Nutritional disorders among workers in North China during national turmoil.

Previously undescribed disorders of nutrition of thiamin, niacin and pyridoxin were observed among the poor people of North China during periods of prolonged deprivation. These disorders were often elicited or exacerbated by physical exertion. Thiamin deficiency syndromes included great toe pain, heel pain, temporomandibular joint click, and painful click of the knee. Syndromes of niacin deficiency included pellagral scrotal dermatitis, hypersecretion of ear wax, and night terrors. Episodic nocturnal motor hyperfunction was caused by pyridoxin deficiency. Several cases with cardiovascular diseases were observed in which nutritional debt appeared to occur simultaneously with oxygen debt following severe physical labor. Intramuscular thiamin HCl ameliorated symptoms of impending stroke. Persons with the same symptoms who did not receive thiamin progressed to fatal stroke.

Folic acid: miscarriages, anomalies, thromboses, cancers.

Folic acid is an essential micronutrient that merits special attention. In spite of plentiful sources in a balanced diet, recent data indicate that folic acid intake of many persons has long been inadequate. To some degree, this is due to destruction of folic acid by storage and processing of foodstuffs and to dietary practices that vary from recommendations. However, the common hereditary thermolabile variant of methylenetetrahydrofolate reductase (MTHFR) imposes an increased folic acid requirement which, if not met, may result in recurrent early pregnancy loss, anomalous progeny, thrombotic disorders, and cancers. There are recent reports that folic acid metabolism is also altered by other hereditary variations of MTHFR and other enzymes involved in folic acid metabolism. Optimal management requires dietary guidance and, for many patients, folate supplements. Caution is required because mandated folate fortification of grain products may produce levels that are inadequate for some patients and excessive for others. Laboratory tests for red cell folate and serum homocysteine are valuable adjuncts.

How can genetics help in the management of obesity?

Obesity usually results from unwanted variations in metabolism. Inadequate neurotransmission, thermogenesis, or acylation underlie about 90% of cases. These are complex, weakly heritable, polygenic traits. Mutations in major gene loci cause another 5% of cases, and still another 5% of cases are due to gluttony. Careful observation can help define the type of obesity. All forms are associated with excess mortality and require lifelong episodic or continuous management. Management centers around diet, exercise, behavior therapy, and life-style counseling. Serotonin agonists and serotonin uptake inhibitors, as well as alternative therapies like phototherapy and 5-hydroxytryptophan are worthwhile for neurotransmitter inadequacy, except in children and pregnant women. When thermogenesis is inadequate, intake may be normal and weight reduction may require subnormal intake. Some degree of obesity may be required for optimal health in patients with inadequate acylation. In some Mendelian syndromes, obesity may balance a metabolic error, and weight reduction may restore metabolic imbalance.

Counseling your patient about heritable breast cancer.

The baseline frequency of breast cancer increases after age 30 from about 1% to about 10% by age 90. Breast cancer gene mutations cause much higher risks. Risks are nearly as high if two or more first-degree relatives (mother, sisters) had breast cancer when less than 50 years old. Risks are also elevated by occurrence of breast cancer at young ages in second-degree relatives (grandmothers, aunts). Certain rare syndromes are also associated with higher risks of breast cancer. Genetic testing for breast cancer gene mutations and for some of the syndromes is available but mutational heterogeneity limits its usefulness. Counseling about these aspects of breast cancer should be within the purview of any physician who manages patients who are at risk. The medical geneticist can assist in recognizing rare syndromes, identifying patients whose risks merit consideration of genetic testing or of prophylactic surgery, and in counseling in complex cases.

Genetic anticipation in a large family with pure autosomal dominant hereditary spastic paraplegia.

We have reinvestigated a large kindred identified over 25 years ago segregating for a form of pure autosomal dominant hereditary spastic paraplegia (HSP). We have examined additional relatives in order to refine the clinical and genetic characteristics of this disorder, and performed an analysis to determine if anticipation is present in this family. Analysis of onset ages in parent-to-child transmissions of HSP is consistent with anticipation. These results provide support for dynamic mutation as the underlying mechanism of this form of HSP, and suggest a trinucleotide repeat instability occurring primarily in the female germ line.

Genetics, aging, and the heart.

Heart disease remains the most frequent cause of death in the general population and is intimately related to aging. Either extreme premature aging or marked longevity may be monogenic, but in most humans aging is a complex polygenic phenomenon. Hypercholesterolemia and hypertension are important factors. Cardiac amyloidosis and vascular elastin degradation may be separate factors. Humans with the greatest longevity are relatively refractory to atherosclerosis. Frequencies of heart deaths among relatives of a heart-death proband without dyslipoproteinemia conform to expectations of a polygenic trait. Careful, attentive medical management of major environmental factors and of heart senescence can result in more successful aging.

A case of insertional translocation involving chromosomes 2 and 4.

