Bilateral periventricular nodular heterotopia and lissencephaly in an infant with unbalanced t(12;17)(q24.31; p13.3) translocation.

Periventricular nodular heterotopia and Miller-Dieker syndrome are two different disorders of brain development. Miller-Dieker syndrome exhibits classical lissencephaly and is related to defects in the lissencephaly gene (LIS1). Periventricular nodular heterotopia is characterized by aggregates of grey matter adjacent to the lateral ventricle and is mainly linked to mutations in the Filamin A (FLNA) gene. We describe a male infant presenting with facial dysmorphisms resembling those of Miller-Dieker syndrome, neuromotor delay, and drug - resistant infantile spasms. Magnetic resonance imaging of the brain showed periventricular nodular heterotopia overlaid by classical lissencephaly with complete agyria. Cytogenetic and molecular investigations detected a maternally inherited unbalanced translocation involving chromosome arms 17p and 12q. This resulted in partial monosomy of 17p13.3-->pter and partial trisomy of 12q24.3-->qter. No mutation was found in the FLNA gene. The patient died at the age of 22 months from respiratory insufficiency during an infection of the lower respiratory tract. Our observation extends the list of the overlying cortical malformations associated with periventricular nodular heterotopia. It remains to be established whether this peculiar neuronal migration disorder represents a phenotype totally linked to 17q13.3 deletion or results from a combination of gene defects at 17q13.3 and 12q24.3.

Epilepsy and electroencephalographic anomalies in chromosome 2 aberrations. A review.

UNLABELLED: Epilepsy and electroencephalographic (EEG) anomalies are common in subjects carrying chromosomal aberrations. We report clinical and EEG investigations on 13 patients carrying chromosome 2 anomalies, including two patients with inversions, six with translocations, two with partial duplications and three with interstitial deletion syndromes. Epilepsy and/or EEG anomalies were found in one patient with a chromosome 2 translocation, in both of those carrying partial duplications and in all three with interstitial deletion syndromes. No epilepsy or EEG anomalies were detected in the remaining patients. CONCLUSIONS: Epilepsy may be associated with chromosome 2 aberrations. Gross rearrangements involving the long arm of chromosome 2 might be more often associated with epilepsy than those involving the short arm. The association of epilepsy with chromosome 2 duplications is less clear. In particular, our observations and a review of the literature appear to suggest that a strict relationship between epilepsy and interstitial deletions involving the 2q24-q31 region. In the latter disorder tonic and focal seizures occur early in life. Generalized and focal myoclonic jerks tend to appear in infancy and are subsequently followed by seizures mixed in type. Seizures usually persist up to late childhood and are drug resistant. Further studies are necessary to better define the electroclinical patterns of patients carrying deletions in 2q24-q31. These may help to direct systematic study of this--probably underestimated--cause of severe epilepsy.

Familial robertsonian 13;14 translocation with mental retardation and epilepsy.

Familial reports of a robertsonian translocation in more than two generations are rare. We report three generations (a daughter, the mother, and the mother's father) with a heterozygous, balanced robertsonian translocation t(13;14)(q11;q11). Central nervous system disease was present, but differentially expressed, in generations I and III. The daughter presented with mental delay and epilepsy, and the mother was apparently healthy, whereas the mother's father was again symptomatic, with borderline intelligence. Fluorescent in situ hybridization analysis was performed to exclude a loss or gain of chromosomal material. No uniparental disomy was present. We concluded that genetic counseling in the presence of this rearrangement was extremely difficult, independent of the affected parent being symptomatic or asymptomatic.

Photoparoxysmal responses in children with chromosomal aberrations.

Electroencephalographic (EEG) anomalies and epilepsy are commonly observed in the clinical picture of patients with chromosomal aberrations. However, no investigations have been performed on the relationship between chromosomal disorders and photoparoxysmal response (PPR). In this study, we evaluate the characteristics of PPRs elicited with intermittent photic stimulation during a routine electroencephalogram in children affected by chromosomal anomalies and correlated this with the clinical profile of the child. A review of the literature has also been performed. PPRs occurred in 14% (4/28) of patients. PPRs were brief (

Global developmental delay, osteopenia and ectodermal defect: a new syndrome.

UNLABELLED: Global developmental delay is a serious social problem. It is often unrecognized and the phenotypes are inadequately studied. To investigate the phenotypes of children with aspecific central nervous system (CNS) impairment (poor speech, maladaptive behavioral symptoms such as temper tantrums, aggressiveness, poor concentration and attention, impulsiveness, and mental retardation). SETTING: Tertiary care hospital. PATIENTS: Three children (two male siblings, and one unrelated girl). METHODS: We used the results from clinical neurological evaluations; imaging and electrodiagnostic studies; metabolic and genetic tests; skin biopsies and bone mineral densitometry. All three children suffered from (A) global developmental delay, (B) osteopenia, and (C) identical skin defects. The skin ultrastructural abnormalities were abnormal keratin differentiation, consisting of hyperkeratosis and granular layer thickening; sweat gland abnormalities, consisting of focal, cytoplasmic clear changes in eccrine secretory cells; and melanocyte abnormalities, with both morphological changes (reduced number and size without evident dendritic processes), and functional changes (defects in the migration of melanosomes in the keratinocytes). These patients present a previously unrecognized syndrome. We retain useful to report this new association, to be recognized, in the next future, as a specific key-sign of a well-defined genetic defect.

Epilepsy and electroencephalographic findings in pericentric inversion of chromosome 12.

