Studies of a synthetic substrate in canine globoid cell leukodystrophy.

Gal et al. ((1977) Clin. Chim. Acta 77, 53-59) reported the use of a new synthetic substrate, 2-hexadecanoylamino-4-nitrophenyl-beta-D-galactopyranoside for the diagnosis of human globoid cell leukodystrophy. Assay of beta-galactosidase in brain homogenates from normal, carrier, and globoid cell leukodystrophy-affected dogs utilizing this new substrate demonstrated overlapping activities. Instead of reflecting specific D-galactosyl-N-acylsphingosine galactohydrolase (EC 3.2.1.46), the 2-hexadecanoylamino-4-nitrophenyl-beta-D-galactopyranoside beta-galactosidase activity in canine brain is highly correlated with nonspecific 4-methylumbelliferyl beta-galactosidase. Optimization of the 2-hexadecanoyl-amino-4-nitrophenyl-beta-D-galactopyranoside assay system for canine brain and the use of varying concentrations of taurocholate or taurodeoxycholate in the assay mixture did not alter the lack of specificity. These results indicate a significant difference in the nature of the underlying defect in galactosylceramide beta-galactosidase in canine globoid cell leukodystrophy compared to human globoid cell leukodystrophy.

Hyperekplexia.

Hyperekplexia is a hereditary neurologic disorder manifested by an exaggerated startle response, generalized muscular rigidity, and prominent nocturnal myoclonus. The distinctive features of this syndrome constitute an unusual clinical entity that is easily mistaken for other disorders. The study of a family provided additional data on various aspects of this condition. The proband was 3 months old when he was referred for persistent generalized stiffness since birth; this stiffness was associated with an exaggerated startle response and intermittent apnea. Similar symptoms in infancy and prominent nocturnal myoclonus with an excessive startle response in adulthood were described in other family members for five generations. Various features of the disorder indicate a relationship to the syndrome of the "jumping Frenchmen of Maine," latah, miryachit, and other unusual startle reactions.

New Marfanoid syndrome with craniosynostosis.

We report on a patient with various connective tissue abnormalities suggesting a distinctive disorder combining some features of the Marfan syndrome with craniosynostosis and other anomalies. A comparison is made with the Marfan syndrome and other phenotypically similar conditions.

Deletion 9p, duplication 18q in two sisters resulting from a maternal (9;18) (p22;q21.3) translocation.

We have studied two sisters with partial deletion 9p and partial duplication 18q resulting from adjacent 1 segregation of a maternal translocation (9;18) (p22;q21.3). The clinical manifestations identified in our patients were compared with those reported in the literature for 9p- and 18q+ patients involving approximately the same amount of genetic material. There was relatively greater similarity with the 9p- syndrome than with dup (18q) syndrome, but typical characteristics of both conditions were lacking.

Congenital lung herniation.

Congenital lung herniation is a rare condition. It is usually associated with a costal cartilage defect. We report on a newborn boy with a partial lung herniation through the parietal pleura and skin associated with a sternal malformation. We propose the herniation occurred around the fifth month of fetal life and interfered with sternal ossification.

Duplication (12q) syndrome in female cousins, resulting from maternal (11;12) (p15.5;q24.2) translocations.

We have studied female cousins with partial duplication of 12q. The cousins' mothers (who are sisters) and the maternal grandmother and great grandmother carried a balanced translocation between chromosomes 11 and 12. We have compared our patients with eight other reported cases of partial duplication of the same chromosome segment (12q24----12qter). Placement of the extra material seems to have little effect on the anomalies present; (only two other cases involved chromosome 11). We propose that our patients provide further evidence that duplication of 12q leads to a clinically identifiable syndrome.

Expanding the phenotype of the Proteus syndrome: a severely affected patient with new findings.

Here we report on a boy who died at 16 1/2 months with hemihypertrophy, eye abnormalities, macrodactyly, hamartomas, pigmented nevi, cerebral involvement, and other anomalies compatible with the Proteus syndrome. In addition, he also had abnormalities previously unreported in the Proteus syndrome including craniosynostosis and complex congenital heart defects. He seems to represent an extremely severe form of the Proteus syndrome and expands the already broad range of the phenotype.

Toward quality assurance for metaphase FISH: a multicenter experience.