We report on a 6-year-old Caucasian boy with direct insertion of genetic material from the short arm of chromosome 4 to the short arm of chromosome 2. He was referred for evaluation because of global developmental delay and seizure disorder. A karyotype performed at 4 1/2 months of age, by a laboratory elsewhere, reportedly showed a deletion of chromosome 4(p12). When we saw him, he had macrocephaly, hypotonia, psychomotor retardation, multiple minor congenital anomalies, and EEG abnormalities. Repeat chromosomes performed by our laboratory revealed that his karyotype was 46,XY,dir ins(2;4)(p24;p15.3p13). Fluorescence in situ hybridization (FISH) analysis, using chromosomes 2 and 4 painting probes confirmed that material from 4p has been translocated to 2p. Also, FISH analysis using the Wolf-Hirschhorn critical region probe revealed that both loci are intact. Parental chromosomes were normal. This complex rearrangement, though it appears balanced, probably might have resulted in either a structural loss of genetic material or functional loss of a gene action. Thus, his phenotype could be explained by this de novo insertion of chromosome 4 material into chromosome 2. There is no reported case of this specific chromosome rearrangement.

Heritable arrhythmias, cardiomyopathies, and valvulopathies.

Arrhythmias, cardiomyopathies, and valvulopathies are the most frequent forms of heart disease that occur during the years of peak productivity. They have interrelated pathogenetic bases and may occur in combinations. Cases in which there is involvement of other body systems are so frequent as to suggest a need for careful cardiological evaluation of any patient with dysmorphic features or an inborn error of metabolism. Recent advances in embryology and molecular genetics have increased our understanding of the heritable arrhythmias, cardiomyopathies, and valvulopathies but clinical delineation of all of them predated those developments. Symptomatology may be confusing or absent, so electrocardiogram and echocardiogram are required for diagnosis. Holter monitoring is productive if echocardiogram and electrocardiogram are not diagnostic. For some varieties of heritable arrhythmias, cardiomyopathies, and valvulopathies, other diagnostic modalities are required. Differentiation between heritable and non-heritable varieties may require testing of relatives. Members of the immediate family are most likely to be affected. For X-linked and recessive types, more extensive genealogical investigation may be required. Medical management, prognosis, and genetic counseling are highly dependent on thorough elucidation.

Nutritional disorders in a concentration camp.

OBJECTIVE: Observations on nutritional disorders were made by a physician inmate in a concentration camp before and during the Great Starvation in China. METHODS/RESULTS: Based on therapeutic response, many unique abnormalities should be considered as a part of clinical picture of malnutrition, such as mucocutaneous pigmentation, nail layering phenomena and intranail hemorrhage, palmar/plantar fissures, vegetative system crisis, a avitaminostic fevers, multiple premature beats, and enlargement of cartilage, lymph nodes, and submandibular glands. DISCUSSION: Thiamin deficiency should be also considered as one, if not the only, etiologic factor of several common disorders, including submandibular gland cyst, Baker's cyst, stenosing tenosynovitis, direct inguinal hernia, among others.

Evaluation of relatives for congenital heart defects.

Current and developing knowledge of mechanisms underlying the embryological development of congenital heart defects strongly suggests that medical evaluation should be extended to relatives of patients. Relatives may be found to have either subclinical or significant heart defects of specific forms that are phylogenetically related to the disorder of the index case. Discovery of the disorder in relatives allows better medical management and lends accuracy to assessment of the risk of congenital heart defects in future progeny of relatives.

Metabolic screening.

The time-honored concept of utilization of the laboratory for screening for metabolic diseases has taken on new meaning in the face of the extensive heterogeneity of genetic diseases that has been revealed by DNA research. Some of the conditions for which screening was used in the past are now known to produce physically identifiable features so more definitive tests may be utilized for them. There remains a set of diseases that are difficult to characterize physically and it is for these that screening tests are most needed. Initial screening procedures for most of them are available in most general hospitals but comprehensive screening is usually done in biochemical genetics laboratories. Numerous and somewhat arcane bedside screening tests have been replaced by a short list of more modern procedures which are much more accurate and reliable.

Genetically controlled enzymatic variation in a southern, biracial, semi-rural community: the Bogalusa heart study.

Caucasian and Afro-American schoolchildren participating in a community-based cardiovascular screening program in Bogalusa, Louisiana are characterized with respect to phenotypic and allelic frequencies at 10 enzymatic and 3 nonenzymatic polymorphic loci. Biracial gene frequencies in Bogalusa are compared with those reported for other populations of similar ethnic composition. Intra- and interracial genetic distances within and between the racial subpopulations of Bogalusa and Seattle, Washington are compared. While the comparisons do not support the concept that northern, urban blacks have more Caucasian admixture than blacks residing in the rural South, they do suggest microdifferentiation of the two white populations.

Brief clinical report: a sixth report (eighth case) of craniosynostosis-radial aplasia (Baller-Gerold) syndrome.

We report a patient with craniosynostosis, radial aplasia, imperforate anus, and several associated congenital anomalies. It is concluded that she has the Baller-Gerold syndrome. Parenteral consanguinity supports the suggestion that this condition is inherited in an autosomal recessive manner.