Autosomal-recessive congenital cerebellar ataxia was identified in Roma patients originating from a small subisolate with a known strong founder effect. Patients presented with global developmental delay, moderate to severe stance and gait ataxia, dysarthria, mild dysdiadochokinesia, dysmetria and tremors, intellectual deficit, and mild pyramidal signs. Brain imaging revealed progressive generalized cerebellar atrophy, and inferior vermian hypoplasia and/or a constitutionally small brain were observed in some patients. Exome sequencing, used for linkage analysis on extracted SNP genotypes and for mutation detection, identified two novel (i.e., not found in any database) variants located 7 bp apart within a unique 6q24 linkage region. Both mutations cosegregated with the disease in five affected families, in which all ten patients were homozygous. The mutated gene, GRM1, encodes metabotropic glutamate receptor mGluR1, which is highly expressed in cerebellar Purkinje cells and plays an important role in cerebellar development and synaptic plasticity. The two mutations affect a gene region critical for alternative splicing and the generation of receptor isoforms; they are a 3 bp exon 8 deletion and an intron 8 splicing mutation (c.2652_2654del and c.2660+2T>G, respectively [RefSeq accession number NM_000838.3]). The functional impact of the deletion is unclear and is overshadowed by the splicing defect. Although ataxia lymphoblastoid cell lines expressed GRM1 at levels comparable to those of control cells, the aberrant transcripts skipped exon 8 or ended in intron 8 and encoded various species of nonfunctional receptors either lacking the transmembrane domain and containing abnormal intracellular tails or completely missing the tail. The study implicates mGluR1 in human hereditary ataxia. It also illustrates the potential of the Roma founder populations for mutation identification by exome sequencing.

The presence of variable degrees of non progressive cognitive impairment is recognized as a clinical feature of patients with Duchenne and Becker muscular dystrophies (DMD and BMD), but its pathogenesis still remains a matter of debate. A number of findings have proved that rearrangements located in the second part of the dystrophin ( DMD ) gene seem to be preferentially associated with cognitive impairment. Dp140 is a distal dystrophin isoform, mainly expressed during fetal brain development, whose role for neuropsychological functioning was suggested. The aims of the current study were to explore the possible association between cognitive impairment and DNA mutations affecting the regulatory regions of Dp140, as well as to compare the neuropsychological functioning of patients affected with DMD and Intermediate muscular dystrophy (IMD) with those affected by Becker muscular dystrophy (BMD). Fiftythree patients genetically diagnosed with DMD, IMD and BMD, subdivided according to sites of mutations along the DMD gene, underwent a neuropsychological assessment, evaluating their general cognitive abilities, verbal memory, attention and executive functions. Twenty patients with mutations, terminating in exon 44 or starting at exon 45 were tested by polymerase chain reaction (PCR) amplification of microsatellites STR44, SK12, SK21 and P20 DXS269, in order to evaluate the integrity of the Dp140 promoter region. According to our statistical results, there was not a significant difference in terms of general intelligence between the allelic forms of the disease, a higher frequency of mental retardation was observed in DMD patients. The patients with BMD had better results on tests, measuring long-term verbal learning memory and executive functions. We found that patients lacking Dp140 performed more poorly on all neuropsychological tests compared to those with preserved Dp140. Overall, our findings suggest that the loss of Dp140 is associated with a higher risk of intellectual impairment among patients with dystrophinopathies and highlights the possible role of this distal isoform in normal cognitive development.

No abstract

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, oculocutaneous telangiectasias, chromosomal instability, radiosensitivity, and cancer predisposition. The gene mutated in the patients, ATM, encodes a member of the phosphatidylinositol 3-kinase family proteins. The ATM protein has a key role in the cellular response to DNA damage. Truncating and splice site mutations in ATM have been found in most patients with the classical AT phenotype. Here we report of our extensive ATM mutation screening on 25 AT patients from 19 families of different ethnic origin. Previously unknown mutations were identified in six patients including a new homozygous missense mutation, c.8110T>C (p.Cys2704Arg), in a severely affected patient. Comprehensive clinical data are presented for all patients described here along with data on ATM function generated by analysis of cell lines established from a subset of the patients.

