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The objective of this study is to compare shear modulus of lower limb muscles between children with hypotonia versus typical development (TD) or developmental disorders associated with altered tone. Nineteen children with mild hypotonia (mean age 9.4 ± 2.3y, 13 male) completed assessment of resting shear modulus of rectus femoris, biceps femoris (BF), tibialis anterior (TA) and gastrocnemius lateralis (GL) at short and long lengths using shear wave elastography. Data was compared with previous data from TD children and a scoping review for children with developmental disorders. Data were collated according to Net-Longitudinal Tension Angle (Net-LTA), which is the muscle length expressed as the net proximal and distal joint angles. Effects of Net-LTA (e.g., short, neutral, long) were examined according to sex, age and body mass index (BMI). In children with hypotonia, shear modulus was: higher at longer versus shorter lengths for four muscles (p < 0.01); correlated with age for BF-short (r = 0.60, p < 0.03) and GL-short (r = -0.54, p < 0.03), with BMI for BF-short (r = 0.71, p < 0.05); and not different between sexes (p > 0.05). The shear modulus values for lower limb muscles for children with mild hypotonia were lower than those for children with Duchenne Muscular Dystrophy (TA-neutral), or Cerebral Palsy (GL-neutral), but not TD children (all four muscles). In conclusion, shear modulus increases with longer muscle length (i.e. higher Net-LTA) in mildly hypotonic children. Children with mild hypotonia have lower shear modulus than children with cerebral palsy and Duchenne muscular dystrophy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Rationale: REM sleep is associated with reduced ventilation and greater obstructive sleep apnea (OSA) severity than non-REM (nREM) sleep for reasons that have not been fully elucidated. Objectives: Here, we use direct physiological measurements to determine whether the pharyngeal compromise in REM sleep OSA is most consistent with 1 ) withdrawal of neural ventilatory drive or 2 ) deficits in pharyngeal pathophysiology per se (i.e., increased collapsibility and decreased muscle responsiveness ). Methods: Sixty-three participants with OSA completed sleep studies with gold standard measurements of ventilatory "drive" (calibrated intraesophageal diaphragm EMG), ventilation (oronasal "ventilation"), and genioglossus EMG activity. Drive withdrawal was assessed by examining these measurements at nadir drive (first decile of drive within a stage). Pharyngeal physiology was assessed by examining collapsibility (lowered ventilation at eupneic drive) and responsiveness (ventilation-drive slope). Mixed-model analysis compared REM sleep with nREM sleep; sensitivity analysis examined phasic REM sleep. Measurements and Main Results: REM sleep (⩾10 min) was obtained in 25 patients. Compared with drive in nREM sleep, drive in REM sleep dipped to markedly lower nadir values (first decile, estimate [95% confidence interval], -21.8% [-31.2% to -12.4%] of eupnea; P  < 0.0001), with an accompanying reduction in ventilation (-25.8% [-31.8% to -19.8%] of eupnea; P  < 0.0001). However, there was no effect of REM sleep on collapsibility (ventilation at eupneic drive), baseline genioglossus EMG activity, or responsiveness. REM sleep was associated with increased OSA severity (+10.1 [1.8 to 19.8] events/h), but this association was not present after adjusting for nadir drive (+4.3 [-4.2 to 14.6] events/h). Drive withdrawal was exacerbated in phasic REM sleep. Conclusions: In patients with OSA, the pharyngeal compromise characteristic of REM sleep appears to be predominantly explained by ventilatory drive withdrawal rather than by preferential decrements in muscle activity or responsiveness. Preventing drive withdrawal may be the leading target for REM sleep OSA.

RBL2/p130, a member of the retinoblastoma family of proteins, is a key regulator of cell division and propagates irreversible senescence. RBL2/p130 is also involved in neuronal differentiation and survival, and eliminating Rbl2 in certain mouse strains leads to embryonic lethality accompanied by an abnormal central nervous system (CNS) phenotype. Conflicting reports exist regarding a role of RBL2/p130 in transcriptional regulation of DNA methyltransferases (DNMTs), as well as the control of telomere length. Here we describe the phenotype of three patients carrying bi-allelic RBL2-truncating variants. All presented with infantile hypotonia, severe developmental delay and microcephaly. Malignancies were not reported in carriers or patients. Previous studies carried out on mice and human cultured cells, associated RBL2 loss to DNA methylation and telomere length dysregulation. Here, we investigated whether patient cells lacking RBL2 display related abnormalities. The study of primary patient fibroblasts did not detect abnormalities in expression of DNMTs. Furthermore, methylation levels of whole genome DNA, and specifically of pericentromeric repeats and subtelomeric regions, were unperturbed. RBL2-null fibroblasts show no evidence for abnormal elongation by telomeric recombination. Finally, gradual telomere shortening, and normal onset of senescence were observed following continuous culturing of RBL2-mutated fibroblasts. Thus, this study resolves uncertainties regarding a potential non-redundant role for RBL2 in DNA methylation and telomere length regulation, and indicates that loss of function variants in RBL2 cause a severe autosomal recessive neurodevelopmental disorder in humans., (© 2021. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Two siblings presented similarly with congenital hypotonia, lactic acidosis, and failure to thrive. Later in childhood, the brother developed cystinuria and nephrolithiasis whereas the older sister suffered from cystinuria and chronic neurobehavioral disturbances. Biopsied muscle studies demonstrated deficient cytochrome c oxidase activities consistent with a mitochondrial disease. Whole exome sequencing (WES), however, revealed a homozygous 2p21 deletion involving two contiquous genes, SLC3A1 (deletion of exons 2-10) and PREPL (deletion of exons 2-14). The molecular findings were consistent with the hypotonia-cystinuria 2p21 deletion syndrome, presenting similarly in infancy with mitochondrial dysfunction but diverging later in childhood and displaying intrafamilial phenotypic variability., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants., (© 2021 Wiley Periodicals LLC.)

Myosin binding protein-C slow (sMyBP-C) comprises a subfamily of cytoskeletal proteins encoded by MYBPC1 that is expressed in skeletal muscles where it contributes to myosin thick filament stabilization and actomyosin cross-bridge regulation. Recently, our group described the causal association of dominant missense pathogenic variants in MYBPC1 with an early-onset myopathy characterized by generalized muscle weakness, hypotonia, dysmorphia, skeletal deformities, and myogenic tremor, occurring in the absence of neuropathy. To mechanistically interrogate the etiologies of this MYBPC1-associated myopathy in vivo, we generated a knock-in mouse model carrying the E248K pathogenic variant. Using a battery of phenotypic, behavioral, and physiological measurements spanning neonatal to young adult life, we found that heterozygous E248K mice faithfully recapitulated the onset and progression of generalized myopathy, tremor occurrence, and skeletal deformities seen in human carriers. Moreover, using a combination of biochemical, ultrastructural, and contractile assessments at the level of the tissue, cell, and myofilaments, we show that the loss-of-function phenotype observed in mutant muscles is primarily driven by disordered and misaligned sarcomeres containing fragmented and out-of-register internal membranes that result in reduced force production and tremor initiation. Collectively, our findings provide mechanistic insights underscoring the E248K-disease pathogenesis and offer a relevant preclinical model for therapeutic discovery.

