[Autism: a diagnostic dilemma]. / Autizm: diagnosticheskaya dilemma.

In the last decades autism diagnosis has shown great differences in prevalence studies, apparently related to methods applied in the evaluation of children with relational and\or communicative difficulties. In the present study a literature evaluation is conducted, suggesting the advantages of an extensive and accurate clinical evaluation of the child with his family, possibly supported by tests like CARS, convergent with this approach and, in contrast, risks related to the use of semi-structured tests. Some of the last-mentioned tests have been considered, decades ago, as `golden standard' for diagnosis, but this was probably an unfortunate illusion, which may have favoured many inappropriate diagnoses. The history of the concept of autism is described, split between the suggestion of dealing with `one' condition and, alternatively, with a behaviour related to different syndromes and disorders. Various examples on positive evolution of this condition are reported, supporting the view of autism as an abnormal behaviour, usually comorbid with other conditions, in some cases curable and amenable to correction up to the removal of the diagnosis.

Rett syndrome: a wide clinical and autonomic picture.

BACKGROUND: Rett Syndrome is a neurodevelopmental disorder almost exclusively affecting females, characterized by a broad clinical spectrum of signs and symptoms and a peculiar course. The disease affects different body systems: nervous, muscolo-skeletal, gastro-enteric. Moreover, part of the symptoms are related to the involvement of the autonomic nervous system. In the Tuscany Rett Center at Versilia Hospital, we collected data from 151 subjects with a clinical diagnosis of classical or variant RTT syndrome. For each subject, we assessed the severity of the condition with clinical-rating scales (ISS, PBZ), we quantified the performance of the autonomic nervous system, and we performed genetic analysis. We used multivariate statistical analysis of the data to evaluate the relation between the different clinical RTT forms, the cardiorespiratory phenotype, the different genetic mutations and the severity of the clinical picture. Individuals were classified according to existing forms: Classical RTT and three atypical RTT: Z-RTT, Hanefeld, Congenital. A correlation between C-Terminal deletions and lower severity of the clinical manifestations was evident, in the previous literature, but, considering the analysis of autonomic behaviour, the original classification can be enriched with a more accurate subdivision of Rett subgroups, which may be useful for early diagnosis. RESULTS: Present data emphasize some differences, not entirely described in the literature, among RTT variants. In our cohort the Z-RTT variant cases show clinical features (communication, growth, epilepsy and development), well documented by specific ISS items, less severe, if compared to classical RTT and show autonomic disorders, previously not reported in the literature. In this form epilepsy is rarely present. In contrast, Hanefeld variant shows the constant presence of epilepsy which has an earlier onset In Hanefeld variant the frequency of apneas was rare and, among the cardiorespiratory phenotypes, the feeble type is lacking. CONCLUSION: A quantitative analysis of the different autonomic components reveals differences across typical and atypical forms of RTT that leads to a more accurate classification of the groups. In our cohort of RTT individuals, the inclusion of autonomic parameter in the classification leads to an improved diagnosis at earlier stages of development.

Diagnostic criteria for the Zappella variant of Rett syndrome (the preserved speech variant).

The preserved speech variant is the milder form of Rett syndrome: affected girls show the same stages of this condition and by the second half of the first decade are making slow progress in manual and verbal abilities. They walk without help, and may be able to make simple drawings and write a few words. Most of them can speak in sentences. Autistic behavior can often be observed. We previously described several cases in the pre-molecular era and subsequently reported a survey of 12 cases with MECP2 mutations. Seventeen new patients with the preserved speech variant and a proven MECP2 mutation have been clinically evaluated. Additional clinical data of our previously described cases are reported. These 29 preserved speech variant cases were compared with 129 classic Rett patients using a clinical severity score system including 22 different signs. There was both statistical and clinical evidence of the existence of this variant. On the basis of their abilities these girls can be distinguished as low-, intermediate- and high-functioning. Girls of the last two groups show a greater homogeneity: they speak in sentences, use their hands more easily, have normal somatic features, mild neurovegetative abnormalities, with autistic behavior in 76%, epilepsy in 30%, while girls of the first group are closer to classic Rett syndrome. The majority of patients carries either missense mutations (especially the p.R133C change) or late truncating mutations in the MECP2 gene. These results confirm the existence of this variant of Rett syndrome (Zappella variant), a clear example of progress of manual and verbal abilities, and not of a "preserved speech" and suggest corresponding diagnostic criteria.

