Novel mutations in the GALK1 gene in patients with galactokinase deficiency.

Galactokinase deficiency is an inborn error of galactose metabolism whose major clinical manifestation is the development of cataracts during the first months of life. Only 20 mutations have been reported to date and understanding of the functionally important domains of the galactokinase protein is still limited. Here we report four novel mutations in GALK1 that were identified in two unrelated patients with galactokinase deficiency. Three of these were amino acid substitutions: 1569C-->T in exon 2 (R68C); 7093C-->T in exon 6 (T288M) and 7538G-->C in exon 8 (A384P). In addition, a single base-pair deletion was found in exon 5 (2833delC), predicted to result in a shift of the reading frame and a premature termination codon at position 263. Some differences with the GALK1 sequence deposited in Genbank are also reported.

Nutritional management of the female with phenylketonuria during pregnancy.

This paper discusses a rational approach to appropriate nutritional management of the pregnant woman with phenylketonuria (PKU). Special food items, including new formulas and low-phenylalanine products, as well as allowable nutral foods are described. Particular emphasis is placed on the nutritional adequacy of this PKU diet during pregnancy. Such a diet should be palatable and tolerated well and should also take into consideration important economic, cultural, and psychological aspects. Clinics caring for PKU individuals should be so prepared because many otheir females are approaching childbearing age.

Seizure disorders in Down syndrome.

The prevalence, onset, and type of seizure disorders, as well as seizure control, were studied in a large cohort of 405 individuals with Down syndrome (age range, 6 months to 45 years). The evaluation of a questionnaire completed by the subjects' parents and of the patients' medical records indicated that 33 (8.1%) of 405 persons with Down syndrome had seizure disorder. With regard to the onset of seizures, a bimodal distribution was noted: 40% of patients began having seizures before the age of 1 year, and another 40% started with seizure activity in the third decade of life. In the younger age group, primarily infantile spasms and tonic-clonic seizures with myoclonus were observed, and the older patients often had partial simplex or partial complex seizures as well as tonic-clonic seizures.

Atlantoaxial instability in individuals with Down syndrome: epidemiologic, radiographic, and clinical studies.

Atlantoaxial instability is a relatively frequent finding in individuals with Down syndrome. We examined 404 patients with this chromosome disorder and observed their atlanto-dens intervals and spinal canal widths to be significantly different from children without Down syndrome. Significant differences were also noted between boys and girls with Down syndrome in spinal canal widths but not in atlanto-dens interval measurements. When different neck positions were compared, measurements obtained in flexion were significantly greater than in extension or in neutral position. In addition, more patients had greater than or equal to 5 mm atlanto-dens interval measurements in flexion than in extension or neutral. A total of 59 (14.6%) of 404 patients displayed atlantoaxial instability. Fifty-three (13.1%) patients had asymptomatic atlantoaxial instability, and special precautions will have to be taken with this group of children. Six (1.5%) patients had symptomatic atlantoaxial instability who underwent surgery to prevent further injury to the spinal cord. In our follow-up studies of 95 patients with Down syndrome, we did not find any significant changes during either clinical or radiographic reexaminations.

A longitudinal study of atlanto-dens relationships in asymptomatic individuals with Down syndrome.

This study was designed to investigate the natural history of atlantoaxial instability in individuals with Down syndrome and to determine whether significant changes in C1-C2 relationship are taking place over time. Although more than 400 patients with Down syndrome who are presently followed at the Child Development Center had cervical spine radiographic examinations in the past, only 141 patients who had serial radiological examinations and whose radiographs were available for reevaluation participated in this study. The results of our investigations revealed that there were only minor changes (1 to 1.5 mm) of atlanto-dens interval measurements over time in 130 (92%) patients with Down syndrome. Eleven patients (8%) had changes of atlanto-dens interval measurements between 2 and 4 mm over time; however, none of these patients had any clinical symptoms. The analyses of data obtained from several subgroups (males and females, various age groups, and patients with and without atlantoaxial instability) did not show any significant changes of atlanto-dens interval measurements of successively obtained radiographs. Our recommendations for and rationale of routine screening for atlantoaxial instability and follow-up examinations are discussed in detail.

Growth charts for children with Down syndrome: 1 month to 18 years of age.

Centile charts for assessment of stature and weight reflecting expected deficient size and growth rate of home-reared children with Down syndrome are presented for two age intervals, 1 to 36 months and 2 to 18 years, based on 4650 observations on 730 children. Data were pooled and used to estimate five centiles which were smoothed using a flexible mathematical function. These data corroborate other studies of growth in children with Down syndrome demonstrating deficient growth rate throughout the growing period, but most marked in infancy and again at adolescence. Children with Down syndrome in the present sample were taller than those from institutionalized samples at all ages throughout the growing period. Children with moderate or severe congenital heart disease on average were 1.5 to 2.0 cm shorter and about 1 kg lighter than those without or with only mild disease. Mean weight and weight divided by stature squared show that children with Down syndrome have a tendency to be overweight beginning in late infancy and throughout the remainder of the growing years.

