Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.

Normal development of the cerebral cortex requires long-range migration of cortical neurons from proliferative regions deep in the brain. Lissencephaly ("smooth brain," from "lissos," meaning smooth, and "encephalos," meaning brain) is a severe developmental disorder in which neuronal migration is impaired, leading to a thickened cerebral cortex whose normally folded contour is simplified and smooth. Two identified lissencephaly genes do not account for all known cases, and additional lissencephaly syndromes have been described. An autosomal recessive form of lissencephaly (LCH) associated with severe abnormalities of the cerebellum, hippocampus and brainstem maps to chromosome 7q22, and is associated with two independent mutations in the human gene encoding reelin (RELN). The mutations disrupt splicing of RELN cDNA, resulting in low or undetectable amounts of reelin protein. LCH parallels the reeler mouse mutant (Reln(rl)), in which Reln mutations cause cerebellar hypoplasia, abnormal cerebral cortical neuronal migration and abnormal axonal connectivity. RELN encodes a large (388 kD) secreted protein that acts on migrating cortical neurons by binding to the very low density lipoprotein receptor (VLDLR), the apolipoprotein E receptor 2 (ApoER2; refs 9-11 ), alpha3beta1 integrin and protocadherins. Although reelin was previously thought to function exclusively in brain, some humans with RELN mutations show abnormal neuromuscular connectivity and congenital lymphoedema, suggesting previously unsuspected functions for reelin in and outside of the brain.

Tracking the mental health of a nation: prevalence and correlates of mental disorders in the second Singapore mental health study.

AIMS: The second Singapore Mental Health Study (SMHS) - a nationwide, cross-sectional, epidemiological survey - was initiated in 2016 with the intent of tracking the state of mental health of the general population in Singapore. The study employed the same methodology as the first survey initiated in 2010. The SMHS 2016 aimed to (i) establish the 12-month and lifetime prevalence and correlates of major depressive disorder (MDD), dysthymia, bipolar disorder, generalised anxiety disorder (GAD), obsessive compulsive disorder (OCD) and alcohol use disorder (AUD) (which included alcohol abuse and dependence) and (ii) compare the prevalence of these disorders with reference to data from the SMHS 2010. METHODS: Door-to-door household surveys were conducted with adult Singapore residents aged 18 years and above from 2016 to 2018 (n = 6126) which yielded a response rate of 69.0%. The subjects were randomly selected using a disproportionate stratified sampling method and assessed using World Health Organization Composite International Diagnostic Interview version 3.0 (WHO-CIDI 3.0). The diagnoses of lifetime and 12-month selected mental disorders including MDD, dysthymia, bipolar disorder, GAD, OCD, and AUD (alcohol abuse and alcohol dependence), were based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. RESULTS: The lifetime prevalence of at least one mood, anxiety or alcohol use disorder was 13.9% in the adult population. MDD had the highest lifetime prevalence (6.3%) followed by alcohol abuse (4.1%). The 12-month prevalence of any DSM-IV mental disorders was 6.5%. OCD had the highest 12-month prevalence (2.9%) followed by MDD (2.3%). Lifetime and 12-month prevalence of mental disorders assessed in SMHS 2016 (13.8% and 6.4%) was significantly higher than that in SMHS 2010 (12.0% and 4.4%). A significant increase was observed in the prevalence of lifetime GAD (0.9% to 1.6%) and alcohol abuse (3.1% to 4.1%). The 12-month prevalence of GAD (0.8% vs. 0.4%) and OCD (2.9% vs. 1.1%) was significantly higher in SMHS 2016 as compared to SMHS 2010. CONCLUSIONS: The high prevalence of OCD and the increase across the two surveys needs to be tackled at a population level both in terms of creating awareness of the disorder and the need for early treatment. Youth emerge as a vulnerable group who are more likely to be associated with mental disorders and thus targeted interventions in this group with a focus on youth friendly and accessible care centres may lead to earlier detection and treatment of mental disorders.

AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome.