Rett syndrome and plasma leptin levels.

OBJECTIVE: To describe in patients with Rett syndrome (classic and preserved-speech variant) plasma leptin levels and their relationship to BMI (body mass index) and age. STUDY DESIGN: Female patients (n = 48; age range 3-20 years) affected by classic Rett syndrome were enrolled into the study. Eleven female patients, age range 3 to 20 years, with preserved-speech variant Rett syndrome were included in the study. Controls were 24 healthy female subjects, age range 3 to 20 years. Blood samples (3 mL) were withdrawn from an antecubital vein in the morning; plasma leptin concentrations were detected by enzyme-linked immunosorbent assay method. RESULTS: Patients with classic Rett syndrome and preserved-speech variant had leptin values significantly higher than controls. Leptin concentrations did not significantly differ between patients with classic Rett and preserved-speech variant. Leptin values positively correlated with age and BMI. CONCLUSIONS: Because in all patients the increased leptin concentrations were not associated to obesity, we hypothesize that in patients with Rett syndrome leptin might participate to clinical manifestations other than weight balance.

Neurocutaneous syndrome with mental delay, autism, blockage in intracellular vescicular trafficking and melanosome defects.

We evaluated a 11-year-old male patient with mental delay, autism and brownish and whitish skin spots. The former resembled those of neurofibromatosis, the latter those of tuberous sclerosis. The patient received a complete clinical work-up to exclude neurofibromatosis, tuberous sclerosis, or any other known neurocutaneous disease, with biochemistry, chromosome analysis and analysis of skin specimens. Being all the other tests not significant, two main ultrastructural defects were observed. The first was a blockage in intracellular vescicular trafficking with sparing of the mitochondria; the second an aberrant presence of melanosomes in vacuoles of several cell lines and abnormal transfer of these organelles to keratinocytes. This patient presented with a unique clinical picture distinct from neurofibromatosis or tuberous sclerosis or any other known neurocutaneous disease. The ultrastructural abnormalities suggested a defect in cell trafficking involving several cell lines and compartments.

Effects of acetyl-L-carnitine on cardiac dysautonomia in Rett syndrome: prevention of sudden death?

There is a higher incidence of sudden death in patients with Rett syndrome than individuals in the general population. Previous studies have implicated cardiac dysautonomia and a long QT interval as causative factors. Because carnitine plays a critical role in cellular metabolism and may have beneficial effects on cardiac and nerve function, we investigated the effects of long-term treatment with acetyl-L-carnitine on heart rate variability and electrocardiographic abnormalities in 10 girls with Rett syndrome and compared the results with 12 control patients (girls with Rett syndrome who were not treated). The age range of the subjects was 2-21 years. The study design called for the evaluation of heart rate variability, corrected QT interval, and QTc dispersion. In the 10 Rett girls treated with acetyl-L-carnitine, a significant increase in heart rate variability was observed. To explain these results, we hypothesize that acetyl-L-carnitine has a neurotrophic action on the cardiac autonomic nervous system. This effect may reduce the risk of sudden death in patients with this syndrome.

CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms.

