Down syndrome: MR quantification of brain structures and comparison with normal control subjects.

For quantification of brain structures from MR scans, a novel, powerful stereologic tool known as Cavalieri's principle was applied. This tool enables an objective estimation of volume. The method was applied to detect differences in various brain structures between persons with Down syndrome and control subjects. On the basis of absolute values, smaller volumes for the whole brain, cerebral cortex, white matter, and cerebellum were seen in persons with Down syndrome. Similar results were observed when a normalization procedure, based on the volume of cranial cavity, was used. Stereologic determinations of the volumes of brain structures from MR images can reliably identify volume differences between persons with Down syndrome and control subjects.

Peripheral nerve involvement in the Rett syndrome.

Clinical and neurophysiological studies were performed on 4 girls aged 9 to 19 years with the Rett syndrome (RS) (stages II and III). In addition to constant foot deformity (pes planus) and brisk tendon reflexes in the lower limbs, they showed muscular atrophy of the calves and mild atrophy of the extensor digitorum brevis muscle. Motor NCVs were within normal values for age, but distal latencies in two girls and compound action potential in one were abnormal, suggesting mild distal, predominantly motor neuropathy. The upper limbs showed nothing abnormal except for mild hand deformities. Neuropathology in 2 autopsy cases (aged 11 and 17 years, stage IV) and sural nerve biopsies in three girls aged 2, 3 and 17 years, all clinical stage II-III without inanition, revealed mild distal axonopathy without demyelination. Selected axons in sural nerve of a girl aged 17 and in the dental pulp of a girl aged 9, both at clinical stage II, showed increased numbers of neurofilaments. Skeletal muscle in two girls aged 11 and 17 years (both stage IV) exhibited mild alterations in the sarcoplasmic reticulum with occasional disordered myofibrils and tubular structures in the Z-filaments, but no neurogenic atrophy or abnormal mitochondria. The reported data do not support spinal denervation (motor neuron degeneration) in RS, but suggest late onset denervation due to mild distal axonopathy of hitherto unknown origin.

A review of the Rett syndrome with a theory of autism.

In a review of results of clinical observations, girls from 2:03 (yrs:mos) at stages III and IV of the Rett syndrome (RS) and autistic children from 4:01 with or without severe mental retardation were compared as to their behavioral traits. Signs of concordance between the extremely low mental, affective and motor developmental levels, such as in the expression of the eyes, are a prominent feature of RS, whereas signs of higher cortical functions that are in contrast with insufficient relations to objects, people and space are a prominent characteristic in autism. It is argued that insistence on sameness, avoidance of social stimuli and self-injurious stereotypies of autistic children are neurotic reactions based on their insufficient object relations. On the basis of the clinical findings a theory is proposed, according to which there exists a system for involuntary contributions to the affective engagement in perception, which is insufficiently developed in autism and in earlier stages of RS. Regarding its structure and function, it is analogous to the phylogenetically old extrapyramidal system and its necessary involuntary emotional contributions to all voluntary movements and postures.

Glycosphingolipids in patients with the Rett syndrome.

We have pursued two blind studies on the plasma glycosphingolipids in patients with the Rett syndrome (RS), other disorders and normal individuals from Baltimore, USA, Vienna, Austria, and Rostock, East Germany. We found the presence of an unusual glycosphingolipid in 70% of patients with RS. Approximately 10% of the plasma from patients with other developmental disorders also contained this glycosphingolipid. However, this glycosphingolipid was absent from the plasma of normal individuals and lipid storage disorders. Further work in this area will be necessary to associate the relevance of this finding to RS.

[Assessing refraction in children with cerebral damage]. / Zur Refraktionsbestimmung zerebralgeschädigter Kinder.

In children with brain damage or multiple disabilities ophthalmological care may involve a variety of problems if it extends beyond mere diagnosis. Above all, difficulties can occur if a patient does not tolerate a trial spectacle frame and/or trial glasses in front of his/her eyes, so that it is impossible to perform retinoscopy in the usual way. If refraction has to be measured as a prerequisite for further treatment (in cases of squint, anisometropia etc.), close range retinoscopy and other modified refraction methods may be useful. The potential and limitations of these methods are described on the basis of the patient collective of a special outpatient department for children with brain damage.

Autism and Rett syndrome: behavioural investigations and differential diagnosis.

