Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. Changes in gene expression underlie the arteriosclerosis and T-cell immunodeficiency of SIOD; therefore, we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila. RESULTS: We found increased expression of components and targets of the Wnt and Notch signaling pathways in the SIOD patient kidney, increased levels of unphosphorylated ß-catenin and Notch1 intracellular domain in the glomeruli of most SIOD patient kidneys, and genetic interaction between the Drosophila SMARCAL1 homologue Marcal1 and genes of the Wnt and Notch signaling pathways. CONCLUSIONS: We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients.

Moyamoya Syndrome in South African Children With HIV-1 Infection.

A national multicenter study identified 17 South African children with vertically acquired HIV-1 infection and HIV-associated vasculopathy. Five of the children (all indigenous African ancestry) had progressive vascular disease, consistent with moyamoya syndrome. Median presentation age 5.8 years (range 2.2-11). The children with moyamoya syndrome presented with abnormal CD4 counts and raised viral loads. Clinical features included motor deficits, neuroregression, and intellectual disability. Neuroimaging supported progressive vascular disease with preceding clinically silent disease course. Neurologic recovery occurred in 1 patient with improved CD4 counts. Four of the 5 children presented during the era when access to antiretroviral therapy was limited, suggesting that with improved management of HIV-1, progressive vasculopathy is less prevalent. However the insidious disease course illustrated indicates that the syndrome can progress "silently," and manifest with misleading phenotypes such as cognitive delay or regression. Sub-Saharan Africa has limited access to neuroimaging and affected children may be underdiagnosed.

Alpha-mannosidosis: a report of 2 siblings and review of the literature.

Alpha-mannosidosis is a rare lysosomal storage disorder with a heterogeneous clinical presentation. We describe a set of siblings with alpha-mannosidosis. The older child presented with a severe phenotype with multisystem involvement and had progressive deterioration in her motor and cognitive functioning. She had a poor outcome. The second child has a less severe disease course. He is being managed symptomatically only because of the family's poor socioeconomic circumstances. Therapeutic options in this condition are limited to bone marrow transplant early in the disease course. These disorders, although rare, should be considered in the approach to a child with dysmorphism, developmental delay, skeletal deformities, and visceromegaly.

Guideline for the diagnosis and management of multiple sclerosis in children.

Paediatric multiple sclerosis (MS) represents a particular MS subgroup with unique diagnostic challenges. Due to the narrow window of environmental exposures and clinical disease expression, children with MS may represent an important study population for gaining a better understanding of the pathogenesis of the disease. The International Paediatric MS Study Group (IPMSSG) was formulated to clarify the diagnostic and therapeutic dilemmas in this population. This guideline was adapted from the International Paediatric Multiple Sclerosis Study Group guideline and endorsed by PANDA, South Africa. 

Neurologic and neurobehavioral sequelae in children with human immunodeficiency virus (HIV-1) infection.

The range and extent of neurologic and neurobehavioral complications of human immunodeficiency virus (HIV-1) infection in children are under-described. Seventy-eight children with HIV-1 infection (32 females) were assessed for neurologic complications. Forty-six children had abnormal neurology examinations. Thirty-three children had global pyramidal tract signs, 5 had a hemiparesis, 4 had peripheral neuropathy, 18 had visual impairment, and 5 had hearing impairment. Thirty-nine of 63 children over 1 year of age had neurobehavioral problems. Of 24 children with HIV encephalopathy, 74% had severe immunosuppression and 45% were not receiving antiretroviral therapy. Twelve children had prior opportunistic central nervous system infections, and 9 had epilepsy. Diverse neurologic and neurobehavioral deficits are common in children with HIV-1 infection. Children with severe immunosuppression, who were not receiving antiretroviral therapy, were growth impaired and less than 1 year of age, were at greatest risk for developing neurologic complications.

Acquired demyelinating disorders of childhood in the Western Cape, South Africa.

In a retrospective review of patients with acquired demyelinating disorders of the central nervous system, 19 children (0.6%) were identified from the Paediatric Neurology database of 3159 patients; 7 had acute disseminated encephalomyelitis, 1 had Schilder's disease, 5 had multiple sclerosis, and 6 had acute transverse myelitis. The median age of presentation was 83 months, with increased incidence during the summer and winter months. The commonest presentation was hemiparesis. The commonest regions of magnetic resonance imaging (MRI) abnormalities were the deep white matter (68%) and cerebellum (48%).The patients with multiple sclerosis had more monosymptomatic presentations (P < .02), raised cerebrospinal fluid protein (P = .022), and contrast enhancement of lesions (P = .05) compared with the acute disseminated encephalomyelitis group. Neuroepidemiological published surveillances of African children provide no data about these disorders. The prevalence of acquired demyelinating disorders in resource-poor settings is under-estimated because of the large burden of infections and limited access to neuroimaging.

Congenital cervical spinal cord lesions: pathogenesis, management, and outcome.

Three patients (2 boys) presented with nontraumatic congenital lesions of the spinal cord resulting in paralysis and contractures of their upper limbs from birth. Limited improvement occurred in all. Two survived. One patient required ventilation support after birth; his upper limbs had lower motor neuron flaccid paralysis, and his lower limbs evolved to pyramidal tract impairment. He died at 9 months of age with an intercurrent chest infection. The other 2 patients had lower motor neuron pathology in their upper limbs and normal lower limb function. One of these patients attained ambulation. All 3 patients retained normal higher mental function. Neuroimaging of the spinal cord from the most affected patient demonstrated atrophy of the cervical and high thoracic regions (C4-T3). Spinal neuroimaging results from the less affected patient were normal. Multidisciplinary management assisted these children to reach their full potential in a resource-poor setting. The etiology of focal pathology to the cervical region in these infants with congenital nontraumatic insults remains undefined, similar to the few cases in the literature. The diverse pathogeneses are hypothesized and the literature reviewed.