Background: We sought to expand our knowledge of the clinical spectrum of GNAO1-related neurodevelopmental disorders through a caregiver survey reviewing medical and developmental history and development of epilepsy and movement disorders., Methods: An online survey was administered to caregivers of individuals diagnosed with GNAO1 pathogenic variants., Results: Eighty-two surveys were completed. Nearly all (99%) reported the first symptom of concern by age one year with the most frequently identified concerns as hypotonia (68%), developmental delay (67%), seizures (29%), difficulty feeding (23%), and abnormal movements (20%). All caregivers reported developmental delays with a spectrum of severity. Movement disorders (76%) were more common than epilepsy (52%), although 33% reported both. The onset of seizures tended to be earlier than abnormal movements. Nearly half (48%) of those with any seizures, reported they were no longer having recurrent seizures. No single most effective medication for movement disorders or epilepsy was noted. Ten participants have had deep brain stimulator for their movement disorder, and all indicated positive effects., Conclusions: GNAO1-related neurodevelopmental disorders most often present within the first year of life with nonspecific symptoms of hypotonia or developmental delay. Although associated epilepsy and movement disorders can be severe, GNAO1-associated epilepsy may not always be medically refractory or lifelong., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Current therapies that allow patients with bladder acontractility to void are limited. The standard therapy is clean intermittent catheterization. Latissimus dorsi detrusor myoplasty (LDDM) has been shown to provide functional contraction and allow patients with bladder acontractility to void voluntarily. Our goal was to summarize experimental studies of LDDM. We hypothesized that experimental studies would show that latissimus dorsi muscle (LDM) flaps for detrusor myoplasty have superior outcomes when compared with other types of flaps. On January 17, 2020, we conducted a systematic review of the PubMed/MEDLINE, Cochrane Clinical Answers, Cochrane Central Register of Controlled Trials, and EMBASE databases, without time frame limitations, to identify articles on the use of LDDM. We excluded studies that investigated other treatments. Of 54 articles identified by the search, three fulfilled the eligibility criteria. A total of 24 dogs underwent procedures and were evaluated with a maximum follow-up of 9 months. Three types of procedures were performed: LDM in situ reconfiguration, LDM myoplasty, and augmentation cystoplasty after supratrigonal cystectomy. Electrical stimulation, cystography, urodynamic and hydrodynamic measurements, and microscopic examinations were performed. Innervated LDM flaps transferred to the bladder were able to contract and promote voiding in response to electrical stimulation. Experimental studies have shown the feasibility of LDDM in canine models. Although no comparison groups were included, innervated LDM flap transferred to the bladder showed promising results regarding contraction capable of voiding., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 International Society of Plastic and Aesthetic Nurses. All rights reserved.)

Aim : To identify abnormalities in muscle tone and motor function associated with congenital Zika syndrome (CZS). Method : A cross-sectional observational study involving 96 children (55 males) with CZS at a mean (SD) age 35.2 ± 2.9 months. Children's muscle tone was investigated using the pull to sit, scarf sign, shoulder suspension and ventral suspension tests and the modified Ashworth scale (MAS). Motor impairment was determined using the Gross Motor Function Classification System (GMFCS) and body segments most affected with motor impairment. Results : 58 (60,5%) children tested positive for ≥1 maneuver used to evaluate muscle tone, while 38 (39.5%) tested negative in all the tests. MAS score was >0 for at least one of the appendicular muscles in 91 children (94.8%). In 88 children (91.7%), all four limbs were affected. Conclusion : Findings suggestive of axial hypotonia and appendicular hypertonia associated with severe motor impairment were prevalent in children with CZS.

Resistance to thyroid hormone alpha (RTHα) is caused by mutations in thyroid hormone receptor α ( THRA ). Little is known about the natural history and treatment of RTHα, and diagnosis before the age of 1 year has not been previously reported. A de novo heterozygous THRA mutation (pC380SfsX9) was identified in a 10-month-old female investigated for developmental delay, hypotonia, macrocephaly, and severe constipation. Treatment with levothyroxine was accompanied by an appropriate rise in thyroxine (T4), triiodothyronine (T3), as well as decrease in thyrotropin levels and in the T3/T4 ratio with a trend toward normalization of peripheral markers of thyroid hormone action. THRA pC380SfsX9 results in extreme RTHα.

Background: The monocarboxylate transporter 8 (Mct8) protein is a primary thyroxine (T4) and triiodothyronine (T3) (thyroid hormone [TH]) transporter. Mutations of the MCT8-encoding, SLC16A2 gene alter thyroid function and TH metabolism and severely impair neurodevelopment (Allan-Herndon-Dudley syndrome [AHDS]). Mct8-deficient mice manifest thyroid alterations but lack neurological signs. It is believed that Mct8 deficiency in mice is compensated by T4 transport through the Slco1c1 -encoded organic anion transporter polypeptide 1c1 (Oatp1c1). This allows local brain generation of sufficient T3 by the Dio2 -encoded type 2 deiodinase, thus preventing brain hypothyroidism. The Slc16a2 / Slco1c1 (MO) and Slc16a2 / Dio2 (MD) double knockout (KO) mice lacking T4 and T3 transport, or T3 transport and T4 deiodination, respectively, should be appropriate models of AHDS. Our goal was to compare the cerebral hypothyroidism of systemic hypothyroidism (SH) caused by thyroid gland blockade with that present in the double KO mice. Methods: We performed RNA sequencing by using RNA from the cerebral cortex and striatum of SH mice and the double KO mice on postnatal days 21-23. Real-time polymerase chain reaction was used to confirm RNA-Seq results in replicate biological samples. Cell type involvement was assessed from cell type-enriched genes. Functional genomic differences were analyzed by functional node activity based on a probabilistic graphical model. Results: Each of the three conditions gave a different pattern of gene expression, with partial overlaps. SH gave a wider and highest variation of gene expression than MD or MO. This was partially due to secondary gene responses to hypothyroidism. The set of primary transcriptional T3 targets showed a tighter overlap, but quantitative gene responses indicated that the gene responses in SH were more severe than in MD or MO. Examination of cell type-enriched genes indicated cellular differences between the three conditions. Conclusions: The results indicate that the neurological impairment of AHDS is too severe to be fully explained by TH deprivation only.

Objective: Scoliosis is frequently seen in children with Prader-Willi syndrome (PWS). There is still concern that growth hormone (GH) treatment might increase the risk of onset or progression of scoliosis. Short-term data suggested no adverse effects of GH on scoliosis, but long-term effects of GH treatment on development of scoliosis in PWS are unknown. This study investigated the effects of 8 years of GH treatment on scoliosis in children with PWS., Design: Open-label, prospective cohort study in 103 children with PWS receiving GH for 8 years was analyzed. Prevalence and severity of scoliosis were compared to a group of 23 age-matched GH-untreated children with PWS., Methods: Spine X-rays and DEXA-scans were performed, and Cobb angel was measured by two independent observers., Results: After 8 years of GH treatment, at median age of 10.8 years, prevalence of scoliosis was 77.7%. No difference in prevalence or severity of scoliosis was found between GH-treated and age-matched untreated children with PWS (P = 0.409 and P = 0.709, respectively). Height SDS and trunkLBM were significantly higher in GH-treated children. Higher bone mineral density of the lumbar spine was found in children without scoliosis after 8 years of GH. Bone mineral apparent density of lumbar spine (BMADLS) SDS was associated with lower Cobb angle (r = -0.270, P = 0.008)., Conclusions: Eight years of GH treatment has no adverse effects on the prevalence and severity of scoliosis in children with PWS until 11 years of age. As BMADLS SDS is inversely associated with Cobb angle, it is pivotal to optimize the BMD status in children with PWS.

