New mutations in two Dutch patients with early infantile galactosialidosis.

Galactosialidosis is an autosomal recessive lysosomal storage disease caused by a combined deficiency of lysosomal beta-galactosidase and neuraminidase as a result of a primary defect in the protective protein/cathepsin A (PPCA). We report the first 2 Dutch cases of early infantile galactosialidosis, both presenting with neonatal ascites. The defect was identified in urine, leukocytes, and fibroblasts. Residual activity was determined with a modified assay for cathepsin A and was <5% in leukocytes and <1% in fibroblasts. Histological examination of the placenta in case 1 showed extensive vacuolization in all cell types. Northern blot analysis of RNA isolated from the patients' cultured fibroblasts showed substantially decreased levels of the PPCA transcript, which nevertheless had the correct size of 2 kb. Mutation analysis of both mRNA and genomic DNA from the patients identified two novel mutations in the PPCA locus. Case 1 was a compound heterozygote, with a single missense mutation in one allele, which resulted in Gly57Ser amino acid substitution, and a single C insertion at nucleotide position 899 in the second allele, which gave rise to a frame shift and premature termination codon. Case 2 was homozygous for the same C899 insertion found in case 1.

Hepatocellular carcinoma in glycogen storage disease type IV.

A 13 year old patient with juvenile type IV glycogen storage disease died of the complications of hepatocellular carcinoma. To our knowledge this is the first reported case of hepatocellular carcinoma in association with type IV glycogen storage disease.

Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations.

Rubinstein-Taybi syndrome (RTS) is a malformation syndrome characterised by facial abnormalities, broad thumbs, broad big toes, and mental retardation. In a subset of RTS patients, microdeletions, translocations, and inversions involving chromosome band 16p13.3 can be detected. We have previously shown that disruption of the human CREB binding protein (CREBBP or CBP) gene, either by these gross chromosomal rearrangements or by point mutations, leads to RTS. CBP is a large nuclear protein involved in transcription regulation, chromatin remodelling, and the integration of several different signal transduction pathways. Here we report diagnostic analysis of CBP in 194 RTS patients, divided into several subsets. In one case the mother is also suspect of having RTS. Analyses of the entire CBP gene by the protein truncation test showed 4/37 truncating mutations. Two point mutations, one 11 bp deletion, and one mutation affecting the splicing of the second exon were detected by subsequent sequencing. Screening the CBP gene for larger deletions, by using different cosmid probes in FISH, showed 14/171 microdeletions. Using five cosmid probes that contain the entire gene, we found 8/89 microdeletions of which 4/8 were 5' or interstitial. This last subset of microdeletions would not have been detected using the commonly used 3' probe RT1, showing the necessity of using all five probes.

[Metabolic acidosis in children: the usefulness of 'anion gap']. / Metabole acidose bij kinderen: het nut van de 'anion gap'.

Metabolic acidosis occurs frequently in small children. The most common causes are hypoxia, sepsis, gastroenteritis and hypovolaemia. Calculation of the anion gap is useful in establishing the cause. An increased anion gap represents unmeasured anions, e.g. lactate in lactic acidosis. Metabolic acidosis was diagnosed in two boys aged one year and six weeks respectively. The first patient had a normal, the second an increased anion gap in blood. By determining the pH and the anion gap in urine it is possible to distinguish between a proximal and a distal tubular disease. The first patient had distal renal tubular acidosis; he recovered after correction of the acidosis. The second patient had a defect in the mitochondrial respiratory chain; he died at the age of seven months.

Molecular analysis of SALL1 mutations in Townes-Brocks syndrome.

Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. Recently, we showed that mutations in the putative zinc finger transcription factor gene SALL1 cause TBS. To determine the spectrum of SALL1 mutations and to investigate the genotype-phenotype correlations in TBS, we examined 23 additional families with TBS or similar phenotypes for SALL1 mutations. In 9 of these families mutations were identified. None of the mutations has previously been described. Two of these mutations are nonsense mutations, one of which occurred in three unrelated families. Five of the mutations are short deletions. All of the mutations are located 5' of the first double zinc finger (DZF) encoding region and are therefore predicted to result in putative prematurely terminated proteins lacking all DZF domains. This suggests that only SALL1 mutations that remove the DZF domains result in TBS. We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome. However, phenotypic differences in TBS do not seem to depend on the site of mutation.

