Cognitive, adaptive, and behavioral features in Joubert syndrome.

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive cerebellar and brainstem malformation recognizable on brain imaging, the so-called molar tooth sign. The full spectrum of cognitive and behavioral phenotypes typical of JS is still far from being elucidated. The aim of this multicentric study was to define the clinical phenotype and neurobehavioral features of a large cohort of subjects with a neuroradiologically confirmed diagnosis of JS. Fifty-four patients aged 10 months to 29 years were enrolled. Each patient underwent a neurological evaluation as well as psychiatric and neuropsychological assessments. Global cognitive functioning was remarkably variable with Full IQ/General Quotient ranging from 32 to 129. Communication skills appeared relatively preserved with respect to both Daily Living and Socialization abilities. The motor domain was the area of greatest vulnerability, with a negative impact on personal care, social, and academic skills. Most children did not show maladaptive behaviors consistent with a psychiatric diagnosis but approximately 40% of them presented emotional and behavioral problems. We conclude that intellectual disability remains a hallmark but cannot be considered a mandatory diagnostic criterion of JS. Despite the high variability in the phenotypic spectrum and the extent of multiorgan involvement, nearly one quarter of JS patients had a favorable long-term outcome with borderline cognitive deficit or even normal cognition. Most of JS population also showed relatively preserved communication skills and overall discrete behavioral functioning in everyday life, independently from the presence and/or level of intellectual disability. © 2016 Wiley Periodicals, Inc.

Pediatric Hashimoto's encephalopathy with peripheral nervous system involvement.

Hashimoto encephalopathy is a syndrome of encephalopathy associated with elevated concentration of circulating serum anti-thyroid antibodies usually responsive to steroid therapy. We report a 13-year-old girl with Hashimoto encephalopathy and peripheral nervous system involvement. The child had experienced high-grade pyrexia, global headache and sleeplessness. After admission she had an ileus with a distended urinary bladder, hallucinations and cognitive impairment. She had reduced deep tendon reflexes and distal sensory deficiency. Anti-thyroglobulin antibodies were raised at 2121 IU/mL (normal, 0-40) and the anti-thyroperoxidase was high at 886 IU/mL (normal, 0-50). Progressive neurological and psychiatric remission was noted after i.v. methylprednisolone. Follow-up magnetic resonance imaging showed complete resolution of the foci of signal abnormality previously yielded. This case report is the first, to the best of our knowledge, to describe peripheral nervous system involvement in a child with a diagnosis of Hashimoto's encephalopathy.

Role of plasma homocysteine levels and MTHFR polymorphisms on IQ scores in children and young adults with epilepsy treated with antiepileptic drugs.

Homocysteine (Hcy) is a sulfur-containing amino acid involved in methionine metabolism. High plasma total Hcy (tHcy) has been quite frequently reported in patients with epilepsy treated with antiepileptic drugs (AEDs) mainly related to plasma folate reduction induced by AEDs themselves. The role of C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene (MTHFR) on the increase of plasma tHcy in patients with epilepsy taking AEDs is still controversial. Cognitive impairment may be associated with epilepsy either as the result of the epileptic syndrome per se or as a side effect induced by the AEDs. High plasma tHcy levels were associated with lower cognitive performances in patients affected by Alzheimer's disease and mild cognitive impairment and in healthy elderly. We searched for a correlation between plasma tHcy levels with the intelligence quotient (IQ) scores in a population of children and young adults with epilepsy treated with old and/or newer AEDs. The study group encompassed 179 patients (92 M, 51.5%) followed at our Unit of Child Neuropsychiatry and aged between 4 and 25years (mean+SD: 14.03±4.25). The inclusion criteria included the following: 1) diagnosis of epilepsy of "unknown cause" (cryptogenic) according to the ILAE classification, 2) age older than 3years, 3) stabilized antiepileptic treatment for at least 6months, and 4) clinical records of cognitive tests, plasma tHcy value, and results of MTHFR polymorphisms. Patients' mean tHcy value was 9.71±3.13µM/L (tHcy<9µM/L as our laboratory cutoff in nonepileptic controls). The mean TIQ score was 85.22 (SD±24.12); the mean VIQ score was 86.32 (SD±20.86); and the mean PIQ score was 86.94 (SD±21.51). C677T and A1298C MTHFR polymorphisms were detected in 74/92 (80%) examined patients and distributed into the following: CT (22.3%), TT (14.9%), CC (10.3%) for C677T, AC (16%), CC (1.1%), and AA (30.3%) for A1298C. Plasma tHcy levels were not significantly related to the IQ scores (TIQ, VIQ, or PIQ). Two significant findings came out. First, patients on AED polytherapy showed significantly lower TIQ, VIQ, and PIQ scores compared with the ones with AED monotherapy (p=0.032; p=0.008; p=0.005, respectively). However, this significant difference was not observed with the plasma tHcy levels compared with AED treatment. Second, patients with the 677TT genotype showed significantly higher tHcy levels versus those with the wt ones (p=0.049). In the latter group of patients, although the mean TIQ score was lower compared with the mean TIQ score in those with the wt ones, the difference only approached statistical significance (p=0.056). To our knowledge, this is the first study investigating the relationship between tHcy levels and cognitive scores in children with epilepsy treated with AEDs. Analysis of wider samples, selective neuropsychological tests, and prospective recruitment of patients might be encouraged.