Background: Mutations of the thyroid hormone (TH)-specific cell membrane transporter, monocarboxylate transporter 8 ( MCT8 ), produce an X-chromosome-linked syndrome of TH deficiency in the brain and excess in peripheral tissues. The clinical consequences include brain hypothyroidism causing severe psychoneuromotor abnormalities (no speech, truncal hypotonia, and spastic quadriplegia) and hypermetabolism (poor weight gain, tachycardia, and increased metabolism, associated with high serum levels of the active TH, T3). Treatment in infancy and childhood with TH analogues that reduce serum triiodothyronine (T3) corrects hypermetabolism, but has no effect on the psychoneuromotor deficits. Studies of brain from a 30-week-old MCT8-deficient embryo indicated that brain abnormalities were already present during fetal life. Methods: A carrier woman with an affected male child (MCT8 A252fs268*), pregnant with a second affected male embryo, elected to carry the pregnancy to term. We treated the fetus with weekly 500 μg intra-amniotic instillation of levothyroxine (LT4) from 18 weeks of gestation until birth at 35 weeks. Thyroxine (T4), T3, and thyrotropin (TSH) were measured in the amniotic fluid and maternal serum. Treatment after birth was continued with LT4 and propylthiouracil. Follow-up included brain magnetic resonance imaging (MRI) and neurodevelopmental evaluation, both compared with the untreated brother. Results: During intrauterine life, T4 and T3 in the amniotic fluid were maintained above threefold to twofold the baseline and TSH was suppressed by 80%, while maternal serum levels remained unchanged. At birth, the infant serum T4 was 14.5 μg/dL and TSH <0.01 mU/L compared with the average in untreated MCT8-deficient infants of 5.1 μg/ and >8 mU/L, respectively. MRI at six months of age showed near-normal brain myelination compared with much reduced in the untreated brother. Neurodevelopmental assessment showed developmental quotients in receptive language and problem-solving, and gross motor and fine motor function ranged from 12 to 25 at 31 months in the treated boy and from 1 to 7 at 58 months in the untreated brother. Conclusions: This is the first demonstration that prenatal treatment improved the neuromotor and neurocognitive function in MCT8 deficiency. Earlier treatment with TH analogues that concentrate in the fetus when given to the mother may further rescue the phenotype.

The phosphatidylinositol glycan anchor biosynthesis class S protein (PIGS) gene has recently been implicated in a novel congenital disorder of glycosylation resulting in autosomal recessive inherited glycosylphosphatidylinositol-anchored protein (GPI-AP) deficiency. Previous studies described seven patients with biallelic variants in the PIGS gene, of whom two presented with fetal akinesia and five with global developmental delay and epileptic developmental encephalopathy. We present the molecular and clinical characteristics of six additional individuals from five families with unreported variants in PIGS. All individuals presented with hypotonia, severe global developmental delay, microcephaly, intractable early infantile epilepsy, and structural brain abnormalities. Additional findings include vision impairment, hearing loss, renal malformation, and hypotonic facial appearances with minor dysmorphic features but without a distinctive facial gestalt. Four individuals died due to neurologic complications. GPI anchoring studies performed on one individual revealed a significant decrease in GPI-APs. We confirm that biallelic variants in PIGS cause vitamin pyridoxine-responsive epilepsy due to inherited GPI deficiency and expand the genotype and phenotype of PIGS-related disorder. Further delineation of the molecular spectrum of PIGS-related disorders would improve management, help develop treatments, and encourage the expansion of diagnostic genetic testing to include this gene as a potential cause of neurodevelopmental disorders and epilepsy., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Food protein-induced enterocolitis syndrome is still a mysterious disease, pathogenically poorly characterized, although the first FPIES case has been described in 1967. Mainly, food protein-induced enterocolitis syndrome diagnosis is based on clinical history. The oral food challenge remains the gold standard to confirm the diagnosis, especially in particular situations. Although there are no diagnostic laboratory or imaging tests which are specific for diagnosis, they could, however, sometimes be helpful to rule out clinical conditions which are similar to food protein-induced enterocolitis syndrome reactions. The purpose of this review is to define the clinical features of FPIES and to summarize the current available tools for the diagnosis of FPIES. This review is intended to be a practical guide for the clinician facing a patient with food protein-induced enterocolitis syndrome avoiding delayed diagnosis with unnecessary laboratory tests and detrimental treatments. Moreover, it highlights the unmet needs in diagnosis that require urgent attention from the scientific community to improve the management of patients with FPIES., (© 2020 John Wiley & Sons Ltd.)

Although spasticity is one of the most common causes of motor disability worldwide, its precise definition and pathophysiology remain elusive, which to date renders its experimental targeting tricky. At least in part, this difficulty is caused by heterogeneous phenotypes of spasticity-causing neurological disorders, all causing spasticity by involving upper motor neurons. The most common clinical symptoms are a series of rapid muscle contractions (clonus), an increased muscle tone (hypertonia), and augmented tendon reflex activity (hyperreflexia). This muscle overactivity is due to disturbed inhibition of spinal reflexes following upper motor neuron dysfunction. Despite a range of physical and pharmacological therapies ameliorating the symptoms, their targeted application remains difficult. Therefore, to date, spasticity impacts rehabilitative therapy, and no therapy exists that reverses the pathology completely. In contrast to the incidence and importance of spasticity, only very little pre-clinical work in animal models exists, and this research is focused on the cat or the rat spastic tail model to decipher altered reflexes and excitability of the motor neurons in the spinal cord. Meanwhile, the characterization of spasticity in clinically more relevant mouse models of neurological disorders, such as stroke, remains understudied. Here, we provide a brief introduction into the clinical knowledge and therapy of spasticity and an in-depth review of pre-clinical studies of spasticity in mice including the current experimental challenges for clinical translation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To determine genotype-phenotype correlation in succinic semialdehyde dehydrogenase (SSADH) deficiency., Methods: ALDH5A1 variants were studied with phenotype correlation in the SSADH natural history study. Assignment of gene variant pathogenicity was based on in silico testing and in vitro enzyme activity after site-directed mutagenesis and expression in HEK293 cells. Phenotypic scoring used a Clinical Severity Score (CSS) designed for the natural history study., Results: Twenty-four patients were enrolled (10 male, 14 female, median age 8.2 years). There were 24 ALDH5A1 variants, including 7 novel pathogenic variants: 2 missense, 3 splice site, and 2 frameshift. Four previously reported variants were identified in >5% of unrelated families. There was a correlation with age and presence ( p = 0.003) and severity ( p = 0.002) of epilepsy and with obsessive-compulsive disorder (OCD) ( p = 0.016). The median IQ score was 53 (Q25-Q75, 49-61). There was no overall correlation between the gene variants and the CSS, although a novel missense variant was associated with the mildest phenotype by CSS in the only patient with a normal IQ, whereas a previously reported variant was consistently associated with the most severe phenotype., Conclusions: Seven novel pathogenic and one previously unpublished benign ALDH5A1 variants were detected. There is an age-dependent association with worsening of epilepsy and presence of OCD in SSADH deficiency. Overall, there does not appear to be a correlation between genotype and phenotypic severity in this cohort of 24 patients. We did find a suspected correlation between a novel pathogenic missense variant and high functionality, and a previously reported pathogenic missense variant and maximal severity., (© 2020 American Academy of Neurology.)

