Congenital Disorders of Glycosylation

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Increased prevalence of Parkinson's disease in alkaptonuria

Abstract Amongst a cohort of 88 alkaptonuria (AKU) patients attending the United Kingdom National Alkaptonuria Centre (NAC), four unrelated patients had co‐existing Parkinson's disease (PD). Two of the NAC patients developed PD before receiving nitisinone (NIT) while the other two developed overt PD during NIT therapy. NIT lowers redox‐active homogentisic acid (HGA) and profoundly increases tyrosine (TYR). A further unpublished case of a Dutch patient with AKU and PD on deep brain stimulation is included in this report. A Pubmed search revealed a further five AKU patients with PD, all without NIT usage. The prevalence of PD in AKU in the NAC appears to be nearly 20‐times higher than in the non‐AKU population (p < 0.001) even when adjusted for age. We propose that life‐long exposure to redox‐active HGA may account for the higher prevalence of PD in AKU. Furthermore, the appearance of PD in AKU patients during NIT therapy may be due to unmasking dopamine deficiency in susceptible individuals, as a result of the tyrosinaemia during NIT therapy inhibiting the rate‐limiting brain tyrosine hydroxylase

Tetrahydrobiopterin responsiveness in phenylketonuria: prediction with the 48-hour loading test and genotype

BACKGROUND: How to efficiently diagnose tetrahydrobiopterin (BH4) responsiveness in patients with phenylketonuria remains unclear. This study investigated the positive predictive value (PPV) of the 48-hour BH4 loading test and the additional value of genotype. METHODS: Data of the 48-hour BH4 loading test (20 mg BH4/kg/day) were collected at six Dutch university hospitals. Patients with >=30% phenylalanine reduction at >=1 time points during the 48 hours (potential responders) were invited for the BH4 extension phase, designed to establish true-positive BH4 responsiveness. This is defined as long-term >=30% reduction in mean phenylalanine concentration and/or >=4 g/day and/or >=50% increase of natural protein intake. Genotype was collected if available. RESULTS: 177/183 patients successfully completed the 48-hour BH4 loading test. 80/177 were potential responders and 67/80 completed the BH4 extension phase. In 58/67 true-positive BH4 responsiveness was confirmed (PPV 87%). The genotype was available for 120/177 patients. 41/44 patients with >=1 mutation associated with long-term BH4 responsiveness showed potential BH4 responsiveness in the 48-hour test and 34/41 completed the BH4 extension phase. In 33/34 true-positive BH4 responsiveness was confirmed. 4/40 patients with two known putative null mutations were potential responders; 2/4 performed the BH4 extension phase but showed no true-positive BH4 responsiveness. CONCLUSIONS: The 48-hour BH4 loading test in combination with a classified genotype is a good parameter in predicting true-positive BH4 responsiveness. We propose assessing genotype first, particularly in the neonatal period. Patients with two known putative null mutations can be excluded from BH4 testing

Outcome of infantile nephropathic cystinosis depends on early intervention, not genotype: A multicenter sibling cohort study

BACKGROUND: Infantile Nephropathic Cystinosis (INC) is an inheritable lysosomal storage disorder characterized by lysosomal cystine accumulation, progressive kidney disease and multiple extra-renal complications (ERC). Cysteamine postpones the onset of end-stage kidney disease (ESKD) and reduces the incidence of ERCs, however, cysteamine is generally initiated upon establishment of the renal Fanconi Syndrome (FS) and partial loss of kidney function, whereas data on long-term effects of cysteamine administered from neonatal age are lacking. MATERIALS & METHODS: An international multicenter retrospective cohort study of siblings with INC was set up to investigate the outcome in relation to age at initiation of cysteamine versus CTNS genotype, with attention to patients treated with cysteamine from neonatal age. RESULTS: None of the siblings treated from neonatal age (n=9; age 10 ± 6 years) had reached ESKD, while 22% of their index counterparts (n=9; age 14 ± 5 years) had commenced renal replacement therapy. Siblings treated with cysteamine from the onset of symptoms at a younger age compared to their index counterparts, reached ESKD at a significant older age (13 ± 3 years vs. 10 ± 3 years, p = 0.002). In contrast, no significant difference in ERCs was observed between sibling and index patients, independently from the age at initiation of cysteamine. The CTNS genotype had no impact on the overall outcome in this cohort. CONCLUSIONS: In INC, presymptomatic treatment with cysteamine results in a better renal outcome in comparison to treatment initiated from the onset of symptoms. This justifies including cystinosis into newborn screening programs