BACKGROUND: Joubert syndrome (JS) is an autosomal recessive disorder characterised by hypotonia, ataxia, mental retardation, altered respiratory pattern, abnormal eye movements, and a brain malformation known as the molar tooth sign (MTS) on cranial MRI. Four genetic loci have been mapped, with two genes identified (AHI1 and NPHP1). METHODS: We screened a cohort of 117 JS subjects for AHI1 mutations by a combination of haplotype analysis and sequencing of the gene, and for the homozygous NPHP1 deletion by sequencing and marker analysis. RESULTS: We identified a total of 15 novel AHI1 mutations in 13 families, including nonsense, missense, splice site, and insertion mutations, with some clustering in the WD40 domains. Eight families were consanguineous, but no single founder mutation was apparent. In addition to the MTS, retinal dystrophy was present in 11 of 12 informative families; however, no subjects exhibited variable features of JS such as polydactyly, encephalocele, colobomas, or liver fibrosis. In contrast to previous reports, we identified two families with affected siblings who developed renal disease consistent with nephronophthisis (NPH) in their 20s. In addition, two individuals with classic NPH were found to have homozygous NPHP1 deletions. CONCLUSIONS: Overall, 11% of subjects had AHI1 mutations, while approximately 2% had the NPHP1 deletion, representing a total of less than 15% in a large JS cohort. Some preliminary genotype-phenotype correlations are possible, notably the association of renal impairment, specifically NPH, in those with NPHP1 deletions. Subjects with AHI1 mutations may be at risk of developing both retinal dystrophy and progressive kidney disease.

Endophthalmitis associated with the Ahmed glaucoma valve implant.

AIM: To investigate the rate, risk factors, clinical course, and treatment outcomes of endophthalmitis following glaucoma drainage implant (GDI) surgery. METHODS: A computerised relational database search was conducted to identify all patients who were implanted with Ahmed glaucoma valve (AGV) and developed endophthalmitis following surgery at the King Khaled Eye Specialist Hospital in Riyadh, Saudi Arabia, between 1 January 1994 and 30 November 2003. Only medical records of the patients who developed endophthalmitis were retrospectively reviewed. RESULTS: 542 eyes of 505 patients who were on active follow up were included in the study. Endophthalmitis developed in nine (1.7%) eyes; the rate was five times higher in children than in adults. Delayed endophthalmitis (developed 6 weeks after surgery) occurred in eight of nine eyes. Conjunctival erosion overlying the AGV tube was present in six of nine eyes. Common organisms isolated in the vitreous included Haemophilus influenzae and Streptococcus species. Multiple regression analysis revealed that younger age and conjunctival erosion over the tube were significant risk factors associated with endophthalmitis. CONCLUSION: Endophthalmitis is a rare complication of GDI surgery that appears to be more common in children. Conjunctival dehiscence over the GDI tube seems to represent a major risk factor for endophthalmitis. Prompt surgical revision of an exposed GDI tube is highly recommended.

Reading-induced absence seizures.

Reading epilepsy usually presents with jaw myoclonus and generalized tonic-clonic seizures. We report a 12-year-old girl with absence seizures induced by reading, which were diagnosed by video EEG. An absence seizure with generalized 3-Hz spike-and-wave discharge occurred within 30 seconds of each reading session. Treatment with valproate caused complete seizure control, with therapy successfully discontinued after 2 years.

Hemisomatic spasms in children.

We report two children with hemisomatic spasms caused by neoplastic lesions in the region of the ipsilateral cerebellopontine angle. In this condition, seizure misdiagnoses are frequent and EEGs are normal, even ictally. MRI should be performed early to prevent delay of appropriate treatment.

Choroido-cerebral calcification syndrome with retardation.

We present a sibship with a rare syndrome characterized by mental retardation, dense calcification of the lateral ventricular choroid plexus, and increased CSF protein. Neurophysiologic studies yielded nonspecific results, and endocrine studies, including parathormone levels, were normal. Simultaneous measurements of CSF and serum calcium, magnesium, and other electrolytes were normal, but the CSF/serum ratio of phosphate was low, suggesting a possible role in the pathogenesis of this syndrome.

