Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization.

Background And Objectives: Genetic white matter disorders (GWMD) are of heterogeneous origin, with >100 causal genes identified to date. Classic targeted approaches achieve a molecular diagnosis in only half of all patients. We aimed to determine the clinical utility of singleton whole-exome sequencing and whole-genome sequencing (sWES-WGS) interpreted with a phenotype- and interactome-driven prioritization algorithm to diagnose GWMD while identifying novel phenotypes and candidate genes.

International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: Diagnosis, treatment and follow up.

Phosphomannomutase 2 (PMM2-CDG) is the most common congenital disorder of N-glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2-CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach.

Lysine Restriction and Pyridoxal Phosphate Administration in a NADK2 Patient.

We report the case of a 10-year-old Spanish girl with mutations in NADK2 Prenatal central nervous system abnormalities showed ventriculomegaly, colpocephaly, and hypoplasia of the corpus callosum. At birth, axial hypotonia, uncoordinated movements, microcephaly, and generalized cerebellar atrophy were detected. Metabolic investigations revealed high lysine, lactate, and pipecolic acid levels in blood and cerebrospinal fluid.

Mutations in TRAPPC11 are associated with a congenital disorder of glycosylation.

Congenital disorders of glycosylation (CDG) are a heterogeneous and rapidly growing group of diseases caused by abnormal glycosylation of proteins and/or lipids. Mutations in genes involved in the homeostasis of the endoplasmic reticulum (ER), the Golgi apparatus (GA), and the vesicular trafficking from the ER to the ER-Golgi intermediate compartment (ERGIC) have been found to be associated with CDG. Here, we report a patient with defects in both N- and O-glycosylation combined with a delayed vesicular transport in the GA due to mutations in TRAPPC11, a subunit of the TRAPPIII complex.

Phosphomannomutase deficiency (PMM2-CDG): ataxia and cerebellar assessment.

Background: Phosphomannomutase deficiency (PMM2-CDG) is the most frequent congenital disorder of glycosylation. The cerebellum is nearly always affected in PMM2-CDG patients, a cerebellar atrophy progression is observed, and cerebellar dysfunction is their main daily functional limitation. Different therapeutic agents are under development, and clinical evaluation of drug candidates will require a standardized score of cerebellar dysfunction.

Cholestane-3β,5α,6β-triol: high levels in Niemann-Pick type C, cerebrotendinous xanthomatosis, and lysosomal acid lipase deficiency.

Niemann-Pick type C (NPC) is a progressive neurodegenerative disease characterized by lysosomal/endosomal accumulation of unesterified cholesterol and glycolipids. Recent studies have shown that plasma cholestane-3β,5α,6β-triol (CT) and 7-ketocholesterol (7-KC) could be potential biomarkers for the diagnosis of NPC patients. We aimed to know the sensitivity and specificity of these biomarkers for the diagnosis of NPC compared with other diseases that can potentially lead to oxysterol alterations.

Autophagy induction halts axonal degeneration in a mouse model of X-adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic disease characterized by the accumulation of very long chain fatty acids (VLCFAs) due to a loss of function of the peroxisomal transporter ABCD1. Here, using in vivo and in vitro models, we demonstrate that autophagic flux was impaired due to elevated mammalian target of rapamycin (mTOR) signaling, which contributed to X-ALD pathogenesis. We also show that excess VLCFAs downregulated autophagy in human fibroblasts.

The proteasome inhibitor bortezomib reduced cholesterol accumulation in fibroblasts from Niemann-Pick type C patients carrying missense mutations.

Niemann-Pick disease type C (NPC) is a lipid storage disorder mainly caused by mutations in the NPC1 gene. Approximately 60% of these mutations are missense changes that may induce reduced NPC1 protein levels by increased degradation via ubiquitin-proteasome. This is the case for the most prevalent worldwide mutation, p.

The role of the abnormalities in the distal pathway of cholesterol biosynthesis in the Conradi-Hünermann-Happle syndrome.

Conradi-Hünermann-Happle syndrome (CDPX2, OMIM 302960) is an inherited X-linked dominant variant of chondrodysplasia punctata (CP) caused by mutations in one gene of the distal pathway of cholesterol biosynthesis. It exhibits intense phenotypic variation and primarily affects the skin, bones and eyes. The ichthyosis following Blaschko's lines, chondrodysplasia punctata and cataracts are the typical clinical findings.

A key role for the peroxisomal ABCD2 transporter in fatty acid homeostasis.

Peroxisomes are essential organelles exerting key functions in fatty acid metabolism such as the degradation of very long-chain fatty acids (VLCFAs). VLCFAs accumulate in X-adrenoleukodystrophy (X-ALD), a disease caused by deficiency of the Abcd1 peroxisomal transporter. Its closest homologue, Abcd2, exhibits a high degree of functional redundancy on the catabolism of VLCFA, being able to prevent X-ALD-related neurodegeneration in the mouse.

Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is a severe neurodegenerative disease caused by loss of function of the peroxisomal transporter ABCD1 (ALD), which results in accumulation of very long chain fatty acids (VLCFAs) in organs and serum, central demyelination and peripheral axonopathy and Addison's disease. Knockout of the ALD gene in the mouse (ALD(-)) results in an adrenomyeloneuropathy-like disease (a late onset form of X-ALD). In the present study, we demonstrate that axonal damage occurs as first pathological event in this model, followed by myelin degeneration.