Neurological and psychomotor functions in children with an increased lead burden.

Fifty-eight children with an increased lead burden underwent comprehensive investigations and were reevaluated 1(1/2) to 3 years later. Of these children 23-27% were noted to have minor neurological dysfunction and various forms of motor impairment during each evaluation. While the initial psychological assessment revealed low average mental abilities in the majority of children, during follow-up examination a significant increase in certain areas of intellectual functioning was observed.

Head circumference of children with Down syndrome (0-36 months)

This study provides statistically appropriate head circumference reference curves for males and females with Down syndrome (DS) from birth to 36 months of age. A total of 239 males and 182 females from five study populations, yielding a combination of cross-sectional and longitudinal data, were used for the analysis. The method of least squares was used to test the fit of the growth model y = a+bx+c[log(x + 1)], where x is age in months. These standardized curves should provide information of value in the medical, physical, and developmental management of children with DS.

X-linked recessive myotubular myopathy: I. Clinical and pathologic findings in a family.

Four neonatal deaths in one family were due to X-linked myotubular myopathy. The characteristic alterations in muscle, described in three cases, are marked fiber hypotrophy, size variability, and the presence of internal nuclei or pale areas. The diagnosis can be verified only by obtaining a careful genetic history. Previous occurrence of male neonatal death or stillbirth, or of hypotonia and respiratory insufficiency, is critical in the identification of suspected cases. There is morphologic justification for retaining the name "myotubular myopathy" to distinguish this X-linked disorder from other congenital conditions involving muscle weakness that have similar morphologic features.

The Richner-Hanhart syndrome: report of a case with associated tyrosinemia.

The Richner-Hanhart syndrome with tyrosinemia was recognized in a mentally retarded adolescent boy. The clinical manifestations, including hyperkeratosis of the volar aspects of the hands and feet, thickening of the conjunctival epithelium, and corneal opacities, as well as biochemical aberrations of tyrosine metabolism, responded to specific treatment with a diet low in phenylalanine and tyrosine. Light and electron microscopical studies illustrate the underlying conjunctival pathologic changes.

Should children with Down syndrome be screened for atlantoaxial instability?

In 1995, the Committee on Sports Medicine and Fitness of the American Academy of Pediatrics (AAP) published a position paper on atlantoaxial instability in children with Down syndrome in which a previous statement on the same subject published in 1984 (Table) was retired. The 1995 statement includes several arguments that disfavor screening of children with Down syndrome for atlantoaxial instability. Whereas some of these arguments are well founded, other lack substantive evidence that would support the statement. In the following discussion, I attempt to analyze some of these arguments made in the 1995 statement and provide a viewpoint that favors radiologic examinations of the cervical spine of children with Down syndrome.

Menstrual cycles and basal body temperature curves in women with Down syndrome.

Menstrual histories were obtained from 51 females with Down syndrome between the ages of 10-27 years. The average age at onset of menstruation of girls in our study was 12 years, 6 months. Seventy-six percent of them had regular menstrual cycles with an average length of menstrual flow of 4 days, and most menstrual cycles lasted 25-30 days. Eight of the women with regular menstrual cycles provided 26 basal body temperature charts. When basal body temperatures were graphed using the smoothed-curve technique, 88.5% had biphasic curves indicative of an ovulatory pattern.

A study of placental transfer mechanisms in nonhuman primates using [14C]phenylalanine.

Placental transfer mechanisms were investigated in pregnant Macaca Fascicularis and Macaca mulatta during the gestational age of 120 to 130 days. These primates underwent an operative procedure that allowed continuous fetal blood sampling. The administration of [14C]phenylalanine into the maternal circulation revealed a significant increase of radioactive material in the fetal circulation, indicating an active placental transport mechanism unidirectional to the fetus. When [14C]phenylalanine was injected into the fetus, radioactive aromatic amino acids in the maternal circulation increased only slightly over time, resembling a simple diffusion process.

Discontinuing the phenylalamine-restricted diet in young children with PKY. Psychosocial aspects.

Analysis of questionnaires, informal group meetings, and individual interviews with parents and their children with phenylketonuria gave insight on the attitudes and experiences surrounding discontinuance of the phenylalanine-restricted diet. The investigation identified important aspects of changing social interactions as termination of the restricted diet progressed. The study suggests that preparatory discussions with parents and children prior to the change in diet should be held to avoid undue stress and conflict in such families.

