Mental retardation and behavioral problems as presenting signs of a creatine synthesis defect.

Recently, 3 patients with a creatine synthesis defect have been described. They presented with developmental regression, extrapyramidal movement abnormalities, and intractable epilepsy, and they improved with treatment of creatine monohydrate. We report 2 unrelated boys with a creatine synthesis defect and nonspecific presenting signs of psychomotor retardation, behavioral problems, and, in 1, mild epilepsy. Metabolic urine screening revealed elevations in all metabolites, expressed as millimoles per mole of creatinine, which suggests decreased creatinine excretion. This finding led to the correct diagnosis. We propose to include the assessment of the overall concentrations of amino acids and organic acids relative to creatinine in routine metabolic urine screening.

The natural course of Gaucher disease in The Netherlands: implications for monitoring of disease manifestations.

This retrospective study in 20 untreated type I Gaucher disease patients shows that in Dutch patients clinical manifestations of Gaucher disease type I are progressive in the majority of patients, children as well as adults. This is in contrast with studies among Jewish patients. Our results emphasize the need for a regular follow-up to enable timely initiation of enzyme therapy.

Monozygotic twin brothers with the fragile X syndrome: different CGG repeats and different mental capacities.

Little is known about the mechanism of CGG instability and the time frame of instability early in embryonic development in the fragile X syndrome. Discordant monozygotic twin brothers with the fragile X syndrome could give us insight into the time frame of the instability. We describe monochorionic diamniotic twin brothers with the fragile X syndrome who had different CGG repeats and different mental capacities, whereas the normal mother had a premutation. The more retarded brother had a full mutation in all his cells and no FMR-1 protein expression in lymphocytes, whereas the less retarded brother had 50%/50% mosaicism for a premutation and full mutation and FMR-1 protein expression in 26% of his lymphocytes. The differences in repeat size could have arisen either before or after the time of splitting. The time of splitting in this type of twin is around day 6-7. Given the high percentage of mosaicism, we hypothesise that the instability started before the time of splitting at day 6-7.

[Allogeneic bone marrow transplantation in the treatment of (lysosomal) storage diseases]. / Allogene beenmergtransplantatie bij de behandeling van (lysosomale) stapelingsziekten.

The first report of a positive effect of allogeneic bone marrow transplantation (BMT) on the clinical course in a patient with a lysosomal storage disease was described in 1981. Since then, over 200 patients have been treated in this way but data are scarce and fragmentary. Allogeneic BMT involves replacement of the patient's haemopoietic system by that of a donor. The new cells that repopulate the body can correct the metabolic disturbance. Most experience with allogeneic BMT was gained in patients with mucopolysaccharidosis type I, metachromatic leukodystrophy and adrenoleukodystrophy. Allogeneic BMT reduces the amount of storage material in internal organs: skeletal abnormalities and neurological symptoms are at best stabilized. Transplantation-related mortality and morbidity are high. The applicability of allogeneic BMT is limited.

Depletion of mitochondrial DNA in the liver of a patient with lactic acidemia and hypoketotic hypoglycemia.

An infant with feeding difficulties, hypotonia, lactic acidemia, and severe hypoketotic hypoglycemia died at the age of 7 months of liver disease. Electron microscopy revealed abnormal mitochondria. Biochemical studies of mitochondrial enzymes in liver showed a decreased activity of complexes I, III, and IV. Mitochondrial DNA (mtDNA) content was reduced in liver 7% of the mean value in control subjects) and in muscle (50%). In kidney, brain, and heart, the mtDNA content was normal. The liver-specific mtDNA depletion syndrome in this patient manifested itself with features of both a respiratory chain defect and a mitochondrial fatty acid oxidation defect. Syndromes involving depletion of mtDNA can be diagnosed only when the activity of the respiratory chain enzymes and the content of mtDNA are investigated in the most affected tissues.

Unsuccessful dietary treatment of Sjögren-Larsson syndrome.

We treated five children with Sjögren-Larsson syndrome. The patients, 5 months to 8 years of age, were given a low fat diet supplemented with medium-chain fatty acids. Plasma octadecanol levels remained unchanged, and skin lesions and neurologic symptoms did not abate. Two patients also failed to respond to dietary supplementation with polyunsaturated fatty acids. We conclude that dietary therapy is usually unsuccessful in patients with Sjögren-Larsson syndrome even when started in early infancy.

Two additional cases of the Ohdo blepharophimosis syndrome.

