The second report of a new hypomyelinating disease due to a defect in the VPS11 gene discloses a massive lysosomal involvement.

Vesicular protein sorting-associated proteins (VPS, including VPS11) are indispensable in the endocytic network, in particular the endosome-lysosome biogenesis. Exome sequencing revealed the homozygous variant p.Leu387_ Gly395del in the VPS11 gene in two siblings. On immunoblotting, the mutant VPS11 protein showed a distinctly reduced immunostaining intensity. The children presented with primary and severe developmental delay associated with myoclonic seizures, spastic tetraplegia, trunk and neck hypotonia, blindness, hearing loss, and microcephaly. Neuro-imaging showed severe hypomyelination affecting cerebral and cerebellar white matter and corpus callosum, in the absence of a peripheral neuropathy. Electron microscopy of a skin biopsy revealed clusters of membranous cytoplasmic bodies in dermal unmyelinated nerve axons, and numbers of vacuoles in eccrine sweat glands, similar to what is seen in a classic lysosomal storage disease (LSD). Bone marrow cytology showed a high number of storage macrophages with a micro-vacuolated cytoplasm. Biochemically, changes in urinary glycosphingolipids were reminiscent of those in prosaposin deficiency (another LSD). The clinical and neuro-imaged features in our patients were almost identical to those in some recently reported patients with another variant in the VPS11 gene, p.Cys846Gly; underlining the presumed pathogenic potential of VPS11 defects. A new feature was the morphological evidence for lysosomal storage in VPS11 deficiency: This newly characterised disease can be viewed as belonging to the complex field of LSD.

The impact of the social environment on children's mental health in a prosperous city: an analysis with data from the city of Munich.

BACKGROUND: Children with a low socioeconomic position are more affected by mental difficulties as compared to children with a higher socioeconomic position. This paper explores whether this socioeconomic pattern persists in the prosperous German city of Munich which features high quality of life and coverage of children mental health specialists that lies well above the national average and is among the highest in Europe. METHODS: 1,265 parents of preschool children participated in a cross-sectional health survey. They were given a self-administered questionnaire (including socioeconomic variables) and the 'Strengths and Difficulties Questionnaire (SDQ)', a well-established method to identify mental difficulties among children and adolescents. Prevalence estimates for the 'SDQ-Total Difficulties Score' were calculated, with a special focus on differences by parental (resp. household) socioeconomic position. The association between parental education, household income, single parenthood, nationality, and parental working status on one hand, and their children's mental health on the other, was explored using multivariable logistic regression models. The coverage of mental health specialists per 100,000 children aged 14 or younger in the city of Munich was also calculated. RESULTS: In Munich, the distribution of mental health difficulties among children follows the same socioeconomic pattern as described previously at the national level, but the overall prevalence is about 30% lower. Comparing different indicators of socioeconomic position, low parental education and household income are the strongest independent variables associated with mental difficulties among children (OR = 2.7; CI = 1.6 - 4.4 and OR = 2.8; CI = 1.4 - 5.6, respectively). CONCLUSIONS: Socioeconomic differences in the prevalence of childhood mental difficulties are very stable. Even in a city such as Munich, which is characterized by high quality of life, high availability of mental health specialists, and low overall prevalence of these mental difficulties, they are about as pronounced as in Germany as a whole. It can be concluded that the effect of several characteristics of socioeconomic position 'overrules' the effect of a health promoting regional environment.

Prosaposin deficiency and saposin B deficiency (activator-deficient metachromatic leukodystrophy): report on two patients detected by analysis of urinary sphingolipids and carrying novel PSAP gene mutations.

Prosaposin deficiency (pSap-d) and saposin B deficiency (SapB-d) are both lipid storage disorders caused by mutations in the PSAP gene that codes for the 65-70 kDa prosaposin protein, which is the precursor for four sphingolipid activator proteins, saposins A-D. We report on two new patients with PSAP gene defects; one, with pSap-d, who had a severe neurovisceral dystrophy and died as a neonate, and the other with SapB-d, who presented with a metachromatic leukodystrophy-like disorder but had normal arylsulfatase activity. Screening for urinary sphingolipids was crucial to the diagnosis of both patients, with electrospray ionization tandem mass spectrometry also providing quantification. The pSap-d patient is the first case with this condition where urinary sphingolipids have been investigated. Multiple sphingolipids were elevated, with globotriaosylceramide showing the greatest increase. Both patients had novel mutations in the PSAP gene. The pSap-d patient was homozygous for a splice-acceptor site mutation two bases upstream of exon 10. This mutation led to a premature stop codon and yielded low levels of transcript. The SapB-d patient was a compound heterozygote with a splice-acceptor site variant exclusively affecting the SapB domain on one allele, and a 2 bp deletion leading to a null, that is, pSap-d mutation, on the other allele. Phenotypically, pSap-d is a relatively uniform disease of the neonate, whereas SapB-d is heterogeneous with a spectrum similar to that in metachromatic leukodystrophy. The possible existence of genotypes and phenotypes intermediate between those of pSap-d and the single saposin deficiencies is speculated.