The most common wrong diagnosis of children with Rett syndrome has been the infantile autistic syndrome, and it is probable that this false diagnosis continues to be made in many places. This paper is a follow-up to the authors' previous study concerning differential diagnosis between the two syndromes and is based on the observation of 63 patients over the age of 22 months in 10 stimulus situations. In Rett syndrome there were very small individual differences in the sensorimotor performances, which correspond only to the third and fourth stages of Piaget's 'sensorimotor intelligence' scale. There were pronounced individual differences in the levels of basic motor development and, independently from these, in autistic behavioural traits. When the children's behaviour was examined in detail, it became evident that girls with Rett syndrome differ in many subtle ways from those with the autistic syndrome. Behaviour observed in some cases of Rett syndrome but in none of the autistic syndrome included: social (non-autistic) behaviour; no chewing, at most sucking of items of food placed in the mouth; monotonous 'hand-washing' movements with arms flexed in front of chest or chin. In all cases of Rett syndrome but in only some of the autistic syndrome there were: no 'social defence reactions' nor 'primary self-injuring activities'; some form of ataxia and a very restricted repertoire of postures and movements, monotonous in form and speed; and the time spent looking at objects and people was at least as long as the time taken to manipulate objects. Some causes of the characteristic stereotypic hand movements observed in Rett syndrome are also suggested.

Reduced concentrations and increased metabolism of biogenic amines in a single case of Rett-syndrome: a postmortem brain study.

Preliminary data of a postmortem brain study in a single case with Rett-syndrome compared to a single control case show a severe reduction of dopamine (DA), noradrenaline (NA), and serotonin (5-HT) in most regions studied and in two regions of adrenaline (A). A marked increase in the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA, homovanillic acid (HVA)/DA, and the 5-hydroxyindole acetic acid (5-HIAA)/5-HT ratios indicates increased metabolism of DA and 5-HT. Also a marked reduction of 3H-spiroperidol-binding in putamen was found. This agrees with the assumption that a defect in maturation processes of central monoaminergic systems could be an underlying cause of Rett-syndrome.

Reduced concentrations of ascorbic acid and glutathione in a single case of Rett syndrome: a postmortem brain study.

Preliminary data of a postmortem brain study in a single case with Rett syndrome compared to a single control case showed a severe reduction of ascorbic acid and reduced glutathione in most brain regions studied. These findings suggest a secondary disturbance of ascorbic acid and glutathione metabolism in the Rett syndrome.

Shift to righthandedness in Rett syndrome around age 7.

This paper confirms Nomura's finding (Nomura et al, 1984) that almost all of those children with Rett syndrome under 7 who grasp objects are lefthanded. It is suggested that the lefthandedness in Rett syndrome up to age 7 comes from a functional lateralization of the cerebral hemispheres similar to that which Birkmayer and Rett proposed for normal infants up to age 1 (Birkmayer and Rett, 1954). However, examination of children over 7 showed that almost all of those patients who grasp objects prefer the right hand and show symptoms of disturbance of the functions of the pyramidal tract that are more pronounced in the left than in the right upper limb. It is suggested that in connection with the severe developmental retardation of the CNS in Rett syndrome the right shift factor of handedness (Annett, 1981) has a belated manifestation. Within the framework of a regression of the CNS there occurs a regression which is more pronounced in the right cerebral hemisphere than in the left.

Rett syndrome and the electroencephalogram.

The EEG is almost always abnormal in patients with Rett syndrome. This is demonstrated in a study based upon 230 EEG records obtained from 44 patients. Rhythmical slowing (mostly 3-5/sec) represents the most common EEG abnormality (30 patients). Diffuse, scattered or bilateral-synchronous spikes or sharp waves were found in 22 patients. Slow spike-wave complexes were present in 9 patients. With advancing age, the EEG abnormalities tend to decline and ill-defined low voltage records may develop. These changes may parallel an intrinsic disease course with an early active phase followed by a phase of residual impairment.

Positron emission tomographic study of D2 dopamine receptor binding and CSF biogenic amine metabolites in Rett syndrome.

We report on the first positron emission tomographic study of dopamine receptor binding in Rett syndrome. The patient is a 25 year old Austrian woman diagnosed at age 2 and followed since then by Rett. A computed axial tomogram (CT scan) showed cortical atrophy, and enlarged ventricles but normal structure of the caudate/putamen. Following the CT scan 20 mCi of 11 C N-methyl spiperone, a butyrophenone with a high affinity for dopamine D2 receptors was administered intravenously. The patient was found to have dopamine D2 receptor binding activity in the low normal range. The caudate/cerebellar activity ratio was below the mean regression line (p = 0.10) that relates the CA/CB ratio as a function of age. Levels of cerebrospinal fluid neurotransmitter metabolites were normal.

Rett syndrome. History and general overview.