A new form of alpha-dystroglycanopathy associated with severe drug-resistant epilepsy and unusual EEG features.

We describe two unrelated girls with congenital muscular dystrophy associated with alpha-dystroglycan deficit with no identified genetic defect, both presenting severe drug-resistant epilepsy with predominant myoclonic seizures and an unusual similar EEG pattern. Severe epilepsy has been unusually described in patients with congenital muscular dystrophies, mainly associated with Walker-Warburg, Fukuyama and muscle-eye-brain diseases. [Published with video sequences].

A novel CDKL5 mutation in a 47,XXY boy with the early-onset seizure variant of Rett syndrome.

Mutations of the cyclin-dependent kinase-like 5 gene (CDKL5), reported almost exclusively in female subjects, have been recently found to be the cause of a phenotype overlapping Rett syndrome with early-onset epileptic encephalopathy. We describe the first CDKL5 mutation detected in a male individual with 47,XXY karyotype. This previously unreported, de novo, mutation truncates the large CDKL5 COOH-terminal region, thought to be crucial for the proper sub-cellular localization of the CDKL5 protein. The resulting phenotype is characterized by a severe early-onset epileptic encephalopathy, global developmental delay, and profound intellectual and motor impairment with features reminiscent of Rett syndrome. In light of the data presented we discuss the possible phenotypic modulatory effects of the supernumerary wild type X allele and pattern of X chromosome inactivation and stress the importance of considering the causal involvement of CDKL5 in developmentally delayed males with early-onset seizures.

Type I hyperprolinemia and proline dehydrogenase (PRODH) mutations in four Italian children with epilepsy and mental retardation.

Type I hyperprolinemia (HPI) is an autosomal recessive disorder caused by proline oxidase deficiency. This enzyme is encoded by the proline dehydrogenase (PRODH) gene on 22q11. The functional consequences of different PRODH mutations on proline oxidase activity have been characterized in vitro. Few patients with HPI with epilepsy and cognitive/behavioral disturbances have been described so far. We screened four Italian children with HPI presenting epilepsy, mental retardation, and behavioral disorders for PRODH gene mutations, and attempted a genotype-phenotype correlation.

Ictal and interictal EEG abnormalities in ADHD children recorded over night by video-polysomnography.

In this paper we explore the prevalence of ictal and interictal epileptiform discharges (IEDs) and sleep disorders in ADHD children referred to a sleep clinic for all night video-PSG. Forty-two ADHD outpatients (35 males and 7 females) underwent video-PSG and a behavioural/neuropsychological assessment. Spearman correlation coefficients (p<0.05 criterion level) were used to assess the association between cognitive, behavioural, clinical (co-morbidity), sleep (sleep efficiency) and EEG (seizures, IEDs, localization of IEDs foci) variables. Sleep disorders were found in 86% of ADHD children; among these, 26% had RLS. 53.1% of ADHD children had IEDs (28.2% centro-temporal spikes, 12.5% frontal spikes, 9.3% temporal-occipital spikes and 2.3% generalized S-W). Nocturnal seizures were recorded in three patients: two with atypical interictal rolandic spikes and one with left frontal slow abnormalities. A significant relationship (p<0.05) emerges between nocturnal seizures and WISC-R IQ score and visual-spatial memory test and between some cognitive variables and interictal rolandic spikes. High levels of inattention, impulsivity/hyperactivity and oppositional behaviours were related (p<0.01 or 0.05) with Restless Leg Syndrome diagnosis. In conclusion, ADHD is a condition often associated with EEG epileptiform abnormalities. Seizures/IEDs presence seems to play a role on cognitive abilities, conversely sleep disorders have a stronger impact on behavioural rather than cognitive indicators.

