A novel ECEL1 mutation expands the phenotype of distal arthrogryposis multiplex congenita type 5D to include pretibial vertical skin creases.

Arthrogryposis multiplex congenita (AMC) is a heterogeneous disorder characterized by multiple joint contractures often in association with other congenital abnormalities. Pretibial linear vertical creases are a rare finding associated with arthrogryposis, and the etiology of the specific condition is unknown. We aimed to genetically and clinically characterize a boy from a consanguineous family, presenting with AMC and pretibial vertical linear creases on the shins. Whole exome sequencing and variant analysis revealed homozygous novel missense variants of ECEL1 (c.1163T > C, p.Leu388Pro, NM_004826) and MUSK (c.2572C > T, p.Arg858Cys, NM_005592). Both variants are predicted to have deleterious effects on the protein function, with amino acid positions highly conserved among species. The variants segregated in the family, with healthy mother, father, and sister being heterozygous carriers and the index patient being homozygous for both mutations. We report on a unique patient with a novel ECEL1 homozygous mutation, expanding the phenotypic spectrum of Distal AMC Type 5D to include vertical linear skin creases. The homozygous mutation in MUSK is of unknown clinical significance. MUSK mutations have previously shown to cause congenital myasthenic syndrome, a neuromuscular disorder with defects in the neuromuscular junction.

Leukoencephalopathy with calcifications and cysts: a purely neurological disorder distinct from coats plus.

OBJECTIVE: With the identification of mutations in the conserved telomere maintenance component 1 (CTC1) gene as the cause of Coats plus (CP) disease, it has become evident that leukoencephalopathy with calcifications and cysts (LCC) is a distinct genetic entity. PATIENTS AND METHODS: A total of 15 patients with LCC were identified from our database of patients with intracranial calcification. The clinical and radiological features are described. RESULTS: The median age (range) at presentation was 10 months (range, 2 days-54 years). Of the 15 patients, 9 presented with epileptic seizures, 5 with motor abnormalities, and 1 with developmental delay. Motor abnormalities developed in 14 patients and cognitive problems in 13 patients. Dense calcification occurred in the basal ganglia, thalami, dentate nucleus, brain stem, deep gyri, deep white matter, and in a pericystic distribution. Diffuse leukoencephalopathy was present in all patients, and it was usually symmetrical involving periventricular, deep, and sometimes subcortical, regions. Cysts developed in the basal ganglia, thalamus, deep white matter, cerebellum, or brain stem. In unaffected areas, normal myelination was present. No patient demonstrated cerebral atrophy. CONCLUSION: LCC shares the neuroradiological features of CP. However, LCC is a purely neurological disorder distinguished genetically by the absence of mutations in CTC1. The molecular cause(s) of LCC has (have) not yet been determined.

Oromotor, word retrieval, and dichotic listening performance in young adults with previous Rolandic epilepsy.

AIMS: Results from a previous study indicated that children with Rolandic epilepsy (RE) exhibit abnormalities of oromotor and dichotic listening performance. The current study aimed to investigate whether the same individuals, 10 years later, still exhibited differences between the groups. Earlier literature suggests that children with RE normalize after remission and as they become adults. More recent studies have, on the contrary, suggested that there is a risk for residual oromotor and language deficits after remission. METHODS: Eleven young adults with RE and 9 matched controls were retested 10 years after participating in a study investigating oromotor ability, articulation, dichotic listening ability, and phonological and semantic word retrieval. RESULTS: Results of this longitudinal study indicated that there was a persistent, albeit reduced, difference between the groups, after remission, in dichotic listening and, to some extent, oromotor performance. Articulation and word retrieval did not differ between the groups. CONCLUSION: Young adults with previous RE in childhood have a moderate risk for persistent difficulties in verbal perception and oromotor performance.

Incomplete hippocampal inversion-is there a relation to epilepsy?

