Biotinidase deficiency is the primary defect in most individuals with late-onset multiple carboxylase deficiency. We have reviewed the presenting clinical features of 31 children with the disorder. Seizures, either alone or with other neurological or cutaneous findings, are the most frequent initial symptom observed. Other neurological symptoms, such as hypotonia, ataxia, hearing loss, optic atrophy, and developmental delay, are seen, in addition to skin rash and alopecia. The disorder is also characterized by ketolactic acidosis and organic aciduria. Biotinidase activity may be diagnosed using a simple, rapid, semiquantitative colorimetric procedure. Samples of whole blood spotted on the same filter paper used by most states to screen for phenylketonuria and other inborn errors of metabolism may be sent to an appropriate reference laboratory. None of the common anticonvulsants or sedatives used to treat newborns and children interfere with the test. Because biotinidase deficiency can be treated readily with biotin, this disorder should be considered in children with infantile seizures, especially in the presence of other characteristic neurological or cutaneous features.

Using the Collaborative Study on the Genetics of Alcoholism (COGA) data, we performed a sib-pair linkage analysis of two smoking-related traits and one alcoholism phenotype. The first trait, EVRNVR, was a dichotomous one we constructed based on epidemiological definitions of smoking. The second trait, PKYRS, used the quantitative pack-year history provided, and the third trait was the COGA alcoholism classification, ALDX1. There was some evidence for linkage of the EVRNVR trait to regions on chromosomes 6, 9, and 14. Smaller numbers of loci provided nominal evidence for linkage to PKYRS, although some candidate gene regions were identified. The number of loci identified using EVRNVR suggests that a threshold-based phenotype may better identify loci affecting smoking history. Approximately one-third of the loci that showed evidence for linkage to EVRNVR at a nominal significance level (p < 0.01) also showed evidence for linkage to ALDX1. Some of these regions may represent loci increasing vulnerability to both smoking and alcoholism.

Juvenile myoclonic epilepsy (JME) is a generalized, non-progressive epilepsy characterized by an adolescent onset of sudden, involuntary myoclonic jerks. Greenberg et al. (American Journal of Medical Genetics 31:185-192, 1988b; Cytogenetics and Cell Genetics 51:1008, 1989b) reported tight linkage of a JME locus to the HLA region of chromosome 6p. We confirm this linkage assignment, although at a larger recombination fraction than previously reported. Twenty-three, mostly nuclear, families were ascertained through a JME proband. The affected status of relatives of the probands was assigned by 4 different clinical criteria, and separate analyses were done assuming an autosomal dominant model with 90% penetrance and an autosomal recessive model with full penetrance. A linear age-of-onset correction with maximum penetrance at age 20 years was incorporated into the analyses. The maximum lod score obtained was 3.11 at (-)m = 0.001, (-)f = 0.20, assuming autosomal dominant inheritance and using the second definition of the disease phenotype. There was strong support for linkage using the other phenotype definitions and the autosomal dominant model, although the lod scores did not exceed 3.0. There was also support for linkage of a JME locus to this region under the autosomal recessive model, although the results varied depending upon the definition of the disease phenotype. There was no significant evidence for linkage heterogeneity.

No abstract

Idiopathic generalized epilepsies, i.e., juvenile myoclonic epilepsy (JME), childhood absence epilepsy, and epilepsy with grand mal [generalized tonic-clonic seizures (GTCS)], are the most common genetic epilepsies. Linkage studies using Bf, HLA serologic, and DNA markers by three independent investigators, one from Los Angeles and two from Berlin, have localized the JME locus to the short arm of chromosome 6 (6p). Because members of the same JME family have the same JME phenotype of childhood absence epilepsy, epilepsy with grand mal (GTCS) seizures, or early childhood myoclonic epilepsy (ECME), our observations give evidence for a single-locus etiology in 6p for JME and for at least some of the childhood absence seizures, epilepsy with grand mal (GTCS) seizures, and ECME. Studies should now address whether locus heterogeneity exists within childhood absence epilepsy, epilepsy with grand mal (GTCS) seizures, or ECME. Markers linked to JME (Bf, HLA serologic, and DNA markers in the DQ region) can be used to resolve etiologic heterogeneity. Using such markers, both linked and unlinked forms of phenotypes that are clinically indistinguishable may be detected and provide evidence for etiologic heterogeneity. Studies should also concentrate on narrowing the JME locus to 2 to 3 cm by screening families with recombinant events using RFLPs, candidate genes, and new expressed sequences on chromosome 6.

No abstract

Four children with biotinidase deficiency were identified during the first year of a neonatal screening program for this disease in the Commonwealth of Virginia. Two unrelated probands were identified among the 81,243 newborn infants who were screened. In addition, two siblings of one of these infants were found to be affected. Both probands had mild neurologic symptoms at two and four months, respectively, and the two older children had more severe neurologic abnormalities, cutaneous findings, and developmental delay at two and three years of age. However, none of the affected children had acute metabolic decompensation. Previous studies have shown that the administration of biotin to affected children can be a lifesaving procedure that can reverse acute symptoms and prevent irreversible neurologic damage. Our findings demonstrate that subtle neurologic abnormalities may appear as early as at two months of age and that developmental abnormalities may occur even in the absence of episodes of overt metabolic decompensation. Since screening and treatment are both inexpensive and effective and the incidence of the disease is well within the range of that of other metabolic diseases for which screening is performed, biotinidase deficiency should be added to the group of metabolic diseases for which screening is done in the neonatal period.

Untreated cultures from normal chorionic villus (CV) or amniotic fluid-derived (AF) samples displayed dramatic cell passage-dependent increases in aberrations in the juxtacentromeric heterochromatin of chromosomes 1 or 16 (1qh or 16qh). They showed negligible levels of chromosomal aberrations in primary culture and no other consistent chromosomal abnormality at any passage. By passage 8 or 9, 82 ± 7% of the CV metaphases from all eight studied samples exhibited 1qh or 16qh decondensation and 25 ± 16% had rearrangements in these regions. All six analyzed late-passage AF cultures displayed this regional decondensation and recombination in 54 ± 16 and 3 ± 3% of the metaphases, respectively. Late-passage skin fibroblasts did not show these aberrations. The chromosomal anomalies resembled those diagnostic for the ICF syndrome (immunodeficiency, centromeric region instability, and facial anomalies). ICF patients have constitutive hypomethylation at satellite 2 DNA (Sat2) in 1qh and 16qh, generally as the result of mutations in the DNA methyltransferase gene DNMT3B. At early and late passages, CV DNA was hypomethylated and AF DNA was hypermethylated both globally and at Sat2. DNMT1, DNMT3A, or DNMT3B RNA levels did not differ significantly between CV and AF cultures or late and early passages. The high degree of methylation of Sat2 in late-passage AF cells indicates that hypomethylation of this repeat is not necessary for 1qh decondensation. Sat2 hypomethylation may nonetheless favor 1qh and 16qh anomalies because CV cultures, with their Sat2 hypomethylation, displayed 1qh and 16qh decondensation and rearrangements at significantly lower passage numbers than did AF cultures. Also, CV cultures had much higher ratios of ICF-like rearrangements to heterochromatin decondensation in chromosomes 1 and 16. These cultures may serve as models to help elucidate the biological consequences of cancer-associated satellite DNA hypomethylation.