Status gelasticus associated with levetiracetam as add-on treatment.

We report the case of a five-year-old girl, presenting with difficult-to-treat, symptomatic focal epilepsy, who developed status gelasticus following the introduction of levetiracetam as add-on treatment to oxcarbazepine and diazepam. Gelastic seizures were documented by video-EEG and were responsive to i.v. administration of diazepam. A possible causative role of levetiracetam is suggested. Specific susceptibility to some AEDs is also discussed, as this patient, at the age of four years, had presented an episode of non-convulsive status epilepticus, following introduction of tiagabine, in association with vigabatrin and nitrazepam.[Published with video sequences].

Mutation spectrum of NF1 gene in Italian patients with neurofibromatosis type 1 using Ion Torrent PGM™ platform.

Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene and is one of the most common human autosomal dominant disorders. The patient shows different signs on the skin and other organs from early childhood. The best known are six or more café au lait spots, axillary or inguinal freckling, increased risk of developing benign nerve sheath tumours and plexiform neurofibromas. Mutation detection is complex, due to the large gene size, the large variety of mutations and the presence of pseudogenes. Using Ion Torrent PGM™ Platform, 73 mutations were identified in 79 NF1 Italian patients, 51% of which turned out to be novel mutations. Pathogenic status of each variant was classified using "American College of Medical Genetics and Genomics" guidelines criteria, thus enabling the classification of 96% of the variants identified as being pathogenic. The use of Next Generation Sequencing has proven to be effective as for costs, and time for analysis, and it allowed us to identify a patient with NF1 mosaicism. Furthermore, we designed a new approach aimed to quantify the mosaicism percentage using electropherogram of capillary electrophoresis performed on Sanger method.

antiphospholipid antibodies syndrome associated with hyperhomocysteinemia related to MTHFR Gene C677T and A1298C heterozygous mutations in a young man with idiopathic hypoparathyroidism (DiGeorge syndrome).

CONTEXT: Antiphospholipid syndrome (APS, or Hughes' syndrome) is a systemic autoimmune disorder characterized by antiphospholipid antibody positivity, which may lead to arterial and/or venous thrombosis. Hyperhomocysteinemia (HHcy), variously associated with 5,10-methylene tetrahydrofolate reductase (MTHFR) gene point mutations, is also implicated in thromboembolic events. The association of APS and HHcy has already been described but has never been reported in patients with DiGeorge syndrome (DGS), the most common contiguous-gene deletion syndrome (22q11.2) in humans, whose phenotype conversely includes bleeding disorders. DATA ACQUISITION: In this report, we present the case of a 19-yr-old patient with a past medical history of learning disability and obesity affected with idiopathic hypoparathyroidism, metabolic syndrome, and diffuse vasculitis disorders. He was referred to our endocrinology clinic for the management of severe hypocalcemia. At the time of presentation he had been taking antiepileptic drugs for 2 wk and displayed facial dysmorphism (short neck, micrognathia, a small mouth, hypoplastic nasal alae, eye hypertelorism, and low-set simple ears). DGS was suspected and confirmed by both fluorescence in situ hybridization analysis and single nucleotide polymorphism-array analysis, which revealed contiguous gene microdeletion of the chromosome 22q11.2 in the minimal DiGeorge critical region, specifically at the gene locus D22S75 (N25). CONCLUSIONS: APS, revealed by anti-beta-2-glycoprotein and anti-prothrombin antibodies positivity, and moderate HHcy related to heterozygous C677T and A1298C point mutations of the MTHFR gene were identified as a possible cause of thrombotic disorder responsible for the widespread presence of cutaneous and cerebral lesions.

Novel CLN1 mutation in two Italian sibs with late infantile neuronal ceroid lipofuscinosis.