Two additional cases of the Ohdo blepharophimosis syndrome are described and compared to the 5 patients previously reported. Blepharophimosis, ptosis, dental hypoplasia, mental retardation, and deafness can be considered as common manifestations of the syndrome. Male patients show cryptorchidism and scrotal hypoplasia.

[Phenylketonuria in spite of screening]. / Fenylketonurie ondanks screening.

A girl with psychomotor retardation is described in whom the diagnosis phenylketonuria (PKU) was made at the age of 6.5 years. Previous investigations were not carried out as she was screened for PKU when she was a baby. Since the nationwide neonatal screening for PKU was started in 1974, 4 children have been detected with a false negative test result.

46,XY del(18)(q21.3q22.2) with mosaicism of r(18) and a milder form of the 18q- syndrome.

A mosaic karyotype: 46,XY,del(18)(q21.3q22.2)/47,XY,del(18) (q21.3q22.2)+ marker, was found in a mentally retarded male with a mild form of the 18q- syndrome and aplasia of the right thumb. By fluorescent in situ hybridisation, the marker chromosome could be identified as a ring chromosome no. 18.

[Gaucher's disease in childhood: presentation and treatment]. / De ziekte van Gaucher op de kinderleeftijd: presentatie en behandeling.

M. Gaucher is a lysosomal storage disorder. Patients present with hepatosplenomegaly or with complaints of the bones. Clinically 3 subtypes can be distinguished; the 'adult' type I is most frequent found. On the basis of 10 case histories the presentation in childhood is reported. Only recently treatment with enzyme replacement therapy became available. The possibilities for the treatment of M. Gaucher are discussed.

A girl with 71,XXXXY karyotype.

A girl with a 71,XXXXY karyotype is described. Internal and external genitalia were female despite the presence of a Y-chromosome.

[Early diagnosis of fragile X mental retardation syndrome]. / Vroegtijdige herkenning van het fragiele-X-mentale-retardatie-syndroom.

Conducting an inquiry among 32 parents of 46 children with fragile-X mental retardation, we investigated the problems on early recognition of the syndrome. From the first call for medical help until establishment of the diagnosis, on average 2 years elapsed. The family history is very important, since in 82.5% of the cases mental retardation also occurred in other family members. We recommend that investigations should be performed in all children who do not repeat words and/or do not walk without help, at the age of 18 months. A high priority must then be given to specific investigations on the X-chromosomal fragile site.

4-Hydroxybutyric aciduria: further clinical heterogeneity in a new case.

A 2.5-year-old girl presented with severely delayed speech development and mild motor retardation. Urinary organic acid analysis showed the presence of 4-hydroxybutyric acid and other metabolites consistent with the diagnosis 4-hydroxybutyric aciduria. Succinic semialdehyde dehydrogenase activity was absent in lymphocyte lysates. The clinical symptoms in this case were unusually mild compared to previously reported patients. No correlation was found between the mild symptoms and the levels of metabolite excretion or the residual succinic semialdehyde dehydrogenase activity in this patient compared to more severely affected cases.

Facial dysmorphia, parathyroid and thymic dysfunction in the father of a newborn with the DiGeorge complex.

A boy born at full-term died after 14 days from cardiac failure. At autopsy DiGeorge complex was diagnosed. The father was found to have facial dysmorphia and hypocalcaemia. Investigations revealed no cause other than hypoparathyroidism associated with normal serum 1,25-dihydroxyvitamin D concentrations and normal renal handling of phosphate. Immunological tests, performed on two occasions with an interval of 9 months, revealed a decrease in the number of CD8+ lymphocytes, compatible with a partial thymus deficiency. The combination of facial dysmorphia with dysfunction of the thymus and the parathyroid glands can constitute a partial DiGeorge complex. The findings in this family are compared with reports of four other families with DiGeorge complex in two generations. In genetic counseling DiGeorge complex should be considered a heterogenous disorder. Screening of the parents for somatic stigmata, hypocalcaemia, disturbed cellular immunity, cardiac and chromosomal abnormalities is essential.

Intermittent thrombocytopenia and absent radii: report of a patient with additional unusual manifestations.

We report on a boy with absent radii and intermittent thrombocytopenia. He has many other manifestations of the thrombocytopenia absent radius (TAR) syndrome but in addition has manifestations not previously described: palatoschisis of the soft palate, subcricoid stenosis, duodenal atresia and extreme sensitivity of chromosomes to X-rays. Our patient could either represent a unique condition or unusual variability of TAR syndrome.