Objective: To describe clinical features and disease progression of Selenoprotein N-related myopathy in a large multicenter cohort of patients., Methods: Cross-sectional multicenter data analysis of 60 patients (53 families) with Selenoprotein N-related myopathy and single-center retrospective longitudinal analysis of 25 patients (21 families) over a median period of 5.3 years., Results: The majority of patients (46/60, 77%) presented before age 2 years with hypotonia, poor head/neck control, and developmental delay. At last assessment (median age 14 years; range 2.5 to 36 years), 10/60 patients had minimal or no ambulation. Ventilatory support was initiated in 50/60 patients at a mean Forced Vital Capacity (FVC) of 38% and at a median age of 13 years. Forty-five/60 patients developed scoliosis (at median age 12.1 years) and 18 had scoliosis surgery at a median age of 13.6 years. Five children needed nasogastric feeds and/or gastrostomy. Longitudinal data analysis on 25 patients showed progressive decline of Hammersmith functional motor scores (estimated annual change -0.55 point), time to walk 10 meter, time standing from sitting, and from lying. Sixteen patients had weights < 2nd centile. The estimated change in FVC % per year was -2.04, with a 95% CI (-2.94, -1.14)., Conclusions: This comprehensive analysis of patients with Selenoprotein N-related myopathy further describes the clinical course of this rare condition. The observed functional motor and respiratory data provide evidence of the slow decline patients experience over time which is useful when considering therapeutic intervention., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: Isolated REM sleep without atonia (iRSWA) is regarded as a prodromal phase of REM sleep behavior disorder and synucleinopathies. In iRSWA patients, we investigated the polysomnographic characteristics that are known to be altered in (prodromal) Parkinson's disease (PD): periodic limb movements of sleep [PLMS] (increased), REM density (reduced), and heart rate variability ([HRV] (reduced)., Methods: We compared video-polysomnographic studies of 49 iRSWA subjects with 41 controls. RSWA and PLMS were scored visually. REM density (REM/hour) and HRV were calculated automatically., Results: We found a higher median total (15.90 vs 7.20; p = 0.001), REM (21.80 vs 11.0; p < 0.001) and non-REM (11.75 vs 5.72; p = 0.027) PLMS index, and a higher mean REM density (342.45 vs 275.96; p = 0.010) in the iRSWA group, with a significant positive correlation between RSWA severity and these variables (r = 0.39; p < 0.00, r = 0.48; p < 0.001, r = 0.24; p = 0.021, r = 0.28; p = 0.012). We found no significant difference in HRV between groups., Conclusions: Our results suggest an association between RWSA and REM density and PLMS, but not HRV. The positive correlation between these variabilities may imply overlapping pathophysiological processes., Significance: The evidence of higher REM density and normal HRV weakens the hypothesis that iRWSA is a prodromal PD stage. An alternative interpretation is, however, that REM density and HRV change during caudal-rostral neurodegeneration., Competing Interests: Disclosure statement All authors: no financial or non-financial disclosures., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Despite its first description more than 75 years ago, effective treatment for "Allan-Herndon-Dudley-Syndrome (AHDS)", an X-linked thyroid hormone transporter defect, is unavailable. Mutations in the SLC16A2 gene have been discovered to be causative for AHDS in 2004, but a comprehensive understanding of the function of the encoded protein, monocarboxylate transporter 8 (MCT8), is incomplete. Patients with AHDS suffer from neurodevelopmental delay, as well as extrapyramidal (dystonia, chorea, athetosis), pyramidal (spasticity), and cerebellar symptoms (ataxia). This suggests an affection of the pyramidal tracts, basal ganglia, and cerebellum , most likely already during fetal brain development. The function of other brain areas relevant for mood, behavior, and vigilance seems to be intact. An optimal treatment strategy should thus aim to deliver T3 to these relevant structures at the correct time points during development. A potential therapeutic strategy meeting these needs might be the delivery of T3 via a "Trojan horse mechanism" by which T3 is delivered into target cells by a thyroid hormone transporter independent T3 internalization., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Significant clinical symptoms of Cohen syndrome (CS), a rare autosomal recessive disorder, include intellectual disability, facial dysmorphism, postnatal microcephaly, retinal dystrophy, and intermittent neutropenia. CS has been associated with mutations in the VPS13B (vacuolar protein sorting 13 homolog B) gene, which regulates vesicle-mediated protein sorting and transport; however, the cellular mechanism underlying CS pathogenesis in patient-derived neurons remains uncertain. This report states that autophagic vacuoles accumulate in CS fibroblasts and the axonal terminals of CS patient-specific induced pluripotent stem cells (CS iPSC)-derived neurons; additionally, autophagic flux was significantly increased in CS-derived neurons compared to control neurons. VPS13B knockout HeLa cell lines generated using the CRISPR/Cas9 genome editing system showed significant upregulation of autophagic flux, indicating that VSP13B may be associated with autophagy in CS. Transcriptomic analysis focusing on the autophagy pathway revealed that genes associated with autophagosome organization were dysregulated in CS-derived neurons. ATG4C is a mammalian ATG4 paralog and a crucial regulatory component of the autophagosome biogenesis/recycling pathway. ATG4C was significantly upregulated in CS-derived neurons, indicating that autophagy is upregulated in CS neurons. The autophagy pathway in CS neurons may be associated with the pathophysiology exhibited in the neural network of CS patients.

Purpose: The aim of this study is to report on the phenotype and genotype of five patients diagnosed with Cohen syndrome, an extremely rare autosomal recessive disorder manifesting with mental and physiological defects., Methods: Five patients from three German families and one Syrian family underwent a comprehensive ophthalmological examination. The scheduled visual acuity measurements, fundus ophthalmoscopy, spectral domain optical coherence tomography (OCT), full-field electrophysiological recordings of scotopic and photopic electroretinograms (ERGs) and colour vision testing could not be carried out in all subjects, because of the mental and physical retardation. The genetic diagnosis was achieved by next-generation sequencing., Results: The ophthalmic and systemic phenotype of the patients is typical for Cohen syndrome including myopia, night blindness, photophobia, fundus pigmentary changes and bull's eye maculopathy. Electroretinograms (ERGs) were extinguished in the four patients, whose recording was possible. Genetic testing revealed homozygous or two heterozygous bi-allelic mutations in the VPS13B (COH1) gene in all five patients, with five different allelic variants observed. The homozygous mutation c.6055&#95;6056delGA; p.Asp2019Glnfs*15 in two sibling patients as well as the homozygous nonsense mutation c.8112C>G;p.Tyr2704* have not previously been reported., Conclusions: The phenotype of the five patients reported here is typical for Cohen syndrome; however, their genotype is heterogeneous. Two new allelic variants were found to be the causative mutation., (© 2019 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Thyroid hormone transporters at the plasma membrane govern intracellular bioavailability of thyroid hormone. Monocarboxylate transporter (MCT) 8 and MCT10, organic anion transporting polypeptide (OATP) 1C1, and SLC17A4 are currently known as transporters displaying the highest specificity toward thyroid hormones. Structure-function studies using homology modeling and mutational screens have led to better understanding of the molecular basis of thyroid hormone transport. Mutations in MCT8 and in OATP1C1 have been associated with clinical disorders. Different animal models have provided insight into the functional role of thyroid hormone transporters, in particular MCT8. Different treatment strategies for MCT8 deficiency have been explored, of which thyroid hormone analogue therapy is currently applied in patients. Future studies may reveal the identity of as-yet-undiscovered thyroid hormone transporters. Complementary studies employing animal and human models will provide further insight into the role of transporters in health and disease. (Endocrine Reviews 41: 1 - 55, 2020)., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Muscle dysfunction such as loss of muscle mass and decreased muscle strength is often observed in patients with hematologic malignancies. However, specific factors associated with muscle function have not been identified. The purpose of this study was to identify significant factors affecting muscle function in patients with hematologic malignancies., Methods: This was a cross-sectional, observational study. Eighty-eight inpatients with hematologic malignancies undergoing chemotherapy were recruited. Participants were evaluated for muscle thickness and isometric knee extensor strength as indicators of muscle function, physical activity, physical symptoms, psychological distress, and self-efficacy at the start date of rehabilitation. Multiple regression analysis with muscle function as the dependent variable and clinical information and other evaluation items as explanatory variables was performed., Results: Lymphocyte count, the geriatric nutritional risk index, and physical activity were significant factors associated with muscle thickness, while physical activity and self-efficacy were significant factors associated with isometric knee extensor strength., Conclusions: Nutritional status, physical activity, and self-efficacy were significant factors associated with muscle function in patients with hematologic malignancies. Rehabilitation intervention focusing on improving physical activity and nutritional status should be considered necessary for enhancing muscle function in patients with hematologic malignancies.