We detected a novel CLN1 mutation (c.125-15t>g) in two Italian siblings. The clinical phenotype is that of a variant late-infantile neuronal ceroid lipofuscinosis and consisted of early-onset visual loss, psychomotor deterioration, and seizures. Ultrastructurally, granular osmiophilic deposits were found in skin biopsy of both patients. The novel mutation occurs in the acceptor sequences for splicing and leads to skipping of multiple exons. This predicts a protein lacking part or all of the active site of the enzyme and the palmitate-binding pocket. Consequently, biochemical activity of the palmitoyl protein thioesterase-1 enzyme was drastically reduced. The new mutation was not identified in a large set of ethnically matched control chromosomes. Our findings support the notion that CLN1 patients are not rare in Southern Europe and facilitate DNA-based mutation and carrier testing in this family.

Effects of Maternal Iodine Nutrition and Thyroid Status on Cognitive Development in Offspring: A Pilot Study.

BACKGROUND AND OBJECTIVE: Maternal iodine nutrition and thyroid status may influence neurocognitive development in offspring. This study investigated the effects on the intelligence quotient (IQ) of children born to mothers with different levels of iodine supplementation, with or without the administration of levothyroxine (LT4), prior to and during pregnancy. PATIENTS AND METHODS: This pilot, prospective, observational study included four study groups, each comprising 15 mother-child pairs, identified on the basis of maternal histories of iodized salt consumption and LT4 treatment prior to and during pregnancy. The groups were labeled as follows: iodine (I), no iodine (no-I), iodine + LT4 (I + T4), and no iodine + LT4 (no-I + T4). IQ tests were administered to children at 6-12 years of age with the Wechsler Intelligence Scale for Children-3rd Edition (WISC-III), with full-scale IQ (FSIQ), verbal IQ (VIQ), and performance IQ (PIQ) being evaluated. RESULTS: Children of I and I + T4 mothers had similar verbal, performance, and FSIQs, which were 14, 10, and 13 points higher, respectively, than children born to no-I and no-I + T4 mothers. A positive association was found between VIQ and maternal urinary iodine (ß = 1.023 [confidence interval (CI) 1.003-1.043]; p = 0.028), but not with maternal free thyroxine concentrations at any stage of pregnancy. Overall, the prevalence of borderline or defective cognitive function was more than threefold higher in the children of mothers not using iodized salt than of those mothers using it (76.9% vs. 23.1%, odds ratio 7.667 [CI 2.365-24.856], χ2 = 12.65; p = 0.0001). CONCLUSIONS: Neuro-intellectual outcomes in children appear to be more dependent on their mothers' nutritional iodine status than on maternal thyroid function. These results support the growing body of evidence that prenatal, mild-to-moderate iodine deficiency adversely affects cognitive development later in life, with a seemingly greater impact on verbal abilities.

Cognitive training modifies frequency EEG bands and neuropsychological measures in Rett syndrome.

Rett syndrome (RS) is a childhood neurodevelopmental disorder characterized by a primary disturbance in neuronal development. Neurological abnormalities in RS are reflected in several behavioral and cognitive impairments such as stereotypies, loss of speech and hand skills, gait apraxia, irregular breathing with hyperventilation while awake, and frequent seizures. Cognitive training can enhance both neuropsychological and neurophysiological parameters. The aim of this study was to investigate whether behaviors and brain activity were modified by training in RS. The modifications were assessed in two phases: (a) after a short-term training (STT) session, i.e., after 30 min of training and (b) after long-term training (LTT), i.e., after 5 days of training. Thirty-four girls with RS were divided into two groups: a training group (21 girls) who underwent the LTT and a control group (13 girls) that did not undergo LTT. The gaze and quantitative EEG (QEEG) data were recorded during the administration of the tasks. A gold-standard eye-tracker and a wearable EEG equipment were used. Results suggest that the participants in the STT task showed a habituation effect, decreased beta activity and increased right asymmetry. The participants in the LTT task looked faster and longer at the target, and show increased beta activity and decreased theta activity, while a leftward asymmetry was re-established. The overall result of this study indicates a positive effect of long-term cognitive training on brain and behavioral parameters in subject with RS.

Topiramate as add-on drug in children, adolescents and young adults with Lennox-Gastaut syndrome: an Italian multicentric study.

