Objective To compare disease progression between different onset forms of metachromatic leukodystrophy (MLD) and to investigate the influence of the type of first symptoms on the natural course and dynamic of disease progression. Methods Clinical, genetic, and biochemical parameters were analyzed within a nationwide study of patients with late-infantile (LI; onset age ≤2.5 years), early-juvenile (EJ; onset age 2.6 to <6 years), late-juvenile (LJ; onset age 6 to <16 years), and adult (onset age ≥16 years) forms of MLD. First symptoms were categorized as motor symptoms only, cognitive symptoms only, or both. Standardized clinical endpoints included loss of motor and language functions, as well as dysphagia/tube feeding. Results Ninety-seven patients with MLD were enrolled. Patients with LI (n = 35) and EJ (n = 18) MLD exhibited similarly rapid disease progression, all starting with motor symptoms (with or without additional cognitive symptoms). In LJ (n = 38) and adult-onset (n = 6) patients, the course of the disease was as rapid as in the early-onset forms, when motor symptoms were present at disease onset, while patients with only cognitive symptoms at disease onset exhibited significantly milder disease progression, independently of their age at onset. A certain genotype-phenotype correlation was observed. Conclusions In addition to age at onset, the type of first symptoms predicts the rate of disease progression in MLD. These findings are important for counseling and therapy. Classification of Evidence This study provides Class II evidence that in patients with MLD, age at onset and the type of first symptoms predict the rate of disease progression.

Most microdeletions involving chromosome sub-bands 9q33.3-9q34.11 to this point have been detected by analyses focused on STXBP1, a gene known to cause early infantile epileptic encephalopathy 4 and other seizure phenotypes. Loss-of-function mutations of STXBP1 have also been identified in some patients with intellectual disability without epilepsy. Consequently, STXBP1 is widely assumed to be the gene causing both seizures and intellectual disability in patients with 9q33.3-q34.11 microdeletions. We report five patients with overlapping microdeletions of chromosome 9q33.3-q34.11, four of them previously unreported. Their common clinical features include intellectual disability, psychomotor developmental delay with delayed or absent speech, muscular hypotonia, and strabismus. Microcephaly and short stature are each present in four of the patients. Two of the patients had seizures. De novo deletions range from 1.23 to 4.13 Mb, whereas the smallest deletion of 432 kb in patient 3 was inherited from her mother who is reported to have mild intellectual disability. The smallest region of overlap (SRO) of these deletions in 9q33.3 does not encompass STXBP1, but includes two genes that have not been previously associated with disease, RALGPS1 and GARNL3. Sequencing of the two SRO genes RALGPS1 and GARNL3 in at least 156 unrelated patients with mild to severe idiopathic intellectual disability detected no causative mutations. Gene expression analyses in our patients demonstrated significantly reduced expression levels of GARNL3, RALGPS1 and STXBP1 only in patients with deletions of the corresponding genes. Thus, reduced expression of STXBP1 was ruled out as a cause for seizures in our patient whose deletion did not encompass STXBP1. We suggest that microdeletions of this region on chromosome 9q cause a clinical spectrum including intellectual disability, developmental delay especially concerning speech, microcephaly, short stature, mild dysmorphisms, strabismus, and seizures of incomplete penetrance, and may constitute a new contiguous gene deletion syndrome which cannot completely be explained by deletion of STXBP1.

Background: To investigate whether ultrasound-based optic nerve sheath diameter (US-ONSD) is a reliable measure to follow up children with idiopathic intracranial hypertension (IIH). In addition, to analyze the inter- and intra-individual relationships between US-ONSD and intracranial pressure (ICP), and to investigate whether an individualized mathematical regression equation obtained from two paired US-ONSD/ICP values can be used to approximate ICP from US-ONSD values. Methods: 159 US examinations and 53 invasive ICP measures via lumbar puncture (LP) were performed in 28 children with IIH. US-ONSD was measured using a 12 Mhz linear transducer and compared to ICP values. In 15 children, a minimum of 2 paired US-ONSD/ICP determinations were performed, and repeated-measures correlation (rmcorr) and intra-individual correlations were analyzed. Results: The cohort correlation between US-ONSD and ICP was moderate (r = 0.504, p < 0.01). Rmcorr (r = 0.91, p < 0.01) and intra-individual correlations (r = 0.956–1) of US-ONSD and ICP were excellent. A mathematical regression equation can be calculated from two paired US-ONSD/ICP values and applied to the individual patient to approximate ICP from US-ONSD. Conclusions: Related to excellent intra-individual correlations between US-ONSD and ICP, an individualized regression formula, created from two pairs of US-ONSD/ICP values, may be used to directly approximate ICP based on US-ONSD values. Hence, US-ONSD may become a non-invasive and reliable measure to control treatment efficacy in pediatric IIH.