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Background Members of two seemingly unrelated kindreds of Arab Moslem origin presented with pronounced early onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis. Methods The authors performed neurological and developmental examinations on the affected individuals. The authors conducted whole genome linkage and haplotype analyses, followed by sequencing of candidate genes; RNA and protein expression studies; and finally proof of principle investigations on knockdown morpholino oligonucleotide injected zebrafish. Results The authors characterise a novel form of autosomal recessive complex hereditary spastic paraparesis (CHSP). MRI studies of brain and spinal cord were normal. Within a single significantly linked locus the authors ultimately identified a homozygous missense mutation c.1146A>T (p.K382N) in the vacuolar protein sorting 37A ( Vps37A ) gene, fully penetrant and segregating with the disease in both families. Mobility was significantly reduced in Vps37A knockdown morpholino oligonucleotide injected zebrafish, supporting the causal relationship between mutations in this gene and the phenotype described in the patients of this study. Conclusions The authors provide evidence for the involvement of Vps37A , a member of the endosomal sorting complex required for transport (ESCRT) system, in upper motor neuron disease. The ESCRT system has been shown to play a central role in intracellular trafficking, in the maturation of multivesicular bodies and the sorting of ubiquitinated membrane proteins into internal luminal vesicles. Further investigation of mechanisms by which dysfunction of this gene causes CHSP will contribute to the understanding of intracellular trafficking of vesicles by the ESCRT machinery and its relevance to CHSP.

Background Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder associated with mitochondrial dysfunction. LS is characterised by elevated lactate and pyruvate and bilateral symmetric hyperintense lesions in the basal ganglia, thalamus, brainstem, cerebral white matter or spinal cord on T2-weighted MRI. LS is a genetically heterogeneous disease, and to date mutations in approximately 40 genes related to mitochondrial function have been linked to the disorder. Methods We investigated a pair of female monozygotic twins diagnosed with LS from consanguineous healthy parents of Indian origin. Their common clinical features included optic atrophy, ophthalmoplegia, spastic paraparesis and mild intellectual disability. High-blood lactate and high-intensity signal in the brainstem on T2-weighted MRI were consistent with a clinical diagnosis of LS. To identify the genetic cause of their condition, we performed whole exome sequencing. Results We identified a homozygous nonsense mutation in C12orf65 (NM_001143905; c.346delG, p.V116*) in the affected twins. Interestingly, the identical mutation was previously reported in an Indian family with Charcot-Marie Tooth disease type 6, which displayed some overlapping clinical features with the twins. Conclusions We demonstrate that the identical nonsense mutation in C12orf65 can result in different clinical features, suggesting the involvement of unknown modifiers.

Introduction Lumbar puncture (LP) is routinely performed as part of the workup evaluation of suspected acute disseminated encephalomyelitis (ADEM). Mild pleocytosis and/or increased CSF protein concentration are common findings in ADEM. However, the CSF opening pressure, reflecting the intracranial pressure (ICP), has not been acknowledged to date in the literature. Methods Chart reviews of paediatric patients hospitalised in the Tel-Aviv Sourasky medical centre, between 2005–2013, that were diagnosed with ADEM, were identified retrospectively. Results Among 35 children diagnosed with ADEM, 20 who had documented CSF opening pressure comprised the study group. The mean age was 5.3 ± 4.1 years, ten males (50%); Mean CSF opening pressure was 27.8 ± 12.4 cmH 2 O, range 10–55 cmH 2 O. Considering the upper normal limit of CSF opening pressure in this age group (18 cmH 2 O), 15/20 (75%) patients had elevated pressure and one sample t-test comparison showed significant elevated CSF opening pressure among patients with ADEM (p v = 0.0023, 95% CI 3.9–15.6). Minimal pleocytosis was present in seven samples (median=2 cells/mm 2 ). Eighteen out of twenty (90%) patients had clinical complaints/signs that can be explained by increased ICP (drowsiness/encephalopathy n = 18, vomiting n = 8, headache n = 8). Discussion This study highlights that increased ICP is a prominent patho-physiologic change occurring in the CNS of ADEM patients. In our cohort, this was the most common CSF abnormal finding, independent of pleocytosis level. This observation is in line with the common non-focal neurological symptoms and signs and the beneficial effect of steroid treatment in ADEM. Furthermore, it suggests a potential efficacy of other reducing ICP treatments in ADEM.