Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation

BACKGROUND: The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA) (OMIM 225400) is a rare inheritable connective tissue disorder characterized by a deficiency of collagen lysyl hydroxylase 1 (LH1; EC 1.14.11.4) due to mutations in PLOD1. Biochemically this results in underhydroxylation of collagen lysyl residues and, hence, an abnormal pattern of lysyl pyridinoline (LP) and hydroxylysyl pyridinoline (HP) crosslinks excreted in the urine. Clinically the disorder is characterized by hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin hyperelasticity and fragility. Severe hypotonia usually leads to delay in gross motor development, whereas cognitive development is reported to be normal. METHODS: We describe the clinical, biochemical and molecular characterisation, as well as electron microscopy findings of skin, in 15 patients newly diagnosed with this rare type of Ehlers-Danlos syndrome. RESULTS: Age at diagnosis ranged from 5 months to 27 years, with only 1/3 of the patients been diagnosed correctly in the first year of life. A similar disease frequency was found in females and males, however a broad disease severity spectrum (intra- and interfamilial), independent of molecular background or biochemical phenotype, was observed. Kyphoscoliosis, one of the main clinical features was not present at birth in 4 patients. Importantly we also noted the occurrence of vascular rupture antenatally and postnatally, as well as developmental delay in 5 patients. CONCLUSION: In view of these findings we propose that EDS VIA is a highly variable clinical entity, presenting with a broad clinical spectrum, which may also be associated with cognitive delay and an increased risk for vascular events. Genotype/phenotype association studies and additional molecular investigations in more extended EDS VIA populations will be necessary to further elucidate the cause of the variability of the disease severity

Dyskinetic crisis in GNAO1-related disorders: clinical perspectives and management strategies

BackgroundGNAO1-related disorders (GNAO1-RD) encompass a diverse spectrum of neurodevelopmental and movement disorders arising from variants in the GNAO1 gene. Dyskinetic crises, marked by sudden and intense exacerbations of abnormal involuntary movements, present a significant challenge in GNAO1-RD.ObjectivesThis study aimed to establish a standardized framework for understanding dyskinetic crises, addressing crucial aspects such as definition, triggers, diagnostic criteria, complications, and management strategies.MethodsA Delphi consensus process was conducted involving international experts in GNAO1-RD. The panel of thirteen experts participated in three voting rounds, discussing 90 statements generated through a literature review and clinical expertise.ResultsConsensus was achieved on 31 statements, defining dyskinetic crises as abrupt, paroxysmal episodes involving distinct abnormal movements in multiple body regions, triggered by emotional stress or infections. Dyskinetic crises may lead to functional impairment and complications, emphasizing the need for prompt recognition. While individualized pharmacological recommendations were not provided, benzodiazepines and clonidine were suggested for acute crisis management. Chronic treatment options included tetrabenazine, benzodiazepines, gabapentin, and clonidine. Deep brain stimulation should be considered early in the treatment of refractory or prolonged dyskinetic crisis.ConclusionThis consensus provides a foundation for understanding and managing dyskinetic crises in GNAO1-RD for clinicians, caregivers, and researchers. The study emphasizes the importance of targeted parental and caregiver education, which enables early recognition and intervention, thereby potentially minimizing both short- and long-term complications. Future research should concentrate on differentiating dyskinetic crises from other neurological events and investigating potential risk factors that influence their occurrence and nature. The proposed standardized framework improves clinical management, stakeholder communication, and future GNAO1-RD research

Otoimmün Epilepsi/Limbik Ensefalit, Uyku İğciklerinde Değişikliğe Neden Olabilir

Introduction: Sleep disorders have been described in patients with autoimmune limbic encephalitis (LE). The changes in sleep structure were also reported. Recently sleep spindle abnormalities such as asynchronous or prolonged spindles were observed children with LE. Methods: We studied the sleep and number of sleep spindles in the continuous electroencephalography-polysomnography (EEG-PSG) recordings of 6 patients with autoimmune epilepsy and/or LE. The longest NREM 2 period was selected. We evaluated the spindle density (spindles per minute), and compared that to the spindle densities of epilepsy patients with bilateral hippocampal sclerosis and healthy controls. Results: We have demonstrated that patients with autoimmune epilepsy and/or LE had reduced slow wave sleep with decreased number of sleep spindles. The mean number of spindles in 60 seconds was 5.86 +/- 5.03 in patients with autoimmune epilepsy and/or LE. But spindle density was higher in two control groups (10.6 +/- 1.65 and 9.95 +/- 0.79). Conclusions: The sleep abnormalities in LE can result from the disruption of thalamo-limbic circuits, and lead to changes in spindle wave activity. Although density of spindles decreased with acute lesions in thalamo-limbic circuits, the relations with structural lesions or chronicity of disease are not clear. That may be related to functional disruption of neural circuitry