Although fluorescent in situ hybridization (FISH) is rapidly becoming a part of clinical cytogenetics, no organization sponsors multicenter determinations of the efficacy of probes. We report on 23 laboratories that volunteered to provide slides and to use a probe for small nuclear ribonucleoprotein polypeptide N (SNRPN) and a control locus. Experiences with FISH for these laboratories during 1994 ranged from 0 to 645 utilizations (median = 84) involving blood, amniotic fluid, and bone marrow. In an initial study of hybridization efficiency, the median percentage of metaphases from normal individuals showing two SNRPN and two control signals for slides prepared at each site was 97.0 (range = 74-100); for slides prepared by a central laboratory, it was 97.8 (range = 81.6-100). In a subsequent blind study, each laboratory attempted to score 5 metaphases from each of 23 specimens [8 with del(15)(q11.2-->q12) and 15 with normal #15 chromosomes]. Of 529 challenges, the correct SNRPN pattern was found in 5 of 5 metaphases in 457 (86%) and in 4 of 5 in 33 (6%). Ambiguous, incomplete, or no results were reported for 32 (6%) challenges. Seven (1%) diagnostic errors were made, including 6 false positives and 1 false negative: 1 laboratory made 3 errors, 1 made 2, and 2 made 1 each. Most errors and inconsistencies seemed due to inexperience with FISH. The working time to process and analyze slides singly averaged 49.5 min; slides processed in batches of 4 and analyzed singly required 36.9 min. We conclude that proficiency testing for FISH by using an extensive array of challenges is possible and that multiple centers can collaborate to test probes and to evaluate costs.

Toward quality assurance for metaphase FISH: a multi-center experience.

Although fluorescent in situ hybridization (FISH) is rapidly becoming a part of clinical cytogenetics, no organization sponsors multi-center determinations of the efficacy of probes. We report on 23 laboratories that volunteered to provide slides and to use a probe for SNRPN and a control locus. Experiences with FISH for these laboratories during 1994 ranged from 0 to 645 utilizations (median = 84) involving blood, amniotic fluid and bone marrow. In an initial study of hybridization efficiency, the median percentage of metaphases from normal individuals showing two SNRPN and 2 control signals for slides prepared at each site was 97.0 (range = 74-100); for slides prepared by a central laboratory, it was 97.8 (range = 81.6-100). In a subsequent blind study, each laboratory attempted to score 5 metaphases from each of 23 specimens [8 with del(15) (q11.2-->q12) and 15 with normal 15 chromosomes]. Of 529 challenges, the correct SNRPN pattern was found in 5 of 5 metaphases in 457 (86%) and in 4 of 5 in 33 (6%). Ambiguous, incomplete or no results were reported for 32 (6%) challenges. Seven (1%) diagnostic errors were made including 6 false positives and 1 false negative: 1 laboratory made 3 errors, 1 made 2, and 2 made 1 each. Most errors and inconsistencies seemed due to inexperience with FISH. The working time to process and analyze slides singly averaged 49.5 minutes; slides processed in batches of 4 and analyzed singly required 36.9 minutes. We conclude that proficiency testing for FISH using an extensive array of challenges is possible and that multiple centers can collaborate to test probes and to evaluate costs.

Antenatal diagnosis of Pena-Shokeir syndrome (type I) with ultrasonography and magnetic resonance imaging.

A case of Pena-Shokeir syndrome type I was diagnosed prenatally with ultrasonography and magnetic resonance imaging (MRI) in a woman with a possible previous occurrence. Initial ultrasonographic examination at 18.5 weeks' gestation demonstrated an unusual appearance of the fetal spine in an otherwise unremarkable fetus. However, subsequent sonographic examinations at 26 and 28.5 weeks demonstrated polyhydramnios and multiple skeletal, brain, and facial abnormalities. Magnetic resonance imaging, performed to further evaluate the fetal brain, confirmed the sonographic findings. However, MRI was not useful in further differentiating the diagnosis. A 1024-g, premature male fetus was delivered at 30 weeks' gestation and died within 30 minutes of delivery. The fetus had multiple congenital anomalies consistent with Pena-Shokeir syndrome type I.

Unilateral retinoblastoma with acquired monosomy 7 and secondary acute myelomonocytic leukemia.

Patients with a nongenetic form of retinoblastoma are not particularly at high risk of developing second malignant neoplasms. We report here a case of treatment-related leukemia (secondary leukemia) with acquired monosomy 7, in a child with unilateral retinoblastoma.

Monozygotic twins with congenital acute lymphoblastic leukemia (ALL) and t(4;11)(q21;q23).

Congenital acute lymphoblastic leukemia (CALL) is a rare disorder and is frequently associated with t(4;11)(q21;q23). To our knowledge this is the first case report of monozygous twins with CALL and t(4;11)(q21;q23).

The effects of psychosine upon growth of human skin fibroblasts from patients with globoid cell leukodystrophy.

[3H]Thymidine incorporation into cultured skin fibroblasts from patients with globoid cell leukodystrophy (GLD) and from control individuals was utilized to monitor the effects of psychosine (galactosylsphingosine) upon cell replication. The concentration of psychosine necessary to inhibit 50% (ID50) of the growth of cultured skin fibroblasts was approximately 15 microgram/ml for both normal and GLD fibroblasts deficient in the enzyme galactosylceramide beta-galactosidase. Growth inhibition curves for GLD and for control fibroblasts were comparable after 3 days and after 7 days exposure to the glycolipid, so that accumulation of psychosine was not a critical factor affecting toxicity. Galactosylceramide, the major substrate for the enzyme galactosylceramide beta-galactosidase, did not inhibit [3H]thymidine incorporation into either normal or GLD fibroblasts at the concentration tested, in contrast to the highly toxic effects of psychosine at similar concentrations. The comparable inhibitory levels of psychosine in control cells and in GLD fibroblasts which are deficient in ability to hydrolyze this glycolipid suggest that the toxicity of psychosine is nonspecific. Therefore, these results are not consistent with the concept that globoid cell leukodystrophy is primarily a psychosine lipidosis.

