Arpad von Moers

Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation

Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transporter, the gene of which is located on the X chromosome. We tested whether mutations in MCT8 cause severe psychomotor retardation and high serum triiodothyronine (T3) concentrations in five unrelated young boys. The coding sequence of MCT8 was analysed by PCR and direct sequencing of its six exons. In two patients, gene deletions of 2.4 kb and 24 kb were recorded and in three patients missense mutations Ala150Val, Arg171 stop, and Leu397Pro were identified. We suggest that this novel syndrome of X-linked psychomotor retardation is due to a defect in T3 entry into neurons through MCT8, resulting in impaired T3 action and metabolism.

Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration

RNA exosomes are multi-subunit complexes conserved throughout evolution and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability. By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596). We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.

Minimal clinical expression of the holoprosencephaly spectrum and of currarino syndrome due to different cytogenetic rearrangements deleting the Sonic Hedgehog gene and the HLXB9 gene at 7q36.3

We report clinical, cytogenetic, and molecular cytogenetic studies on four patients with subtle or submicroscopic 7q36 deletions either of de novo origin or resulting from a cryptic parental translocation. Fluorescence in situ hybridization (FISH) studies indicated that in all four patients, the Sonic Hedgehog gene (SHH) and the homeobox gene HLXB9, among others, are comprised in the deletions. Besides mental retardation and short stature, all patients showed only minimal manifestations of the holoprosencephaly (HPE) spectrum and only one displayed symptoms of the Currarino syndrome. Patient 1 had a de novo 7q36.1‐qter deletion and showed microcephaly, ptosis, sacral agenesis, tethered cord, but no structural brain anomaly. Patient 2 had a submicroscopic de novo 7q36 deletion detected by FISH, and showed facial and cerebral microsigns of the HPE spectrum. Patient 3 had a 7q36 deletion found by subtelomere FISH testing that was the unbalanced product of a subtle maternal 7q;10q translocation. She presented facial and ocular microsigns, but no structural abnormality of the brain. Patient 4 showed no specific syndromal pattern and was found to have a cryptic unbalanced de novo translocation of the terminal parts of chromosomes 7q and 9p by subtelomere FISH. Patients 2, 3, and 4 represent the first report of a de novo submicroscopic 7q36 deletion, the second report of a familial subtle translocation of 7q36, and the first report of an unbalanced de novo submicroscopic translocation of 7q36, respectively. Our results stress the importance of 7q36 deletion studies by FISH in patients with microsigns of the HPE spectrum.

EEG Features of Glut-1 Deficiency Syndrome

Summary:  Purpose: Glut‐1 deficiency syndrome (Glut‐1 DS) is caused by the deficiency of the major glucose transporter in cerebral microvessels.

Ataxia, Intellectual Disability, and Ocular Apraxia with Cerebellar Cysts: A New Disease?

Cerebellar cysts are rare findings in pediatric neuroimaging and rather characteristic for dystroglycanopathies and GPR56-related encephalopathy. We aim to report on seven children with cerebellar cysts showing absence of weakness and ruling out mutations within eight dystroglycanopathy genes and GPR56. Data about neurological and ophthalmological features, outcome, and creatine kinase values were collected from clinical histories and follow-up examinations. All MR images were qualitatively evaluated for infra- and supratentorial abnormalities. A SNP 6.0-Array was performed in three children. The POMT1, POMT2, POMGnT1, FKRP, FKTN, LARGE, ISPD, B3GALNT2, and GPR56 genes were screened in all patients by Sanger sequencing. Seven children from five families were studied. Ataxia, intellectual disability, and language impairment were found in all patients, ocular motor apraxia in five, and severe myopia in three. None of the patients had weakness, only three a minimally increased creatine kinase value. Qualitative neuroimaging evaluation showed cerebellar cysts and dysplasia in the cerebellar hemispheres and vermis in all children. Additional findings were an enlarged fourth ventricle in all children, vermian hypoplasia and brain stem morphological abnormalities in five. The SNP array showed no pathogenetic imbalances in all children evaluated. In all patients, no mutations were found in POMT1, POMT2, POMGnT1, FKRP, FKTN, LARGE, ISPD, B3GALNT2, and GPR56. The peculiar combination of the same clinical and neuroimaging findings in our patients highly suggests that this phenotype may represent a novel entity, possibly falling within the spectrum of dystroglycanopathies.

Models for transition clinics

Transition is a purposeful, planned process that addresses the medical, psychosocial, educational, and vocational needs of adolescents and young adults with chronic medical conditions, as they advance from a pediatric and family‐centered to an adult, individual focused health care provider. This article describes some of the models for transition clinics or services for epilepsy in five countries (Canada, France, Colombia, Germany, and the United Kingdom). These models include joint adult and pediatric clinics, algorithm‐driven service, and a check list system in the context of pediatric care. Evaluation of these models is limited, and it is not possible to choose an optimal program. The attitude and motivation of health care providers may be the most important elements.