Incomplete hippocampal inversion (IHI) has been described in patients with epilepsy or severe midline malformations but also in nonepileptic subjects without obvious developmental anomalies. We studied the frequency of IHI in different epilepsy syndromes to evaluate their relationship. Three hundred patients were drawn from the regional epilepsy register. Of these, 99 were excluded because of a disease or condition affecting the temporal lobes or incomplete data. Controls were 150 subjects without epilepsy or obvious intracranial developmental anomalies. The coronal MR images were analysed without knowledge of the clinical data. Among epilepsy patients, 30% had IHI (40 left-sided, 4 right-sided, 16 bilateral). Of controls, 18% had IHI (20 left-sided, 8 bilateral). The difference was statistically significant (P < 0.05). Of temporal lobe epilepsy (TLE) patients, 25% had IHI, which was not a significantly higher frequency than in controls (P = 0.34). There was no correlation between EEG and IHI laterality. A total of 44% of Rolandic epilepsy patients and 57% of cryptogenic generalised epilepsy patients had IHI. The IHI frequency was very high in some epileptic syndromes, but not significantly higher in TLE compared to controls. No causality between TLE and IHI could be found. IHI can be a sign of disturbed cerebral development affecting other parts of the brain, maybe leading to epilepsy.

Oxidative proteome alterations during skeletal muscle ageing.

Sarcopenia corresponds to the degenerative loss of skeletal muscle mass, quality, and strength associated with ageing and leads to a progressive impairment of mobility and quality of life. However, the cellular and molecular mechanisms involved in this process are not completely understood. A hallmark of cellular and tissular ageing is the accumulation of oxidatively modified (carbonylated) proteins, leading to a decreased quality of the cellular proteome that could directly impact on normal cellular functions. Although increased oxidative stress has been reported during skeletal muscle ageing, the oxidized protein targets, also referred as to the 'oxi-proteome' or 'carbonylome', have not been characterized yet. To better understand the mechanisms by which these damaged proteins build up and potentially affect muscle function, proteins targeted by these modifications have been identified in human rectus abdominis muscle obtained from young and old healthy donors using a bi-dimensional gel electrophoresis-based proteomic approach coupled with immunodetection of carbonylated proteins. Among evidenced protein spots, 17 were found as increased carbonylated in biopsies from old donors comparing to young counterparts. These proteins are involved in key cellular functions such as cellular morphology and transport, muscle contraction and energy metabolism. Importantly, impairment of these pathways has been described in skeletal muscle during ageing. Functional decline of these proteins due to irreversible oxidation may therefore impact directly on the above-mentioned pathways, hence contributing to the generation of the sarcopenic phenotype.

Rolandic epilepsy: a challenge in terminology and classification.

History and present definition of rolandic epilepsy (RE) is briefly presented. In the literature there has often been misconceptions in the description of the syndrome, and the affinity to related conditions and structural abnormalities with rolandic discharges is often unclear. This has resulted in confusion regarding the definition and delineation of RE. A spectrum of RE based on a maturational continuum is possible. Until more is known about the genetic background of RE, a simple classification is proposed: 1) RE "pure" according to the original definition; 2) RE "plus"; 3) RE-related disorders; 4) Structural brain lesions with signs and symptoms as in RE. A summary of results from neuroimaging, neuropsychological and oromotor studies in RE "pure" is presented. Accurate clinical assessment and EEG analysis is essential for a proper classification of RE.

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus.

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.

Incomplete inversion of the hippocampus--a common developmental anomaly.

Incomplete inversion of the hippocampus, an imperfect fetal development, has been described in patients with epilepsy or severe midline malformations. We studied this condition in a nonepileptic population without obvious developmental anomalies. We analyzed the coronal MR images of 50 women and 50 men who did not have epilepsy. Twenty of them were healthy volunteers and 80 were patients without obvious intracranial developmental anomalies, intracranial masses, hydrocephalus or any condition affecting the temporal lobes. If the entire hippocampus (the head could not be evaluated) were affected, the incomplete inversion was classified as total, otherwise as partial. Incomplete inversion of the hippocampus was found in 19/100 subjects (9 women, 10 men). It was unilateral, always on the left side, in 13 subjects (4 women, 9 men): 9 were of the total type, 4 were partial. It was bilateral in six subjects (five women, one man): four subjects had total types bilaterally, two had a combination of total and partial types. The collateral sulcus was vertically oriented in all subjects with a deviating hippocampal shape. We conclude that incomplete inversion of the hippocampus is not an unusual morphologic variety in a nonepileptic population without other obvious intracranial developmental anomalies.