Treatment of osteogenesis imperfecta with the bisphosphonate olpadronate (dimethylaminohydroxypropylidene bisphosphonate).

UNLABELLED: Osteoporosis is an important feature of osteogenesis imperfecta (OI). So far, no effective medical treatment is available. We treated three boys with severe OI type III and vertebral deformities for 5-7 years with continuous oral administration of the bisphosphonate, olpadronate. Treatment resulted in a decreased number of bone fractures, an increased calcification of the long bones and an amelioration of vertebral shape. No side-effects were encountered. CONCLUSION: These preliminary but long-term observations suggest that the bisphosphonate olpadronate may be a useful treatment for patients with OI and vertebral fractures. Bisphosphonates may be promising drugs for children with OI.

MRI screening of kindred at risk of developing paragangliomas: support for genomic imprinting in hereditary glomus tumours.

Paragangliomas of the head and neck (glomus tumours) can occur in a hereditary pattern and may be hormonally active as well as being associated with paragangliomas elsewhere. A number of these tumours may be present without symptoms. To detect the presence of subclinical paragangliomas we screened 83 members of a family at risk of developing hereditary paragangliomas using whole body MRI and urinary catecholamine testing. In eight previously diagnosed members, eight known glomus tumours of which one functioning, and two unknown glomus tumours and one unknown pheochromocytoma were present. Six unsuspected members showed ten glomus tumours and one pheochromocytoma. It has been suggested that the manifestation of hereditary glomus tumours is determined by the sex of the transmitting parent. There were no tumours in the descendants of female gene carriers. Comparing the likelihood of inheritance with genomic imprinting versus inheritance without genomic imprinting we found an odds ratio of 23375 in favour of genomic imprinting.

Oculoauriculovertebral spectrum and cerebral anomalies.

We report on three Dutch children with a clinical diagnosis of oculoauriculovertebral spectrum (OAVS) and hydrocephalus. The clinical features are compared to 15 published cases of OAVS and hydrocephalus. Several other cerebral abnormalities were present in the whole group. About half of the cases had cleft lip/palate, anophthalmia/microphthalmia, or a cardiac defect. Mental retardation was found in five of the surviving 11 patients and early death occurred in one-third. We compared the cases with OAVS and hydrocephalus with published reports of OAVS and other cerebral anomalies and found no significant clinical differences. However, the clinical characteristics were clearly more severely expressed than generally found in patients with OAVS. Children with OAVS and more severe clinical features, especially anophthalmia/microphthalmia and cleft lip/palate, seem to be at an increased risk for cerebral malformations and for mental retardation.

beta-Glucuronidase deficiency as a cause of fetal hydrops.

Mucopolysaccharidosis type VII (MPS VII) was diagnosed in a case of severe fetal hydrops. beta-glucuronidase deficiency was demonstrated in the amniotic fluid, which was obtained at 25 weeks of gestation, and in the fibroblasts of the child, which were cultured after fetal death in the 26th week of gestation. In the amniotic fluid the two-dimensional electrophoresis pattern of glycosaminoglycans was in agreement with MPS VII. Based on these results, prenatal diagnosis could be offered to the couple for the next pregnancy.

Adult adrenoleukodystrophy: the clinical spectrum in a large Dutch family.

A large family with adrenoleukodystrophy is described and the case histories of two clinically symptomatic and related male patients are presented. Clinical, biochemical and genetic screening of their family demonstrated two clinically affected males, one biochemically affected male and five carrier females. Two women were symptomatic; one suffered an acute exacerbation. One female was diagnosed as a carrier, based on genetic analysis and the family history only. Endocrinological screening was performed in the five affected males, demonstrating an elevated adrenocorticotrophic hormone level and a normal cortisol level in two, as evidence of compensated adrenocortical failure.

Linkage analysis in X-linked adrenoleukodystrophy and application in post- and prenatal diagnosis.

