Asim Cenani

LRP4 Mutations Alter Wnt/β-Catenin Signaling and Cause Limb and Kidney Malformations in Cenani-Lenz Syndrome

Cenani-Lenz syndrome (CLS) is an autosomal-recessive congenital disorder affecting distal limb development. It is characterized mainly by syndactyly and/or oligodactyly and is now shown to be commonly associated with kidney anomalies. We used a homozygosity-mapping approach to map the CLS1 locus to chromosome 11p11.2-q13.1. By sequencing candidate genes, we identified recessive LRP4 mutations in 12 families with CLS. LRP4 belongs to the low-density lipoprotein (LDL) receptor-related proteins (LRPs), which are essential for various developmental processes. LRP4 is known to antagonize LRP6-mediated activation of canonical Wnt signaling, a function that is lost by the identified mutations. Our findings increase the spectrum of congenital anomalies associated with abnormal lipoprotein receptor-dependent signaling.

Meckel-Gruber syndrome

Abstract Meckel-Gruber syndrome is a congenital disorder characterized by occipital encephalocele, polydactyly and polycystic kidneys. This rare syndrome has been reported in the literature as incompatible with life. We present the case of a newborn afflicted with the clinical triad of Meckel-Gruber syndrome. Appropriate treatment instituted in our case led to a good early outcome.

Effects of carbamazepine and valproate on brainstem auditory evoked potentials in epileptic children

Brainstem auditory evoked potentials (BAEPs) were recorded in 18 epileptic children receiving carbamazepine and 10 epileptic children receiving valproate. BAEPs were recorded before the administration of antiepileptic drugs (AEDs) and 13 months later during which the children received AEDs. Statistical analysis of peak latencies and interpeak intervals of waves I–III–V were made. Carbamazepine treatment resulted in prolongation of peak latencies of waves I–III–V and interpeak intervals I–III and I–V. Valproate monotherapy, on the other hand, caused no consistent changes on BAEP. On the basis of these results we suggest that chronic carbamazepine therapy exerts a suppressive influence on the auditory pathways, both peripherally at the level of the cochlea and/or auditory nerve, and centrally at the brainstem.

Serum thyroid hormones and pituitary response to thyrotropin-releasing hormone in epileptic children receiving anti-epileptic medication

Thyroid hormones and pituitary function were assessed in 49 children with epilepsy who were receiving either a single medication of carbamazepine, phenobarbital and valproate or a combination of carbamazepine with phenobarbital or valproate. All therapeutic regimens except valproate monotherapy were associated with low levels of circulating thyroxine, free tri‐iodothyronine and free thyroxine. Carbamazepine with valproate was associated with the lowest serum concentration of thyroid hormones. It seems probable that accelerated hormone metabolism is responsible for these hormonal changes. However, all drug regimens also had effects on the function of the hypothalamic pituitary axis. Because of these findings, thyroid hormones should be checked frequently during anti‐epileptic drug treatment, although clinical hypothyroidism was not seen in our patients.

Effect of valproate and carbamazepine on visual evoked potentials in epileptic children

The effects of carbamazepine (CBZ) and sodium valproate (SV) monotherapy on visual evoked potentials (VEP) were studied in 18 epileptic children receiving CBZ and nine epileptic children receiving SV. Pattern reversal VEP were determined before the administration of antiepileptic drugs (AED) and 1 year later during which time the patients had received AED. The VEP amplitude showed no consistent changes after 1 year of CBZ and SV therapy, but VEP P‐100 latencies were significantly prolonged after 1 year of CBZ therapy. We conclude that CBZ causes a slowing down of central impulse conduction and that VEP is useful to evaluate the effects of AED within the central nervous system.

N-acetyl-β-glucosaminidase and β-galactosidase activity in children receiving antiepileptic drugs

To evaluate renal tubular function in children receiving antiepileptic drugs the urinary activity of two lysosomal enzymes, N-acetyl-β-glucosaminidase and β-galactosidase, were measured. The enzyme levels were determined before the administration of antiepileptic drugs and 8 months after. Fourteen epileptic children received valproate, and 17 received carbamazepine. The urinary activity of these enzymes in 25 healthy control patients also was examined. Increased N-acetyl-β-glucosaminidase activity was found in 50% of patients taking valproate and in 17.6% of patients taking carbamazepine. Increased β-galactosidase activity was found in 28.5% of patients taking valproate and 11.7% of patients taking carbamazepine compared with the results before treatment. On the basis of these results, it is suggested that patients taking antiepileptic drugs, especially valproate, may demonstrate minor signs of tubular dysfunction. In those patients who use these drugs at increased dosage levels or for long periods, the possibility of tubular dysfunction may be increased, and these dysfunctions may manifest in clinical symptoms.

Anophthalmia-Waardenburg syndrome: a report of three cases.

We report on 2 Turkish families with children who had bilateral anophthalmia, upper and lower limb abnormalities, mental retardation and consanguineous parents. We have evaluated the 2 cases in the first family and the only case in the second as anophthalmia-Waardenburg syndrome. This is an extremely rare autosomal recessive syndrome.

Consanguineous marriages among parents of Down patients

In order to reveal if there is an effect on the genesis of meiotic‐ or early zygotic non‐disjunctions, data related to 1598 Down syndrome patients from 1578 families studied in five different genetic centers in Turkey are reported. Parental consanguinity and the inbreeding coefficient were found to be lower among patients of 21‐trisomics than in parents without Down offspring. It was concluded that available information does not support the presence of a “non‐disjunction gene” in man.

Dermatoglyphics in patients with Cenani‐Lenz type syndactyly: Studies in a new case

We describe an additional case of Cenani-Lenz syndactylism in a 4 1/2-year-old boy from a consanguineous Turkish family. The digital anomalies consisted partly of synostosis and partly of malformations of the phalanges. Although there was no radio-ulnar synostosis or abnormality of the bones of the feet, the findings are comparable to those described in the Cenani-Lenz type of syndactyly. We analysed the dermatoglyphics of our patient and compared them with those previously reported. We also investigated the relationship between the bony malformations and the dermatoglyphic patterns in our patient and in the literature.

Influence of long-term carbamazepine treatment on thyroid function

We have studied the effects of carbamazepine on thyroid function in sixteen recently diagnosed epileptic children and thirteen epileptic children receiving long‐term carbamazepine therapy and compared these findings with the thyroid function of thirteen healthy control subjects. Thyrotropin (TSH), tri‐iodothyronine (T3), thyroxine (T4), free tri‐iodothyorinine (FT3) and free thyroxine (FT4) serum levels were determined in both recently diagnosed but as yet untreated epileptic children and normal controls. These hormone levels were determined again after 2 months of treatment and 12 months of treatment in epileptic children. No statistically significant difference was found in the endocrine parameters of untreated epileptic children and the normal control group. After both 2 months and 12 months of carbamazepine therapy, serum levels of T4, FT4 and FT3 were found to be low, but the serum T3 concentration was unaffected. Baseline TSH levels were not changed during carbamazepine therapy either. Serum TSH levels increased rapidly after thyrotropin‐releasing hormone stimulation in both the before and 12 months after carbamazepine treatment groups, but the response was higher in the 12 months treatment group. The findings of the present study suggest that accelerated hormone metabolism is responsible for hormonal changes found in patients treated with carbamazepine. Carbamazepine also had effects on the function of the hypothalamo‐pituitary axis.