The purpose of the study was to evaluate the efficacy and safety of topiramate (TPM) as adjunctive therapy in children, adolescents and young adults with Lennox-Gastaut syndrome (LGS). We performed a prospective open label add-on study in 45 patients (age 4-34 years, mean 15.9 years) with LGS and refractory seizures. TPM was added to one or two other baseline drugs and the efficacy was rated according to seizure type and frequency. TPM was initiated at the daily dose of 0.5-1 mg/kg, followed by a 2-week titration at increments of 1-3 mg/kg/24 h, up to a maximum daily dose of 12 mg/kg. After a mean period of 15.8 months of treatment (range 3-98 months), at a mean dose of 4.1 mg/kg/24 h (range 1.4-12 mg/kg), 18 patients (40%) had a seizure reduction more than 50%. TPM appeared to be effective mainly in major seizures (drop attacks, tonic and tonic-clonic seizures). Mild to moderate adverse events were present in 24 patients (53.3%), mostly represented by drowsiness, nervousness, hyporexia with or without weight loss and cognitive dulling. In conclusion, TPM adjunctive therapy reduced the number of drop attacks and major motor seizures in 40% of patients with LGS and produced only mild or moderate adverse events.

Levetiracetam during 1-year follow-up in children, adolescents, and young adults with refractory epilepsy.

PURPOSE: To evaluate the efficacy and safety of levetiracetam (LEV) in refractory crypto/symptomatic, partial or generalised epilepsy in children, adolescents and young adults. METHODS: We performed a prospective open label add-on study in 99 patients (age 12 months to 32 years, mean 14 years) with partial or generalised, crypto/symptomatic seizures. Levetiracetam was added to no more than two baseline AEDs and the efficacy was rated according to seizure type and frequency. RESULTS: LEV was initiated at the starting dose of 10mg/kg/day with 5-day increments up to 50 mg/kg/day, unless it was not tolerated. Concomitant therapy was generally not modified throughout the study. After a mean follow-up period of 6.7 months (range 3 weeks to 29 months), 11 patients (11.1%) were free of seizures (cryptogenic partial epilepsy, 5; symptomatic partial epilepsy, 6). A more than 75% seizure decrease was found in 14 patients (14.1%) and >50% in 8 (8.1%). Seizures were unchanged in 38 (38.4%), and worsened in 23 (23.2%). Mild and transient adverse side effects were found in 17 patients (17.2%), mostly represented by irritability and drowsiness. CONCLUSION: LEV appears to be well tolerated in children and adolescents with severe epilepsy and seems to be a broad spectrum AED, though in our experience, it was more effective against partial seizures with or without secondarily generalisation. LEV efficacy in other epilepsy syndrome should be evaluated further in homogeneous, more selected patients.

Topiramate as add-on drug in severe myoclonic epilepsy in infancy: an Italian multicenter open trial.

PURPOSE: This study was to evaluate the efficacy and safety of topiramate (TPM) in patients with severe myoclonic epilepsy in infancy (SMEI) and refractory seizures. METHODS: We performed a prospective multicentric open label add-on study in 18 patients (age 2-21 years, mean 9 years) with SMEI and refractory seizures of different types. TPM was added to one or two other baseline drugs and the efficacy was rated according to seizure type and frequency. RESULTS: TPM was initiated at a daily dose of 0.5-1 mg/kg, followed by a 2-week titration at increments of 1-3 mg/kg/24 h up to a maximum daily dose of 12 mg/kg. After a mean period of 11.9 months (range 2-24 months), three patients (16.7%) had 100% fewer seizures and ten patients (55.5%) had a more than 50% seizure decrease. In no patient there was a seizure worsening. Mild to moderate adverse events were present in four patients (22.2%), represented by weight loss, hypermenorrhoea, renal microlithiasis, nervousness and dysarthric speech. CONCLUSION: TPM may be a useful drug in patients with SMEI, being particularly effective against generalized tonic-clonic seizures. Further studies are needed to evaluate the early use of this drug in such a severe syndrome.

Long-term neuropsychiatric follow-up in hyperprolinemia type I.