Ascending paralysis due to myelitis in a newborn with congenital toxoplasmosis.

We present a female neonate in her second week of life with borderline microcephaly, microphthalmia and progressive ascending sensory and motor deficit leading to complete paralysis with respiratory failure and death at 27 days of age. Neurological imaging revealed, in addition to cerebral atrophy, marked hydrocephalus, ependymal basal ganglia calcification, leptomeningeal enhancement, and patchy myelitis throughout the entire spinal cord. CSF cytological examination revealed the presence of a mononuclear pleocytosis with Toxoplasma gondii trophozoites free in the CSF and within the cytoplasm of some macrophages, and a 100-fold raised protein content. To our knowledge, this is the first reported case of clinical acute spinal cord involvement in congenital toxoplasma infection, proven by the presence of toxoplasma trophozoite in the CSF.

Non-progressive familial congenital cerebellar hypoplasia.

A syndrome is reported of congenital non-progressive, gradually slightly improving, ataxia in 3 out of 5 male sibs, issues of a first-order consanguineous mating. Additional characteristic features included: moderate microcephaly, generalised muscle weakness and hypotonia, nystagmus, and moderate mental retardation. A pyramidal syndrome of hyperreflexia and Babinski signs, without any spasticity, became manifest in the 2nd or 3rd year of life. In all three, the caudal part of the vermis was absent, the enlarged IVth ventricle opening up via Magendie's foramen into the cisterna magna. The middle and rostral vermian parts as well as the sagittal paravermian parts of the cerebellar hemispheres were hypoplastic. The differential diagnosis of this syndrome is analysed and the developmental pathogenetic mechanisms likely to produce the typifying distribution of aplasia are indicated.

Schwartz-Jampel syndrome: evidence of central nervous system dysfunction.

We report four patients with Schwartz-Jampel syndrome showing evidence of central conduction impairment documented by somatosensory evoked potentials. Median nerve somatosensory evoked potential showed normal latencies to Erb's point and N13 in all patients. Interpeak latencies between N13 and N19 were prolonged in five nerves, with complete block in three nerves. Posterior tibial nerve somatosensory evoked potentials were performed in three patients. Peripheral latencies were normal in all patients. Interpeak latencies between lumbar and cervical potentials were prolonged in two patients, with conduction delay between cervical and cortical potentials in five of the six nerves tested. Visually evoked potentials, brainstem auditory evoked potentials, electromyography, and nerve conduction velocity studies were normal in all patients. Parents' median nerve and posterior tibial nerve somatosensory evoked potentials were normal.

Hyperekplexia-like syndromes without mutations in the GLRA1 gene.

Hyperekplexia (MIM: 149400), or startle disease, is an autosomal dominant neurological disorder characterized by an extreme generalized stiffness immediately after birth, normalizing during the first years of life. Other features of this disorder are excessive startle reactions to unexpected, particularly auditory, stimuli together with a short period of generalized stiffness during which voluntary movements are impossible. Linkage analysis mapped a gene for this disorder to chromosome 5q33-q35. Subsequently, mutations in the GLRA1 gene encoding the alpha 1-subunit of the glycine receptor proved to be causally related to the disease. In the present study, mutation analysis of all exon and flanking intron sequences of this gene was performed in sporadic patients and their parents. Moreover, a branch of the original Dutch hyperekplexia family with a very severely affected individual was screened for an additional mutation in the GLRA1 gene. Except for two polymorphisms, of which one results in an amino acid change, no potentially disease causing mutations were found in the alpha 1-subunit of the glycine receptor. Together with haplotype analysis these results exclude a recessive inheritance or new mutation etiology in these hyperekplexia-like syndrome and emphasize that hyperekplexia-like syndromes can be caused by other genetic factors. The involvement of other genes encoding subunits of the functional glycine receptor complex has not been excluded.

Jervell and Lange-Nielsen QT syndrome: a case report from Saudi Arabia.

