Joseph Hayek

A randomized trial of oral betamethasone to reduce ataxia symptoms in ataxia telangiectasia.

No controlled studies exist regarding the pharmaceutical reduction of ataxia symptoms in ataxia telangiectasia (A‐T). In a multicenter, double‐blind, randomized, placebo‐controlled crossover trial, oral betamethasone (BETA) and placebo were compared in terms of their reduction of ataxia symptoms as assessed with the International Cooperative Ataxia Rating Scale (ICARS). In this study of 13 A‐T children, betamethasone reduced the ICARS total score by a median of 13 points in the intent‐to‐treat population and 16 points in the per‐protocol population (ie, median percent decreases of ataxia symptoms of 28% and 31%, respectively). In conclusion, Oral betamethasone could be a promising therapy to relieve ataxia symptoms in A‐T patients; however, long‐term effectiveness and safety must be established. (Current Controlled Trials, number ISRCTN08774933.)

Widening the Mutation Spectrum of EVC and EVC2: Ectopic Expression of Weyer Variants in NIH 3T3 Fibroblasts Disrupts Hedgehog Signaling

Autosomal recessive Ellis‐van Creveld syndrome and autosomal dominant Weyer acrodental dysostosis are allelic conditions caused by mutations in EVC or EVC2. We performed a mutation screening study in 36 EvC cases and 3 cases of Weyer acrodental dysostosis, and identified pathogenic changes either in EVC or in EVC2 in all cases. We detected 40 independent EVC/EVC2 mutations of which 29 were novel changes in Ellis‐van Creveld cases and 2 were novel mutations identified in Weyer pedigrees. Of interest one EvC patient had a T>G nucleotide substitution in intron 7 of EVC (c.940−150T>G), which creates a new donor splice site and results in the inclusion of a new exon. The T>G substitution is at nucleotide +5 of the novel 5′ splice site. The three Weyer mutations occurred in the final exon of EVC2 (exon 22), suggesting that specific residues encoded by this exon are a key part of the protein. Using murine versions of EVC2 exon 22 mutations we demonstrate that the expression of a Weyer variant, but not the expression of a truncated protein that mimics an Ellis‐van Creveld syndrome mutation, impairs Hedgehog signal transduction in NIH 3T3 cells in keeping with its dominant effect. Hum Mutat 30:1–9, 2009.

Magnesium profile in autism.

The aim of the present study was to determine and compare plasma and erythrocyte concentrations of magnesium in 12 autistic children (10 boys, 2 girls), 17 children with other autistic spectrum disorders (14 boys, 3 girls), 5 girls with classic Rett syndrome, and 14 normal children (7 boys, 7 girls) of the same age. No differences in intracellular Mg were found between controls and pathological subjects; however, autistic children and children with other autistic spectrum disorders had significantly lower plasma concentrations of Mg than normal subjects (p=0.013 and p=0.02, respectively). Although our study population was small, we conclude that children with autistic spectrum disorders require special dietary management. If these cases are diagnosed at an early stage, they can be helped through diet.

Long-term plasma levels of leptin and adiponectin in Rett syndrome.

Objective  Rett syndrome is a progressive neurological disorder affecting almost exclusively females after age 6 months and characterised by acquired microcephaly, psychomotor retardation, growth failure, purposeless hand movements, autistic‐like behaviour and wide‐based and stiff legged gait. Leptin and adiponectin, peptides secreted by adipose tissue, are involved in the regulation of body weight and energy expenditure.

Variations of plasma leptin and adiponectin levels in autistic patients.

Autism is a neurodevelopmental disorder with pathogenesis not completely understood. Although a genetic origin has been recognized, it has been hypothesized a role for environmental factors, immune dysfunctions, and alterations of neurotransmitter systems. In young autistic patients we investigated plasma leptin and adiponectin levels over a year period. Thirty-five patients, mean age at the basal time 14.1+/-5.4 years, were enrolled. Controls were 35 healthy subjects, sex and age matched. Blood samples were withdrawn in the morning at the baseline and 1 year after. In patients leptin concentrations significantly increased, while adiponectin did not significantly change. Leptin values in patients were significantly higher than those found in controls at each time; adiponectin values did not differ at each time between patients and controls. Since patients were not obese, we could hypothesize that leptin might participate to clinical manifestations other than weight balance. The role of adiponectin in autism is still debatable.