Infantile sialic acid storage disease associated with renal disease.

A child with infantile sialic acid storage disease is reported. Ultrasonography demonstrated fetal ascites. At birth, the infant appeared hydropic and presented with numerous dysmorphic features, including sparse white hair, coarse facies, hypertelorism, epicanthal folds, anteverted nostrils, and a long philtrum. In addition, he had visceromegaly, bilateral inguinal hernias, and a slight gibbus deformity. Lymphocytes were vacuolated and bone marrow contained large numbers of foam cells. There were generalized vacuolations of both reticuloendothelial and parenchymal cells in the examined tissues. Neuropathologic studies revealed wide-spread neuronal storage, myelin loss, axonal spheroids, and gliosis. Neurons, endothelial cells, and Kupffer cells stained with wheat germ agglutinin indicated an accumulation of sialic acid. Free sialic acid was significantly increased in urine and serum, as well as in liver, heart, and brain tissues. The alpha-neuraminidase activity was normal. It is assumed that the basic defect of infantile sialic acid storage disease lies in impaired transport of sialic acid across the lysosomal membrane.

Computerized tomography in persons with Down syndrome and atlantoaxial instability.

Atlantoaxial instability has been reported to occur in 9-31% of persons with Down syndrome. The authors studied a subsample of patients with this chromosomal disorder who had both routine roentgenograms and computerized tomographic examinations. Computerized tomography revealed numerous skeletal anomalies of the C1-C2 region as well as spinal cord compression that were not visualized on plain roentgenograms. In addition, an apparent discrepancy of the atlanto-dens interval measurements between the two procedures was noted. The measurements of the plain roentgenograms were significantly greater than those obtained by computerized tomography, which is due to the magnification factor in plain roentgenograms.

Macrocytosis in Down syndrome.

The mean corpuscular volume of erythrocytes in persons with Down syndrome is larger than normal in the absence of anemia. The mean mean corpuscular volume among our 61 subjects with trisomy 21 was 99.08 fl (range = 90 to 107). Red blood cell survival half-time was substantially shorter than normal in many of these patients. These findings suggest that erythrocytes have a younger mean age in persons with Down syndrome. The increased red blood cell turnover in this population may indicate an accelerated aging process of red blood cells.

Fetomaternal placental transfer mechanisms of aromatic amino acids in Macaca mulatta.

We investigated aromatic amino acid transfer mechanisms from fetus to mother in third-trimester pregnancies in rhesus monkeys after the administration of radioactive phenylalanine to the fetal circulation. The results indicated that fetomaternal transfer takes place mainly by facilitated diffusion via specific membrane carriers. This mechanism might participate in regulating amino acid concentrations in the fetus.

Pseudodementia in the mentally retarded. A case report and review.

Intellectual and behavioral deterioration in an individual who is mentally retarded presents a diagnostic challenge to the clinician, since the deterioration may be the result of the primary disorder or a new process. The mentally retarded individual's limitations in communication make the diagnostic assessment more difficult. The authors report the case of pseudodementia in a mentally retarded teenager presumed to have been caused by impacted otic cerumen and corrected by removal of the cerumen. The discussion includes a review of medical, neurologic, psychiatric, and environmental causes of intellectual and behavioral deterioration.

Growth hormone response after administration of L-dopa, clonidine, and growth hormone releasing hormone in children with Down syndrome.

We studied the response of growth hormone secretion after the administration of L-dopa, clonidine, and growth hormone releasing hormone in eight growth-retarded children with Down syndrome aged 1 to 6.5 years. After L-dopa administration, five children had low growth hormone secretion (M = 3.7 ng/ml, SD = 2.12 at 30 min) and three children had elevated growth hormone levels (> 30 ng/ml). After clonidine administration, six children had relatively low growth hormone levels (M = 3.15 ng/ml, SD = 2.53 at 60 min) and two children had high levels (38.3 ng/ml and 16.8 ng/ml, respectively). There was a better response after growth hormone releasing hormone administration; only one child had a growth hormone level of < 10 ng/ml. Most of the children had a modified response of growth hormone secretion subsequent to the various stimulation tests. All children, however, were able to secrete some growth hormone (> or = 10 ng/ml) at least during one of the stimulation tests. In comparison with peak growth hormone levels reported in normal children, our cohort had significantly lower growth hormone levels only after clonidine administration. It is postulated that children with Down syndrome have both anatomical and biochemical hypothalamic derangements that may result in decreased growth hormone secretion and reduced linear growth. In addition, other mechanisms that may be in part responsible for the observed growth retardation are discussed.