Epilepsy, together with mental retardation, represents a common manifestation of chromosomal aberrations. Specific electroencephalographic (EEG) and epileptic patterns have been described in several chromosomal disorders, such as Angelman's syndrome, Miller-Dieker syndrome, Wolf-Hirschhorn syndrome, and ring 20 syndrome. A peculiar electroclinical pattern has also been identified in trisomy 12p syndrome. We report three patients with a pericentric inversion of chromosome 12, with breakpoints localized to p11-q13 and affected by epilepsy or EEG anomalies. Two suffered from epilepsy, which, in the clinical course, was mainly characterized by complex partial seizures with a semiology related to the temporal lobe. In one patient, myoclonic absences, head drop, and massive jerky attacks were also present. In both patients, generalized 3 Hz bursts were registered, together with multifocal and focal paroxysmal activity, which were most prominent in the temporoparietal and temporal areas, respectively. In the other patient, who had no epilepsy, EEG showed bioccipital paroxysmal activity. In all patients, the clinical picture was characterized by the presence of moderate mental retardation and behavioral disorders. The incidence of epilepsy or EEG anomalies among patients with a pericentric inversion of chromosome 12 remains to be ascertained. However, the present study confirms that chromosome 12 anomalies can be associated with epilepsy. Although myoclonic absence-like episodes can occasionally be part of the epileptic phenotype, the electroclinical pattern in pericentric inversion of chromosome 12 seems to be more polymorphic when compared with that observed in trisomy 12p syndrome.

Electroencephalographic and epileptic patterns in X chromosome anomalies.

Although epilepsy and mental retardation are commonly observed in individuals with chromosomal aberrations, the identification of EEG/epileptic profiles in those with specific chromosome anomalies remains difficult. A few syndromes seem to show peculiar clinical and EEG associations. The authors report an electroclinical investigation on a group of patients carrying X chromosome anomalies: 16 patients with Turner's syndrome, 17 with Klinefelter's syndrome, 1 with an X-autosomal rearrangement, 2 with Xq isochromosome [Xq(i)], and 7 with triple X syndrome. Epilepsy and/or EEG anomalies were found in three of the patients with Klinefelter's syndrome, in one patient with an X-autosomal rearrangement, and in five of those with triple X syndrome. No epilepsy or EEG anomalies were detected in the other patients. Epilepsy may be associated with Klinefelter's syndrome. In addition, the authors found that an electroclinical pattern, represented by paroxysmal activity in the posterior regions (temporo-parieto-occipital areas) with complex partial seizures and easily controlled by antiepileptic drugs, may be present in patients with triple X syndrome. In contrast, gross X-autosomal rearrangements are associated with polymorphic EEG/epileptic findings. Although further studies are needed to validate these observations, they clearly confirm the strict relationship between X chromosome anomalies and epilepsy.

De novo complete trisomy 5p: clinical and neuroradiological findings.

Partial or complete duplication of 5p is a rare chromosomal abnormality in which genotype-phenotype correlation studies are hampered by other commonly associated chromosomal abnormalities. We report on a new patient in whom a complete de novo trisomy 5p in all metaphases represented the only chromosomal aberration. The present case further contributes to delineate the typical clinical picture of the trisomy 5p syndrome. Long-term clinical follow-up demonstrated low levels of secretory immunoglobulin A (IgA) on several occasions and likely related to the patient's recurrent respiratory infections (RRIs), a main clinical feature of the trisomy 5p syndrome. An extensive neuroradiological study detected a progressive triventricular hydrocephalus during the fist year of life with subsequent stabilization. Neuronal migration disorders were also present and probably account for the drug-resistant epilepsy presented by the patient.

Hereditary neuronal intranuclear inclusion disease with autonomic failure and cerebellar degeneration.

BACKGROUND: Neuronal intranuclear inclusion disease (NIID), a multiple-system degeneration, occurs usually as a sporadic disorder with onset in childhood. The disease has been found in monozygotic twins and in siblings. In 2 previously described families, the disorder has affected 2 generations. OBJECTIVE: To investigate the clinical, anatomical, and electrophysiological characteristics of NIID that affect the central nervous system and the central and peripheral components of the autonomic nervous system in 2 successive generations of a family. DESIGN: Case report. SETTING: Tertiary care hospital. PATIENTS: A 53-year old woman and her sons, aged 28 and 25 years. Symptoms began in childhood in 2 of the 3 cases, and consisted of urinary and fecal incontinence, erectile dysfunction in the men, and recurrent orthostatic hypotension. METHODS: We used results of clinical neurological evaluations; cranial magnetic resonance imaging; skeletal muscle and sphincter electromyography (EMG); peripheral nerve conduction and bulbocavernosus reflex studies; autonomic function tests; brainstem, visual, somatosensory, and motor evoked potentials; auditory and vestibular testing; metabolic and molecular genetic testing; and muscle and rectal biopsy with immunohistochemistry. RESULTS: We found variable degrees of ocular dysmetria in 2 cases, ataxic dysarthria and limb ataxia in 1, and hyperreflexia in 2. Magnetic resonance imaging revealed cerebellar atrophy in all 3 cases and diffuse cerebral cortical atrophy in 1. Results of peripheral nerve conduction studies were normal. Sphincter EMG findings were abnormal in 2 of the 3 cases, and results of autonomic function tests were abnormal in the same 2. The EMG in 1 case revealed a chronic neurogenic pattern in the distal limb muscles. Metabolic and molecular genetic testing revealed no abnormal findings. Results of the muscle biopsy were negative, but results of the rectal biopsy revealed eosinophilic ubiquitinated intranuclear inclusions in neurons. CONCLUSION: Transmission of NIID in 2 generations presenting with autonomic failure and cerebellar ataxia was hereditary.