An extremely severe phenotype attributed to WDR81 nonsense mutations

no abstract availabl

Cavitating and tigroid-like leukoencephalopathy in a case of NDUFA2-related disorder

Biallelic variants in nuclear gene NDUFA2 have been reported so far in only three children with variable presentations including Leigh syndrome or leukoencephalopathy. Herein, we report a further female child affected by NDUFA2-related disorder presenting with cavitating and tigroid-like pattern of leukodystrophy and without systemic biochemical abnormalities of mitochondrial disorders

Contribution of Genetic Test to Early Diagnosis of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency: The Experience of a Reference Center in Southern Italy.

BACKGROUND the deficiency of 5,10-Methylenetetrahydrofolate reductase (MTHFR) constitutes a rare and severe metabolic disease and is included in most expanded newborn screening (NBS) programs worldwide. Patients with severe MTHFR deficiency develop neurological disorders and premature vascular disease. Timely diagnosis through NBS allows early treatment, resulting in improved outcomes. METHODS we report the diagnostic yield of genetic testing for MTHFR deficiency diagnosis, in a reference Centre of Southern Italy between 2017 and 2022. MTHFR deficiency was suspected in four newborns showing hypomethioninemia and hyperhomocysteinemia; otherwise, one patient born in pre-screening era showed clinical symptoms and laboratory signs that prompted to perform genetic testing for MTHFR deficiency. RESULTS molecular analysis of the MTHFR gene revealed a genotype compatible with MTHFR deficiency in two NBS-positive newborns and in the symptomatic patient. This allowed for promptly beginning the adequate metabolic therapy. CONCLUSIONS our results strongly support the need for genetic testing to quickly support the definitive diagnosis of MTHFR deficiency and start therapy. Furthermore, our study extends knowledge of the molecular epidemiology of MTHFR deficiency by identifying a novel mutation in the MTHFR gene.This research received no external funding.S

Expansion of the phenotype of lateral meningocele syndrome

Lateral meningocele syndrome (LMS) is due to specific pathogenic variants in the last exon of NOTCH3 gene. Besides the lateral meningoceles, this condition presents with dysmorphic features, short stature, congenital heart defects, and feeding difficulties. Here, we report a girl with neurosensorial hearing loss, severe gastroesophageal reflux disease, congenital heart defects, multiple renal cysts, kyphosis and left-convex scoliosis, dysmorphic features, and mild developmental delay. Exome sequencing detected the previously unreported de novo loss-of-function variant in exon 33 of NOTCH3 p.(Lys2137fs). Following the identification of the gene defect, MRI of the brain and spine revealed temporal encephaloceles, inner ears anomalies, multiple spinal lateral meningoceles, and intra- and extra-dural arachnoid spinal cysts. This case illustrates the power of reverse phenotyping to establish clinical diagnosis and expands the spectrum of clinical manifestations related to LMS to include inner ear abnormalities and multi-cystic kidney disease

A child with Myhre syndrome presenting with corectopia and tetralogy of Fallot

Myhre syndrome is a rare autosomal dominant disorder caused by a narrow spectrum of missense mutations in the SMAD4 gene. Typical features of this disorder are distinctive facial appearance, deafness, intellectual disability, cardiovascular abnormalities, short stature, short hands and feet, compact build, joint stiffness, and skeletal anomalies. The clinical features generally appear during childhood and become more evident in older patients. Therefore, the diagnosis of this syndrome in the first years of life is challenging. We report a 2-year-old girl diagnosed with Myhre syndrome by whole exome sequencing (WES) that revealed the recurrent p.Ile500Val mutation in the SMAD4 gene. Our patient presented with growth deficiency, dysmorphic features, tetralogy of Fallot, and corectopia (also known as ectopia pupillae). The girl we described is the youngest patient with Myhre syndrome. Moreover, corectopia and tetralogy of Fallot have not been previously reported in this disorder

Gait disturbance and lower limb pain in a patient with PIK3CA-related disorder

Post-zygotic activating mutations in PIK3CA and other genes encoding members of PI3K-AKT-mTOR pathway have been found in various overgrowth syndromes that have been grouped together as PIK3CA-related overgrowth spectrum (PROS). We report a female patient with gait disturbance, leg pain, isolated macrodactyly of the foot, and mild intellectual disability. Imaging of the lower limb showed a lipoblastoma of the right thigh. A mosaic gain-of-function mutation in the catalytic domain of PIK3CA (c.3140 A > G; p.His1047Arg) was detected in the adipose tissue and in skin cultured fibroblasts from the macrodactyly but not in blood. The leg pain and the severe walking disturbance improved slightly over time and serial MRI of the lower limbs suggested that the size of the lipoblastoma relative to the lower limb muscles or to the whole lower limb was unchanged as consequence of limb growth. This case report illustrates that pain and gait disturbance can be features of PROS and highlights the need of better knowledge about the natural history of the disease

Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet

<div><p>Global metabolomic profiling offers novel opportunities for the discovery of biomarkers and for the elucidation of pathogenic mechanisms that might lead to the development of novel therapies. GLUT1 deficiency syndrome (GLUT1-DS) is an inborn error of metabolism due to reduced function of glucose transporter type 1. Clinical presentation of GLUT1-DS is heterogeneous and the disorder mirrors patients with epilepsy, movement disorders, or any paroxysmal events or unexplained neurological manifestation triggered by exercise or fasting. The diagnostic biochemical hallmark of the disease is a reduced cerebrospinal fluid (CSF)/blood glucose ratio and the only available treatment is ketogenic diet. This study aimed at advancing our understanding of the biochemical perturbations in GLUT1-DS pathogenesis through biochemical phenotyping and the treatment of GLUT1-DS with a ketogenic diet. Metabolomic analysis of three CSF samples from GLUT1-DS patients not on ketogenic diet was feasible inasmuch as CSF sampling was used for diagnosis before to start with ketogenic diet. The analysis of plasma and urine samples obtained from GLUT1-DS patients treated with a ketogenic diet showed alterations in lipid and amino acid profiles. While subtle, these were consistent findings across the patients with GLUT1-DS on ketogenic diet, suggesting impacts on mitochondrial physiology. Moreover, low levels of free carnitine were present suggesting its consumption in GLUT1-DS on ketogenic diet. 3-hydroxybutyrate, 3-hydroxybutyrylcarnitine, 3-methyladipate, and N-acetylglycine were identified as potential biomarkers of GLUT1-DS on ketogenic diet. This is the first study to identify CSF, plasma, and urine metabolites associated with GLUT1-DS, as well as biochemical changes impacted by a ketogenic diet. Potential biomarkers and metabolic insights deserve further investigation.</p></div

Significant free carnitine and carnitine derivatives for 6 patients with GLUT1-DS patients.

<p>Significant free carnitine and carnitine derivatives for 6 patients with GLUT1-DS patients.</p