SCN1A, the gene encoding for the Nav1.1 channel, exhibits dominant interneuron-specific expression, whereby variants disrupting the channel’s function affect the initiation and propagation of action ...potentials and neuronal excitability causing various types of epilepsy. Dravet syndrome (DS), the first described clinical presentation of SCN1A channelopathy, is characterized by severe myoclonic epilepsy in infancy (SMEI). Variants’ characteristics and other genetic or epigenetic factors lead to extreme clinical heterogeneity, ranging from non-epileptic conditions to developmental and epileptic encephalopathy (DEE). This current study reports on findings from 343 patients referred by physicians in hospitals and tertiary care centers in Greece between 2017 and 2023. Positive family history for specific neurologic disorders was disclosed in 89 cases and the one common clinical feature was the onset of seizures, at a mean age of 17 months (range from birth to 15 years old). Most patients were specifically referred for SCN1A investigation (Sanger Sequencing and MLPA) and only five for next generation sequencing. Twenty-six SCN1A variants were detected, including nine novel causative variants (c.4567A>Τ, c.5564C>A, c.2176+2T>C, c.3646G>C, c.4331C>A, c.1130_1131delGAinsAC, c.1574_1580delCTGAGGA, c.4620A>G and c.5462A>C), and are herein presented, along with subsequent genotype–phenotype associations. The identification of novel variants complements SCN1A databases extending our expertise on genetic counseling and patient and family management including gene-based personalized interventions.
Greece ranks among the first countries suffering from the obesity epidemic globally. The aim of the study was to evaluate body composition in Greek patients with Duchenne muscular dystrophy (DMD). We ...hypothesized that able-bodied patients would not differ from controls, in terms of adiposity, based on clinical observations during everyday practice. Study design: Cross-sectional study of steroid-dependent DMD subjects, who underwent dual-energy X-ray absorptiometry and laboratory metabolic bone profile evaluation. Forty-two patients and thirty-one controls were studied. Overall, DMD subjects were shorter (height
Z
-score = −1.4,
p
= 0.01). Their bone mineral density (BMD) was low (lumbar spine BMD
Z
-score = −1.2,
p
< 0.01, subcranial total body BMD
Z
-score = −1.8,
p
< 0.01). Lean tissue mass (LTM) was also decreased (LTM
Z
-score = −2.2,
p
< 0.01). The above findings were more pronounced in adolescence. Regarding adiposity, increased fat mass (FM) was found only in pubertal DMD patients (FM
Z
-score = 1.4,
p
< 0.01), whereas prepubertal, able-bodied patients did not differ from controls, thus confirming the initial hypothesis. Finally, 65 % of DMD subjects had increased bone resorption markers and 57 % had suboptimal vitamin D levels. The importance of using native population as controls for body composition analysis is highlighted. In Greece, abnormal body composition in DMD patients is more striking when loss of ambulation occurs and not during the prepubertal period, due to the concurrent presence of obesity in the pediatric population. Thus, adolescents with this neuromuscular disorder should be targeted toward prompt lifestyle interventions.
Promising genetic treatments targeting the molecular defect of severe early-onset genetic conditions are expected to dramatically improve patients' quality of life and disease epidemiology. Spinal ...Muscular Atrophy (SMA), is one of these conditions and approved therapeutic approaches have recently become available to patients.
Analysis of genetic and clinical data from SMA patients referred to the single public-sector provider of genetic services for the disease throughout Greece followed by a retrospective assessment in the context of epidemiology and genotype-phenotype associations.
Molecular genetic analysis and retrospective evaluation of findings for 361 patients tested positive for SMA- and 862 apparently healthy subjects from the general population. Spearman rank test and generalized linear models were applied to evaluate secondary modifying factors with respect to their impact on clinical severity and age of onset.
Causative variations- including 5 novel variants- were detected indicating a minimal incidence of about 1/12,000, and a prevalence of at least 1.5/100,000. For prognosis a minimal model pertaining disease onset before 18 months was proposed to include copy numbers of NAIP (OR = 9.9;95% CI, 4.7 to 21) and SMN2 (OR = 6.2;95% CI, 2.5-15.2) genes as well as gender (OR = 2.2;95% CI, 1.04 to 4.6).
This long-term survey shares valuable information on the current status and practices for SMA diagnosis on a population basis and provides an important reference point for the future assessment of strategic advances towards disease prevention and health care planning.
Diabetic neuropathy (DN) is the least recognized complication of diabetes mellitus and may start early in the course of the disease. Aldose reductase (AKR1B1) gene promoter Z-2/Z-2 polymorphism ...increases the expression of AKR1B1 enzyme and may contribute to DN.
We evaluated 108 Type 1 diabetes (T1D) children and adolescents (mean ± SD age: 13.5 ± 3.46 years, disease duration: 5.3 ± 3.4 years) and 150 healthy controls (age: 11.9 ± 2.7 years).
