Rett's syndrome and ornithine carbamoyltransferase deficiency

Abstract

Rett's syndrome (RS) is a neurodegenerative disorder which affects 1 in 10000-t5 000 girls. Arrest of development usually occurs at 6-18 months and there is a loss of acquired hand skills and development of stereotypical hand movements. Communication and motor skills are severely impaired (Rett, 1977).Many clues to the possible pathogenesis of the disorder have been described including chromosomal fragile sites at Xp22, abnormal metabolism of biotin and tetrahydrobiopterin, and disturbed X inactivation (Riccardi, 1986). Hyperammonaemia has been described in some cases and the link with the urea cycle enzymes is strengthened by recent reports of increased orotic acid excretion following intravenous alanine loading (Thomas et al, 1987).In this study we describe the results of measurement of plasma ammonia and orotic acid excretion following intravenous alanine loading in five affected girls and their mothers. PATIENTS AND METHODSFive girls from four families and their mothers were given alanine loads according to the method of Kay et al. (1987). L-alanine (0.25 g/kg) in an aqueous solution of 1.12mmol/L was administered over about 10 rain. Plasma samples for ammonia estimation were taken pre-load and at about 10min intervals for 1 h. Basal urines were followed by random specimens collected over a 4-h period post-load. Plasma ammonia was estimated by an enzymatic assay and urinary orotic acid by high performance liquid chromatography.The five girls tested included two sisters, both of whom show many of the characteristic features of RS. The younger girl (case2) is somewhat less severely retarded than her sister but the evidence suggests she does have the same disorder. The three other cases studied all have RS based on the criteria of the Rett Syndrome Diagnostic Work Group (1988). 308

Rett syndrome: Clinical update and review of recent genetic advances

“…Transient and variable hyperammonaemia has been reported in a minority of females with RS, and increased orotic acid has also been found in some cases, as in female carriers of ornithine transcarbamylase deficiency. 7,33,[58][59][60] Subsequent studies of ammonia levels following alanine loading in nine RS girls aged 2-10 years were normal in all patients. 61 There have been reports of abnormalities of intermediary carbohydrate metabolism in girls with RS, with modest elevations of plasma lactate and pyruvate levels, 62,63 along with elevated levels of pyruvate and lactate in the cerebrospinal fluid (CSF).…”

Metabolic dysfunction in Russell‐Silver syndrome

“…Pyruvate dehydrogenase deficiency can present with dysmorphic features similar to those of fetal alcohol syndrome, as well as agenesis of the corpus callosum, cerebral cortical cystic changes and brainstem abnormalities (Robison et al 1987). Different biochemical abnormalities can accompany Rett syndrome, in which the phenotype, ii~apparent at birth, develops with time (Carpenter et al 1990).…”