Citations

Chanarin‐Dorfman syndrome also known as neutral lipid storage disease is a rare multisystemic autosomal recessive disorder. It is mostly encountered in patients of Mediterranean and Middle Eastern origin. Most patients are brought to medical attention secondary to dermatological manifestations namely ichthyosis. Here, we report a 10‐year‐old Kurdish male patient with ichthyosis, who was referred to pediatric liver clinic for transaminase elevation of unknown etiology despite elaborate workup. Histological findings on liver biopsy were consistent with nonalcoholic steatohepatitis. Genetic testing identified homozygous mutation C.776G>A (p.G259D) in the Abhydrolase domain containing 5 gene on chromosome 3 described in patients with Chanarin‐Dorfman syndrome. After the initiation of a diet with high medium chain triglycerides/long chain triglycerides ratio, aerobic exercise, and vitamin E, the patient liver enzymes improved. Due to debilitating ichthyosis, he was started on acitretin therapy that was discontinued due to transaminases elevation. Patient is currently stable and doing well.

PMM2-CDG is a rare disease, causing hypoglycosylation of multiple proteins, hence preventing full functionality. So far, no direct genotype–phenotype correlations have been identified. We carried out a retrospective cohort study on 26 PMM2-CDG patients. We collected the identified genotype, as well as continuous variables indicating the disease severity (based on Nijmegen Pediatric CDG Rating Score or NPCRS) and dichotomous variables reflecting the patients’ phenotype. The phenotypic effects of patients’ genotype were studied using non-parametric and Chi-Square tests. Seventeen different pathogenic variants have been studied. Variants with zero enzyme activity had no significant impact on the Nijmegen score. Pathogenic variants involving the stabilization/folding domain have a significantly lower total NPCRS (p = 0.017): presence of the p.Cys241Ser mutation had a significantly lower subscore 1,3 and NPCRS (p = 0.04) and thus result in a less severe phenotype. On the other hand, variants involving the dimerization domain, p.Pro113Leu and p.Phe119Leu, resulted in a significantly higher NPCRS score (p = 0.002), which indicates a worse clinical course. These concepts give a better insight in the phenotypic prognosis of PMM2-CDG, according to their molecular base.

AbstractObjectiveTo delineate the full phenotypic spectrum of BCS1L‐related disease, provide better understanding of the genotype–phenotype correlations and identify reliable prognostic disease markers.MethodsWe performed a retrospective multinational cohort study of previously unpublished patients followed in 15 centres from 10 countries. Patients with confirmed biallelic pathogenic BCS1L variants were considered eligible. Clinical, laboratory, neuroimaging and genetic data were analysed. Patients were stratified into different groups based on the age of disease onset, whether homozygous or compound heterozygous for the c.232A>G (p.Ser78Gly) variant, and those with other pathogenic BCS1L variants.ResultsThirty‐three patients were included. We found that growth failure, lactic acidosis, tubulopathy, hepatopathy and early death were more frequent in those with disease onset within the first month of life. In those with onset after 1 month, neurological features including movement disorders and seizures were more frequent. Novel phenotypes, particularly involving movement disorder, were identified in this group. The presence of the c.232A>G (p.Ser78Gly) variant was associated with significantly worse survival and exclusively found in those with disease onset within the first month of life, whilst other pathogenic BCS1L variants were more frequent in those with later symptom onset.InterpretationThe phenotypic spectrum of BCS1L‐related disease comprises a continuum of clinical features rather than a set of separate syndromic clinical identities. Age of onset defines BCS1L‐related disease clinically and early presentation is associated with poor prognosis. Genotype correlates with phenotype in the presence of the c.232A>G (p.Ser78Gly) variant.

ObjectiveEpalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2‐congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2‐CDG.MethodsWe performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2‐deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2‐CDG for 12 months.ResultsPMM enzyme activity increased post‐epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2‐deficient fibroblasts, 46% of which improved upon treatment. Total protein N‐glycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts’ glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2‐CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2‐CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months.InterpretationEpalrestat improved PMM enzyme activity, N‐glycosylation, and glycosylation biomarkers in vitro. Leveraging cellular glycoproteome assessment, we provided a systems‐level view of treatment efficacy and discovered potential novel biosignatures of therapy response. Epalrestat was well‐tolerated and led to significant clinical improvements in the first pediatric patient with PMM2‐CDG treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2‐CDG. ANN NEUROL 20219999:n/a–n/a

Significance By evaluating children with a malformed cerebral cortex, we identified an ATPase pump (ATP1A3) with an early role in brain development. The ATP1A3 pump maintains the physiological concentration of sodium and potassium ions in cells, a process critical for osmotic equilibrium and membrane potential across several developing cell populations. We employed single-cell sequencing approaches to identify key enrichments for ATP1A3 expression during human cortex development. Unravelling this early cell-type–specific pathophysiology in the developing brain offers a potential basis for the treatment of ATP1A3 -related diseases affecting prenatal and early childhood development.

AbstractPhosphoglucomutase 1 (PGM1) catalyzes the interconversion of glucose‐6‐phosphate to glucose‐1‐phosphate and is a key enzyme of glycolysis, glycogenesis, and glycogenolysis. PGM1 deficiency (OMIM: 614921) was initially defined as a glycogen storage disorder (type XIV), and later re‐classified as a PGM1‐congenital disorder of glycosylation (PGM1‐CDG). Serum transferrin (Tf) glycan isoform analysis by liquid chromatography‐mass spectrometry (LC‐MS) is used as a primary diagnostic screen tool, and reveals a very unique CDG profile described as a mixture of CDG‐type I and CDG‐type II patterns. Oral d‐galactose supplementation shows significant clinical and metabolic improvements, which are indicated by the Tf glycan isoform normalization over time in patients with PGM1‐CDG. Thus, there is a need for biomarkers to guide d‐galactose dosage in patients in order to maintain effective and safe drug levels. Here, we present a simplified algorithm called PGM1‐CDG Treatment Monitoring Index (PGM1‐TMI) for assessing the response of PGM1‐CDG patients to d‐galactose supplementation. For our single‐center cohort of 16 PGM1‐CDG patients, the Tf glycan profile analysis provided the biochemical diagnosis in all of them. In addition, the PGM1‐TMI was reduced in PGM1‐CDG patients under d‐galactose supplementation as compared with their corresponding values before treatment, indicating that glycosylation proceeds towards normalization. PGM1‐TMI allows tracking Tf glycan isoform normalization over time when the patients are on d‐galactose supplementation.

AbstractBranchio‐oto‐renal spectrum disorder (BORSD) is a rare autosomal dominant condition characterized by ear abnormalities with hard of hearing/deafness, second branchial arch malformations and renal anomalies. Pathogenic variations in EYA1 gene are found in the majority of clinically diagnosed individuals with BORSD. We describe an infant with BORSD related to a paternally inherited heterozygous pathogenic variation in EYA1 gene presenting with poor growth and hypoglycemia due to growth hormone deficiency. Magnetic resonance imaging revealed a diminutive pituitary gland and morphologically abnormal sella. Upon initiation of growth hormone therapy, the hypoglycemia resolved and catch up growth ensued. Pituitary abnormalities have not been reported previously in patients with BORSD. The zebrafish ortholog of eya1 is important for the development of adenohypophysis, suggesting that this patient's growth hormone deficiency and pituitary abnormality are part of BORSD. Inclusion of screening for pituitary hormone deficiency and pituitary imaging should be considered as a part of surveillance in patients with BORSD.