Mosaicism for GJB1 mutation causes milder Charcot-Marie-Tooth X1 phenotype in a heterozygous man than in a manifesting heterozygous woman.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous disorder of the peripheral nervous system that collectively affects approximately 1 in 2,500 individuals, thus making it the most common inherited neurologic disorder. X-linked inheritance may account for 10-20 % of CMT neuropathy. We report a Czech family with a 30-year-old woman affected by CMT since the age of 10 years, originally as an isolated case. Nerve conduction study (NCS) showed demyelinating neuropathy, and DNA testing revealed a novel heterozygous gap junction beta-1 protein (GJB1) mutation c.784_786delTA. The same mutation, but surprisingly in heterozygous state, was subsequently found in her subjectively healthy father and later also in one of her sisters but not in her two other sisters. NCS showed intermediate type of motor and sensory neuropathy in these two females manifesting heterozygotes and normal results in the other healthy sisters and one brother, all without the c.784_786delTA mutation. The father has a phenotype milder than his daughter and has only subclinical signs of CMT. The index female patient had normal karyotype 46, XX, and normal FISH for centromeric X chromosome. We concluded that the proband's father is a heterozygote due to the somatic mosaicism for the GJB1 mutation in his leukocytes (detected by DNA sequencing) and also in his germ cells as confirmed by the unexpectedly different genotypes in his four daughters. Quantitative analysis revealed a mutated signal in 25:75 allele proportion of mutated to healthy allele in the mosaic father. This study has important consequences for genetic counseling and prognosis in CMTX1 families.

[Alternating hemiplegia of childhood (AHC)]. / Alternující hemiplegie v detství--longitudinální studie.

BACKGROUND: Alternating hemiplegia of childhood (AHC) is a rare neurological disease of unknown aetiology characterized by recurrent paroxysmal attacks of side-alternating hemiplegias of variable duration associated with other paroxysmal dysfunctions. Paroxysmal attacks start in infants but neurological deficits become progressive with the age. METHODS AND RESULTS: During the last 20 years 8 patients (5 boys, 3 girls) with AHC were followed. Mean age at the time of diagnosis was 2.75 years, age range 2-5 years; mean follow up period 13.9 years (range 1 month-20 years) The diagnosis was based on clinical history and neurological findings, completed by neurophysiological and neuroimaging methods (SPECT, PET), and results of psychological and biochemical findings. Paroxysmal phenomena (occulo-motor, tonic, choreo-athetotic, autonomic) appearing at the age of 4.1 +/- 2.2 months and followed by repeated attacks of hemiplegia (age onset 16.3 +/- 13.0 months) were the first symptoms. Progressive neurological impairment covering spasticity, dyskinetic syndrome, cerebellar ataxia and intellectual deficit was present in all cases, epileptic seizures in 7 out of 8 patients. On ictal SPECT/PET examination hypoperfusion/glucose hypometabolism were demonstrated above affected hemispheres including basal ganglia, both thalami and cerebellar hemispheres. Improvement of hemiparesis was illustrated by nocturnal videomonitoring. CONCLUSIONS: AHC is a chronic disease with progressive neurological deficit. A flunarizine therapy has a favorable effect on frequency and severity of paroxysmal attacks, but does not prevent a progressive neurological impairment.

[Cardiac problems in patients with progressive muscular dystrophy]. / Kardiologická problematika u nemocných s progresivní svalovou dystrofií.

Progressive muscular dystrophy causes both skeletal and significant cardiological changes. Electrocardiographic and echocardiographic examinations were provided in 30 patients with muscular dystrophy (17 of them with progressive muscular dystrophy Duchenne type, 13 with skeletal muscular dystrophy). In 50% cases were found left ventricle filling disorder, in two cases echocardiographic signs of pulmonary hypertension. ECG showed in one third of cases incomplete right bundle branch block, supraventricular tachycardia was also frequently found.

Alternating hemiplegia in childhood: a cross-sectional study.

Six patients with alternating hemiplegia in childhood (AHC) were followed, some of them up to childhood. Progressive intellectual deterioration and disturbance of pyramidal, extrapyramidal and cerebellar functions were found in all of them. Multimodal evoked potential abnormalities, changes of sleep structure and HMPAO-SPECT results were correlated with increasing clinical handicap. In older patients increases in the plasma level of lactate, as well as in the lactate: pyruvate ratio, were revealed, accompanied by elevated inorganic phosphate (Pi) values on 31P MR spectroscopy. These findings support the hypothesis of a possible secondary mitochondrial deficit in AHC. However, no specific bioptic changes (muscle, skin, or buccal mucous membrane) were found, and thus the etiology of AHC remains unclear.

[Nonstandard therapy of epileptics and psychotics]. / Nestandardní lécba epileptiku a psychotiku.