Neonatal encephalopathy in two boys in families with recurrent Rett syndrome.

Rett syndrome (RTT) has been described in its classic form only in females. Although the majority of cases are sporadic, familial cases give valuable insight into the genetic basis and phenotypic variability of the disorder. The exclusive occurrence of classic Rett syndrome in females led to the hypothesis that the Rett syndrome locus is likely to be X-linked and mutations are lethal in hemizygous males. We identified two boys in families with recurrent Rett syndrome who had encephalopathies with neonatal onset and who may represent the phenotype of males harboring Rett syndrome mutations. The difference in severity of disease in these males and their female relatives supports the location of Rett syndrome locus on the X-chromosome.

Mitochondrial alterations in Rett syndrome.

Findings in the muscle biopsies from 2 patients with Rett syndrome are presented. Routine light microscopy and muscle histochemistry were unremarkable. Electron microscopy revealed mitochondrial alterations, including distention, vacuolation, and membranous changes. The results suggest the possibility of a mitochondrial defect in Rett syndrome.

Long-term L-carnitine treatment in isovaleric acidemia.

A 5-year-old girl with isovaleric acidemia was treated with long-term L-carnitine and no supplemental glycine. Clinical and laboratory data are presented. Following diagnosis and treatment at age 2 years, the frequency of acute exacerbations of metabolic acidosis was reduced and she resumed normal growth and development. L-carnitine supplementation and protein restriction may be sufficient for effective therapy of isovaleric acidemia.

Head-upright tilt table testing in evaluation of recurrent, unexplained syncope.

Recurrent syncope is one of the most common problems referred to the pediatric neurologist for evaluation. Traditional evaluations are time consuming and expensive, and leave 40% of patients without a precise diagnosis. Vasovagal syncope has been believed to be a common cause of syncope; however, no reliable diagnostic modality has been available to confirm this theory. Head-upright tilt table testing has recently emerged as a useful tool in the evaluation and management of recurrent, unexplained syncope. In this review, we present the pathophysiologic mechanisms of vasovagal syncope and relate them to the reflexes triggered during head-upright tilt table testing. Additionally, we review the clinical data on the uses of this test in unexplained syncope, suggest a practical testing protocol, and elaborate potential therapeutic modalities that can be employed to prevent further episodes. Head-upright tilt table testing will likely become a standard test employed by both adult and child neurologists.

Carnitine deficiency associated with ornithine transcarbamylase deficiency.

An infant with X-linked recessive ornithine transcarbamylase deficiency is described who also had severe deficiency of plasma and liver carnitine during normoammonemic periods. Treatment with L-carnitine (100 mg/kg/day) for 12 months decreased the frequency of hospitalizations for hyperammonemia, although it did not alter his neurologic status. This report demonstrates that persistent carnitine deficiency may be present in patients with ornithine transcarbamylase deficiency even when plasma ammonia is normal. Carnitine evaluation and supplementation may be important in the treatment of patients with this metabolic disorder.

Autosomal recessive neurodegenerative disorder with trichorrhexis invaginata and ectodermal dysplasia.

Two siblings are reported with an autosomal recessive syndrome characterized by hair and skin abnormalities, hypoplastic nails, generalized hypotonia, absent reflexes, and progressive neurologic deterioration. Although this disorder shares clinical features with an ectodermal dysplasia syndrome with neurodegenerative changes, no specific neuropathologic findings were present. Instead, trichorrhexis invaginata was found in some hair shafts. Hair analysis may be helpful in classifying clinically confusing neurologic conditions.

Elevated maternal serum alpha-fetoprotein values. How low is high?

Most maternal serum alpha-fetoprotein (MSAFP) screening programs are set up with the goal of prenatal detection of fetal neural tube defects. It is also commonly accepted that MSAFP testing yields many false-positive results. Screening programs commonly utilize schemata that identify abnormal levels of MSAFP as greater than 2.5 multiples of the median (MOM) and also recommend two abnormal values before initiating ultrasound evaluation. Our pilot program evaluating obstetric outcomes found that 21 of the 29 women with elevated MSAFP values (greater than 2.0 MOM) eventually developed significant pregnancy management changes or complications of pregnancy. Thus, we believe that the use of MSAFP screening solely for the purpose of detecting fetal neural tube defects is inconsequential relative to its usefulness in detecting other pregnancy abnormalities. We also believe that ultrasound evaluation should be accomplished after the first abnormal value and that the cutoff of 2.5 MOM should be lowered to at least 2.0.