Association between Lysine Reduction Therapies and Cognitive Outcomes in Patients with Pyridoxine-Dependent Epilepsy

BACKGROUND AND OBJECTIVES: Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a developmental epileptic encephalopathy characterized by seizure improvement after pyridoxine supplementation. Adjunct lysine reduction therapies (LRTs) reduce the accumulation of putative neurotoxic metabolites with the goal to improve developmental outcomes. Our objective was to examine the association between treatment with LRTs and cognitive outcomes. METHODS: Participants were recruited from within the International Registry for Patients with Pyridoxine-Dependent Epilepsy from August 2014 through March 2021. The primary outcome was standardized developmental test scores associated with overall cognitive ability. The relationship between test scores and treatment was analyzed with multivariable linear regression using a mixed-effects model. A priori, we hypothesized that treatment in early infancy with pyridoxine and LRTs would result in a normal developmental outcome. A subanalysis was performed to evaluate the association between cognitive outcome and LRTs initiated in the first 6 months of life. RESULTS: A total of 112 test scores from 60 participants were available. On average, treatment with pyridoxine and LRTs was associated with a nonsignificant increase of 6.9 points (95% CI −2.7 to 16.5) on developmental testing compared with treatment with pyridoxine alone. For the subanalysis, a total of 14 developmental testing scores were available from 8 participants. On average, treatment with pyridoxine and LRTs in the first 6 months of life was associated with a significant increase of 21.9 points (95% CI 1.7–42.0) on developmental testing. DISCUSSION: Pyridoxine and LRTs at any age was associated with mild improvement in developmental testing, and treatment in early infancy was associated with a clinically significant increase in developmental test scores. These results provide insight into the mechanism of intellectual and developmental disability in PDE-ALDH7A1 and emphasize the importance of treatment in early infancy with both pyridoxine and LRTs. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in PDE-ALDH7A1, pyridoxine and LRTs compared with pyridoxine alone is not significantly associated with overall higher developmental testing scores, but treatment in the first 6 months of life is associated with significantly higher developmental testing scores

Iron refractory iron deficiency anemia: a heterogeneous disease that is not always iron refractory

TMPRSS6 variants that affect protein function result in impaired matriptase-2 function and consequently uninhibited hepcidin production, leading to iron refractory iron deficiency anemia (IRIDA). This disease is characterized by microcytic, hypochromic anemia and serum hepcidin values that are inappropriately high for body iron levels. Much is still unknown about its pathophysiology, genotype-phenotype correlation, and optimal clinical management. We describe 14 different TMPRSS6 variants, of which 9 are novel, in 21 phenotypically affected IRIDA patients from 20 families living in the Netherlands; 16 out of 21 patients were female. In 7 out of 21 cases DNA sequencing and multiplex ligation dependent probe amplification demonstrated only heterozygous TMPRSS6 variants. The age at presentation, disease severity, and response to iron supplementation were highly variable, even for patients and relatives with similar TMPRSS6 genotypes. Mono-allelic IRIDA patients had a milder phenotype with respect to hemoglobin and MCV and presented significantly later in life with anemia than bi-allelic patients. Transferrin saturation (TSAT)/hepcidin ratios were lower in IRIDA probands than in healthy relatives. Most patients required parenteral iron. Genotype alone was not predictive for the response to oral iron. We conclude that IRIDA is a genotypically and phenotypically heterogeneous disease. The high proportion of female patients and the discrepancy between phenotypes of probands and relatives with the same genotype, suggest a complex interplay between genetic and acquired factors in the pathogenesis of IRIDA. In the absence of inflammation, the TSAT/hepcidin ratio is a promising diagnostic tool, even after iron supplementation has been given. Am. J. Hematol. 91:E482-E490, 2016. © 2016 Wiley Periodicals, Inc.status: publishe