Classic infantile Pompe patients approaching adulthood: A cohort study on consequences for the brain

Aim: To examine the long-term consequences of glycogen storage in the central nervous system (CNS) for classic infantile Pompe disease using enzyme replacement therapy. Method: Using neuropsychological tests and brain magnetic resonance imaging (MRI), we prospectively assessed a cohort of 11 classic infantile Pompe patients aged up to 17 years. Results: From approximately age 2 years onwards, brain MRI showed involvement of the periventricular white matter and centrum semiovale. After 8 years of age, additional white-matter abnormalities occurred in the corpus callosum, internal and external capsule, and subcortical areas. From 11 years of age, white-matter abnormalities were also found in the brainstem. Although there seemed to be a characteristic pattern of involvement over time, there were considerable variations between patients, reflected by variations in neuropsychological development. Cognitive development ranged from stable and normal to declines that lead to intellectual disabilities. Interpretation: As treatment enables patients with classic infantile Pompe disease to reach adulthood, white-matter abnormalities are becoming increasingly evident, affecting the neuropsychological development. Therefore, we advise follow-up programs are expanded to capture CNS involvement in larger, international patient cohorts, to incorporate our findings in the counselling of parents before the start of treatment, and to include the brain as an additional target in the development of next-generation therapeutic strategies for classic infantile Pompe disease. What this paper adds: In our long-term survivors treated intravenously with enzyme replacement therapy, we found slowly progressive symmetric white-matter abnormalities. Cognitive development varied from stable and normal to declines towards intellectual disabilities

Defining the phenotypical spectrum associated with variants in TUBB2A

Background Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. Methods In order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed. Results We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. Conclusion The imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype-phenotype correlations could be established, suggesting the role of additional modifiers.</p

Risk factors for elevated levels of 17-hydroxyprogesterone during neonatal intensive care unit admission.

Introduction: Screening for congenital adrenal hyperplasia (CAH) by measurement of 17-hydroxyprogesterone (17-OHP) in dried blood spots results in a high false positive rate among preterm newborns admitted in a neonatal intensive care unit (NICU). We searched for risk factors of this population for raised 17-OHP levels. Methods: We retrospectively collected clinical characteristics (prenatal, at birth, postnatal) in newborns with an increased 17-OHP level at initial screening (&gt; 30 nmol/L for a birth weight &gt; 2000 g and &gt; or = 60 nmol/L for a birth weight &lt; or = 2000 g), that turned out to be false positive (no CAH). The correlation of these characteristics with individual 17-OHP levels was evaluated. We also performed a case-control study matched for gestational age (GA). Results: In 94 screened newborns 17-OHP levels were raised at initial screening. Negative correlations were found between 17-OHP levels and GA and birth weight, positive correlations with prenatal betamethasone administration and several parameters of respiratory disease. In a multiple regression model GA was the dominant variable. In the case control study with 91 index patients admitted to the NICU (91/1275 newborns admitted to the NICU, 7.1%) a positive correlation with respiratory disease was confirmed and cases had a significant higher birth weight and a significant lower incidence of prenatal betamethasone administration. Application of new cutoff tables adjusted by GA and/or day of sampling would have resulted in a reduction in false positive rate. Conclusion: The dominant risk factor for a false positive screening during NICU admission is GA. Prenatal administration of betamethasone and birth weight are more complex risk factors. These observations support the use of new cut-off values based on GA to reduce the problem of false positive screening.</p

Risk factors for elevated levels of 17-hydroxyprogesterone during neonatal intensive care unit admission.

Introduction: Screening for congenital adrenal hyperplasia (CAH) by measurement of 17-hydroxyprogesterone (17-OHP) in dried blood spots results in a high false positive rate among preterm newborns admitted in a neonatal intensive care unit (NICU). We searched for risk factors of this population for raised 17-OHP levels. Methods: We retrospectively collected clinical characteristics (prenatal, at birth, postnatal) in newborns with an increased 17-OHP level at initial screening (&gt; 30 nmol/L for a birth weight &gt; 2000 g and &gt; or = 60 nmol/L for a birth weight &lt; or = 2000 g), that turned out to be false positive (no CAH). The correlation of these characteristics with individual 17-OHP levels was evaluated. We also performed a case-control study matched for gestational age (GA). Results: In 94 screened newborns 17-OHP levels were raised at initial screening. Negative correlations were found between 17-OHP levels and GA and birth weight, positive correlations with prenatal betamethasone administration and several parameters of respiratory disease. In a multiple regression model GA was the dominant variable. In the case control study with 91 index patients admitted to the NICU (91/1275 newborns admitted to the NICU, 7.1%) a positive correlation with respiratory disease was confirmed and cases had a significant higher birth weight and a significant lower incidence of prenatal betamethasone administration. Application of new cutoff tables adjusted by GA and/or day of sampling would have resulted in a reduction in false positive rate. Conclusion: The dominant risk factor for a false positive screening during NICU admission is GA. Prenatal administration of betamethasone and birth weight are more complex risk factors. These observations support the use of new cut-off values based on GA to reduce the problem of false positive screening.</p

