These results suggest that NTE-dependent alteration of phospholipid homeostasis in GHS causes both neurodegeneration and impaired LH release from pituitary gonadotropes, leading to nHH.

BackgroundPhenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability. The present study aimed to review published cases of such PKU patients.MethodsTo this purpose, we conducted a literature search in PubMed and EMBASE up to 8th of September 2017 to identify cases with 1) PKU diagnosis and start of treatment after 7 years of age; 2) untreated plasma phenylalanine concentrations ≥1200 μmol/l; and 3) IQ ≥80. Literature search, checking reference lists, selection of articles, and extraction of data were performed by two independent researchers.ResultsIn total, we identified 59 published cases of patients with late-diagnosed PKU and unexpected favorable outcome who met the inclusion criteria. Although all investigated patients had intellectual functioning within the normal range, at least 19 showed other neurological, psychological, and/or behavioral symptoms.ConclusionsBased on the present findings, the classical symptomatology of untreated or late-treated PKU may need to be rewritten, not only in the sense that intellectual dysfunction is not obligatory, but also in the sense that intellectual functioning does not (re)present the full picture of brain damage due to high plasma phenylalanine concentrations. Further identification of such patients and additional analyses are necessary to better understand these differences between PKU patients.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0890-7) contains supplementary material, which is available to authorized users.

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Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare and severe neurometabolic disease. We present two siblings with BVVLS with a novel homozygous mutation in SLC52A3 (formerly C20orf54) gene. The first sibling was admitted with respiratory insufficiency and required mechanical ventilation. After administration of a high dose of riboflavin, all his clinical symptoms were resolved, which also strongly suggested the diagnosis of BVVLS. The second sibling was also found to have the same genetic mutation as her brother. Although she was symptom-free, riboflavin was initiated empirically. On follow-up, she developed no neurologic or metabolic problems with entirely normal growth and development. BVVLS should be considered in the differential diagnosis of unexplained neurologic symptoms such as polyneuropathy and respiratory insufficiency, as BVVLS and multiple acyl-CoA dehydrogenation defect have broadly overlapping symptoms. Furthermore, our cases once again suggest that with proper diagnosis and early high-dose riboflavin treatment, complete reversal of neurologic deficits in BVVLS is possible.

Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of rare lysosomal storage disorders characterized by acid ceramidase deficiency (ACD), resulting from pathogenic variants in N‐acylsphingosine amidohydrolase 1 (ASAH1). Other than simple listings provided in literature reviews, a curated, comprehensive list of ASAH1 mutations associated with ACD clinical phenotypes has not yet been published. This publication includes mutations in ASAH1 collected through the Observational and Cross‐Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NHS), http://ClinicalTrials.gov identifier NCT03233841, in combination with an up‐to‐date curated list of published mutations. The NHS is the first to collect retrospective and prospective data on living and deceased patients with ACD presenting as Farber disease, who had or had not undergone hematopoietic stem cell transplantation. Forty‐five patients representing the known clinical spectrum of Farber disease (living patients aged 1–28 years) were enrolled. The curation of known ASAH1 pathogenic variants using a single reference transcript includes 10 previously unpublished from the NHS and 63 that were previously reported. The publication of ASAH1 variants will be greatly beneficial to patients undergoing genetic testing in the future by providing a significantly expanded reference list of disease‐causing variants.