We have performed linkage analysis with the DNA markers DXS52 and the clotting factor VIII gene (F8C), in several large families with X-linked adrenoleukodystrophy (ALD). The tight linkage to DXS52 could be extended giving a maximal LOD score of 22.5 at 1 cM. F8C was also tightly linked to ALD with a maximal LOD score of 7.8 without recombination. Multipoint linkage analysis with the markers DXS304, DXS52, and F8C indicated that both the gene for ALD and for F8C are distal to DXS52. In four patients with ALD, no major structural rearrangement in the Xqter region was observed; in particular, there were no abnormalities in the vision blindness genes. DNA analysis appeared to be of use in determination of the carrier status of females at risk, for the determination of the origin of the mutation in a particular family, and for prenatal diagnosis.

Familial vascular retinopathy. A preliminary report.

We describe a new hereditary syndrome with an autosomal dominant mode of inheritance, with vascular retinopathy, migraine and Raynaud's phenomenon as the most striking features. The retinopathy is characterized by tortuosity and variable caliber of the retinal vessels, haemorrhages, telangiectases and both central and peripheral vascular occlusions, leading finally to a proliferative retinopathy.

[Focal dermal hypoplasia, or the Goltz-Gorlin syndrome]. / Focale dermale hypoplasie, ofwel het syndroom van Goltz-Gorlin.

A female newborn is reported with focal dermal hypoplasia (Goltz-Gorlin syndrome) presenting multiple skin and extremity-abnormalities. A short review of today's literature in relation to mode of inheritance and clinical manifestations is given.

Genomic imprinting in hereditary glomus tumours: evidence for new genetic theory.

A study based on fifteen pedigrees showed that familial glomus tumours are inherited almost exclusively via the paternal line, a finding inconsistent with autosomal dominant transmission. The results can be explained in terms of the genomic imprinting hypothesis--the maternally derived gene is inactivated during female oogenesis and can be reactivated only during spermatogenesis. Genomic imprinting may have considerable implications for genetic counselling with respect to glomus tumours and also for the understanding of other hereditary diseases.

Werdnig-Hoffmann disease in a Nigerian infant.

A Nigerian infant with the classical features of Werdnig-Hoffmann disease is described. According to the literature the incidence in black Africans is very low. Attention is drawn to the fact that neurological illnesses are often overlooked in negroid races; several reasons are given.

Holoprosencephaly: variation of expression in face and brain in three sibs.

A family is described containing three sibs with holoprosencephaly. They showed a striking diversity of both cerebral and facial abnormalities. Autosomal recessive inheritance seems most likely. Because of the great variety in expression of this disorder, it is of importance for genetic counselling to examine both sibs and parents.

[An infant with hereditary methemoglobinemia]. / Een zuigeling met erfelijke methemoglobinemie.

Autosomal recessive hereditary methemoglobinemia associated with mental retardation is a rare syndrome caused by a deficiency of the enzyme NADH cytochrome b5 reductase. A patient suffering from this disorder is described. The etiology of the syndrome and the (im)possibilities of treatment and prenatal diagnosis are discussed.

Dicarboxylicaciduria and secondary carnitine deficiency in glycogenosis type IV.

A 3 year old boy developed an unusually mild form of glycogen storage disease type IV. Metabolic investigations showed severe abnormalities of fatty acid and carnitine metabolism. A muscle carnitine deficiency was found. Treatment with L-carnitine orally led to a notable improvement in muscle strength.

Congenital microcephaly, infantile spasms, psychomotor retardation, and nephrotic syndrome in two sibs.

Two boys are described with congenital microcephaly, infantile spasms, psychomotor retardation and an early-onset nephrotic syndrome. The autopsy findings of one patient are described in detail. Polymicrogyria was the most prominent feature and the kidneys showed focal segmental glomerulosclerosis. These findings have been described as a clinical entity, the leading symptoms being congenital microcephaly, early-onset nephrotic syndrome and mental retardation, accompanied by various other clinical symptoms. A review of the literature suggests an autosomal recessive mode of inheritance.