance for Tay-Sachs disease, where the gene is at high frequency in Ashkenazi Jewish populations. Screening for adult carriers, with prenatal diagnosis offered to couples who both carry pathogenic variants in the gene, has been successfully applied in many Jewish communities in the United Kingdom, Canada, the United States and Australia; the carrier frequency is approximately 1 in 30 in many of these communities. A comparable approach has also been developed in Finland, Quebec and Israel, where the genes for some other specific metabolic neurodegenerations are at high frequency. Carrier screening programmes have started to switch technologies to high-throughput DNA sequencing, which allows a wider range of disorders to be screened for in ‘extended carrier screening’ programmes that can be applied to entire populations without the need to target the screening according to an individual's ancestry (see Chapter 34).
Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
The sphingolipidosis disorders refer to a group of lysosomal storage disorders that in their classical form are notable for progressive and relentless neurological decline with relatively few other organ manifestations. In the severe forms of the conditions, onset is in infancy and is rapidly progressive over months leading to severe encephalopathy and death. These children usually have, albeit sometimes brief, a period of normal development followed by a plateauing of developmental progress and then actual regression. This may be exacerbated by intercurrent illness. Features such as epilepsy, macrocephaly, hyperacusis, visual impairment and spasticity are seen. The degree of irritability especially in Krabbe is extremely distressing to the family. There are no skeletal manifestations, usually minimal hepatomegaly (except in Niemann-Pick disease) and unlike in MPS disorders, coarse facial features are not seen. Retinal cherry red spots can sometimes be observed and loss of vision is common. The late infantile onset metachromatic leukodystrophy (MLD) has a very classical presentation whereby the previously near normal development plateaus at between 12 months to 2 years with subsequent aggressive regression and loss of any skills.
The nervous system and the eye
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
James A.R. Nicoll, William Stewart, Fiona Roberts
The disorders in this group usually develop in early life; although uncommon, they make a considerable contribution to morbidity and mortality in children. They may present with neurological symptoms alone or with other systemic abnormalities. Different diseases may share a common phenotype such as a cherry-red spot of the macula. Many are inherited as autosomal recessive diseases and a few show X-linked recessive inheritance. In most a critical enzyme system is absent or inactive. Many of these disorders are due to deficiencies of particular lysosomal enzymes, which play an essential role in the degradation of normal metabolites or cell-breakdown products, e.g. lipids, carbohydrates, mucopolysaccharides (Figure 12.31) or amino acids. As a result the undegraded material accumulates in and enlarges the lysosomes of certain cells, the distribution depending on the particular enzyme deficiency. Some disorders affect neurons which become enlarged with a ballooned appearance (neuronal storage disorders); others affect white matter (leukodystrophies). Diagnosis by assay of the relevant lysosomal enzymes in blood, urine, leukocytes, or cultured fibroblasts is now often possible and increasingly genetic tests are available. The lipid storage disorders (sphingolipidoses) are probably the most important group. The sphingolipids include gangliosides, cerebrosides, sulphatides and sphingomyelins. One of the most common storage disorders affecting especially the neurons is Tay–Sachs disease, in which there is deficiency of hexosaminidase A, resulting from a mutation in the HEXA gene on chromosome 15 and causing abnormal accumulation (i.e. ‘storage’) of its substrate ganglioside.
Rapidly progressive case of type I Madelung disease with bilateral parotid and minor salivary glands involvement
Published in British Journal of Biomedical Science, 2020
The following day other tests were performed. As obesity and the buffalo hump may reflect Cushing’s syndrome, tests were arranged, as were autoantibody and immunological tests. A free larynx entrance and preserved vocal cords, without any inflammatory alterations, were observed on laryngoscope. A head-neck-chest CT with contrast found an increased symmetrically adipose tissue, in the subcutaneous area of the neck, parotid glands, supraclavicular region and larynx, which extended up to the sternocleidomastoid muscle and cervical area (Figure 3). The accumulated adipose tissue compressed the nearby structures and the adjacent muscles and vessels, which led to deformations. The fat mass had the same density as the normal adipose tissue and there were no inflammatory alterations. Thyroid gland had a normal structure. The lungs and the airways were normally structured, without pleural effusions. The thoracic and abdominal aorta, the superior and inferior vena cava were normal. An absent uterus and ovary glands (post hysterosalpingo-oophorectomy) were noted. At that point attention changed direction towards pathologies characterized by adipose tissue accumulation such as sphingolipidoses, lipomatosis etc.
Still More ICD-10-CM Updates!
Published in Oncology Issues, 2018
There was no change to code E75.2 (other sphingolipidosis), but one new subcategory was added and another included a revised definition: Code E75.26 (sulfatase deficiency), multiple sulfatase deficiency was added.Code E75.29 (other sphingolipidosis) was not changed but “sulfatase deficiency” was deleted from the definition.