Ornithine transcarbamylase deficiency
Ornithine transcarbamylase deficiency (OTCD) is the most common inherited urea cycle disorder and the only one to be transmitted as an X-linked trait.
Aug. 17, 2021
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This article includes discussion of congenital disorders of glycosylation, Jaeken syndrome, carbohydrate-deficient glycoprotein syndrome (CDGS), ALG1-CGD, ALG6-CGD, COG-related disease, congenital myasthenia syndromes, cutis laxa syndromes, PMM2-CDG, and PGM1-CDG. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
The congenital disorders of glycosylation constitute a large group of inherited disorders with multiorgan expression of symptoms. In most patients there are signs of nervous system involvement where typical manifestations include structural abnormalities (eg, rapidly progressive cerebellar atrophy), developmental delay, intellectual disability, stroke-like episodes, epileptic seizures, myopathies (including congenital muscular dystrophies and limb-girdle dystrophies), myasthenia, and demyelinating neuropathy. Patient presentations can demonstrate significant differences between and within the different subgroups. In this article, the author explains the basic genetic and biochemical background to these syndromes and describes the most common subtypes in terms of initial clinical signs, diagnostic work-up, prognosis and clinical progression, and, in a few instances, treatment.
• The congenital disorders of glycosylation (CDG) syndromes constitute a group of severe syndromes with a broad phenotypic expression within and between subtypes.
• A majority (60%) can be detected using a transferrin glycosylation test.
• There is no specific treatment in most subtypes.
• CDG should be excluded in all patients with unclear intellectual disability in combination with symptoms of dysfunction in other organ systems.
Historical note. In 1980, the Belgian professor Jaak Jaeken described the first patients affected with congenital disorders of glycosylation in an abstract in Pediatric Research (31). The patients (2-year-old twin sisters) presented with psychomotor retardation, delayed bone growth, and fluctuating levels of several glycoprotein hormones. Some years later, it was shown that these patients also had deficient glycosylation of transferrin (28), and the term “carbohydrate-deficient glycoprotein syndrome” (CDGS) was eventually suggested (30). More clinical phenotypes emerged, and several subtypes were coined (CDGS-Ia, -Ib, -IIa, etc.). In 1995, the first molecular cause of CDGS was published, deficiency of phosphomannomutase 2 (CDGS-Ia; now PMM2-CDG). PMM2 catalyzes the interconversion of mannose-6-P and mannose-1-P (63). Subsequently, the cause of CDGS-IIa (MGAT2-CDG) as well as the cause and a suggested therapy (alimentary addition of mannose) of CDGS-Ib (MPI-CDG) were published (07; 47).
Nomenclature. In 1999, the first international workshop on CDGS was held, and the participating scientists agreed on a modified nomenclature, including a change in the translation of the acronym CDG to “congenital disorder of glycosylation.” Naming subtypes was based on CDG type (I or II, see below) and chronological order of detection (next available lower-case letter); that is, CDGS-Ia became CDG-Ia, CDGS-IIa became CDG-IIa, and so forth.
Biochemically, one can distinguish between 2 pathological patterns of transferrin underglycosylation, coined CDG type I and type II. Type I deficiencies suggest errors in the synthesis or transfer of the dolichol-linked precursor for N-glycosylation (located to the cytosol or the endoplasmic reticulum), whereas type II deficiencies impair trimming or modification of the protein-bound oligosaccharides (late endoplasmic reticulum and the Golgi). Patients with an unknown gene deficiency were referred to as either CDG-Ix or IIx. Due to improved diagnostic techniques, the number of new subtypes increased rapidly during the beginning of this century (18).
In 2009, yet another nomenclature was suggested because glycosylation disorders were identified in other glycosylation pathways (such as O-linked glycosylation and lipid glycosylation) in addition to defects of enzymes and transporters in N-linked protein glycosylation. The revised nomenclature uses the official gene symbol followed by “-CDG” as designation of the individual subtypes; hence, CDG-Ia is now referred to as PMM2-CDG, CDG-Ib is PMI-CDG, CDG-IIa is MGAT2-CDG, and so forth (29).
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