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• W1966719564 abstract "To the Editor: Although the association between some chromosomal alterations and epilepsy is well known, few chromosomal abnormalities specifically associated with epilepsy are recognized by neurologists (1). We report a patient affected by a de novo apparently balanced translocation involving the long arm of chromosome 4 (4q34) and the short arm of chromosome 9 (9p22). This 10-year-old girl is the third child of nonconsanguineous, healthy parents. An older sister died at birth of unknown causes. The family history was unremarkable except for a grandmother who had rare generalized tonic–clonic seizures during adulthood. The patient was born at term after a normal pregnancy. Growth measurements at birth were normal. Developmental stages were delayed: the patient started to walk at age 14 months and started using single words at age 18 months. When she was 2 years old, she had brief nocturnal episodes of nonmotivated crying associated with extension of the upper limbs and staring, followed by loss of consciousness. Between ages 3 and 5 years, she had clusters of spasms with sudden adduction of the upper limbs and eye deviation to right. At age 7 years, the patient began to have atonic seizures without loss of consciousness. Antiepileptic drugs, used singly or in association, failed to control the epilepsy. At age 9 years, the girl was referred to our clinic. Physical examination revealed hypertelorism, bushy eyebrows, broad nasal bridge, low-set hair, short neck and extremities, abnormal dermatoglyphic pattern, clinodactyly of the fifth finger and syndactyly of the second and third fingers of both hands, syndactyly of the first three toes, diffuse hirsutism, and genu valgum (Fig. 1). She was 133 cm tall (50th–75th centile), weighed 42 kg, and had a head circumference of 50 cm (25th–50th centile). Phenotype of the patient. The patient showed hypertelorism, bushy eyebrows, broad nasal bridge, low-set hair, short neck and extremities, clinodactyly of the fifth finger and syndactyly of the second and third fingers, and diffuse hirsutism. The happy facial expression and the hand stereotypies also are shown. Neurologic examination showed a happy facial expression, clumsy, broad-based gait, intentional hand tremor, dysmetria, and hand-washing stereotypies. Routine blood and urine analyses, lactate and pyruvate levels in the serum, plasma amino acid concentrations, and lysosomal enzyme activities were normal. Interictal EEG showed continuous sharp- and slow-wave complexes on the left frontotemporal regions. With video-EEG, we recorded several brief episodes of interruption of stereotypies and of staring and unresponsiveness. Seizure onset was accompanied by irregular sharp- and slow-wave complexes preceded by a low-voltage recruiting rhythm on the same areas. The 1.5-Tesla brain magnetic resonance imaging was unremarkable, but angio sequences showed aplasia of the right internal carotid without evidence of aneurysm. Neuropsychological testing indicated mental retardation (IQ <50) with verbal language limited to only two to three words. During hospitalization, seizures were controlled with a combination of lamotrigine (LTG), topiramate (TPM), and levetiracetam (LEV). Chromosome and fluorescence in situ hybridization (FISH) analyses of all subtelomeric regions showed a de novo apparently balanced t(4;9)(q34;p22) translocation. Whole chromosome painting excluded the involvement of other chromosomes. FISH analyses with bacterial artificial chromosomes (BACs) (2) excluded deletions in both chromosomes. The breakpoint on chromosome 4 mapped in a region close to the 2-kb overlap between clone RP11–182A9, which was not involved in the translocation, and the adjacent clone RP11–11N5, whose FISH signal was restricted to the der(9) chromosome. The chromosome 9 breakpoint occurred in a region of ∼176 kb that included BAC RP11–73E6, whose FISH signal appeared in the two derivative chromosomes (Fig. 2). Fluorescence in situ hybridization (FISH) images of the bacterial artificial chromosome (BAC) clones RP11–182A9 (A), RP11–11N5 (B), and RP11–73E6 (C) on the metaphase chromosomes of the patient. The green signal on the normal chromosome 4 (A, B), as well as on the derivative chromosomes 4 (A) and 9 (B), indicates that these BACs spanned the translocation breakpoint on chromosome 4. The green signal on the normal chromosome 9 and on both derivative chromosomes (C) indicates that this BAC spanned the translocation breakpoint on chromosome 9. Sequence analysis showed that this BAC contains part of the coding sequence (exons 3 and 4) of the myeloid/lymphoid or mixed-lineage leukemia gene (MLLT3), which is consequently disrupted by the rearrangement. No genes were structurally affected on the chromosome 4 breakpoint. The sodium/potassium/calcium exchanger 2 gene (SLC24A2), located ∼500 kb telomeric to the chromosome 9 breakpoint, and the tumor-suppressor gene (FAT), located on BAC RP11–182A9, also were selected as candidate genes. A detailed analysis of the electroclinical pattern of epilepsy associated with chromosomal disorders can help to define the phenotype and to detect genes related to seizure susceptibility (3). Our patient had a de novo apparently balanced translocation involving chromosomes 4q and 9p. The epilepsy began early in life and consisted of different seizure types, although EEG always showed focal paroxysmal activity. The happy facial expression, the severe speech impairment, ataxia, and tremulous hand movements recall Angelman syndrome (4). However, this syndrome is characterized by atypical absences and myoclonic seizures, and EEG findings differ from those obtained in our patient (4). Her grandmother had rare generalized seizures during adulthood but had normal mental status and unremarkable neurologic findings. Thus we speculate that the association was a chance event. To our knowledge, the chromosomal rearrangement reported herein has not previously been associated with malformation, mental retardation, behavioral disturbances, and partial epilepsy. Several other apparently balanced translocations have been reported: t(17;20)(p13.3;q13.33) in a patient with mental retardation and multiple physical anomalies (5); t(1;22)(q24.3;q13.1) in a woman initially diagnosed with Costello syndrome (6); t(2;20)(q21.3;p12) in a two-generation family with Alagille syndrome, which is a dominantly inherited disorder affecting the liver, heart, face, eyes, and vertebrae (7); and, last, two balanced rearrangements involving chromosomes 2;7 and 5;20 in three members of a family with a dominantly inherited syndrome (microcephaly, short stature, peculiar facies, and mental retardation) (8). In our patient, the apparently balanced translocation disrupted the MLLT3 gene, on region 9p22; no other gene was affected. MLLT3 is an oncogene that encodes a serine/proline-rich protein, and it does not seem to be related to epileptogenesis. However, it would be interesting to include apparently balanced chromosome rearrangements among the cytogenetic and molecular analyses conducted in patients with dysmorphic features, developmental delay, and epilepsy, to identify genes associated with the epileptic phenotype." @default.
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• W1966719564 date "2005-08-01" @default.
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• W1966719564 title "A t(4;9)(q34;p22) Translocation Associated with Partial Epilepsy, Mental Retardation, and Dysmorphism" @default.
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