The syndrome under discussion probably has a much longer history than we know. The first description of 20 years ago noted only the similarities of behavior and neurological, psychological, and social symptoms of the affected patients. The publication by B Hagberg in the US drew world-wide attention to the syndrome. Since the development of the child proceeds unremarkably during the first year of life parents find it particularly difficult to understand and to cope with the subsequent arrest of motor, language and intellectual development. The present lack of a causally effective treatment does not relieve us from the task to do all we can to preserve existing capabilities and functions. Experience tells us that the gaze of the affected children, which seems very intense and is accompanied by hypomimia or amimia, is the focus of any possibility for social contact. Parents often report on their visual contact with the child which should spur greater efforts to work on that phenomenon.

Preliminary brain autopsy findings in progredient Rett syndrome.

Postmortem human brain analyses have been performed to further evaluate pathogenetic aspects of the Rett syndrome. While there are no significant abnormalities with respect to amino acid concentrations in putamen, caudate nucleus, red nucleus and thalamus, the concentration of kynurenine is increased in putamen, caudate nucleus, gl. pallidus, raphe and amygdaloid n. In contrast, serotonin and its metabolite 5-hydroxyindole acetic acid are below normal levels. D2-receptor number is decreased and there is a significant drop in the concentration of the iron-binding protein ferritin. It can be concluded, that reduction of D2-receptors is due to loss of cholinergic and GABA-ergic cell bodies in the striatum or may be a response to iron deficiency. Low serotonergic and high kynurenergic activity may be of pathogenetic importance in the frequently observed cerebral seizures in Rett syndrome.

Biotin and Rett syndrome.

A protein load with an ensuing 20 hr fast was performed to assess the function of biotin dependent carboxylases in 3 girls with Rett syndrome. In plasma a moderate increase of ammonia and propionate was found. The fact that these discrete biochemical alterations were found in all of the patients supports earlier conclusions that further studies on biotin metabolism and carboxylase function should be performed, perhaps preferably in cerebrospinal fluid.

Rett syndrome--natural history in 70 cases.

We evaluated, at our institute, 70 females with Rett syndrome between 2 1/2 to 34 1/2 years old. This provided an opportunity of observing the natural history of this condition. The evolution of a subacute encephalopathy of very early onset, maximizing in the second year of life, with slow recovery and devastating sequelae, was recognized. The hyperorality, visual auditory and tactile agnosia with aphasia and seizures resembled symptoms described in human Kluver Bucy syndrome. Over interpretation of behavioral abnormalities as seizures was common. Scoliosis was not a necessary concomitant of age. A consistent biochemical or neurophysiological abnormality was not detectable in understanding the cause and pathogenesis of this disease process. Life span appears to be unaffected though life tables have not yet been established.

[Ophthalmological symptoms of infantile cerebral palsy]. / Ophthalmologische Symptome bei infantiler Zerebralparese.

136 patients with infantile cerebral palsy (C.P.) aged between 9 months and 24 years were examined in a special ophthalmology clinic for disabled children. 56% revealed strabismus, which was accompanied by variation in the concomitant squint angle and/or nystagmus in over two thirds of the cases. Strabismus divergens is over 3 times more frequent than in normally developed children. Strabismus in C.P. is more or less independent of the stage of refraction. There is no connection between the different types of C.P. and the various forms of strabismus. 6% of the cerebral paretic children showed gaze palsy combined with nystagmus on attempting to look down.

Hepatitis A and B in non-institutionalized mentally retarded patients.

The high incidence of hepatitis A and B in institutionalized patients with Down's syndrome is not fully understood. Under poor hygienic conditions immunological alterations might predispose to these infections. To minimize environmental influences, 125 patients with Down's syndrome (mean age 11.9 years) living at home with their families were studied for the occurrence of serological markers of Hepatitis A and B. 106 outpatients with mental retardation of other genesis (mean age 12.4 years), and 114 consecutive voluntary blood donors (mean age 18.0 years) from the same area served as controls. Evidence of previous hepatitis A virus infection was found in 5.6% of Down's patients, in 9.4% of other mentally retarded patients, and in 16.7% of healthy controls. Evidence of previous or ongoing hepatitis B virus infection was a common finding in both groups of mental retardation (Down's syndrome 20.0%, other mentally retarded patients 11.3%) in sharp contrast to healthy blood donors (0.9%, p less than 0.05). Patients with Down's syndrome, however, revealed a much higher incidence of HBs-antigenemia as compared with other mentally retarded patients (12.8% vs. 2.8%, p less than 0.01). All HBs antigen-positive cases had normal transaminase levels and no overt clinical signs of liver disease, suggesting an asymptomatic carrier state. These data indicate that hepatitis A is not a special risk for mentally retarded outpatients, while hepatitis B virus infection is hyperendemic even in not-institutionalized patients.(ABSTRACT TRUNCATED AT 250 WORDS)