Homozygous nonsense mutation in SCHIP1/IQCJ-SCHIP1 causes a neurodevelopmental brain malformation syndrome.

We report a consanguineous Arab family with 3 affected siblings who display a disorder of global developmental delay, learning difficulties, facial dysmorphism, hearing impairments, and cataract. The clinical phenotype was associated with characteristic brain magnetic resonance imaging (MRI) features of axonal guidance defects involving anterior commissure agenesis as well as scattered areas of polymicrogyria-cobblestone complex. Whole genome sequencing revealed a novel nonsense mutation (159609921C>T) that segregated in the family consistent in an autosomal recessive pattern. This mutation located in the C-terminal region shared by the Schwanomin-Interacting Protein1 (SCHIP1) isoforms including the IQCJ-SCHIP1. The in vitro expression of SCHIP1 and IQCJ-SCHIP1 truncated mutant isoforms (NM_001197109.1; p.R209* and NM_001197114.1; p.R501*, respectively) were markedly reduced as compared to their full-length versions suggesting protein stability/folding impairment. The pathogenic nature of this mutation is supported by a previously reported mouse knockout of Schip1 isoforms, which phenocopied the human axon guidance abnormality. This is the first report of a SCHIP1/IQCJ-SCHIP1 point mutation in humans associated with a neurological-developmental phenotype.

Non-truncating LIFR mutation: causal for prominent congenital pain insensitivity phenotype with progressive vertebral destruction?

We present a Qatari family with two children who displayed a characteristic phenotype of congenital marked pain insensitivity with hypohidrosis and progressive aseptic destruction of joints and vertebrae resembling that of hereditary sensory and autonomic neuropathies (HSANs). The patients, aged 10 and 14, remained of uncertain genetic diagnosis until whole genome sequencing was pursued. Genome sequencing identified a novel homozygous C65S mutation in the LIFR gene that is predicted to markedly destabilize and alter the structure of a particular domain and consequently to affect the functionality of the whole multi-domain LIFR protein. The C65S mutant LIFR showed altered glycosylation and an elevated expression level that might be attributed to a slow turnover of the mutant form. LIFR mutations have been reported in Stüve-Wiedemann syndrome (SWS), a severe autosomal recessive skeletal dysplasia often resulting in early death. Our patients share some clinical features of rare cases of SWS long-term survivors; however, they also phenocopy HSAN due to the marked pain insensitivity phenotype and progressive bone destruction. Screening for LIFR mutations might be warranted in genetically unresolved HSAN phenotypes.

Autosomal recessive inheritance of GLUT1 deficiency syndrome.

GLUT1 deficiency syndrome (GLUT1DS) is understood as a monogenetic disease caused by heterozygous SLC2A1 gene mutations with autosomaldominant and sporadic transmission. We report on a six-year-old girl from an inbred Arab family with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Molecular analysis of the SLC2A1 gene identified a novel homozygous c1402C>T (p. Arg468Trp) mutation in exon 10 in the index patient and her asymptomatic younger sister. The mutation was absent in 120 control alleles of healthy individuals as well as in 400 alleles of other GLUT1DS patients. Arg468 represents a highly conserved, functionally important amino acid residue in the GLUT1 carboxy-terminus essential for substrate recognition and transport. Both unaffected parents were heterozygous for the mutation. A younger brother and two family members were healthy and carried the GLUT1 wild type. A ketogenic diet effectively controlled seizures in the index patient. We conclude that GLUT1DS can be transmitted as an autosomal recessive disease and provide new insights into genetic counselling for this treatable disorder.

Recurrence risk after a first febrile convulsion.

OBJECTIVE: Fever is the most common cause of convulsions, in infancy and childhood. Parents usually are concerned by the risk of recurrence. Our aim is to determine this risk of subsequent convulsions within the first year of the first episode of convulsion. METHODS: This is a prospective study over one year, May 97 to April 98 in which all children with first febrile seizure were enrolled. RESULTS: There were two hundred and thirty six children who had their first febrile convulsion within the study period. Male-to-female ratio was 1.2:1; the mean age at onset was 19 months (standard deviation 14.4). Generalized seizure occurred in 95.6% of the patients with an average duration of 7 minutes (SD 6.4). Ten percent of patients needed anticonvulsant drugs to stop convulsion. Seizure clusters occurred in 13.6 %, and complex febrile seizure was noticed in 21%. Family history was positive for epilepsy in 6.6% and febrile convulsions in 22%. Recurrence within a year from onset occurred in 52 (21%) of the patients. Factors associated with recurrence were: male sex, as male to female ratio was 2.25:1 (P = 0.02) and history of seizure clusters, 23/52, 44% (P = 0.00001). CONCLUSION: Risk factors for recurrence noted were male sex, and complex febrile seizures.

Neuro-brucellosis in children.

Brucellosis is an infection caused by gram negative cocobacilli (Brucellae). Presentation is usually non-specific and diagnosis depends on high index of suspicion. Nervous system involvement in children is rare as only 47 cases were reported until 1998. We are reporting two patients with neurobrucellosis. The first case was an 8-year-old boy who presented with papillodeoma, and neck stiffness of one month duration. Cerebrospinal fluid pressure was 360mm/water, protein 0.63gm/dl, and cerebrospinal fluid sugar/serum sugar 0.2/4.7mmol. Brucella titer was high in serum and cerebrospinal fluid. The second case was a 3-year-old girl with congenital hydrocephalus, with history of fever, loss of weight, and abdominal cyst around the distal end of ventriculo-peritoneal shunt tube. Brucella mellitenesis was isolated from cerebrospinal fluid and blood. Both cases were treated successfully by 3 antibiotics for 8-12 week.