BACKGROUND: Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterised by a wide spectrum of clinical manifestations. Both the classic form and preserved speech variant of Rett syndrome are due to mutations in the MECP2 gene. Several other variants of Rett syndrome have been described. In 1985, Hanefeld described a variant with the early appearance of convulsions. In this variant, the normal perinatal period is soon followed by the appearance of seizures, usually infantile spasms. We have observed two patients with signs of Rett syndrome showing acquired microcephaly and stereotypic midline hand movements. The disease started with generalised convulsions and myoclonic fits at 1.5 months in the first patient and with spasms at 10 days in the other, suggesting a diagnosis of the Hanefeld variant. In these patients, MECP2 point mutations and gross rearrangements were excluded by denaturing high performance liquid chromatography and real time quantitative PCR. The ARX and CDKL5 genes have been associated with West syndrome (infantile spasms, hypsarrhythmia, and mental retardation). METHODS: Based on the clinical overlap between the Hanefeld variant and West syndrome, we analysed ARX and CDKL5 in the two girls. RESULTS: We found frameshift deletions in CDKL5 in both patients; one in exon 5 (c.163_166delGAAA) and the other in exon 18 (c.2635_2636delCT). CDKL5 was then analysed in 19 classic Rett and 15 preserved speech variant patients, all MECP2 negative, but no mutations were found. CONCLUSION: Our results show that CDKL5 is responsible for a rare variant of Rett syndrome characterised by early development of convulsions, usually of the spasm type.

Germline mosaicism in Rett syndrome identified by prenatal diagnosis.

Rett syndrome is an X-linked neurodevelopmental dominant disorder that affects almost exclusively girls. The vast majority of cases are sporadic and are caused by de novo mutations in the MECP2 gene, located in Xq28. Only few familial cases have been reported: in four cases, the mother was an asymptomatic carrier and in other four cases, the germline mosaicism in the mother was postulated. Owing to the above reported cases of germline mosaicism, we decided to offer prenatal diagnosis to all expectant mothers with a Rett daughter despite the absence of the causative mutation in parents' blood. We describe here the outcome of the first nine cases of prenatal diagnosis followed by our center. In eight cases, the fetus did not carry the mutation. In one case, the female fetus did carry the same mutation of the affected sister. The couple decided to interrupt the pregnancy and to devolve fetal tissues for research purposes. Our results indicate that prenatal diagnosis should be proposed to all couples with a Rett daughter, even when the mutation is apparently de novo. Moreover, one positive prenatal test among the first nine cases indicates that germline mosaicism may be seriously considered for the assessment of recurrence risk during genetic counseling.

Cardiac dysautonomia and serotonin plasma levels in Rett syndrome.

BACKGROUND: In Rett syndrome the autonomic nervous system is abnormal at various levels, from the central to the peripheral nervous system. A role for serotoninergic dysfunction has been suggested. OBJECTIVES: The aim of our study was to evaluate the relation between cardiac dysautonomia (expressed by means of heart rate variability) and plasma serotonin levels in girls affected with Rett syndrome. Heart rate variability and plasma serotonin levels were evaluated in 28 Rett girls aged 1-14 years. A Pearson correlation was used to determine whether there was a relationship between plasma serotonin levels and each heart rate variability parameter. RESULTS: In untreated Rett girls the plasma serotonin levels correlated with the sympathovagal balance, as expressed by the low frequency (LF) to high frequency (HF) ratio (p<0.05). CONCLUSIONS: Our results suggest that cardiac dysautonomia could be linked to serotoninergic dysfunction and that treatment with a serotonin analogue could be useful in improving the sympathovagal balance.

Nerve growth factor plasma levels and ventricular repolarization in Rett syndrome.

Rett syndrome is a severe neurological developmental disorder. In this syndrome, the high incidence of sudden death is correlated with an alteration of ventricular repolarization. The purpose of this study was to evaluate plasmatic levels of nerve growth factor (NGF) in Rett patients with prolonged corrected QT (QTc) interval in comparison with those of Rett patients with normal QTc. We observed 23 female Rett patients (9.9+/-4.7 years). NGF plasma levels and QTc interval were measured in all patients. Student t-test was performed for statistical analysis. NGF plasma levels were significantly lower in Rett patients with QTc interval prolongation (QTc > 0.44 sec) in comparison with Rett patients with a normal QTc interval (4.5+/-4.5 vs 11+/-8.3 pg/ml, p = 0.02). The alteration of NGF levels, observed in Rett patients with a long QTc interval, may explain the presence of an altered ventricular repolarization associated with a higher risk of cardiac arrhythmias.