Pontocerebellar hypoplasia type 6 (PCH6) is a rare infantile-onset progressive encephalopathy caused by biallelic mutations in RARS2 that encodes the mitochondrial arginine-tRNA synthetase enzyme (mtArgRS). The clinical presentation overlaps that of PEHO syndrome (Progressive Encephalopathy with edema, Hypsarrhythmia and Optic atrophy). The proband presented with severe intellectual disability, epilepsy with varying seizure types, optic atrophy, axial hypotonia, acquired microcephaly, dysmorphic features and progressive cerebral and cerebellar atrophy and delayed myelination on MRI. The presentation had resemblance to PEHO syndrome but sequencing of ZNHIT3 did not identify pathogenic variants. Subsequent whole genome sequencing revealed novel compound heterozygous variants in RARS2, a missense variant affecting a highly conserved amino acid and a frameshift variant with consequent degradation of the transcript resulting in decreased mtArgRS protein level confirming the diagnosis of PCH6. Features distinguishing the proband's phenotype from PEHO syndrome were later appearance of hypotonia and elevated lactate levels in blood and cerebrospinal fluid. On MRI the proband presented with more severe supratentorial atrophy and lesser degree of abnormal myelination than PEHO syndrome patients. The study highlights the challenges in clinical diagnosis of patients with neonatal and early infantile encephalopathies with overlapping clinical features and brain MRI findings., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Introduction: Biotinidase deficiency is an inherited disorder of biotin metabolism that is untreated may present within the first few month of life., Objective: We report the exceptional observation of a biotinidase deficiency in Morocco. The rarity of this pathology, its age of onset, its mode of revelation and the lack of treatment in Morocco make the particularity of this observation., Observation: A newborn child born from a 24-year-old mother, followed by an estimated pregnancy of 37 weeks of amenorrhea according to the Farr score (morphological maturation score used for the dating of the pregnancy term). The infant presented at 7 days of life with a cutaneous-mucous eruption with icithiosic dry erythroderma of interest to the trunk, the face, the scalp associated with alopecia and depilation of the eyebrow. The biotinoidase deficiency was confirmed by its low serum concentration at 49 nka / l. The newborn died at 20 days of life before starting the specific treatment., Conclusion: Biotinidase deficiency is a rare condition requiring early screening and rapid management. The delay in diagnosis and the unavailability of treatment in Morocco can have fatal consequences.

Potassium channels are a heterogeneous group of membrane-bound proteins, whose functions support a diverse range of biological processes. Genetic disorders arising from mutations in potassium channels are classically recognized by symptoms arising from acute channel dysfunction, such as periodic paralysis, ataxia, seizures, or cardiac conduction abnormalities, often in a patient with otherwise normal examination findings. In this chapter, we review a distinct subgroup of rare potassium channelopathies whose presentations are instead suggestive of a developmental disorder, with features including intellectual disability, craniofacial dysmorphism or other physical anomalies. Known conditions within this subgroup are: Andersen-Tawil syndrome, Birk-Barel syndrome, Cantú syndrome, Keppen-Lubinsky syndrome, Temple-Baraitser syndrome, Zimmerman-Laband syndrome and a very similar disorder called Bauer-Tartaglia or FHEIG syndrome. Ion channelopathies are unlikely to be routinely considered in the differential diagnosis of children presenting with developmental concerns, and so detailed description and photographs of the clinical phenotype are provided to aid recognition. For several of these disorders, functional characterization of the genetic mutations responsible has led to identification of candidate therapies, including drugs already commonly used for other indications, which adds further impetus to their prompt recognition. Together, these cases illustrate the potential for mechanistic insights gained from genetic diagnosis to drive translational work toward targeted, disease-modifying therapies for rare disorders., (© 2020 Elsevier Inc. All rights reserved.)

Objective: Little is known regarding food anaphylaxis in infancy. We aimed to describe specificities of food anaphylaxis in infants (≤12 months) as compared to preschool children (1-6 years)., Methods: We conducted a retrospective study of all food anaphylaxis cases recorded by the Allergy Vigilance Network from 2002 to 2018, in preschool children focusing on infants., Results: Of 1951 food anaphylaxis reactions, 61 (3%) occurred in infants and 386 (20%) in preschool children. Two infants had two anaphylaxis reactions; thus, we analyzed data among 59 infants (male: 51%; mean age: 6 months [SD: 2.9]); 31% had a history of atopic dermatitis, 11% of previous food allergy. The main food allergens were cow's milk (59%), hen's egg (20%), wheat (7%) and peanut (3%) in infants as compared with peanut (27%) and cashew (23%) in preschool children. Anaphylaxis occurred in 28/61 (46%) cases at the first cow's milk intake after breastfeeding discontinuation. Clinical manifestations were mainly mucocutaneous (79%), gastrointestinal (49%), respiratory (48%) and cardiovascular (21%); 25% of infants received adrenaline. Hives, hypotension and neurologic symptoms were more likely to be reported in infants than in preschool children (P = .02; P = .004; P = .002, respectively). Antihistamines and corticosteroids were more often prescribed in preschool children than in infants (P = .005; P = .025, respectively)., Conclusion: Our study found that in infants presenting with their first food allergy, in a setting with a high rate of infant formula use, the most predominant trigger was cow's milk. As compared to older preschool children, hives, hypotonia and hypotension were more likely to be reported in infants. We believe that this represents a distinct food anaphylaxis phenotype that can further support developing the clinical anaphylaxis criteria in infants., (© 2019 John Wiley & Sons Ltd.)

Aims: To investigate the accuracy of phenotypic early-onset ataxia (EOA) recognition among developmental conditions, including developmental coordination disorder (DCD) and hypotonia of central nervous system origin, and the effect of scientifically validated EOA features on changing phenotypic consensus., Method: We included 32 children (4-17y) diagnosed with EOA (n=11), DCD (n=10), and central hypotonia (n=11). Three paediatric neurologists independently assessed videotaped motor behaviour phenotypically and quantitatively (using the Scale for Assessment and Rating of Ataxia [SARA]). We determined: (1) phenotypic interobserver agreement and phenotypic homogeneity (percentage of phenotypes with full consensus by all three observers according to the underlying diagnosis); (2) SARA (sub)score profiles; and (3) the effect of three scientifically validated EOA features on phenotypic consensus., Results: Phenotypic homogeneity occurred in 8 out of 11, 2 out of 10, and 1 out of 11 patients with EOA, DCD, and central hypotonia respectively. Homogeneous phenotypic discrimination of EOA from DCD and central hypotonia occurred in 16 out of 21 and 22 out of 22 patients respectively. Inhomogeneously discriminated EOA and DCD phenotypes (5 out of 21) revealed overlapping SARA scores with different SARA subscore profiles. After phenotypic reassessment with scientifically validated EOA features, phenotypic homogeneity changed from 16 to 18 patients., Interpretation: In contrast to complete distinction between EOA and central hypotonia, the paediatric motor phenotype did not reliably distinguish between EOA and DCD. Reassessment with scientifically validated EOA features could contribute to a higher phenotypic consensus. Early-onset ataxia (EOA) and central hypotonia motor phenotypes were reliably distinguished. EOA and developmental coordination disorder (DCD) motor phenotypes were not reliably distinguished. The EOA and DCD phenotypes have different profiles of the Scale for Assessment and Rating of Ataxia., (© 2019 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Background: Infantile hereditary proximal spinal muscular atrophy (SMA) type 1 is characterized by onset in the first 6 months of life and severe and progressive muscle weakness. Dysphagia is a common complication but has not been studied in detail., Objective: To study feeding and swallowing problems in infants with SMA type 1, and to explore the relation between these problems and functional motor scores., Methods: We prospectively included 16 infants with SMA type 1 between September 2016 and October 2018. Eleven infants received palliative care and five infants best supportive care in combination with nusinersen. We compiled and used an observation list with feeding related issues and observed feeding sessions during inpatient and outpatient visits. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) was used as a measure of motor function., Results: All infants in the palliative care group (median onset of disease 14 days (range 1-56); median inclusion in the study 52 days (range 16-252) demonstrated symptoms of fatigue during feeding and unsafe swallowing. Symptoms were short nursing sessions (10-15 minutes), and not being able to finish the recommended feeding volumes (72%); increased frequency of feeding sessions (55%); coughing when drinking or eating (91%), and wet breathing during and after feeding (64%).Two out of five infants in the nusinersen group (median onset of disease 38 days (range 21-90); inclusion in the study at 63 days (range 3-218) were clinically pre-symptomatic at the start of treatment. The other three infants showed symptoms of fatigue and unsafe swallowing at inclusion in the study. These symptoms initially decreased after the start of the treatment, but (re)appeared in all five infants between the ages of 8 to 12 months, requiring the start tube of feeding. In the same period motor function scores significantly improved (median increase CHOP INTEND 16 points)., Conclusion: Impaired feeding and swallowing remain important complications in infants with SMA type 1 after the start of nusinersen. Improvement of motor function does not imply similar gains in bulbar function.