Children with rolandic epilepsy have abnormalities of oromotor and dichotic listening performance.

Twenty children (11 females; age range 8y 2mo to 14y 7mo, mean 10y 6mo, SD 1y 8mo) with electroclinically typical rolandic epilepsy (RE), were investigated to demonstrate possible occurrence of abnormal oromotor functions and oral sensibility, linguistic problems, and impaired auditory discrimination. Twelve children were treated with an antiepileptic drug (carbamazepine, valproate, or sulthiame). They were compared with an age- and sex-matched control group of 24 children (14 females; age range 8y 2mo to 14y 5mo, mean 11y, SD 1y 8mo). The test battery included tests for facial expressions, lip and tongue movements, repeated syllables, and articulation using nonsense and tongue-twisting words. Sensibility on tongue and lips was tested with two-point discrimination. As language tests, Rapid Confrontation Naming, orthographic, and phonologic decoding tests were used. A dichotic listening test was performed in 13 children with RE and in 14 controls. Compared to control children, those with RE had significantly greater problems concerning tongue movements (p < 0.05) and articulation (nonsense words and tongue-twisting words; p < 0.01), and worse performance on dichotic listening (p < 0.05). Oro-lingual sensibility and results of language tests did not differ between those with RE and control children. The results indicate that children with RE have distinct but mild problems with oromotor performance and auditory discrimination.

Hippocampal region asymmetry assessed by 1H-MRS in rolandic epilepsy.

PURPOSE: In a previous study, we reported hippocampal abnormalities on magnetic resonance imaging (MRI) in six of 18 children with rolandic epilepsy (RE). In this study, metabolic changes were analyzed in the hippocampal region with proton magnetic resonance spectroscopy (1H-MRS). METHODS: In 13 children with electroclinically typical RE and 15 healthy controls, 1H-MRS results of both hippocampal regions were analyzed. The voxels, 2 x 2 x 4-cm each, were placed to include the head and body of the hippocampus. A PRESS sequence with TR 2,000 ms and TE 32 ms was used. Total N-acetylaspartate (tNAA), glutamine and glutamate (Glx), and choline compounds (tCho) were related to total creatine (tCr), and asymmetry indices (AIs) were calculated. MRI was performed in all 13 patients and in 13 controls. RESULTS: The tNAA/tCr AI of the hippocampal region was significantly higher in children with RE than in control children (z = 4.49; p < 0.001). The AIs of Glx/tCr and tCho/tCr did not show a significant difference between the groups. Lateralization of the interictal epileptiform activity corresponded with the lower tNAA/tCr ratio in 10 of 13 patients. MRI revealed a hippocampal asymmetry in four of 13 in the RE group, three of them showed concordance between the lateralization of the lower tNAA/tCr ratio and the smaller hippocampus. In the control group, a subtle asymmetry in four of 13 children was found. CONCLUSIONS: A significant asymmetry of the hippocampal regions, measured by tNAA/tCr ratios, indicates an abnormal neuronal function in children with RE.

Development of cognitive functions in children with rolandic epilepsy.

An initial investigation of cognitive functions in 32 children, aged 7 to 15 years, with rolandic epilepsy (RE), using an extensive test battery, was followed 2.5 to 3 years later by a second assessment of 26 of these children, using the same technique. The initial investigation reported cognitive deficits in memory and learning of auditory-verbal material together with executive functions compared with controls. At the second assessment, the ability for immediate memory, memory and learning of visuospatial as well as auditory-verbal material and delayed recall was the same in the RE group as in the control group. On one of the tests measuring executive functions, Verbal Fluency, the RE group scored significantly lower than controls. With respect to reading and writing ability, the children with RE had some difficulty with word comprehension. Nonverbal reasoning was the same in the two groups, as was general IQ. In conclusion, the children with RE did not present any major cognitive difficulties when a mean of approximately 5 years had passed since onset of the typical syndrome, and at a time when most of them were seizure-free. Maturational factors apparently are of importance to the course of RE.