Chromosome 2 deletion encompassing the MAP2 gene in a patient with autism and Rett-like features.

We present here a unique case of a 14-year-old female with autism and some features similar to Rett syndrome (RTT). Genetic analysis demonstrated a large deletion of chromosome 2q instead of a MECP2 mutation. Like a Rett patient, she is dyspraxic and shows frequent hand-washing stereotypic activities, hyperpnea, and bruxism. Like a preserved speech variant (PSV) of RTT, she is obese, able to speak in second and third persons, frequently echolalic, and has final normal head circumference and autistic behavior. In addition, she has dysmorphic features such as down-slanting palpebral fissures, low set ears without lobuli, bilateral flat feet, and bilateral syndactyly of the second and third toes, which do not belong to the Rett spectrum. She has a de novo chromosomal deletion in 2q34 of paternal origin. Gene content analysis of the deleted region showed the presence of 47 genes (14 putative and 33 known genes). This region contains some interesting genes such as ADAM23/MDC3, CREB1, KLF7, and MAP2. Because alteration of neuronal maturation, dendritic anomalies, and a decrease in MAP2 immunoreactivity in white matter neurons are well documented in RTT patients, we propose MAP2 gene as a good candidate for the generation of PSV phenotype in this case.

18q-syndrome and ectodermal dysplasia syndrome: description of a child and his family.

The 18q- syndrome [MIM #601808] is a terminal deletion of the long arm of chromosome 18. The most common deletion extends from region q21 to qter. We report here a nine-year-old boy possessing a simple 18q- deletion who had abnormalities of the brain, skull, face, tooth, hair, bone, and skin, plus joint laxity, tongue palsy, subtle sensoneural deafness, mental and speech delay, attention deficit hyperactivity disorder (ADHD), tic, and restless legs syndromes. His karyotype was 46, XY, del (18)(q21.31-qter). The size of the deletion was approximately 45 cM. Most of these abnormalities were not explained by the 18q- deletion. The family pedigree suggested the presence of a subtle involvement of ectodermal and/or mesodermal structures. Karyotypes of the other family members were normal.

Septo-optic dysplasia with digital anomalies associated with maternal multidrug abuse during pregnancy.

We describe a 16-year-old female affected by septo-optic dysplasia (SOD) with digital anomalies as additional feature. This rare developmental anomaly of midline brain structures can result from different pathogenetical events, including mutations of the homeo box gene HESX1, recently suggested as the etiological cause at least in a subset of patients. The absence of mutational involvement of this gene in our patient led us to consider, in alternative terms of pathogenesis, the maternal multidrug abuse occurring during pregnancy. Our report, in accord with previous experimental evidences, points out that illicit drug use might have played a causative role in brain development anomalies, thus our patient could represent an additional case of birth defects caused by a prenatal toxic exposure. The neurologic abnormalities and the clinical history of the patient are extensively reviewed. The need to include the SOD phenotype amongst the possible teratogenic effects of multidrug abuse is evidenced.

Early-onset Tourette syndrome with reversible autistic behaviour: a dysmaturational disorder.

Early-onset Tourette syndrome comorbid with reversible autistic behaviour is described in twelve young males. After a normal gestation, delivery and first-year development, regression set in between the age of one and two with loss of various abilities and the emergence of autistic behaviour. At this time, or slightly later, they showed multiple motor and vocal tics, simple and complex: the latter could also be traced to most of their parents. Following an intervention based on intense cuddling, motor activation and paedagogic guidance, these children's abilities rapidly improved, reaching at follow-up a normal or borderline intellectual functioning and with the disappearance of their initial autistic behaviour. At follow-up tics were present in all, usually with the features of a full-blown Tourette syndrome, often comorbid with ADHD, and in some cases with OCD.

MECP2 gene mutation analysis in the British and Italian Rett Syndrome patients: hot spot map of the most recurrent mutations and bioinformatic analysis of a new MECP2 conserved region.