Down syndrome (DS) is the most often diagnosed chromosomal disorder in newborns. The incidence is 1:792 live births. The article describes the irregularities and characteristics found in trisomy 21, which greatly affect the functioning of the stomatognathic system. The most significant disorders include the following: false macroglossia, muscular hypotonia and gothic palate. These abnormalities affect articulation, breathing, food intake, and swallowing. We analyzed the morphological characteristics of the craniofacial region in children with DS based on the current literature review. The following databases were used for the analysis: MEDLINE (via PubMed), Scopus, Infona, and Dentistry & Oral Sciences Source. In the course of the study, 199 pieces of literature were analyzed; the analysis also included 18 articles on children and adults with DS. It also took into account the structure of the palate, dental and skeletal defects, size of the tongue, muscular hypotonia, and temporomandibular joint dysfunction. Down syndrome is still a current subject of research. Although macroglossia, hypotonia, malocclusion, and temporomandibular joint abnormalities are not features exclusive to DS, numerous dysfunctions and parafunctions as well as retarded psychomotor development greatly complicate the treatment. Therefore, interdisciplinary treatment of patients with trisomy 21 and early treatment in the first months of life with the use of the Castillo-Morales plate are very important, as they ensure better adaptation to the subsequently used apparatus and reduce the risk of disorders of the stomatognathic system.

Study Objectives: Values for normative REM sleep without atonia (RSWA) remain unclear. Older age and male sex are associated with greater RSWA, and isolated elevated RSWA has been reported. We aimed to describe normative RSWA and characterize isolated RSWA frequency in adults without REM sleep behavior disorder (RBD)., Methods: We visually quantified phasic, "any," and tonic RSWA in the submentalis (SM) and anterior tibialis (AT) muscles, and the automated Ferri REM Atonia Index during polysomnography in adults without RBD aged 21-88. We calculated RSWA percentiles across age and sex deciles and compared RSWA in older (≥ 65) versus younger (<65) men and women. Isolated RSWA (exceeding diagnostic RBD cutoffs, or >95th percentile) frequency was also determined., Results: Overall, 95th percentile RSWA percentages were SM phasic, any, tonic = 8.6%, 9.1%, 0.99%; AT phasic and "any" = 17.0%; combined SM/AT phasic, "any" = 22.3%, 25.5%; and RAI = 0.85. Most phasic RSWA burst durations were ≤1.0 s (85th percentiles: SM = 1.07, AT = 0.86 seconds). Older men had significantly higher AT RSWA than older women and younger patients (all p < 0.04). Twenty-nine (25%, 18 men) had RSWA exceeding the cohort 95th percentile, while 17 (14%, 12 men) fulfilled diagnostic cutoffs for phasic or automated RBD RSWA thresholds., Conclusions: RSWA levels are highest in older men, mirroring the demographic characteristics of RBD, suggesting that older men frequently have altered REM sleep atonia control. These data establish normative adult RSWA values and thresholds for determination of isolated RSWA elevation, potentially aiding RBD diagnosis and discussions concerning incidental RSWA in clinical sleep medicine practice., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Proper function of pharyngeal dilator muscles, including the genioglossus muscle of the tongue, is required to maintain upper airway patency. During sleep, the activity of these muscles is suppressed, and as a result individuals with obstructive sleep apnea experience repeated episodes of upper airway closure when they are asleep, in particular during rapid-eye-movement (REM) sleep. Blocking cholinergic transmission in the hypoglossal motor nucleus (MoXII) restores REM sleep genioglossus activity, highlighting the importance of cholinergic transmission in the inhibition of hypoglossal motor neurons (HMNs) during REM sleep. Glutamatergic afferent input from neurons in the parahypoglossal (PH) region to the HMNs is critical for MoXII respiratory motor output. We hypothesized that state-dependent cholinergic regulation may be mediated by this pathway. Here we studied the effects of cholinergic transmission in HMNs in adult male and female mice using patch-clamp recordings in brain slices. Using channelrhodopsin-2-assisted circuit mapping, we first demonstrated that PH glutamatergic neurons directly and robustly activate HMNs (PH Glut → HMNs). We then show that carbachol consistently depresses this input and that this effect is presynaptic. Additionally, carbachol directly affects HMNs by a variable combination of muscarinic-mediated excitatory and inhibitory responses. Altogether, our results suggest that cholinergic signaling impairs upper airway dilator muscle activity by suppressing glutamatergic input from PH premotoneurons to HMNs and by directly inhibiting HMNs. Our findings highlight the complexity of cholinergic control of HMNs at both the presynaptic and postsynaptic levels and provide a possible mechanism for REM sleep suppression of upper airway muscle activity. SIGNIFICANCE STATEMENT Individuals with obstructive sleep apnea can breathe adequately when awake but experience repeated episodes of upper airway closure when asleep, in particular during REM sleep. Similar to skeletal postural muscles, pharyngeal dilator muscles responsible for maintaining an open upper airway become hypotonic during REM sleep. Unlike spinal motoneurons controlling postural muscles that are inhibited by glycinergic transmission during REM sleep, hypoglossal motoneurons that control the upper airway muscles are inhibited in REM sleep by the combination of monoaminergic disfacilitation and cholinergic inhibition. In this study, we demonstrated how cholinergic signaling inhibits hypoglossal motoneurons through presynaptic and postsynaptic muscarinic receptors. Our results provide a potential mechanism for upper airway hypotonia during REM sleep., (Copyright © 2019 the authors.)

