James V. Higgins

Clinical phenotype associated with terminal 2q37 deletion

Three children with deletions of the terminal portion of the long arm of chomosome 2 [del (2) (q37)] are described and their clinical findings compared to published cases of 2q terminal deletions. Common clinical findings include development delay, macrocephaly, frontal bossing, depressed nasal bridge and cardiac anomaly. Hypotonia and repetitive behavior are also seen during different times of development. The facial characteristics of children with 2q terminal deletions are not uniform, but development delay is a constant finding. Chromosomal analysis of such children using high resolution banding may uncover the diagnosis of a small chromosomal deletion.

Alpha-ketoadipic aciduria: a description of a new metabolic error in lysine-tryptophan degradation.

Extract: Our studies of a mentally retarded male with extremely elevated levels of α-aminoadipic acid and α-ketoadipic acid in his urine have led to the description of a new metabolic defect, α-ketoadipic aciduria. Analysis of the urine and serum from the patients family revealed that the patient (KW) had a mentally and physically normal sister (CW) with the same metabolites elevated, but the rest of the family appeared normal.Speculation: The presence of elevated levels of α-ketoadipate in the urine of the reported sibs suggests a reduced level of α-ketoadipic acid dehydrogenase. This enzyme has not been purified in humans, but is considered to be α-ketoglutaric acid dehydrogenase in several nonhuman animals. We are presenting evidence that would suggest that in humans these may be separate enzymes, or that more than one form of the α-ketoglutaric acid dehydrogenase exists.

Clinical aspects of the MASA syndrome in a large family, including expressing females

We have evaluated, both clinically and by linkage analysis, a large family with 22 known affected males with the MASA syndrome (McKusick 303300). Clinical findings varied widely amongst the affected family members, with some appearing initially to have the MASA syndrome and others to have X‐linked hydrocephalus (HSAS) (McKusick 307000). Important findings included the presence of adducted thumbs in two obligate carriers, learning problems or mild mental retardation in three females, two of whom were obligate carriers, and hydrocephalus with neonatal death in three females born to obligate carriers. X‐inactivation analysis in lymphocytes from the two women with adducted thumbs revealed preferential inactivation of one X chromosome, suggesting that nonrandom X‐inactivation may be responsible for clinical expression in females. The presence of HSAS in some individuals of this family and the MASA syndrome in others further supports the hypothesis that these two conditions are the result of a mutation in the same gene.

Partial tetrasomy 9 in a liveborn infant

An unusual rearrangement of chromosome 9 was identified in a male infant with multiple congenital malformations. The rearrangement appeared as a fusion of two number 9 chromosomes with similar long‐arm breakpoints. Since the infant also possessed two normal 9s, the presence of the additional chromosome resulted in partial tetrasomy: 47,XY, + tdic(9;9)(q22;q22). Clinical and autopsy examinations revealed many features reminiscent of trisomy 13.

Acute Lymphoblastic Leukemia with a Unique Rearrangement Between Chromosomes 4 and 11

A case of pre-B cell acute lymphoblastic leukemia (pre-B ALL) with a dir ins(11;4)(q23;q21q31) chromosome rearrangement is presented. The patients clinical findings and history were similar to those described for the t(4;11)(q21;q23) subgroup of childhood ALL. These findings suggest that the interfacing of the distal breakpoint at band 4q21 to the proximal breakpoint of band 11q23 represents the primary cytogenetic change observed in this subgroup of ALL.

Metabolism of alpha-aminoadipic and alpha-ketoadipic acids: Studies using rat and beef liver, and human leukocytes

The reported studies have shown that alpha-DL-amino [1-14C]adipic acid is metabolized to radioactive alpha-ketoadipic acid and then to 14CO2 in rat and beef liver homogenates. It was also demonstrated that alpha-keto [1-14C]adipic acid is decarboxylated to 14CO2. The effects of several co-factors and other variables, i.e. alpha-ketoglutarate, pyridoxal phosphate, NAD, thiamine pyrophosphate (TPP), FAD, LA, and pH have also been delimited. These reactions and the effects of the co-factors were also established in freshly drawn leukocytes. Using the methods outlined, a technique for studying the metabolism of alpha-amino-adipate and alpha-ketoadipate in the leukocytes from 10 ml of blood was developed.

Omphalocele in half‐siblings

A family is described in which half‐siblings, a boy and a girl born to unrelated mothers and a phenotypically normal father, were affected with omphalocele. The suggested mode of transmission remains unclear. Prenatal diagnosis to detect an affected fetus should be offered to relatives of omphalocele‐affected individuals.

Detection of Mosaicism in amniotic fluid cultures: A CYT02000 collaborative study

Purpose: To evaluate the assumptions on which the American College of Medical Genetics (ACMG) Standards and Guidelines for detecting mosaicism in amniotic fluid cultures are based.Methods: Data from 653 cases of amniotic fluid mosaicism were collected from 26 laboratories. A chi-square goodness-of-fit test was used to compare the observed number of mosaic cases with the expected number based on binomial distribution theory.Results: Comparison of observed data from the in situ colony cases with the expected distribution of cases detected based on the binomial distribution did not reveal a significant difference (P = 0.525).Conclusions: The empirical data fit the binomial distribution. Therefore, binomial theory can be used as an initial discussion point for determining whether ACMG Standards and Guidelines are adequate for detecting mosaicism.

Amniocentesis use and risk awareness: Comparison of knowledge and beliefs among older Gravida

Abstract A secondary analysis of public‐health survey data collected from 298 women, age 40 or older, delivering a live‐bom child in Michigan distinguished four respondent groups: those exposed to medical advice about amniocentesis and their decision about the procedure (Medically‐informed Tested vs. Medically‐informed Untested) and those unexposed to medical advice who reported being either aware or unaware of the procedure (Medically‐uninformed Aware vs. Medically‐uninformed Unaware). The two medically‐informed groups differed in their estimates of risk for Down syndrome (DS), risk of test injury to the fetus, and aversion to the risk of birth defects. A regression analysis determined that perceived risk for DS due to maternal age best distinguished between the two groups. The tested women differed from the other three groups on several sociodemographic variables. The discussion draws from the Health Belief Model to identify strategies for creating a risk awareness in the target population.

Fine mapping of X-linked clasped thumb and mental retardation (MASA syndrome) in Xq28

The MASA syndrome is an X‐linked disorder with mental retardation, spastic paraparesis, and adducted thumbs as the most characteristic features. We performed linkage analysis, using Xq28 markers, on a large MASA syndrome family. The maximum lodscore was 6.37 at 0 recombination for DXS52 and 5.99 at 0 recombination for DXS305. Crossovers were demonstrated between the disorder and DXS455. Clinical and linkage data from this family further support the hypothesis that the MASA syndrome and X‐linked hydrocephalus are allelic disorders.