Rett syndrome (RTT) is an X-linked dominant neurological disorder, which appears to be the most common genetic cause of profound combined intellectual and physical disability in Caucasian females. This syndrome has been associated with mutations of the MECP2 gene, a transcriptional repressor of unknown target genes. We report a detailed mutational analysis of a large cohort of RTT patients from the UK and Italy. This study has permitted us to produce a hot spot map of the mutations identified. Bioinformatic analysis of the mutations, taking advantage of structural and evolutionary data, leads us to postulate the existence of a new functional domain in the MeCP2 protein, conserved among brain-specific regulatory factors.

Preserved speech variants of the Rett syndrome: molecular and clinical analysis.

Mutations in the MECP2 gene cause the severe neurodevelopmental disorder called Rett syndrome. Preliminary evidence suggests that MECP2 may be involved in a broader phenotype than classical Rett syndrome including preserved speech variants (PSV). Here we report clinical and mutation analysis of 18 PSV patients. Ten of them had a MECP2 mutation (55%). The clinical features of these girls have been characterized and two subgroups defined. All of them had slow recovery of verbal and praxic abilities, evident autistic behavior, and normal head circumference. Six were overweight, often obese, had kyphosis, coarse face, and mental age of two-to-three years, and were able to speak in sentences; four had normal weight, mental age not beyond one-to-two years, and spoke in single words and two-word phrases. The course of the disorder was in stages as in classic Rett syndrome. Hand-washing was present in the first years of life but often subsequently disappeared. Significantly, all mutations found in PSV are either missense or late truncating mutations. In particular, we did not find the four early truncating hot spots: R168X, R255X, R270X, R294X. These results suggest that early truncating mutations lead to a poor prognosis (classic Rett), while late truncating and missense mutations lead either to classic Rett or PSV. We hypothesize that a missense or late truncating mutation is necessary but not sufficient to produce a PSV, based on the presence of one (or more) modifier genes whose product may interact in a epistatic manner with MeCP2 protein.

Possible case of Pitt-Hopkins syndrome in sibs.

In this article, we describe two sibs, a brother and sister, with severe mental retardation and multiple congenital anomalies including "coarse" facial features, short stature, seizures, hypertrichosis, short great toes, and overbreathing. Comparison of these patients with previous reports suggests that they could represent the first familial cases of the Pitt-Hopkins syndrome. The recurrence in sibs within the same family supports autosomal recessive inheritance for the condition. Variable expression of the respiratory symptoms, which has not been reported earlier, is underlined.

Progressive cardiac dysautonomia observed in patients affected by classic Rett syndrome and not in the preserved speech variant.

Incidence of sudden death in Rett syndrome is greater than that of the general population, and cardiac electrical instability is a prime suspect cause. The objective of the present study was the evaluation of heart rate variability, a marker of autonomic activity, in females affected by classic Rett syndrome and atypical variants for a possible explanation of the higher risk for sudden death observed in these subjects. Our study showed that girls with classic Rett syndrome had significantly lower heart rate variability and longer corrected QT intervals than in atypical Rett syndrome and age-matched healthy girls. Reduction of heart rate variability progresses with age and with the clinical stage of the syndrome. These results suggest the possible role of the progressive cardiac dysfunction in the sudden death associated with Rett syndrome.

Additional case of Marden-Walker syndrome: support for the autosomal-recessive inheritance adn refinement of phenotype in a surviving patient.

In this report, we present a 14-year-old girl, born to consanguineous parents, who presented with severe mental retardation, hypotonia, short stature, and congenital joint contractures. The craniofacial features were scaphocephaly, thin/long and immobile face, marked hypoplasia of the midface, temporal narrowness, blepharophimosis, palpebral ptosis, and strabismus. The combination of such a distinctive craniofacial appearance and psychomotor retardation allows us to recognize a new case of the Marden-Walker syndrome. Our patient represents one of the rare cases in which consanguineous mating supports the autosomal-recessive pattern of inheritance of this condition. Furthermore, through refining the phenotype of a surviving patient, this report may contribute to a better recognition of this disorder in older affected children.