Objectives: Isolated REM sleep without atonia (iRSWA) is regarded as prodromal phase of REM sleep behavior disorder (RBD) and synucleinopathies. Other factors, however, have also been described to cause RSWA, including sleep apnea, antidepressants use and narcolepsy. We investigated the frequency of RSWA and its different etiologies., Methods: We investigated RSWA in patients that underwent a clinical video polysomnography. In iRSWA subjects, we examined polysomnography indication and two markers of prodromal Parkinson's disease: excessive daytime sleepiness and depressive symptoms, with a case-control design., Results: Of the 864 included polysomnographies, 188 were positive for RSWA (21.8%), 17 for RBD (2.0%) and 48 for iRSWA (5.6%). Mean Epworth Sleepiness Scale scores were 9.8 ± 4.8 (iRSWA subjects) and 7.5 ± 4.9 (controls), p = 0.014. Mean Beck Depression Inventory-II scores were 11.3 ± 7.9 (iRSWA subjects) and 9.5 ± 8.4 (controls), p = 0.229. Excessive daytime sleepiness was more often the polysomnography indication in the iRSWA group (p = 0.006)., Conclusions: RSWA is a frequent finding in the context of antidepressant use or synucleinopathies. iRSWA subjects reported increased excessive daytime sleepiness and more often had excessive daytime sleepiness as polysomnography indication., Significance: Our study provides evidence for high frequency of RSWA, underscoring the need for longitudinal studies in iRSWA patients, with interest for conversion to synucleinopathies., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To determine whether REM sleep without atonia (RSWA) during polysomnography (PSG) predicts phenoconversion in patients with idiopathic REM sleep behavior disorder (iRBD), a prodromal feature of a neurodegenerative disease., Methods: We analyzed RSWA in 60 patients with iRBD, including manual phasic, tonic, and any muscle activity in the submentalis and anterior tibialis muscles and the automated REM atonia index in the submentals. We identified patients who developed parkinsonism or mild cognitive impairment (MCI) during at least 3 years of follow-up after PSG. Kaplan-Meier analysis was performed and receiver operator curves were calculated to determine RSWA cutoffs predicting faster phenoconversion., Results: Twenty-six (43%) patients developed parkinsonism (n = 17) or MCI (n = 9). Phenoconverters were older at iRBD diagnosis ( p = 0.02). Median time to phenoconversion was 3.9 ± 2.5 years. iRBD phenoconverters had significantly more RSWA at diagnosis. Phenoconversion risk from iRBD diagnosis was 20% and 35% at 3 and 5 years, respectively, with greater risk in patients with iRBD with >46.4% any combined RSWA, which increased further to 30% and 55% at 3 and 5 years for patients >65 years of age at diagnosis., Conclusions: Patients with iRBD with higher amounts of polysomnographic RSWA had a greater risk of developing Parkinson disease or MCI. Patients with older age and higher RSWA amounts had more rapid phenoconversion than younger patients with RBD. Our study suggests that RSWA is a potential biomarker for risk stratification of iRBD phenoconversion that could facilitate prognostication for patients with iRBD., Classification of Evidence: This study provides Class II evidence that for patients with iRBD, increased RSWA correlates with increased risk for developing parkinsonism or MCI., (© 2019 American Academy of Neurology.)

Study Objectives: Rapid eye movement (REM) sleep without atonia (RWA) is the main polysomnographic feature of idiopathic REM sleep behavior disorder (iRBD) and is considered to be a promising biomarker predicting conversion to manifested synucleinopathy. Besides conventionally evaluated tonic, phasic and any RWA, we took into consideration also periods, when phasic and tonic RWA appeared simultaneously and we called this activity "mixed RWA." The study aimed to evaluate different types of RWA, to reveal the most relevant biomarker to the conversion., Methods: A total of 55 patients with confirmed iRBD were recruited with mean follow-up duration 2.3 ± 0.7 years. Scoring of RWA was based on Sleep Innsbruck Barcelona rules. Positive phenocoversion was ascertained according to standard diagnostic criteria during follow-up. Receiver operator characteristic analysis was applied to evaluate predictive performance of different RWA types., Results: A total of nine patients (16%) developed neurodegenerative diseases. Yearly phenoconversion rate was 5.5%. Significantly higher amounts of mixed (p = 0.009), tonic (p = 0.020), and any RWA (p = 0.049) were found in converters. Optimal cutoffs differentiating the prediction were 16.4% (sensitivity 88.9; specificity 69.6) for tonic, 4.4% (sensitivity 88.9; specificity 60.9) for mixed, and 36.8% (sensitivity 77.8; specificity 65.2) for any RWA. With area under the curve (AUC) 0.778, mixed RWA has proven to be the best predictive test followed by tonic (AUC 0.749) and any (AUC 0.710)., Conclusions: Mixed, tonic and any RWA may serve as biomarkers predicting the conversion into neurodegenerative disease in iRBD. The best predictive value lies within mixed RWA, thus it should be considered as standard biomarker., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Study Objectives: The neurophysiological hallmark of REM sleep behavior disorder (RBD) is loss of atonia during REM sleep. Indeed, signs and symptoms of neurodegeneration can occur after years, even decades, from its beginning. This study aimed to measure neurophysiological alterations of the brainstem that potentially correlate with the severity of atonia loss, and determining whether a prodromal neurodegenerative disorder underlines this condition when it occurs as an isolated condition (iRBD)., Methods: Subjects with iRBD and matched healthy controls were recruited. The study included the recording of one-night polysomnography, vestibular-evoked myogenic potentials (VEMPs), and a [123I]-FP-CIT dopamine transporter (DAT) scan. The quantification of REM sleep without atonia (RSWA) was made according to two previously published manual methods and one automated method., Results: The rate of alteration of VEMPs and VEMP score were significantly higher in iRBD patients than controls. Moreover, VEMP score was negatively correlated with the automated REM atonia index; a marginal statistical significance was also reached for the positive correlation with the visual tonic electromyographic parameter, while the other correlations, including that with DAT-scan score were not statistically significant., Conclusions: Brainstem neurophysiology in iRBD can be assessed by VEMPs and their alterations may possibly indicate an early expression of the neurodegenerative process underlying this disorder at the brainstem level, which awaits future longitudinal confirmation. The correlation between RSWA and VEMP alteration might also represent a prodromal aspect anticipating the possible evolution from iRBD to neurodegeneration, whereas DAT-scan abnormalities might represent a later step in this evolution., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

De novo pathogenic variants in the human immunodeficiency virus enhancer type I binding protein 2 (HIVEP2) gene, a large transcription factor predominantly expressed in the brain have previously been associated with intellectual disability (ID) and dysmorphic features in nine patients. We describe the phenotype and genotype of two additional patients with novel de novo pathogenic HIVEP2 variants, who have previously unreported features, including hyperphagia and Angelman-like features. Exome sequencing was utilized in the investigation of the patients who had previously incurred a rigorous genetic workup for their neurodevelopmental delay, and in whom no genetic cause had been detected. Information pertaining to phenotype and genotype for new patients was collated along with data from previous reports, showing that the phenotypic spectrum of patients with HIVEP2 variants is broader than first noted. Additional characteristics are: an increased body mass index; and features of Angelman-like syndromes including: ID, limited speech, post-natal microcephaly, and hypotonia. Dysmorphic features vary between patients. As yet, no clear association between the type of gene aberration and phenotype can be concluded. HIVEP2-related ID needs to be considered in the differential diagnosis of patients with Angelman-like phenotypes and hyperphagia, and whole-exome sequencing should be considered in the genetic diagnostic armamentarium for patients with ID of inconclusive etiology., (© 2019 Wiley Periodicals, Inc.)

