Distinctive neurological phenotype associated with partial trisomy of chromosome 16.

We present a case of a live born female infant who presented in early life with a movement disorder, lack of developmental progress and neutropenia. Extensive neuro-metabolic investigation was non-diagnostic. Chromosome analysis of cultured lymphocyte cells showed an abnormal chromosome 16 with additional material noted in the proximal long arm. Additional fluorescence in situ hybridisation studies identified this additional material to represent a duplication of the long arm of chromosome 16 between 16q11.2 and 16q21. There was progressive decline and death by 10 months. Dystonia cortical blindness and neutropenia have not been a reported feature of trisomy 16 to date.

Kohlschutter syndrome in siblings.

Kohlschutter syndrome is a rare neurodegenerative disorder presenting with intractable seizures, developmental regression and characteristic hypoplastic dental enamel indicative of amelogenesis imperfecta. We report a new family with two affected siblings.

Hyper IgD syndrome (HIDS) associated with in vitro evidence of defective monocyte TNFRSF1A shedding and partial response to TNF receptor blockade with etanercept.

Hereditary periodic fever syndromes comprise a group of distinct disease entities linked by the defining feature of recurrent febrile episodes. Hyper IgD with periodic fever syndrome (HIDS) is caused by mutations in the mevalonate kinase (MVK) gene. The mechanisms by which defects in the MVK gene cause febrile episodes are unclear and there is no uniformly effective treatment. Mutations of the TNFRSF1A gene may also cause periodic fever syndrome (TRAPS). Treatment with the TNFR-Fc fusion protein, etanercept, is effective in some patients with TRAPS, but its clinical usefulness in HIDS has not been reported. We describe a 3-year-old boy in whom genetic screening revealed a rare combination of two MVK mutations producing clinical HIDS as well as a TNFRSF1A P46L variant present in about 1% of the population. In vitro functional assays demonstrated reduced receptor shedding in proband's monocytes. The proband therefore appears to have a novel clinical entity combining Hyper IgD syndrome with defective TNFRSF1A homeostasis, which is partially responsive to etanercept.

Miller-Dieker syndrome resulting from rearrangement of a familial chromosome 17 inversion detected by fluorescence in situ hybridisation.

We report a case of Miller-Dieker syndrome (MDS) owing to an unbalanced rearrangement of a familial pericentric inversion of chromosome 17 (inv(17) (p13.3q25.1)). In addition to lissencephaly and the facial features of MDS, the affected child had other congenital malformations consistent with distal 17q duplication. Initial cytogenetic analysis failed to show any abnormality and fluorescence in situ hybridisation (FISH) studies confirmed the 17p deletion in the proband and identified the chromosome 17 inversion in his mother. FISH studies were performed in other relatives and enabled first trimester prenatal diagnosis by chorionic villus sampling in a subsequent pregnancy of the proband's mother. These findings underline the value of FISH in the investigation of MDS families.

Fatal liver failure following generalized tonic-clonic seizures.

We present three cases of fatal hepatic necrosis in patients with epilepsy taking anticonvulsants, in which the terminal illness presented as an unusually severe generalized tonic-clonic seizure with failure to regain consciousness. In two cases acute renal failure also occurred. It is not certain to what extent drug therapy, physiological and metabolic changes consequent on prolonged seizures, hitherto undiscovered infective agents, or a combination of any of these may play in such a process. We suggest, however, that the case against the drugs alone has yet to be proved.

A study on carbamazepine levels, including estimation of 10-11 epoxy-carbamazepine and levels in free plasma and saliva.

Blood and saliva were collected from 48 children, aged three to 17 years, before a morning dose of carbamazepine and then at three, six and eight hours afterward. There was no significant difference in the ratio of 10-11 epoxy-carbamazepine to total carbamazepine for children on carbamazepine alone (0.18) and those on an additional anticonvulsant (0.19). 11 children were studied on their first day of therapy. Though four of them achieved levels of total carbamazepine which would have given a readily measurable 10-11 epoxide on the above ratio, 10 of the 11 consistently had levels less than 4 mumol/l. This may be of help in detecting non-compliance. For 16 children free carbamazepine also was estimated and there was an over-all correlation coefficient of 0.85 between saliva and free-drug levels. The proportion of free to total carbamazepine varied between 19 and 54 per cent. There was a significantly higher proportion of free drug at the pre-dose sampling time than at other times. Protein binding of carbamazepine therefore is very variable and saliva estimations can contribute usefully to the monitoring of drug levels.