Clinical, computed tomographic (CT), and magnetic resonance imaging (MRI) correlations of subacute sclerosing panencephalitis with an atypical onset are presented in three children. In all three patients, the disease began similarly, with unilateral neurologic deficit followed by gnosis, praxis, and memory dysfunction corresponding to massive one-sided lesions. The first patient demonstrated right frontal-lobe syndrome and polymorphic extrapyramidal hyperkinesias; MRI showed a large high-signal lesion in the right frontal lobe, while CT was normal. The second patient displayed a disease onset with left-sided hemiparkinsonism and involuntary movements correlating to the MRI finding, ie, a massive rightsided occipitotemporoparietal subcortical lesion. An acute, stroke-like episode represented the first symptom in the third child. CT visualized cerebral, mainly left-sided cortical atrophy. In all three children, CT and MRI revealed significantly progressing brain atrophy at the disease's latest stages. We discuss the role of MRI in detecting early pathologic changes in children with subacute sclerosing panencephalitis.

We report a rare case of cerebellar degeneration as a paraneoplastic syndrome in an 8-year-old boy with Hodgkin lymphoma that presented during first-line treatment. Antibodies against Purkinje cells (anti-Tr antibodies) were detected in the serum of the patient. After successful treatment of the lymphoma, the cerebellar symptoms resolved partially. Childhood presentation of paraneoplastic cerebellar degeneration is extremely rare, with only a few reports in the literature. For this reason, the description of all such cases contributes to the enrichment of the medical knowledge and will improve the diagnosis and the treatment of this complication.

ObjectiveGenetic diagnosis and mutation identification are now compulsory for Duchenne (DMD) and Becker muscular dystrophies (BMD), which are due to dystrophin (DMD) gene mutations, either for disease prevention or personalized therapies. To evaluate the ethnic-related genetic assortments of DMD mutations, which may impact on DMD genetic diagnosis pipelines, we studied 328 patients with DMD and BMD from non-European countries.MethodsWe performed a full DMD mutation detection in 328 patients from 10 Eastern European countries (Poland, Hungary, Lithuania, Romania, Serbia, Croatia, Bosnia, Bulgaria, Ukraine, and Russia) and 2 non-European countries (Cyprus and Algeria). We used both conventional methods (multiplex ligation-dependent probe amplification [MLPA] followed by gene-specific sequencing) and whole-exome sequencing (WES) as a pivotal study ran in 28 patients where DMD mutations were already identified by standard techniques. WES output was also interrogated for DMD gene modifiers.ResultsWe identified DMD gene mutations in 222 male patients. We identified a remarkable allele heterogeneity among different populations with a mutation landscape often country specific. We also showed that WES is effective for picking up all DMD deletions and small mutations and its adoption could allow a detection rate close to 90% of all occurring mutations. Gene modifiers haplotypes were identified with some ethnic-specific configurations.ConclusionsOur data provide unreported mutation landscapes in different countries, suggesting that ethnicity may orient genetic diagnosis flowchart, which can be adjusted depending on the mutation type frequency, with impact in drug eligibility.

The aim of the study was to analyze cerebrovascular hypoplasia in childhood and its clinical manifestations in a clinical population of 205 children aged 3 to 14 years. Cerebrovascular hypoplasias were diagnosed using angiography (n=63), magnetic resonance angiography, and transcranial Doppler ultrasonography. Hypoplasias were localized in the internal carotid artery in 41.9% of patients, in the middle cerebral artery in 54.1%, the anterior cerebral artery in 1.0%, and in the vertebro-basilar system in 3.0%. Clinical manifestations included transient ischemic attacks (21% of patients), cerebral infarcts (17%), progressive unilateral cerebral hemisphere atrophy (1.0%), focal and secondary generalized epileptic seizures (56.1%), and migraine-like headache (4.9%). Hypoplasias of the internal carotid artery and middle cerebral artery manifested as focal and secondary generalized epileptic seizures, transient ischemic attacks, cerebral infarcts, migraine-like headache, and progressive unilateral cerebral hemisphere atrophy, in descending order of frequency. Hypoplasias in the anterior cerebral artery or the basilar artery caused cerebral infarcts, and hypoplasias in the vertebral arteries caused transient ischemic attacks. This article discusses the pathophysiology of ischemia in the territory of the hypoplastic cerebral artery in childhood, as well as possibilities for noninvasive neuroimaging for diagnosis of cerebrovascular hypoplasias.