Background: Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high serum tri-iodothyronine (T 3 ) concentrations (Allan-Herndon-Dudley syndrome). This chronic thyrotoxicosis leads to progressive deterioration in bodyweight, tachycardia, and muscle wasting, predisposing affected individuals to substantial morbidity and mortality. Treatment that safely alleviates peripheral thyrotoxicosis and reverses cerebral hypothyroidism is not yet available. We aimed to investigate the effects of treatment with the T 3 analogue Triac (3,3',5-tri-iodothyroacetic acid, or tiratricol), in patients with MCT8 deficiency., Methods: In this investigator-initiated, multicentre, open-label, single-arm, phase 2, pragmatic trial, we investigated the effectiveness and safety of oral Triac in male paediatric and adult patients with MCT8 deficiency in eight countries in Europe and one site in South Africa. Triac was administered in a predefined escalating dose schedule-after the initial dose of once-daily 350 μg Triac, the daily dose was increased progressively in 350 μg increments, with the goal of attaining serum total T 3 concentrations within the target range of 1·4-2·5 nmol/L. We assessed changes in several clinical and biochemical signs of hyperthyroidism between baseline and 12 months of treatment. The prespecified primary endpoint was the change in serum T 3 concentrations from baseline to month 12. The co-primary endpoints were changes in concentrations of serum thyroid-stimulating hormone (TSH), free and total thyroxine (T 4 ), and total reverse T 3 from baseline to month 12. These analyses were done in patients who received at least one dose of Triac and had at least one post-baseline evaluation of serum throid function. This trial is registered with ClinicalTrials.gov, number NCT02060474., Findings: Between Oct 15, 2014, and June 1, 2017, we screened 50 patients, all of whom were eligible. Of these patients, four (8%) patients decided not to participate because of travel commitments. 46 (92%) patients were therefore enrolled in the trial to receive Triac (median age 7·1 years [range 0·8-66·8]). 45 (98%) participants received Triac and had at least one follow-up measurement of thyroid function and thus were included in the analyses of the primary endpoints. Of these 45 patients, five did not complete the trial (two patients withdrew [travel burden, severe pre-existing comorbidity], one was lost to follow-up, one developed of Graves disease, and one died of sepsis). Patients required a mean dose of 38.3 μg/kg of bodyweight (range 6·4-84·3) to attain T 3 concentrations within the target range. Serum T 3 concentration decreased from 4·97 nmol/L (SD 1·55) at baseline to 1·82 nmol/L (0·69) at month 12 (mean decrease 3·15 nmol/L, 95% CI 2·68-3·62; p<0·0001), while serum TSH concentrations decreased from 2·91 mU/L (SD 1·68) to 1·02 mU/L (1·14; mean decrease 1·89 mU/L, 1·39-2·39; p<0·0001) and serum free T 4 concentrations decreased from 9·5 pmol/L (SD 2·5) to 3·4 (1·6; mean decrease 6·1 pmol/L (5·4-6·8; p<0·0001). Additionally, serum total T 4 concentrations decreased by 31·6 nmol/L (28·0-35·2; p<0·0001) and reverse T 3 by 0·08 nmol/L (0·05-0·10; p<0·0001). Seven treatment-related adverse events (transiently increased perspiration or irritability) occurred in six (13%) patients. 26 serious adverse events that were considered unrelated to treatment occurred in 18 (39%) patients (mostly hospital admissions because of infections). One patient died from pulmonary sepsis leading to multi-organ failure, which was unrelated to Triac treatment., Interpretation: Key features of peripheral thyrotoxicosis were alleviated in paediatric and adult patients with MCT8 deficiency who were treated with Triac. Triac seems a reasonable treatment strategy to ameliorate the consequences of untreated peripheral thyrotoxicosis in patients with MCT8 deficiency., Funding: Dutch Scientific Organization, Sherman Foundation, NeMO Foundation, Wellcome Trust, UK National Institute for Health Research Cambridge Biomedical Centre, Toulouse University Hospital, and Una Vita Rara ONLUS., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Importance: Floppy eyelid syndrome "plasty" (FESplasty) is a surgical technique that addresses underlying superior tarsal plate and lateral canthal instability in floppy eyelid syndrome (FES) and aims to restore normal anatomical and physiological function to the upper eyelid., Background: To describe the use of FESplasty in the surgical management of FES, and to report outcomes in an initial patient cohort., Design: Retrospective study., Participants: Seven patients (nine eyelids) with FES undergoing FESplasty., Methods: A single surgeon (G.W.) performed all procedures. FESplasty utilizes a periosteal flap based at the inferolateral orbital rim, and applied to the anterior surface of the upper tarsal plate. It is combined with a titrated shortening procedure of the upper eyelid. Patient demographics, comorbidities and ocular symptoms and signs were recorded preoperatively. Pre- and postoperative upper eyelid distractibility were graded and documented., Main Outcome Measures: Postoperative improvement in upper eyelid distractibility and symptomatology, operative complications and FES recurrence., Results: FES symptoms and upper eyelid laxity improved at last follow-up (average 24 weeks) in all patients, with no FES recurrences after a maximum follow-up of 36 weeks. One patient, in whom FESplasty exacerbated his pre-existing aponeurotic ptosis, required definitive ptosis surgery subsequently. There was one case of postoperative wound infection. Obstructive sleep apnoea was present in four of the seven patients. The remaining three patients were awaiting assessment., Conclusions and Relevance: FESplasty is likely to confer long-term effective stabilization of the lateral canthal tendon, lateral commissure and superior tarsal plate. Anatomical and functional results appeared to have been successfully achieved., (© 2019 Royal Australian and New Zealand College of Ophthalmologists.)

Titin, encoded by the gene TTN, is one of the main sarcomere components. It is involved in not only maintaining the structure of cardiac and skeletal muscles, but also in their development, extensibility, elasticity, and signaling events. Congenital titinopathy increasingly appears an important and common form of axial predominant congenital myopathy. The pathophysiological role of TTN in congenital titinopathy and pediatric heart diseases is yet to be explored. Here, we delineate the phenotype of two female siblings who developed severe congenital multi-minicore disease without cardiac involvement. Genetic investigation by whole exome sequencing demonstrated compound heterozygous TTN mutations (c.15496+1G>A, p.5166&#95;5258del; c.18597&#95;18598insC, p.Thr6200Hisfs*15), corresponding to the Ig domain of the proximal I-band. Aberrant splicing causing exon skipping was verified by in vitro minigene analysis. Our results suggest that TTN mutations affecting the Ig domain of the proximal I-band may be a cause of severe congenital defect in skeletal muscles without severe cardiac involvement, thereby providing evidence for the hypothesis that congenital titinopathy patients carrying biallelic N2BA only mutations are at lower cardiac risk than those with other combinations of mutations. Meanwhile, this study confirm the hypothesis on recessive truncating variants of TTN experimentally and thus support earlier reported genotype-phenotype correlations., (Copyright © 2019. Published by Elsevier B.V.)

Objective: To assess the clinical and biochemical features as well as outcome of hyperphenylalaninemia patients., Methods: The descriptive retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised data from January 2013 to February 2017 of plasma amino acid analysed at the Biochemical Genetic Laboratory of patients with phenylalanine levels >120 umol/L. Medical charts of patients registered with the Metabolic Clinics were reviewed, while outside referrals were contacted by telephone to collect data on a pre-structured questionnaire. Data was analysed using SPSS 21., Results: Of the 18 patients, 13(72%) were males. Overall median age was 606 days (interquartile range: 761) and median phenylalanine levels were 1280 (interquartile range: 935) umol/L. Phenylalanine hydroxylase deficiency was present in 5(28%) patients while 3(16.6%) had defects in the metabolism or regeneration of tetrahydrobiopterin. The most common clinical features was intellectual deficit and seizures 14(78%) each, followed by lighter hair colour 10(55.5%) and hypotonia 11(61%). High treatment cost was the leading reason for cessation of therapy in 7(39%) followed by refusal by patient's family 5(28%)., Conclusions: Most hyperphenylalaninemia cases were diagnosed late when intellectual disability had already developed.

Objective: To identify the genetic and physiologic basis for recessive myasthenic congenital myopathy in 2 families, suggestive of a channelopathy involving the sodium channel gene, SCN4A ., Methods: A combination of whole exome sequencing and targeted mutation analysis, followed by voltage-clamp studies of mutant sodium channels expressed in fibroblasts (HEK cells) and Xenopus oocytes., Results: Missense mutations of the same residue in the skeletal muscle sodium channel, R1460 of Na V 1.4, were identified in a family and a single patient of Finnish origin (p.R1460Q) and a proband in the United States (p.R1460W). Congenital hypotonia, breathing difficulties, bulbar weakness, and fatigability had recessive inheritance (homozygous p.R1460W or compound heterozygous p.R1460Q and p.R1059X), whereas carriers were either asymptomatic (p.R1460W) or had myotonia (p.R1460Q). Sodium currents conducted by mutant channels showed unusual mixed defects with both loss-of-function (reduced amplitude, hyperpolarized shift of inactivation) and gain-of-function (slower entry and faster recovery from inactivation) changes., Conclusions: Novel mutations in families with myasthenic congenital myopathy have been identified at p.R1460 of the sodium channel. Recessive inheritance, with experimentally established loss-of-function, is a consistent feature of sodium channel based myasthenia, whereas the mixed gain of function for p.R1460 may also cause susceptibility to myotonia., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)