In both groups, pupillary dilation (PD) in darkness, postural blood pressure test (PBPT), and vibration sensation thresholds (VST) in upper and lower limbs were estimated as indices of autonomic and peripheral neuropathy, respectively. Nerve conduction studies (NCS) were performed in patients as peripheral neuropathy index. The polymorphisms of AKR1B1 gene were evaluated using microsatellite (AC)n sequence Z.
PBPT, PD, and VST impairments were more frequent in patient group compared with controls, while 38.6% of patients exhibited NCS abnormality. Gender, age, pubertal status, height, body mass index, diabetes duration, HbA1c, and anti-GAD titers were associated with neuropathy indices in patients. There was a strong correlation between PD and NCS in patients, while homozygous patients for Z-2 AKR1B1 gene polymorphism had higher prevalence of abnormal NCS (83.3% vs. 34.6%), PD (62.5% vs. 31.5%), and PBPT values compared with heterozygous or negative patients. Homozygous AKR1B1 status predicted PD, NCS, and PBPT variance, while PD, VST, NCS, and PBPT parameters accurately discriminated homozygous AKR1B1 patients.
Impaired indices of peripheral and autonomic DN were present in a significant proportion of young T1D patients. PD, VST, NCS, and PBPT parameters were simultaneously associated with homozygous state of AKR1B1 Z-2 gene polymorphism, implicating polyol metabolism with both autonomic and peripheral neuropathies.
Highlights • The simultaneous assessment of impaired indices of peripheral neuropathy with the persistence of autoantibodies against glutamic acid decarboxylase (GADA) and islet antigen 2 (IA-2A) in ...a pediatric cohort of type 1 DM patients. • The electrophysiological study of the sensory fibers of the peroneal nerve, which has not been frequently examined in reports including pediatric patients. Moreover the median (motor and sensory), the sural and the motor peroneal nerves were examined. The sensory peroneal nerve exhibited the highest rates of abnormalities in our study population. • The persistence of GADA and IA-2A was associated with slower action potentials in the sensory fibers of the peroneal nerve. Thus we introduce the idea that the autoantibodies may be involved in the development of axonal degeneration in the early stages of diabetic neuropathy.
Genetics of epilepsy are highly heterogeneous and complex. Lesions detected involve genes encoding various types of channels, transcription factors, and other proteins implicated in numerous cellular ...processes, such as synaptogenesis. Consequently, a wide spectrum of clinical presentations and overlapping phenotypes hinders differential diagnosis and highlights the need for molecular investigations toward delineation of underlying mechanisms and final diagnosis. Characterization of defects may also contribute valuable data on genetic landscapes and networks implicated in epileptogenesis.
This study reports on genetic findings from exome sequencing (ES) data of 107 patients with variable types of seizures, with or without additional symptoms, in the context of neurodevelopmental disorders.
Multidisciplinary evaluation of ES, including ancillary detection of copy number variants (CNVs) with the ExomeDepth tool, supported a definite diagnosis in 59.8% of the patients, reflecting one of the highest diagnostic yields in epilepsy.
Emerging advances of next-generation technologies and '
' analysis tools offer the possibility to simultaneously detect several types of variations. Wide assessment of variable findings, specifically those found to be novel and least expected, reflects the ever-evolving genetic landscape of seizure development, potentially beneficial for increased opportunities for trial recruitment and enrollment, and optimized, even personalized, medical management.
Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). ...This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone).
A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2.
A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine TTSTAND velocity, week 24 least squares mean LSM SE 0.052 0.0130 rises/s vs week 48 LSM SE 0.0446 0.0138). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM SE 0.49 1.14; 95% CI -1.80 to 2.78,
= 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups.
Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone.
ClinicalTrials.gov Identifier: NCT03439670.
This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.
Spinal cord compression and associate neurological impairment is rare in patients with scoliosis and neurofibromatosis. Common reasons are vertebral subluxation, dislocation, angulation and tumorous ...lesions around the spinal canal. Only twelve cases of intraspinal rib dislocation have been reported in the literature. The aim of this report is to present a case of rib penetration through neural foramen at the apex of a scoliotic curve in neurofibromatosis and to introduce a new clinical sign for its detection.
A 13-year-old girl was evaluated for progressive left thoracic kyphoscoliotic curve due to a type I neurofibromatosis. Clinical examination revealed multiple large thoracic and abdominal "cafe-au-lait" spots, neurological impairment of the lower limbs and the presence of a thoracic gibbous that was painful to pressure at the level of the left eighth rib (Painful Rib Hump). CT-scan showed detachment and translocation of the cephalic end of the left eighth rib into the adjacent enlarged neural foramen. The M.R.I. examination of the spine showed neither cord abnormality nor neurogenic tumor.
The patient underwent resection of the intraspinal mobile eighth rib head and posterior spinal instrumentation and was neurologically fully recovered six months postoperatively.
Spine surgeons should be aware of intraspinal rib displacement in scoliotic curves in neurofibromatosis. Painful rib hump is a valuable diagnostic tool for this rare clinical entity.
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