3-Methylglutaconic aciduria: A marker for as yet unspecified disorders and the relevance of prenatal diagnosis in a ‘new’ type (‘type 4’)

Summary The Mendelian disorder known as 3-methylgutaconic aciduria (McKusick 250950) gives evidence of allelic and locus heterogeneity. Type 1 has a mild clinical phenotype and confirmed 3-methylgutaconyl-CoA hydratase deficiency; inheritance is autosomal recessive. Other forms have major clinical manifestations and subdivide into X-linked (type 2), a form in Iraqi Jews with optic atrophy (so-called type 3); and untyped (putative autosomal recessive) forms without identified enzyme defects. In the latter, 3-methylglutaconic aciduria may simply be a marker for another metabolic disorder.We describe a male proband with 3-methylglutaconic aciduria designated here as type 4 (autosomal recessive, with severe psychomotor phenotype and cerebellar dysgenesis). He is the offspring of Italian consanguineous parents. Born with congenital malformations, he has been followed for 18 years, showing profound developmental delay and cerebellar dysgenesis. Measures of hydratase activity in cultured fibroblasts from the proband and 11 additional patients (two with type 1 disease, 9 with either type 2 or an unspecified form) revealed deficient enzyme activity in type 1 cases and normal activity in the proband and the other 11 cases. Two of the untyped cases probably have 3-methylglutaconic aciduria of the type described here.Prenatal diagnosis in the form described here may be feasible by analysis of amniotic fluid metabolites in pregnancies at risk if the mother does not entirely remove elevated concentrations. A female sibling of the proband had normal metabolite values in amniotic fluid. Postnatal follow-up confirmed absence of the disease. We give the normal values for amniotic fluid and results on these additional fetuses at risk (none affected).     

Functional and Morphological Studies of Platelet Reactivity with Vessel Wall Subendothelium in Chronic Myeloproliferative Disease

S ummary . Mechanisms of thrombus formation in myeloproliferative disease were studied using a technique which visualized platelet-vessel wall interactions under physiological conditions of blood flow. Whole blood from four patients with chronic myelogenous leukaemia and three with thrombocythaemia were pumped through perfusion chambers containing de-endothelialized artery segments. Platelet reactivity with vessel walls (thrombus formation) was measured in sections of vessels by light microscopy and quantitative morphometric analysis. Five patients produced platelet reactivity values of 130-258% of controls while two gave decreased values. The two highest platelet reactivity values occurred in samples with elevated platelet counts and normal haematocrits. In contrast, when anti-platelet drugs were administered to three patients with high platelet counts, reactivity values decreased to 11-34% of controls. Clinical correlations revealed that patients with highest platelet reactivity values (165-258%) were those subjects who also exhibited thrombotic or haemorrhagic complications. Thus absolute platelet count and haematocrit may be major determinants in predicting these complications. Qualitative evaluations of thrombus formations by light and electron microscopy provide further evidence that platelets in myeloproliferative disease also possess qualitative abnormalities.     

Auditory sensory memory and the aging brain: A mismatch negativity study

The mismatch negativity (MMN) component of the auditory event-related potential has been used in the past to study between group differences in the accuracy and retention of information in auditory sensory memory (ASM). The MMN is elicited by infrequent 'deviant' tones that differ from a repeating 'standard' tone. In the present study, the type of deviant and the time interval between tones (stimulus-onset asynchrony: SOA) were manipulated in a study of normal aging. MMN responses of an elderly (mean age = 69) and a young group (mean age = 21) to both a duration and a frequency deviant tone were measured at a short (450 ms) and long (3 s) SOA. A smaller and later MMN (recorded at Fz) was observed in the elderly relative to the young group across SOA and Deviant conditions. The results are consistent with an age-related deficit in the encoding of sound properties in ASM. However, analysis of the MMN reversal at the mastoids provides some support for the proposal that the elderly have an additional deficit related to the retention of information in ASM.