A family with two of its members having Jervell and Lange-Nielsen syndrome is reported for the first time from Saudi Arabia. A history of syncopal attack in a child with hearing loss and the sudden death of her brother while playing suggested the possibility of the syndrome. Electrocardiogram and full ENT and audiological assessment revealed Jervell and Lange-Nielsen syndrome in the living child. Treatment was given and the condition is now under control.

GJA12 mutations in children with recessive hypomyelinating leukoencephalopathy.

BACKGROUND: Pelizaeus-Merzbacher-like disease (PMLD) is an inherited hypomyelinating leukoencephalopathy with onset in early infancy. Like Pelizaeus-Merzbacher disease (PMD), PMLD is characterized clinically by nystagmus, cerebellar ataxia, and spasticity, due to a permanent lack of myelin deposition in the brain. Mutations in the GJA12 gene, encoding connexin 47 (Cx47), were recently reported in five children with autosomal recessive PMLD. OBJECTIVES: To evaluate the impact of mutations in the GJA12 gene in, and define the clinical and neuroimaging features of, autosomal recessive PMLD. RESULTS: The authors screened for GJA12 mutations in 10 additional PMLD families originating from Italy, Pakistan, and Saudi Arabia. Three novel homozygous GJA12 mutations were identified in 12 mutant cases distributed in 3 of 10 families. The mutations segregated with the disease according to an autosomal recessive trait and included one missense (G236S) and two nonsense (L281fs285X and P131fs144X) changes. CONCLUSIONS: The identification of homozygous mutations predicting the synthesis of aberrant and truncated polypeptides, and their tight segregation with the disease in very large families, clearly demonstrate that the loss of Cx47 function is the cause of the disease. The phenotype of GJA12-related Pelizaeus-Merzbacher-like disease is fairly homogeneous and similar to that of Pelizaeus-Merzbacher disease. However, slower progression of symptoms, greater preservation of cognitive functions, and partial myelination of corticospinal tracts at MRI were distinctive features, which could help in the differential diagnosis.

Mobius syndrome with basal ganglia calcification.

Basal ganglia calcification has not been described in Mobius syndrome. A family with two children with Mobius syndrome are reported. Bilateral basal ganglia calcification was seen on computed tomography in both. This is the first family where cerebral involvement has been clearly documented in this syndrome.

Microsurgical selective peripheral neurotomy in the treatment of spasticity in cerebral-palsy children.

Spasticity represents the most handicapping sequelae of cerebral palsy in children. In this study, 28 children with spastic cerebral palsy were treated over the last 4 years by microsurgical selective peripheral neurotomy: 28 times the posterior tibial nerve for spastic foot deformity, 3 times the ulnar and median nerves for spastic flexion of wrist and fingers, 2 times the sciatic nerve for spastic knee flexion associated with spastic foot deformity and 3 times obturator nerves for spastic adductors. Results on spasticity with follow-up ranging from 3 to 48 months were as follows: spastic foot deformity was corrected in all patients with pure spasticity, 2 out of the 3 children with ulnar and median neurotomy improved, knee flexion and hip adduction were improved in the other 5 patients. Selective peripheral neurotomy is an effective procedure in the treatment of segmental harmful spasticity after failure of a well-conducted conservative treatment associating physiotherapy and antispasmodic medications. It must be performed before the fixed deformities and other orthopedic complications arise.

Idiopathic long QT syndrome: asking the right question.

Infants and young children cannot describe symptoms of cardiogenic syncope accurately. If the attention in such cases is focused on the seizure activity that may follow, the patient will be treated inappropriately with anticonvulsants. We report such a presentation in 4 infants and young children (ages 6 to 48 months) with idiopathic long QT syndrome. All patients presented with recurrent seizures. All patients had a corrected QT interval (QTc) > or = 0.44 s and none had deafness. The diagnosis was suspected by careful history-taking which revealed episodes of loss of consciousness before convulsions in all patients. All patients were treated successfully with propranolol and remained free of symptoms during the follow-up period of 1-2 years. Screening the other family members revealed a prolonged QTc in 9 out of 16, and a history of 3 sudden and unexplained deaths in two families.