Guanidinoacetate methyltransferase (GAMT) deficiency diagnosed by proton NMR spectroscopy of body fluids

In patients with guanidinoacetate methyltransferase (GAMT) deficiency several parameters may point towards the diagnosis of GAMT deficiency. These include the low levels of creatine and creatinine in urine, the high concentration of guanidinoacetic acid (GAA) in urine and the low levels of creatine and creatinine in the cerebrospinal fluid (CSF). In this study, body fluids from 10 GAMT deficient patients were analysed using 1H NMR spectroscopy. The urine 1D 1H NMR spectra of all the patients showed a doublet resonance at 3.98 ppm (pH 2.50) derived from GAA present in high concentration. For this compound, a good recovery and good correlation was found between an LC‐MS/MS method and 1H NMR spectroscopy. In CSF NMR spectra of these patients, the singlet resonances of creatine and creatinine (3.05 and 3.13 ppm, respectively) were absent (normally always present in 1H NMR spectra of CSF). Due to overlap by other resonances, the doublet of GAA could not be observed. Our data demonstrate that 1H NMR spectroscopy of urine and CSF can be used to diagnose patients with GAMT deficiency. Copyright

EEG features and epilepsy in MECP2-mutated patients with the Zappella variant of Rett syndrome

OBJECTIVE To assess the presence/absence of peculiar EEG features and epilepsy in MECP2-mutated Rett patients with the Zappella-Rett variant (Z-RTT) also known as preserved speech variant. METHODS Retrospective analysis of 16 (age 19.4+/-8.4years; range 8-38years) MECP2 mutated Z-RTT cases, including 11 high or intermediate performance (HIP), and five low-performance (LP) patients was performed. Peculiar EEG features were analyzed as a function of the HIP or LP Z-RTT categories: (1) centro-temporal spikes, (2) multifocal EEG activity, (3) EEG encephalopathy (i.e. multifocal EEG activity associated with the presence of background slowing and diffuse slow activity), (4) spindles and K-complex. Furthermore, we assessed the occurrence of epilepsy. Correlations between electroclinical features and category of Z-RTT genotype (missense or truncation mutation) were also tested. RESULTS The Z-RTT HIP group showed a very abnormal EEG (presence of centro-temporal spikes: p=0.004808), although the cases studied were not epileptogenic and did not develop encephalopathy. The LP group showed multifocal EEG activity (p=0.000229), EEG encephalopathy (p=0.000229) and epilepsy (p=0.299451). No significant differences between the prevalence of centro-temporal spikes, multifocal EEG activity, EEG encephalopathy, and epilepsy between the patients with the truncation or missense mutation were observed. CONCLUSIONS EEG electrophysiological patterns and epileptogenic susceptibility differ in Z-RTT according to the level of performance (i.e. HIP or LP). SIGNIFICANCE These results indicate that HIP and LP Z-RTT should be considered as distinct entities, not only on a clinical basis, but also as it concerns EEG features and epileptogenic susceptibility. These results could offer support in the practical management of patients and family counseling.

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.

Polydactyly With Ectodermal Defect, Osteopenia, and Mental Delay

Five members from 3 generations, including a 35-year-old woman and her 2 sons, both mentally impaired to a different degree, were studied in a tertiary care hospital. Anamnestic, clinical, neurological, and radiological evaluations were used to describe phenotypes. A and B postaxial polydactyly, transmitted likely as autosomal dominant, was associated with an extensive variability of phenotypic features: (1) cutaneous syndactyly, (2) nail–teeth dysplasia, (3) osteopenia, and (4) mental delay. The likelihood that the constellation of observations we report here is caused by mutation of a single gene that subsequently affects multiple physiological activities, although fascinating, remains to be proven. Instead, we hypothesize that it likely develops as a contiguous gene syndrome.

Silent increase of urinary ethylmalonic acid is an indicator of nonspecific brain dysfunction.

Our aim was to compare urinary ethylmalonic acid (EMA) levels in subjects who had no apparent clinical reason to have increased levels of this substance but were suffering from non‐specific CNS impairment, and healthy controls. Urinary EMA concentrations detected by 1H‐NMR spectroscopy were studied in 130 subjects with CNS impairment of unknown origin (with no definite diagnosis, no specific symptoms or signs, and normal common biochemical and metabolic screening results) and 130 age‐ and sex‐matched healthy subjects. EMA levels exceeding two standard deviations (SD) above normal (i.e. 8.1 mmol/molCn) were found in a subgroup of CNS‐impaired patients and healthy controls. EMA levels exceeding 2 SD above normal were fourfold prevalent in the urine of patients with non‐specific CNS impairment compared to from the EMA levels in healthy controls. Moreover, we found that the level exceeding > 8.1 mmol/molCn (i.e. > + 2 SD) had sufficient discrimination accuracy in identifying subjects with non‐specific CNS impairment; the level exceeding 12 mmol/molCn (i.e. > + 6 SD) reaches suitable accuracy (i.e. 100% specificity and 78.6% sensitivity). These observations are of importance, as we found that subtle increases in urinary EMA levels are frequent in patients with non‐specific CNS impairment. The reasons for this association remain unknown. Copyright