ALG11-CDG: Three novel mutations and further characterization of the phenotype

We report on two novel patients with ALG11-CDG. The phenotype was characterized by severe psychomotor disability, progressive microcephaly, sensorineural hearing loss, therapy-resistant epilepsy with burst suppression EEG, cerebral atrophy with, in one of them, neuronal heterotopia, and early lethality. Analysis of ALG11 revealed compound heterozygosity involving three novel mutations: the splice site mutation c.45-2A > T, the c.36dupG duplication, and the missense mutation c.479G > T (p.G160V) that was present in both.status: publishe

Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations.

The Zellweger spectrum disorders (ZSDs) are known to be severe disorders with onset in the newborn period or later in childhood, frequently resulting in death during childhood or adolescence. Here, we report a case of ZSD due to mutations in the PEX2 gene, with very mild phenotype. A 51-year-old Italian man was referred to us because of a clinical picture characterized by ataxia, areflexia, nystagmus, and strabismus, with childhood onset and slowly progressive course. The patient showed no cognitive impairment. Neurological examination revealed gait ataxia, dysarthria, dysmetria, areflexia, and bilateral pes cavus. Nerve conduction studies indicated a severe axonal sensorimotor polyneuropathy. Brain MRI showed marked cerebellar atrophy and absence of white matter involvement. MR spectroscopy uncovered a decreased N-acetyl aspartate peak. Biochemical analyses suggested a mild peroxisomal defect. Sequence analysis of the PEX2 gene identified two heterozygous mutations. The clinical phenotype of our patient differs from previously reported ZSD patients with PEX2 gene mutations and suggests that genetic screening of PEX2 is warranted in children and adults with otherwise unexplained autosomal recessive ataxia. MRI findings diverged from the "classic" spectrum observed in ZSDs. The moderate impairment in peroxisome biogenesis seems to affect predominantly neuronal cells in cerebellum, leading to cerebellar atroph

RFT1-CDG: Deafness as a novel feature of congenital disorders of glycosylation

Congenital disorders of glycosylation (CDG) are genetic diseases due to defects in the synthesis of glycans and in the attachment of glycans to lipids and proteins. Actually, some 42 CDG are known including defects in protein N-glycosylation, in protein O-glycosylation, in lipid glycosylation, and in multiple and other glycosylation pathways. Most CDG are multisystem diseases and a large number of signs and symptoms have already been reported in CDG. An exception to this is deafness. This symptom has not been observed as a consistent feature in CDG. In 2008, a novel defect was identified in protein N-glycosylation, namely in RFT1. This is a defect in the assembly of N-glycans. RFT1 is involved in the transfer of Man(5)GlcNAc(2)-PP-Dol from the cytoplasmic to the luminal side of the endoplasmic reticulum. According to the novel nomenclature (non-italicized gene symbol followed by -CDG) this defect is named RFT1-CDG. Recently, three other patients with RFT1-CDG have been reported and here we report two novel patients. Remarkably, all six patients with RFT1-CDG show sensorineural deafness as part of a severe neurological syndrome. We conclude that RFT1-CDG is the first 'deafness-CDG'. CDG should be included in the work-up of congenital, particularly syndromic, hearing loss

PREPL deficiency : Delineation of the phenotype and development of a functional blood assay

PurposePREPL deficiency causes neonatal hypotonia, ptosis, neonatal feeding difficulties, childhood obesity, xerostomia, and growth hormone deficiency. Different recessive contiguous gene deletion syndromes involving PREPL and a variable combination of SLC3A1 (hypotonia-cystinuria syndrome), CAMKMT (atypical hypotonia-cystinuria syndrome), and PPM1B (2p21 deletion syndrome) have been described. In isolated PREPL deficiency, previously described only once, the absence of cystinuria complicates the diagnosis. Therefore, we developed a PREPL blood assay and further delineated the phenotype.MethodsClinical features of new subjects with PREPL deficiency were recorded. The presence of PREPL in lymphocytes and its reactivity with an activity-based probe were evaluated by western blot.ResultsFive subjects with isolated PREPL deficiency, three with hypotonia-cystinuria syndrome, and two with atypical hypotonia-cystinuria syndrome had nine novel alleles. Their IQs ranged from 64 to 112. Adult neuromuscular signs included ptosis, nasal dysarthria, facial weakness, and variable proximal and neck flexor weakness. Autonomic features are prevalent. PREPL protein and reactivity were absent in lymphocytes from subjects with PREPL deficiency, but normal in the clinically similar Prader-Willi syndrome.ConclusionPREPL deficiency causes neuromuscular, autonomic, cognitive, endocrine, and dysmorphic clinical features. PREPL is not deficient in Prader-Willi syndrome. The novel blood test should facilitate the confirmation of PREPL deficiency