Cobalamin C Disease Missed By Newborn Screening In A Patient With Low Carnitine Level

Cobalamin C (CblC) disease is the most common inherited disorder of intracellular cobalamin metabolism. It is a multisystemic disorder mainly affecting the eye and brain and characterized biochemically by methylmalonic aciduria, low methionine level, and homocystinuria. We report a patient found to have CblC disease who initially presented with low carnitine and normal propionylcarnitine (C3) levels on newborn screen. Newborn screening likely failed to detect CblC in this patient because of both his low carnitine level and the presence of a mild phenotype.Wo

NERVE CONDUCTION STUDIES IN CHARCOT-MARIE-TOOTH DISEASE IN A COHORT FROM TURKEY

Introduction: In the demyelinating form of Charcot-Marie-Tooth disease, median motor conduction velocity (MCV) was noted to be around 20 m/s in peripheral myelin protein 22 (PMP22) duplications, in contrast to higher MCVs in connexin 32 gene (Cx32) mutations and lower MCVs in the demyelinating form of myelin protein zero gene (MPZ) mutations. Methods: Nerve conduction studies were performed in 64 families with both common and rare mutations. Results: Mean MCV of the median nerve was 20 +/- 5 m/s in PMP22 duplications, 34 +/- 6 m/s in Cx32 mutations, 20 +/- 9 m/s in KIAA1985 (SH3TC2) mutations, and 11 +/- 8 m/s in MPZ mutations. Conduction was generally uniform; however, conduction blocks were present in 1 patient each with the MPZ mutation and PMP22 duplication, both with unusual phenotypes. Conclusion: Our results confirm those of the other investigators. Electrophysiological results of the rare KIAA1985 (SH3TC2) mutation reveal that their MCVs span a broad range and that conduction is uniform. Muscle Nerve 43: 657-664, 201

Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome in a Child With Klinefelter Syndrome.

Klinefelter syndrome is characterized by gynecomastia, hypogonadism, small testes, elevated levels of follicle-stimulating hormone and an extra X chromosome (ie, 47,XXY).1 These patients tend to have an increased risk of developing male breast cancer and mediastinal germ cell tumors.2,3 Hematologic malignancies including acute or chronic leukemia are also observed in these patients,4 but only a few case reports with Klinefelter syndrome who developed myelodysplastic syndrome (MDS) were published.4–7Wo

Access to Pediatric Neurology training and services worldwide: A survey by the International Child Neurology Association

Pediatric neurology is the medical subspecialty responsible for diagnosing and managing diseases and disorders of the nervous system in childhood and adolescence. In many, but not all, regions of the world the discipline of pediatric neurology is recognized as a specialty or subspecialty of either Neurology or Pediatrics. Significant knowledge and competencies in this area are necessary to be effective in clinical practice. The need for this is driven by the high burden of disease from neurological conditions in children and the impact on their families. As the first part of a multi-staged project under the auspices of the International Child Neurology Association, in collaboration with key stakeholders, a survey was undertaken to establish which countries have practicing child neurologists. For those countries that have child neurologists, the survey established the number of practitioners, and which countries have access to in-country child neurology training. Responses were obtained from 177 countries. Worldwide there is a median of 0.07 and mean of 0.39 child neurologists per 100 000 population. The greatest deficits in child neurology specialists and access to training were evident in countries which fell under the world bank rating of low income country status (range of 0 to 0.008 child neurologists per 100 000 population). Seventy-three percent of low income countries lack access to child neurologists: the majority are in the African and South-East Asia Regions. For the population of 1.37 billion in the continent of Africa there were 324 child neurologists, equating to median 0.01 per 100 000 population in comparison to a median of 0.59 child neurologists per 100 000 across high income countries. Ninety-four countries had capacity to support in-country pediatric neurology training. Worldwide there are inadequate numbers of child neurologists and great need for increased training capacity