The authors present their experience with a number of drugs which are not antiepileptics nor antipsychotic drugs but influence the cholinergic and noradrenergic system and glucose and protein metabolism of neurons. Their efficiency in severe epileptics with psychic changes is about 60%. Standard epileptic treatment, mono- and polytherapy, failed completely in these patients. To the authors' "modulating" and "nootropic" therapy applies the same what applies to stereotactic treatment of epilepsy, i.e. that treatment must be started before the epileptic or psychotic process becomes chronic. Epileptogenesis is divided into the following stages: 1. insulation of the brain and development of a lesion (trauma, asphyxia, infection), 2. A. latency, an epileptic focus develops in the lesion, 2. B. latency, secondary and tertiary epileptic foci develop, in particular in the corpus amygdaloideum, hippocampus and fronto-orbital area and from there frequently also psychic changes arise, 2. C. the focus acts also on the thalamo-cortical reverbation circle and gradually "teaches" it epileptic discharges which sometimes can be followed on the EEG, although this stage is still in the latent period, i.e. clinically inapparent. 2. D. modulating structures of the stem fail, REM, i.e. paradox sleep, diminishes. Because these stages resemble those in the development of some psychoses, the psychogenesis of this epileptogenesis is similar; in schizophrenia the deepest stage of NONREM sleep declines. In this stage of epilepsy the inhibitory protective influence of noradrenergic, serotoninergic and dopaminergic (?) systems disappears. The 3rd stage is manifestation of clinical attacks or psychotic behaviour which may be enhanced by some provocation, e.g. alcohol, sleep deprivation, psychic stress, which influence emotivity and the sleep profile. With regard to these stages (insulation, latency, manifestation) treatment should be provided. In the 1st and 2nd stage "nootropic and modulating" treatment should be administered to a greater extent.

Differences between facial configuration and development in complete and incomplete unilateral cleft lip and palate during the prepubertal period.

Mixed-longitudinal roentgencephalometric data were used for the determination of differences between the configuration and development of the face in complete and incomplete unilateral cleft lip and palate at the age of 8 to 12 years. As compared to incomplete clefts patients with complete clefts had a reduced height of the upper face and thus also of the face as a whole and an increased width of the nasal cavity. These findings were in agreement with the situation in adults, but contrary to adults we failed to disclose any difference in the depth of the maxilla and thus there were also no differences of the retrusion of the upper jaw, sagittal jaw relations, facial convexity, occlusion of incisors and the prominence of the upper lip. The thickness of the upper lip did not differ as well. The global results showed that the differences between facial configuration in these two types of clefts were much smaller up to the onset of puberty than in adults. Throughout the investigated period of time the growth and development of the investigated parameters proceeded identically in both forms of clefts. The reduction of upper face height in complete clefts confirmed an early, probably prenatal origin of this deviation from normal.

Syndrome of secondary polymyositis with leukemia.

A boy with neurofibromatosis suffered mumps at the age of 5. A full-blown juvenile polymyositis developed shortly afterwards. First hematological consultation was done for monocytosis in peripheral blood at the age of 7. He suffered varicella at the age of 8. Diagnosis of acute nonlymphocytic leukemia with monosomy 7 was done before the age of 9. The boy died at the age of 10.

Membranocystic lesion in the brain in cerebrotendinous xanthomatosis. Histochemical and ultrastructural study with evidence of its ceroid nature.

A case is described of cerebrotendinous xanthomatosis with purely neurological manifestations. Cholestanol deposition in both affected and unaffected brain regions was markedly increased, reaching 18.5-20.8% of the sterol fraction. The unilateral lesions localized in the basal ganglia and cerebellar white matter featured perivascular accumulation of foam cells containing apolar lipid and ceroid. Necrosis with lipid-rich debris was a frequent finding often accompanied by prominent collagen deposition. Within these lesions there were numerous refractile thick membranes which, according to lipid histochemical techniques, could be qualified as ceroid-type lipopigment. It is suggested that the ceroid membranes arise extracellularly directly from the lipid-rich debris. Ultrastructurally, they were composed of convolutes of highly organized trilaminar membranes about 15 nm thick similar to those seen in intracellular ceroid granules. The membranes were embedded in an amorphous substance of low or medium density and were identical in their general appearance, stainability and fine structure to the membranocystic lesion in Nasu-Hakola disease and to the extracellular ceroid in atherosclerotic plaques.

Paroxysmal hemipareses in childhood.

The authors report three patients suffering since infancy from transient attacks of paresis. The flaccid pareses most frequently affect the extremities in a hemiplegic fashion, but occasionally there is monoparesis or quadriparesis. The laterality and degree of the paresis are variable. Conciousness is always preserved, and in two cases attacks were preceded by ocular motor disturbances (skew deviation, nystagmoid jerks and conjugate deviations). Exceptionally, the transient hemiparesis may be preceded by a grand mal epileptic fit, though they are more likely to appear sporadically and independently of the paretic changes. In the interparoxysmal periods the children showed pronounced hypotonia, hyperkinetic extrapyramidal features and oligophrenia. Neuroradiological procedures have excluded brain anomalies of vascular or other aetiology and simple biochemical analyses were negative. EMG during paretic periods have revealed central motor neuron lesions, while EEG demonstrated non-specific paroxysmal features. A brain-stem dysfunction in the aetiology is postulated.