Antisense oligonucleotides and short interfering RNAs silencing the cyclin-dependent kinase inhibitor p21 improve proliferation of Duchenne muscular dystrophy patients’ primary skeletal myoblasts

Increased levels of the cyclin-dependent kinase inhibitor p21 associated with decreased myoblast proliferation may be involved in the dystrophic process in Duchenne muscular dystrophy (DMD). Therefore we are interested to improve the proliferation of primary myoblasts of DMD patients by a reduction in p21 using either antisense oligonucleotides (ASO) or short interfering RNAs (siRNA). After transient transfection of myoblasts in cell culture proliferation was analyzed using a 5-bromo-2′-deoxyuridine assay comparing specific transfected cells with untransfected cells and cells transfected with scrambled ASO and luciferase siRNA, respectively. Four of five Dystrophin-deficient (Dys−) cell culture samples revealed an increase in proliferation between 7% and 18% compared to untransfected cells and between 8% and 36% compared to cells transfected with scrambled ASO. Transfection with siRNA was performed for selected samples to determine whether siRNA is more effective in gene silencing than ASO. The increase in proliferation using luciferase siRNA as reference was comparable to or less than ASO data using scrambled ASO as reference. Using untransfected cells as reference, the increase in proliferation was higher for siRNA than ASO (20–47% vs. 7–18%), but the data must be carefully interpreted with respect to nonspecific effects on gene expression by siRNA. Our findings of transient p21 gene silencing represent a basis for viral vector-mediated drug-inducible p21 shRNA expression in Dys− myoblasts which might enhance, prolong and regulate the proliferation effect.

Clinical, neuroradiological and molecular characterization of cerebellar dysplasia with cysts (Poretti-Boltshauser syndrome).

Cerebellar dysplasia with cysts and abnormal shape of the fourth ventricle, in the absence of significant supratentorial anomalies and of muscular involvement, defines recessively inherited Poretti–Boltshauser syndrome (PBS). Clinical features comprise non-progressive cerebellar ataxia, intellectual disability of variable degree, language impairment, ocular motor apraxia and frequent occurrence of myopia or retinopathy. Recently, loss-of-function variants in the LAMA1 gene were identified in six probands with PBS. Here we report the detailed clinical, neuroimaging and genetic characterization of 18 PBS patients from 15 unrelated families. Biallelic LAMA1 variants were identified in 14 families (93%). The only non-mutated proband presented atypical clinical and neuroimaging features, challenging the diagnosis of PBS. Sixteen distinct variants were identified, which were all novel. In particular, the frameshift variant c.[2935delA] recurred in six unrelated families on a shared haplotype, suggesting a founder effect. No LAMA1 variants could be detected in 27 probands with different cerebellar dysplasias or non-progressive cerebellar ataxia, confirming the strong correlate between LAMA1 variants and PBS.

Spontaneous Scalp Arteriovenous Fistula in a Child with Hartnup Disease

Purpose: To report the endovascular treatment of a spontaneous scalp arteriovenous fistula (AVF) in a child with Hartnup disease. Case Report: A 6-year-old girl with Hartnup disease presented with recurrent attacks of intense, migraine-like, right-sided headache; a tender, pulsatile small mass was observed in the scalp. Selective digital subtraction angiography revealed a high-flow scalp AVF fed by the frontal branch of the right superficial temporal artery draining via the scalp veins. Endovascular treatment was performed by direct puncture of the distal feeding artery and injection of 2 mL of a 50% mixture of N-butyl-cyanoacrylate and Lipiodol. Serial arteriograms performed 6 months and 2 years later documented complete resolution of the lesion. The patient has had no recurrence of clinical symptoms or local signs for recanalization. Conclusions: Scalp AVFs may progress in size, causing significantly disabling symptoms, particularly in children. We recommend endovascular treatment at the earliest possible stage.

Dystrophinopathy in a boy with Chediak–Higashi syndrome

Chediak-Higashi syndrome (CHS) is a hereditary, biphasic immunodeficiency syndrome which usually leads to early death, during the first decade. The second phase is characterized by a lymphoproliferative syndrome with histiocytic infiltrations in various tissues. Recently the gene has been identified on chromosome 1q43. In the patient presented here, a mutation within codon 3197 was found, resulting in a frame-shift. Additionally, Duchenne muscular dystrophy (DMD) was diagnosed by immunostaining of the muscle. Unusual for both CHS and DMD muscle weakness and hypotonia became evident during the first months of life. Compared to typical DMD cases we found an increased histiocytic infiltration in the muscle. The underlying muscular dystrophy probably predisposes to the affection of muscle in the second phase of CHS. This patient is presented as an example of modification of the phenotype by a second genetic disease.