The neuropsychiatric phenotype associated with hyperprolinemia type I (HPI) is still under debate. To our knowledge, no long-term follow-up on patients with HPI has been reported so far. We have previously described the clinical, biochemical, and molecular features of four patients with HPI. Here, we report on the neuropsychiatric and genotype features of an expanded sample of 10 patients with HPI with a mean follow-up duration of 11 years. Epileptic manifestations and/or cognitive impairment were prevalent at onset, but they were subsequently replaced by psychiatric disorders. Social behavior and relational skills were considerably impaired in the majority of cases. Learning disability was present in one patient. The complex neurochemical effects of proline on the central nervous system and genotype/phenotype correlations were discussed.

Acute cerebellar ataxia following meningococcal group C conjugate vaccination.

Acute cerebellar ataxia is the most common cause of childhood ataxia, usually resulting from infections or vaccinations. Cases of acute cerebellar ataxia have been reported as a consequence of several viral and bacterial infections as well as immunizing agents, such as varicella, influenza, hepatitis B, and diphtheria-pertussis-tetanus vaccines. Although immunization with meningococcal group C conjugate vaccines has been associated with several neurological side effects, acute cerebellar ataxia has not been previously reported. The authors describe a case of a 12-year-old girl exhibiting acute cerebellar ataxia following meningococcal group C conjugate vaccination. In this patient, cerebellar symptoms started within 24 hours from the vaccination, and infective causes have been ruled out by serum and liquoral analyses. Magnetic resonance imaging findings were normal. Progressive clinical improvement was obtained after corticosteroid treatment. This case increases the small number of postvaccinal ataxias and contributes to further clarifying the complex pathogenesis of this disorder.

Pediatric idiopathic intracranial hypertension and the underlying endocrine-metabolic dysfunction: a pilot study.

AIM: To unravel the potential idiopathic intracranial hypertension (IIH) endocrine-metabolic comorbidities by studying the natural (and targeted drug-modified) history of disease in children. IIH is a disorder of unclear pathophysiology, characterized by raised intracranial pressure without hydrocephalus or space-occupying lesion coupled with normal cerebrospinal fluid (CSF) composition. METHODS: Retrospective study (years 2001-2010) of clinical records and images and prospective follow-up (years 2010-2013) in 15 children (11 girls, 4 boys; aged 5-16 years) diagnosed previously as "IIH", according to the criteria for pediatric IIH proposed by Rangwala, at four university pediatric centers in northern, central, and southern Italy. RESULTS: We identified six potential endocrine-metabolic comorbidities including, weight gain and obesity (n=5), recombinant growth hormone therapy (n=3), obesity and metabolic syndrome (n=1), secondary hyperaldosteronism (n=1), hypervitaminosis A (n=1), and corticosteroid therapy (n=1). Response to etiologically targeted treatments (e.g., spironolactone, octreotide) was documented. CONCLUSIONS: IIH is a protean syndrome caused by various potential (risk and) associative factors. Several conditions could influence the pressure regulation of CSF. An endocrine-metabolic altered homeostasis could be suggested in some IIH patients, and in this context, etiologically targeted therapies (spironolactone) should be considered.

Cognitive decline in Dravet syndrome: is there a cerebellar role?

PURPOSE: The aim of the study was to perform a detailed assessment of cognitive abilities and behaviour in a series of epileptic patients with Dravet syndrome (DS) in order to establish a possible cerebellar-like pattern. METHODS: Nine children with DS without major behavioural disturbances and with cognitive abilities compatible with the assessment of specific cognitive skills (IQ>45) were enrolled in the study, in parallel with another group of nine epileptic patients (cryptogenic or symptomatic with minor brain injuries) consecutively admitted into the hospital matched for chronological age and IQ. All cases underwent neurological examination, long term EEG monitoring, neuroimaging and genetic analysis as well as a neuropsychological assessment including specific cognitive skills. RESULTS: On neurological examination 8 of the 9 DS patients had cerebellar signs, which were mild in six and more severe in the other two cases. DS patients had a constant discrepancy between verbal and performance items scales (verbal better than visual-spatial) that was not found in the control group. As to specific cognitive competence, the DS patients differ from the control group in the pattern of cognitive defects involving four main areas of cognitive abilities (a) expressive language with relatively spared comprehension, (b) visual-spatial organization, (c) executive function defects, (d) behavioural disorders. CUNCLUSIONS: The pattern of cognitive difficulties found in DS patients is consistent with what is reported in literature as cerebellar cognitive syndrome and may account for a possible cerebellar origin (at least as co-factor) of the cognitive decline observed in DS patients, as suggested by other clinical and experimental studies.