A novel PLP1 mutation further expands the clinical heterogeneity at the locus

Objectives: To characterize at clinical and molecular levels a family presenting with X-linked recessive Hereditary Spastic Paraplegia (HSP). Background: HSPs are a large group of genetically heterogeneous neurodegenerative disorders characterized by progressive upper motor neuron signs. Mutations in the proteolipid protein (PLP1) gene have been identified in families linked to the SPG2 locus on chromosome Xq22. However, Pelizaeus-Merzbacher disease (PMD) is also an X-linked recessive neurological disorder caused by PLP1 mutations. Methods: The SPG2 locus was investigated by linkage analysis in the family. The PLP1 gene was screened by sequencing. We present findings in a large French-Canadian family with an X-linked recessive HSP. The proband presented early with developmental delay and developed progressive spastic paraplegia. He has been wheelchair-bound since the age of three years. At the latest follow-up, he was 20 years-old and had severe spasticity predominantly affecting the lower extremities, moderate cerebellar dysfunction, and optic atrophy. Results: Linkage to SPG2 was established and a G to A mutation (MIR) in the initiation codon of the PLP1 gene was identified, likely resulting in the complete absence of proteolipid protein. Conclusions: We report a new PLP1 gene mutation in a patient with a clinical phenotype consistent with a PLP1 null syndrome

Perinatal regionalization and implications for long-term health outcomes in cerebral palsy

Background: Perinatal regionalization is linked to improved neonatal outcomes; however, the effects on long-term outcomes in cerebral palsy (CP) are not known. We estimate the effect of highest levels of neonatal care available at delivery on the risk of developing a nonambulatory CP status. Methods: Children with CP born in Quebec from the Canadian CP Registry excluding postneonatal causes were included (N=360). We estimate the effect of level of care available at delivery on risk of nonambulatory status among children with CP using propensity score matching and instrumental variables methods to adjust for differences in case mix among the three groups of hospitals. The outcome variable is an indicator for CP nonambulation assigned according to Gross Motor Function Classification System (levels IV and V). This study used data that predated therapeutic hypothermia in Quebec. Results: Propensity score estimates of change in the adjusted risk of having a nonambulatory CP status because of birth at level II versus level I is −0.081, 95% confidence interval (CI; −0.2182 to 0.0562); level III versus level I is −0.072 95% CI (−0.225 to 0.08), and level III versus level II is 0.157 95% CI (0.027 to 0.286). Conclusions: Differences in levels of neonatal care available at hospital where the delivery was carried out are not associated with the risk of a nonambulatory CP phenotype. This suggests that level of care and associated medical technology within the Quebec regionalized neonatal-perinatal system is used efficiently because it does not offer any further marginal benefit in the reduction of severe CP outcomes. The system works well as it is, which is supportive of the perinatal regionalization. The success of the neonatal resuscitation program and referral of high-risk births to regional hospitals with sufficient obstetric and perinatal competence and resources may contribute to this lack of variability

Two Novel Mutations in 2 Families With Benign Familial Neonatal Convulsions

Benign familial neonatal convulsion is a rare autosomal dominant inherited epilepsy syndrome characterized by unprovoked seizures in the first few days of life, normal psychomotor development, and a positive intergenerational family history of neonatal seizures. Over 90% of the affected individuals have inherited causal mutations in KCNQ2 , which encodes for the potassium voltage-gated channel subfamily Q, member 2. Mutations in KCNQ2 are also associated with a severe neonatal encephalopathy phenotype associated with poor seizure control and neurodevelopmental deficits. The authors report the clinical presentations, response to medication, and intrafamilial phenotypic variability in 2 families with benign familial neonatal convulsions, carrying previously unreported heterozygous missense mutations, c.1066C>G (p.Leu356Val) and c.1721G < A (p.Gly574Asp), in KCNQ2 . The cases reported herein suggest that inherited missense mutations in KCNQ2 can be associated with an intermediate phenotype and illustrate the challenges associated with prognosis and counselling for individuals with inherited missense mutations in KCNQ2